Hydrophobic labeling of (Na+,K+)-ATPase: further evidence that the beta subunit is embedded in the membrane bilayer.

O-Hexanoyl-3,5-diiodo-N-(4-azido-2-nitro-phenyl)tyramine has been used after photochemical conversion into the reactive nitrene to label (Na+,K+)-ATPase from Bufo marinus toad kidney. Immunochemical evidence indicates that the reagent labels both subunits of the enzyme in partially purified form as well as in microsomal membranes. These results support the view that the glycoprotein subunit, like the catalytic subunit, possesses hydrophobic domains by which it is integrated into the plasma membrane.

Drogues d’abús en detinguts al jutjat de guàrdia: repercusió a l’àmbit de l’execució penal i l’Administració de justícia

L’estudi de la saliva com a matriu d’anàlisis de drogues d’abús en conductors es fa des dels anys 80. Els investigadors trobaven dificultats però el major inconvenient va ser l’existència de tècniques analítiques no prou sensibles per a la detecció de les drogues. A finals de les anys 90 la saliva es va considerar un fluid molt adequat i es van anar publicant treballs que investigaven aquesta temàtica. No obstant això encara no n ’hi ha molts treballs, especialment al nostre país. A Catalunya no s’han fet estudis encara que s’ha contribuït en alguns projectes realitats fora de la nostra comunitat. Objectius: Obtenir dades del consum de drogues d’abús en una mostra de conductors de vehicles a motor. Obtenir dades dels tòxics més freqüents trobats en les mostres analitzades. Relacionar el consum de tòxics amb alteracions en la conducta o conduccions temeràries en la població que es sotmet a l’estudi. Metodologia: Estudi d’una mostra de subjectes que són aturats per la Guàrdia Urbana de Barcelona, Girona ,Tarragona i policia local de el Prat de Llobregat conduint vehicles a motor. Obtenció d’una mostra de saliva als subjectes que es consideren que poden trobar-se sota la influència de les drogues. Anàlisis de les mostres per immunoassaig mitjançant el kit Cozart DDS com a test de camp i confirmació dels resultats per cromatografia de gasos i espectrometria de masses. Resultats: Es descriuen en els resultats obtinguts, les freqüències de consum, les principals drogues d’abús trobades i es valoren els símptomes clínics que presentaven els subjectes. Conclusions: Les drogues d’abús estan presents en conductors de vehicles a motor. El kit utilitzat per la determinació de drogues a peu de carretera és una bona eina atès que es confirmen els resultats especialment per a la cocaïna i opiacis.

The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review

In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae). Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

Abortion in public reason

What abortion laws a liberal political community ought to have? Much has been said about the moral problem of abortion, but there has not been yet (to my knowledge) a fully articulate account of the bearing of the competing answers to this ethical problem on liberal public reason. The first part of my project consists in a critical review of the different attempts to solve the various philosophical puzzles, both metaphysical and moral, posed by the abortion problem. Why is it wrong to kill beings like you and me? By answering this question we shall gain a better insight into those properties we have that give us such strong reasons against killing beings like us. Here we face a tremendous philosophical diffuculty, for it is not possible to determine what the robustest account of the wrongness of killing is without dealing with deeper metaethical and metaphysical problems. Indeed, consequentialist and nonconsequentialist moral theories differ in what it is that makes an action morally wrong -is it just the outcome of the action as compared with the outcomes of its alternatives? Or is it something else? Also, what are we essentially? Is the foetus merely our precursor? Then killing a foetus is relevantly similar to contraception. Or is the foetus one of us? If so, when we kill it, are we depriving it of a future as valuable as ours? Perhaps the relation of identity (the fact that it is its future as opposed to someone else's) doesn't matter. That may be because the foetus is an aggregate of biological and psychological facts and perhaps aggregates are not substances. Or maybe it is a substance but only psychological realtions matter, not personal identity. The second part of my project has to do with the different status these metaphisical and ethical positions ought to have in liberal public reason. Though this is the part in which most research is still needed, my own intuition is that, given the depth of the philosphical views in competition, restrictive abortion laws ought to be considered unrespectful to citizens' autonomy.

