A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones

Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer.

There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8(+) T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8(+) T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials.

Suicide par sulfure d'hydrogène et délai post mortem long : à propos d'un cas. [Suicide by hydrogen sulfide inhalation and significant post mortem delay: A case report].

L'hydrogène sulfuré (H2S) est un gaz toxique retrouvé à l'état naturel et dans certains milieux industriels, à l'origine d'intoxication accidentelle, mais pouvant être également et facilement synthétisé de manière domestique. Des cas de suicide par hydrogène sulfuré ont ainsi été décrits à partir de produits ménagers dans la littérature depuis 2009, aux États-Unis et au Japon. La plupart présentait des délais post mortem (DPM) courts (moins de 72 heures). En France, les intoxications aiguës à l'H2S demeurent rares et sont le plus souvent liées à des accidents du travail. Nous rapportons ici le cas d'un homme âgé de 37 ans découvert à son domicile, en état de décomposition avancée avec un DPM de deux mois. Compte tenu de la présence d'une importante signalétique avisant du danger potentiel d'exposition à l'H2S, des mesures de précaution ont été mises en oeuvre dès la découverte du corps et poursuivies jusqu'aux opérations d'autopsie. Les analyses toxicologiques ont confirmé la présence d'H2S au niveau des prélèvements de cerveau et de muscle. Le cas présenté constitue le premier cas de suicide avec un délai post mortem long à l'H2S rapporté en France. Dans la littérature, les constatations macroscopiques à l'autopsie ne sont pas spécifiques tandis que les analyses toxicologiques reposent essentiellement sur la recherche et la quantification d'H2S. En raison de leur redistribution post mortem, les résultats de ces analyses doivent être interprétés avec prudence, et encore plus en cas de délai post mortem long et de phénomènes de putréfaction qui peuvent également être une source de génération d'H2S post mortem. Hydrogen sulfide (H2S) which is a poisonous gas found either in the natural state or in industrial environments and potentially linked with accidental intoxication, can also be easily handmade. Several cases of suicide by inhaling H2S produced by mixing household products have been reported in the literature since 2009 in USA and Japan. Most of them involved short post mortem delays up to 72 hours. In France, acute H2S poisoning remains rare and mostly accidental. We report the case of a 37-year-old man found at home, in an advanced stage of decomposition with a 2-month post mortem delay. As numerous warning signs about a high risk of H2S exposure were present, some precautionary measures were taken from the discovery of the cadaver to the autopsy. Toxicological analyses confirmed the presence of H2S in brain and muscle samples. This observation is the first French case with a long post mortem delay. As macroscopic findings in such cases are described to be unspecific in literature, toxicological analysis must focus on the detection and the quantification of H2S. However, due to the phenomena of post mortem drug redistribution and neo-formation, their results should be interpreted with much more caution when the post mortem delay is long. The potential increase in such voluntary-intoxication-related-deaths in France, similar to the recent Japanese and American waves of suicides, requires for forensic scientists, a good knowledge of both thanatological and toxicological pictures, and precautionary measures to adopt in such situations.

Occurrence of the "applause sign" in patients with amyotrophic lateral sclerosis.

The applause sign was originally described as a quick bedside test to discriminate progressive supranuclear palsy (PSP) (positive applause sign, PAS) from Parkinson's disease (PD) and frontotemporal dementia (FTD) (negative applause sign). However, recent research demonstrated that the test is positive not only in a subset of patients with PD and FTD, but also in other neurodegenerative diseases. We tested 22 patients with amyotrophic lateral sclerosis (ALS) together with 22 healthy sex- and age-matched controls for the occurrence of PAS. Furthermore, we performed neuropsychological testing with the EXIT-25 battery to correlate PAS with neuropsychological deficits, especially frontal lobe dysfunction. Five ALS patients (23%) and none of the controls displayed PAS (p≤0.05). The occurrence of PAS in ALS patients was not correlated with pathologic EXIT-25 scores or subtests for aberrant motor behaviour. We describe for the first time the occurrence of the applause sign in ALS and provide additional evidence that PAS is not specific for Parkinsonian disorders. Although its occurrence has been related to aberrant motor behaviour due to frontal involvement, in our study PAS did not correlate with executive dysfunction as tested by the EXIT-25 test battery, or with subtests of aberrant motor behaviour.

