The lay of the land: Associations between environmental features and personality.

OBJECTIVE: Personality traits cluster across countries, regions, cities, and neighborhoods. What drives the formation of these clusters? Ecological theory suggests that physical locations shape humans' patterns of behaviors and psychological characteristics. Based on this theory, we examined whether and how differential land-cover relates to individual personality. METHOD: We followed a preregistered three-pronged analysis approach to investigate the associations between personality (N = 2,690,878) and land-cover across the United States. We used eleven land-cover categories to classify landscapes and tested their association with personality against broad physical and socioeconomic factors. RESULTS: Urban areas were positively associated with openness to experience and negatively associated with conscientiousness. Coastal areas were positively associated with openness to experience and neuroticism but negatively associated with agreeableness and conscientiousness. Cultivated areas were negatively associated with openness. Landscapes at the periphery of human activity, such as shrubs, bare lands, or permanent snows, were not reliably associated with personality traits. CONCLUSIONS: Bivariate correlations, multilevel, and random forest models uncovered robust associations between landscapes and personality traits. These findings align with ecological theory suggesting that an individual's environment contributes to their behaviors, thoughts, and feelings.

Heterogeneidad del tratamiento para cándida parapsilosis en endocarditis micótica de válvula nativa / Types of treatments for native-valve endocarditis due to candida parapsilosis

Introducción: las infecciones por cándida en el ámbito intrahospitalario han ido en ascenso en las últimas décadas en especial en las unidades de cuidado intensivo (UCI), dado el uso cada vez más frecuente de antibióticos de amplio espectro y de procedimientos invasivos tanto diagnósticos como terapéuticos. Hoy se consideran las especies de cándida como la cuarta causa de infección del torrente sanguíneo en los Estados Unidos de Norteamérica, con alto riesgo de complicaciones que incluyen endocarditis, trombosis y embolismo séptico al sistema nervioso central (SNC) entre otros. En relación con la endocarditis por especies de cándida, se ha considerado de mal pronóstico por el alto riesgo de afectación al SNC, por lo que se ha recomendado el manejo quirúrgico como piedra angular de su tratamiento. Presentación del caso: se describe el caso clínico de un paciente con endocarditis y con candidemia por Candida parapsilosis a quien se le realizó manejo médico.

Nosocomial Candida infections have increased in the last decades particularly in the intensive care units (ICU) due to the rise in broad-spectrum antibiotics usage and invasive diagnostic and therapeutic procedures usage. Today, Candida species are recognized as the fourth causative organisms of endovascular infection in the United States of America posing a high risk of endocarditis, thrombosis and septic embolization to the central nervous system (CNS). Endocarditis due to Candida species is associated with a poor prognosis because of the increased risk of CNS involvement for which surgical approach has been recommended as the cornerstone of therapy. We hereby report a patient with endocarditis and candidemia due to Candida parapsilosis, who received medical management.

Manifestaciones atípicas del síndrome de vasculitis-angeítis- endotelitis (SVAE) cutánea / Atypical manifestations of cutaneous vasculitis- angeitis-endotheliitis syndrome

Se reportan dos pacientes con diagnóstico histopatológico de vasculitis cutánea de presentación clínica atípica. Un joven de 13 años con lesiones bullosas y flictenulares generalizadas de 2-3 cm sin sobreinfección, que se iniciaron en la cavidad oral y se extendieron al tórax anterior y extremidades, asociadas con infección ventilo-respiratoria tipo neumonía adquirida en la comunidad (NAC), que requirió antibióticos y corticoides sistémicos, con resolución completa a los 17 días y diagnóstico definitivo de vasculitis por hipersensibilidad. El otro paciente corresponde a un adulto de 58 años con historia de 18 meses de lesiones maculares purpúricas en miembros superiores e inferiores, algunas confluyen generando placas violáceas no mayores de 5 cm. Cursó con diabetes, retinopatía e hipertensión arterial. La biopsia mostró vasculitis leucocitoclásica con "signo de promontorio", por lo cual se sospechó sarcoma de Kaposi que se descartó. El diagnóstico definitivo fue vasculitis linfocítica en pitiriasis liquenoide crónica (PLC).

Two patients with histopathological diagnosis of cutaneous vasculitis of atypical clinical course are presented. The first patient was a 13-year-old boy with bullous lesions and generalized phlyctenules measuring 2-3 cm with no superinfection, which began in the oral cavity and extended to the anterior chest and extremities, associated with ventilation-respiratory community acquired pneumonia (CAP), which required antibiotic therapy and systemic corticoids, with complete resolution at 17 days and definitive diagnosis of hypersensitivity vasculitis. The other patient corresponds to a 58-year-old man with purpuric macular lesions in upper and lower extremities of 18 months duration. Some of them were confluent purpuric plaques not greater than 5 cm. Patient had associated diabetes, retinopathy and hypertension. Biopsy showed leukocytoclastic vasculitis with the presence of "promontory sign" suggestive of Kaposi ́s sarcoma which was ruled out. The definitive diagnosis was lymphocytic vasculitis in a patient with pytriasis lichenoids chronica (PLC).