Usefulness of postmortem biochemistry in forensic pathology: illustrative case reports.

The aim of this work is to present some practical, postmortem biochemistry applications to illustrate the usefulness of this discipline and reassert the importance of carrying out biochemical investigations as an integral part of the autopsy process. Five case reports are presented pertaining to diabetic ketoacidosis in an adult who was not known to suffer from diabetes and in presence of multiple psychotropic substances; fatal flecainide intoxication in a poor metabolizer also presenting an impaired renal function; diabetic ketoacidosis showing severe postmortem changes; primary aldosteronism presented with intracranial hemorrhage and hypothermia showing severe postmortem changes. The cases herein presented can be considered representative examples of the importance of postmortem biochemistry investigations, which may provide significant information useful in determining the cause of death in routine forensic casework or contribute to understanding the pathophysiological mechanisms involved in the death process.

Similarities and dissimilarities of branching and septation during lung development.

The lungs of small premature babies are at a developmental stage of finalizing their airway tree by a process called branching morphogenesis, and of creating terminal gas exchange units by a mechanism called septation. If the branching process is disturbed, the lung has a propensity to be hypoplastic. If septation is impaired, the terminal gas exchange units, the alveoli, tend to be enlarged and reduced in number, an entity known as bronchopulmonary dysplasia. Here, we review current knowledge of key molecules influencing branching and septation. In particular, we discuss the molecular similarities and dissimilarities between the two processes of airspace enlargement. Understanding of the molecular mechanisms regulating branching and septation may provide perinatologists with targets for improving lung growth and maturation.

Execució penal de sancions a conductors sota els efectes de drogues d’abús basats en estudi de saliva: ingerència i repercussió futura en el Codi penal

El consum de drogues no institucionalitzades té una important dimensió epidemiològica. En l'actualitat augmenta el consum de cocaïna i de cànnabis i s'estabilitza o disminueix el de opiacis. En la majoria dels països hi ha una relació entre la drogoaddicció i el delicte. Objectius: 1) Obtenir dades sociodemogràfiques en una població detinguda en els jutjats de guàrdia que passen a disposició judicial; 2) Obtenir dades sanitàries referents a infecció per VIH, VHC I VHB; 3) Obtenir dades de consums de cocaïna, haxis, heroïna, benzodiazepines i drogues de síntesis; 4) Conèixer la correlació o concordança clínico-analítica i, 5) Valorar la relació de l'addicció a drogues amb la delictologia. Subjectes i Mètodes: Estudi realitzat en una població de 151 subjectes consumidors de drogues il·legals detinguts a disposició judicial al Jutjat de guàrdia de la ciutat de Barcelona. Temps de l'estudi: 1,5 anys. Mètodes: Administració d'un qüestionari amb dades sociodemogràfiques, sanitàries i de consums de tòxics. Obtenció d'una mostra d'orina que es va analitzar per immunoassaig en l'analitzador AsXym (*Abbot). Els resultats es van interpretar com positius o negatius segons el punt de tall establert per al mètode. Resultats: El perfil de la mostra és un home solter, edat mitjana de 31.4 anys, amb estudis primaris i sense professió qualificada. La droga il·legal més consumida és la cocaïna, 77,5%, seguida dels opiacis 62,9%, del cànnabis 60,3% i benzodiazepines 61.6% (auto-medicades 40,9%). La prevalença de HIV va ser del 16,7%, VHC 37,9% i VHB 19,1%. La via intravenosa és utilitzada pel 46% dels cocainòmans i pel 53.8% del heroinòmans. Un 45.5% tenen signes compatibles amb UDVP. Només un 14.2% presentava signes de deteriorament físic i un 23.1% una clara síndrome d’abstinència. Existeix un 74.3% de correlació o concordança clínico-analítica. El delicte més relacionat amb el consum de drogues va ser els delictes contra la propietat. Conclusions i Discusió: Es detecta un alt consum de cocaïna i disminució de l'heroïna. El consum de cànnabis i benzodiazepines és elevat. Els delictes contra la propietat estan associats al consum de drogues il·legals. Propostes: L'estudi té aplicabilitat en medicina forense. El screening rutinari d'orina en població detinguda és una mesura d'utilitat. Permet obtenir dades objectives quan se sol·liciten informes de drogoaddicció als perits. Els detinguts poden beneficiar-se de circumstàncies modificadores de la responsabilitat criminal en cas de ser consumidors de tòxics, d’acord amb la legislació actual. Els lletrats i l'autoritat judicial tindran una prova objectiva en les seves actuacions per poder resoldre amb més coneixement els procediments on es troben implicats els consumidors de drogues d'abús.