Germaniumin talteenotto ioninvaihtohartseilla

Työssä tutkittiin laboratorio-olosuhteissa germaniumin talteenottoa happamista hydrometallurgisista sulfaattiliuoksista käyttäen kaupallisia ioninvaihtohartseja. Germaniumin talteenottoa tutkittiin sekä tasapaino- että kolonnikokein syöttöliuoksista joiden pH oli alueella 0,8–3,0. Tutkituista hartseista parhaiten germanium voitiin erottaa käyttäen emäsmuotoista N-metyyli-D-glukamiini-tyyppistä ioninvaihtohartsia (esim. Rohm & Haasin IRA-743). Germaniumille määritettiin adsorptioisotermit tasapainokokein sekä emäs- että happomuotoisilla hartseilla. Adsorptioisotermien perusteella parhaiten germa-niumia adsorboi emäsmuotoinen IRA-743-hartsi kun liuoksen alku-pH oli tutkitun alueen korkein. Lämpötilassa 25 °C kapasiteetti oli 114 mg Ge/g. Tasapainokokein määritettiin emäsmuotoisilla hartseilla germaniumin lisäksi myös kuparia ja kobolttia sisältävillä liuoksilla Ge:n jakaantumisvakiot sekä erotustekijät Ge/Cu ja Ge/Co. Havaittiin, että IRA-743:lla alku-pH:ssa 3,0 Ge:n jakaantumisvakiot sekä erotustekijät Ge/Cu ja Ge/Co olivat selvästi suuremmat kuin muilla tutkituilla hartseilla. Arseenin, nikkelin, sinkin ja rauta(III):n adsorboitumista emäsmuotoiseen IRA-743:een tutkittiin monimetallisella liuoksella syöttöliuoksen pH:n ollessa alueella 1,4–3,6. Kokeissa havaittiin, että hartsi adsorboi hieman Ni:a ja Zn:a tasapaino-pH:n ollessa yli 5,5. Arseenia ei tutkitulla pH-alueella havaittu adsorboituvan. Lisäksi huomattiin, että rauta alkaa saostua pH:n ollessa hieman alle kolme. Kolonnikokeissa havaittiin, että emäsmuotoinen IRA-743-hartsi toimii hyvin germaniumin talteenotossa myös kolonnissa. Pelkästään germaniumia ja kobolttia sisältäneellä liuoksella hartsin dynaamiseksi kapasiteetiksi saatiin 54 mg Ge/g. Germaniumin eluointi IRA-743:sta onnistui parhaiten 0,5 M H2SO4:lla. Kolonnikokeita IRA-743:lla ajettiin myös monimetallisilla liuoksilla, mutta silloin havaittiin hartsin kapasiteetin pienenevän hartsin myrkyttymisen takia.

Prognostication of Mortality in Critically Ill Patients With Severe Infections.

BACKGROUND: The purpose of this study was to confirm the prognostic value of pancreatic stone protein (PSP) in patients with severe infections requiring ICU management and to develop and validate a model to enhance mortality prediction by combining severity scores with biomarkers. METHODS: We enrolled prospectively patients with severe sepsis or septic shock in mixed tertiary ICUs in Switzerland (derivation cohort) and Brazil (validation cohort). Severity scores (APACHE [Acute Physiology and Chronic Health Evaluation] II or Simplified Acute Physiology Score [SAPS] II) were combined with biomarkers obtained at the time of diagnosis of sepsis, including C-reactive-protein, procalcitonin (PCT), and PSP. Logistic regression models with the lowest prediction errors were selected to predict in-hospital mortality. RESULTS: Mortality rates of patients with septic shock enrolled in the derivation cohort (103 out of 158) and the validation cohort (53 out of 91) were 37% and 57%, respectively. APACHE II and PSP were significantly higher in dying patients. In the derivation cohort, the models combining either APACHE II, PCT, and PSP (area under the receiver operating characteristic curve [AUC], 0.721; 95% CI, 0.632-0.812) or SAPS II, PCT, and PSP (AUC, 0.710; 95% CI, 0.617-0.802) performed better than each individual biomarker (AUC PCT, 0.534; 95% CI, 0.433-0.636; AUC PSP, 0.665; 95% CI, 0.572-0.758) or severity score (AUC APACHE II, 0.638; 95% CI, 0.543-0.733; AUC SAPS II, 0.598; 95% CI, 0.499-0.698). These models were externally confirmed in the independent validation cohort. CONCLUSIONS: We confirmed the prognostic value of PSP in patients with severe sepsis and septic shock requiring ICU management. A model combining severity scores with PCT and PSP improves mortality prediction in these patients.

Normal values for pancreatic stone protein in different age groups.

BACKGROUND: Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS: PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS: PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS: This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.

Intoxication aiguë au baclofène. Particularités et principes thérapeutiques

En raison de sa prescription croissante pour des indications d'aide à la réduction des consommations ou au maintien de l'abstinence à l'alcool, le risque d'intoxication volontaire ou accidentelle au baclofène s'accroît et favorise l'admission aux urgences ou en réanimation de comas profonds. La difficulté diagnostique repose sur une relative méconnaissance de cette substance et sur le fait que le baclofène ne fait pas partie des substances mises en évidence par les examens toxicologiques de dépistage habituels. La modification de la pharmaco- cinétique du baclofène en cas de surdosage expose le patient à un coma prolongé, nécessitant dès lors un soutien ventilatoire de longue durée. De manière paradoxale, le baclofène expose également à un risque potentiel de convulsions. En cas de prise en charge adéquate, le pronostic est excellent dans la majorité des cas. En partant d'un cas clinique illustratif et d'une revue de littérature, nous proposons une synthèse des principes de prise en charge d'une intoxication aiguë au baclofène. Baclofen is widely used for the treatment of neurological spastic syndromes and has been recently proposed for the treatment of alcohol dependence. The risk of accidental or self- intoxication with baclofen may therefore increase in the future. Baclofen overdose affects the autonomic nervous system and produces an inhibitory effect on the central nervous system. The classic clinical presentation involves prolonged impaired consciousness or coma and neurovegetative symptoms. Paradoxically, baclofen overdose may also promote the occurrence of seizures. The emergency management is mainly supportive and, in the majority of cases, the prognosis appears excellent. Herein we report a case of baclofen self-intoxication and review the literature regarding the toxicity of baclofen, the clinical presentation of an acute baclofen poisoning and the related principles of management.