Aggregation mediated by faeces and footprints in Triatoma pseudomaculata (Heteroptera: Reduviidae), a Chagas disease vector

The behavioural response of Triatoma pseudomaculata to chemical substances present in their faeces or cuticle (footprints) was analyzed. Groups of larvae were simultaneously exposed to a clean filter paper and to another paper impregnated with a chemical stimulus in a circular arena. In these choice experiments, the insects aggregated significantly around papers impregnated with dry faeces. In addition, the bugs also showed a significant aggregation response to papers impregnated with compounds derived from their cuticle that were deposited by contact on the substrate. These results indicate that chemical compounds that affect the behaviour of T. pseudomaculata are present in the faeces and in the cuticle of this species. Results are discussed in relation to chemical communication in the Triatominae, as well as to the potential use of these substances in traps or sensors for the detection of this species.

Toxic and drug-induced peripheral neuropathies: updates on causes, mechanisms and management.

PURPOSE OF REVIEW: This review discusses publications highlighting current research on toxic, chemotherapy-induced peripheral neuropathies (CIPNs), and drug-induced peripheral neuropathies (DIPNs). RECENT FINDINGS: The emphasis in clinical studies is on the early detection and grading of peripheral neuropathies, whereas recent studies in animal models have given insights into molecular mechanisms, with the discovery of novel neuronal, axonal, and Schwann cell targets. Some substances trigger inflammatory changes in the peripheral nerves. Pharmacogenetic techniques are underway to identify genes that may help to predict individuals at higher risk of developing DIPNs. Several papers have been published on chemoprotectants; however, to date, this approach has not been shown effective in clinical trials. SUMMARY: Both length and nonlength-dependent neuropathies are encountered, including small-fiber involvement. The introduction of new diagnostic techniques, such as excitability studies, skin laser Doppler flowmetry, and pharmacogenetics, holds promise for early detection and to elucidate underlying mechanisms. New approaches to improve functions and quality of life in CIPN patients are discussed. Apart from developing less neurotoxic anticancer therapies, there is still hope to identify chemoprotective agents (erythropoietin and substances involved in the endocannabinoid system are promising) able to prevent or correct painful CIPNs.

History of offending behavior in first episode psychosis patients: A marker of specific clinical needs and a call for early detection strategies among young offenders.

OBJECTIVES: Previous literature suggests that early psychosis (EP) patients with a history of offending behavior (HOB) have specific clinical needs. The aims of this study were to assess: (1) the prevalence of HOB in a representative sample of EP; (2) the premorbid and baseline characteristics of patients with HOB, and (3) the potential differences in short-term outcome of such patients when compared to patients without HOB. METHODS: The Early Psychosis Prevention and Intervention Centre (EPPIC) admitted 786 EP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. Data of 647 patients could be analyzed. RESULTS: HOB patients (29% of the sample) were more likely to be male with lower level of premorbid functioning and education, have used illicit substances and have attempted suicide. They presented with a more complex clinical picture and had poorer 18-month outcome. Most importantly, they had a significantly longer duration of untreated psychosis. CONCLUSIONS: On the basis of the high prevalence and specific features of EP patients with HOB, our study confirms a need for additional research in this domain and for the development of specific treatment strategies. Most importantly, it suggests a need for the promotion of early detection strategies among the populations of young offenders, considering that some of them may be going through the early phases of a psychotic disorder and that reduction of treatment delay and provision of well adapted interventions may have a significant impact at numerous levels in such patients.

CTL activation is induced by cross-linking of TCR/MHC-peptide-CD8/p56lck adducts in rafts.