Aetiologies of pulseless electrical activity in out-of-hospital cardiac arrests:A retrospective study and analysis of specific causes

Background: Pulseless electrical activity (PEA) cardiac arrest is defined as a cardiac arrest (CA) presenting with a residual organized electrical activity on the electrocardiogram. In the last decades, the incidence of PEA has regularly increased, compared to other types of CA like ventricular fibrillation or pulseless ventricular tachycardia. PEA is frequently induced by reversible conditions. The "4 (or 5) H" & "4 (or 5) T" are proposed as a mnemonic to asses for Hypoxia, Hypovolemia, Hypo- /Hyperkalaemia, Hypothermia, Thrombosis (cardiac or pulmonary), cardiac Tamponade, Toxins, and Tension pneumothorax. Other pathologies (intracranial haemorrhage, severe sepsis, myocardial contraction dysfunction) have been identified as potential causes for PEA, but their respective probability and frequencies are unclear and they are not yet included into the resuscitation guidelines. The aim of this study was to analyse the aetiologies of PEA out-of-hospital CA, in order to evaluate the relative frequencies of each cause and therefore to improve the management of patients suffering a PEA cardiac arrest. Method: This retrospective study was based on data routinely and prospectively collected for each PEMS intervention. All adult patients treated from January 1st 2002 to December 2012 31st by the PEMS for out-of-hospital cardiac arrest, with PEA as the first recorded rhythm, and admitted to the emergency department (ED) of the Lausanne University Hospital were included. The aetiologies of PEA cardiac arrest were classified into subgroups, based on the classical H&T's classification, supplemented by four other subgroups analysis: trauma, intra-cranial haemorrhage (ICH), non-ischemic cardiomyopathy (NIC) and undetermined cause. Results: 1866 OHCA were treated by the PEMS. PEA was the first recorded rhythm in 240 adult patients (13.8 %). After exclusion of 96 patients, 144 patients with a PEA cardiac arrest admitted to the ED were included in the analysis. The mean age was 63.8 ± 20.0 years, 58.3% were men and the survival rate at 48 hours was 29%. 32 different causes of OHCA PEA were established for 119 patients. For 25 patients (17.4 %), we were unable to attribute a specific cause for the PEA cardiac arrest. Hypoxia (23.6 %), acute coronary syndrome (12.5%) and trauma (12.5 %) were the three most frequent causes. Pulmonary embolism, Hypovolemia, Intoxication and Hyperkaliemia occurs in less than 10% of the cases (7.6 %, 5.6 %, 3.5%, respectively 2.1 %). Non ischemic cardiomyopathy and intra-cranial haemorrhage occur in 8.3 % and 6.9 %, respectively. Conclusions: According to our results, intra-cranial haemorrhage and non-ischemic cardiomyopathy represent noticeable causes of PEA in OHCA, with a prevalence equalling or exceeding the frequency of classical 4 H's and 4 T's aetiologies. These two pathologies are potentially accessible to simple diagnostic procedures (native CT-scan or echocardiography) and should be included into the 4 H's and 4 T's mnemonic.

Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens

Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB.

Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

Estudo do efeito do cloreto em catalisadores de paládio usando a análise no infravermelho e de fotoelétrons excitados por raios x

Chloride poisoning is known as having an inhibitor effect in the activity of metal catalysis. In this work in situ infrared spectroscopy (FTIR) of adsorbed carbon monoxide and x-ray photoelectron spectroscopy (XPS) were used to investigate the effect of chloride presence in the electronic metal density in the d subshell of palladium dispersed on alumina. The chloride poisoning effect was interpreted as an electronic effect since a weak back-bonded Pd-CO was formed due to the decrease in the electronic density of the d subshell of palladium, which could be also detected by the higher Pd 3d5/2 binding energy in the chloride presence. A similar poisoning effect was also observed for chloride free Pd/Al2O3 reduced at 500 ºC, and it was interpreted based on the interaction of metal with the alumina surface. The use of molybdena/alumina binary system as support, yield a contrary effect due to the metal-support interaction.

Contaminação ambiental por compostos organoestânicos

The occurrence and the effects of organotin compounds (OTs) have been studied since a long time, due to their widespread use and deleterious effects. Some OTs are used as pesticides in crops, or as biocides in antifouling paints, applied in the ship hulls to avoid attachment and growth of tube worms, mussels and barnacles. However, "nontarget" organisms may be exposed, resulting in the poisoning of biological system, originating mutations and sentencing species to extinction. In this work we reported a revision study on the history of OTs and the techniques developed for its assessment and control.