To investigate the role of the coreceptor CD8 and lipid rafts in cytotoxic T lymphocyte (CTL) activation, we used soluble mono-and multimeric H-2Kd-peptide complexes and cloned S14 CTL specific for a photoreactive derivative of the Plasmodium berghei circumsporozoite (PbCS) peptide 252-260 [PbCS(ABA)]. We report that activation of CTL in suspension requires multimeric Kd-PbCS(ABA) complexes co-engaging TCR and CD8. Using TCR ligand photo-cross-linking, we find that monomeric Kd-PbCS(ABA) complexes promote association of TCR/CD3 with CD8/p56lck. Dimerization of these adducts results in activation of p56lck in lipid rafts, where phosphatases are excluded. Additional cross-linking further increases p56lck kinase activity, induces translocation of TCR/CD3 and other signaling molecules to lipid rafts and intracellular calcium mobilization. These events are prevented by blocking Src kinases or CD8 binding to TCR-associated Kd molecules, indicating that CTL activation is initiated by cross-linking of CD8-associated p56lck. They are also inhibited by methyl-beta-cyclodextrin, which disrupts rafts and by dipalmitoyl phosphatidylethanolamine, which interferes with TCR signaling. Because efficient association of CD8 and p56lck takes place in rafts, both reagents, though in different ways, impair coupling of p56lck to TCR, thereby inhibiting the initial and essential activation of p56lck induced by cross-linking of engaged TCR.

Untargeted profiling of urinary steroid metabolites after testosterone ingestion: opening new perspectives for antidoping testing.

AIM: Antidoping procedures are expected to greatly benefit from untargeted metabolomic approaches through the discovery of new biomarkers of prohibited substances abuse. RESULTS: Endogenous steroid metabolites were monitored in urine samples from a controlled elimination study of testosterone undecanoate after ingestion. A platform coupling ultra-high pressure LC with high-resolution quadrupole TOF MS was used and high between-subject metabolic variability was successfully handled using a multiblock data analysis strategy. Links between specific subsets of metabolites and influential genetic polymorphisms of the UGT2B17 enzyme were highlighted. CONCLUSION: This exploratory metabolomic strategy constitutes a first step toward a better understanding of the underlying patterns driving the high interindividual variability of steroid metabolism. Promising biomarkers were selected for further targeted study.

Hypertension artérielle réfractaire au traitement due au syndrome d'apnées du sommeil et à la prise de médicaments [Obstructive sleep apnea and drugs as causes of treatment-resistant hypertension].

Treatment-resistant hypertension is still common despite the availability of several types of antihypertensive agents acting by different mechanisms. The existence of refractory hypertension should lead to rule out "white-coat hypertension", poor adherence to prescribed drugs as well as classical causes of secondary hypertension such as renal artery stenosis, primary aldosteronism, pheochromocytoma and renal disease. It is also important to consider the possible existence of obstructive sleep apnea or the regular intake of vasopressive drugs or substances.

Exploration of the contribution of isotope ratio mass spectrometry to the investigation of explosives: A study of black powders and ammonium nitrate fertilisers

The increasing number of bomb attacks involving improvised explosive devices, as well as the nature of the explosives, give rise to concern among safety and law enforcement agencies. The substances used in explosive charges are often everyday products diverted from their primary licit applications. Thus, reducing or limiting their accessibility for prevention purposes is difficult. Ammonium nitrate, employed in agriculture as a fertiliser, is used worldwide in small and large homemade bombs. Black powder, dedicated to hunting and shooting sports, is used illegally as a filling in pipe bombs causing extensive damage. If the main developments of instrumental techniques in explosive analysis have been constantly pushing the limits of detection, their actual contribution to the investigation of explosives in terms of source discrimination is limited. Forensic science has seen the emergence of a new technology, isotope ratio mass spectrometry (IRMS), that shows promising results. Its very first application in forensic science dates back to 1979. Liu et al. analysed cannabis plants coming from different countries [Liu et al. 1979]. This preliminary study highlighted its potential to discriminate specimens coming from different sources. Thirty years later, the keen interest in this new technology has given rise to a flourishing number of publications in forensic science. The countless applications of IRMS to a wide range of materials and substances attest to its success and suggest that the technique is ready to be used in forensic science. However, many studies are characterised by a lack of methodology and fundamental data. They have been undertaken in a top-down approach, applying this technique in an exploratory manner on a restricted sampling. This manner of procedure often does not allow the researcher to answer a number of questions, such as: do the specimens come from the same source, what do we mean by source or what is the inherent variability of a substance? The production of positive results has prevailed at the expense of forensic fundamentals. This research focused on the evaluation of the contribution of the information provided by isotopic analysis to the investigation of explosives. More specifically, this evaluation was based on a sampling of black powders and ammonium nitrate fertilisers coming from known sources. Not only has the methodology developed in this work enabled us to highlight crucial elements inherent to the methods themselves, but also to evaluate both the longitudinal and transversal variabilities of the information. First, the study of the variability of the profile over time was undertaken. Secondly, the variability of black powders and ammonium nitrate fertilisers within the same source and between different sources was evaluated. The contribution of this information to the investigation of explosives was then evaluated and discussed. --------------------------------------------------------------------------------------------------- Le nombre croissant d'attentats à la bombe impliquant des engins explosifs artisanaux, ainsi que la nature des charges explosives, constituent une préoccupation majeure pour les autorités d'application de la loi et les organismes de sécurité. Les substances utilisées dans les charges explosives sont souvent des produits du quotidien, détournés de leurs applications licites. Par conséquent, réduire ou limiter l'accessibilité de ces produits dans un but de prévention est difficile. Le nitrate d'ammonium, employé dans l'agriculture comme engrais, est utilisé dans des petits et grands engins explosifs artisanaux. La poudre noire, initialement dédiée à la chasse et au tir sportif, est fréquemment utilisée comme charge explosive dans les pipe bombs, qui causent des dommages importants. Si les développements des techniques d'analyse des explosifs n'ont cessé de repousser les limites de détection, leur contribution réelle à l'investigation des explosifs est limitée en termes de discrimination de sources. Une nouvelle technologie qui donne des résultats prometteurs a fait son apparition en science forensique: la spectrométrie de masse à rapport isotopique (IRMS). Sa première application en science forensique remonte à 1979. Liu et al. ont analysé des plants de cannabis provenant de différents pays [Liu et al. 1979]. Cette étude préliminaire, basée sur quelques analyses, a mis en évidence le potentiel de l'IRMS à discriminer des spécimens provenant de sources différentes. Trente ans plus tard, l'intérêt marqué pour cette nouvelle technologie en science forensique se traduit par un nombre florissant de publications. Les innombrables applications de l'IRMS à une large gamme de matériaux et de substances attestent de son succès et suggèrent que la technique est prête à être utilisée en science forensique. Cependant, de nombreuses études sont caractérisées par un manque de méthodologie et de données fondamentales. Elles ont été menées sans définir les hypothèses de recherche et en appliquant cette technique de façon exploratoire sur un échantillonnage restreint. Cette manière de procéder ne permet souvent pas au chercheur de répondre à un certain nombre de questions, tels que: est-ce que deux spécimens proviennent de la même source, qu'entend-on par source ou encore quelle est l'intravariabilité d'une substance? La production de résultats positifs a prévalu au détriment des fondamentaux de science forensique. Cette recherche s'est attachée à évaluer la contribution réelle de l'information isotopique dans les investigations en matière d'explosifs. Plus particulièrement, cette évaluation s'est basée sur un échantillonnage constitué de poudres noires et d'engrais à base de nitrate d'ammonium provenant de sources connues. La méthodologie développée dans ce travail a permis non seulement de mettre en évidence des éléments cruciaux relatifs à la méthode d'analyse elle-même, mais également d'évaluer la variabilité de l'information isotopique d'un point de vue longitudinal et transversal. Dans un premier temps, l'évolution du profil en fonction du temps a été étudiée. Dans un second temps, la variabilité du profil des poudres noires et des engrais à base de nitrate d'ammonium au sein d'une même source et entre différentes sources a été évaluée. La contribution de cette information dans le cadre des investigations d'explosifs a ensuite été discutée et évaluée.