Variation in Childhood Diarrheal Morbidity and Mortality in Africa, 2000-2015.

BACKGROUND: Diarrheal diseases are the third leading cause of disease and death in children younger than 5 years of age in Africa and were responsible for an estimated 30 million cases of severe diarrhea (95% credible interval, 27 million to 33 million) and 330,000 deaths (95% credible interval, 270,000 to 380,000) in 2015. The development of targeted approaches to address this burden has been hampered by a paucity of comprehensive, fine-scale estimates of diarrhea-related disease and death among and within countries. METHODS: We produced annual estimates of the prevalence and incidence of diarrhea and diarrhea-related mortality with high geographic detail (5 km2) across Africa from 2000 through 2015. Estimates were created with the use of Bayesian geostatistical techniques and were calibrated to the results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. RESULTS: The results revealed geographic inequality with regard to diarrhea risk in Africa. Of the estimated 330,000 childhood deaths that were attributable to diarrhea in 2015, more than 50% occurred in 55 of the 782 first-level administrative subdivisions (e.g., states). In 2015, mortality rates among first-level administrative subdivisions in Nigeria differed by up to a factor of 6. The case fatality rates were highly varied at the national level across Africa, with the highest values observed in Benin, Lesotho, Mali, Nigeria, and Sierra Leone. CONCLUSIONS: Our findings showed concentrated areas of diarrheal disease and diarrhea-related death in countries that had a consistently high burden as well as in countries that had considerable national-level reductions in diarrhea burden. (Funded by the Bill and Melinda Gates Foundation.).

Targeting of organophosphorus compound bioscavengers to the surface of red blood cells.

To develop a prophylactic for organophosphorus (OP) poisoning utilizing catalytic bioscavengers, the circulatory stability of the enzymes needs to be increased. One strategy for increasing the bioavailability of OP bioscavengers is to target them to the surface of red blood cells (RBCs). Given the circulatory lifespan of 120 days for human RBCs, this strategy has the potential for creating a persistent pool of bioscavenger. Here we report the development of fusion proteins with a single chain variable fragment (scFv) of Ter119, a molecule that associates with glycophorin A on the surface of RBCs, and the VIID11 variant of paraoxonase 1 (scFv-PON1). We show that scFv-PON1 variants expressed by Trichoplusia ni larvae are catalytically active and that one variant in particular can successfully bind to the surface of murine RBCs both in vitro and in vivo. This study represents a proof of concept for targeting catalytic bioscavengers to the surface of RBCs and is an early step in developing catalytic bioscavengers that can remain in circulation for an extended period of time.

Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle.

Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD50) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD50 of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD50s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity.

Multitarget drug design strategy: quinone-tacrine hybrids designed to block amyloid-ß aggregation and to exert anticholinesterase and antioxidant effects.

We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-ß (Aß) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Aß. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.

The involvement of secondary neuronal damage in the development of neuropsychiatric disorders following brain insults.

Neuropsychiatric disorders are one of the leading causes of disability worldwide and affect the health of billions of people. Previous publications have demonstrated that neuropsychiatric disorders can cause histomorphological damage in particular regions of the brain. By using a clinical symptom-comparing approach, 55 neuropsychiatric signs or symptoms related usually to 14 types of acute and chronic brain insults were identified and categorized in the present study. Forty percent of the 55 neuropsychiatric signs and symptoms have been found to be commonly shared by the 14 brain insults. A meta-analysis supports existence of the same neuropsychiatric signs or symptoms in all brain insults. The results suggest that neuronal damage might be occurring in the same or similar regions or structures of the brain. Neuronal cell death, neural loss, and axonal degeneration in some parts of the brain (the limbic system, basal ganglia system, brainstem, cerebellum, and cerebral cortex) might be the histomorphological basis that is responsible for the neuropsychiatric symptom clusters. These morphological alterations may be the result of secondary neuronal damage (a cascade of progressive neural injury and neuronal cell death that is triggered by the initial insult). Secondary neuronal damage causes neuronal cell death and neural injury in not only the initial injured site but also remote brain regions. It may be a major contributor to subsequent neuropsychiatric disorders following brain insults.

Biophysical aspects of cyclodextrin interaction with paraoxon.

Cyclodextrins are torus-shaped polymers of glucose that can bind organophosphorous compounds such as nerve agents and pesticides. We demonstrate here that cyclodextrin can bind up to two paraoxon molecules with a K(av) of 6775 M(-1). Molecular modeling shows that the paraoxon appears to bind in polar opposite orientation and have an average binding energy of -89 Kcals/mol. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Técnicas didácticas: método de caso clínico con la utilización de video como herramienta de apoyo en la enseñanza de la medicina / Teaching techniques: clinical case approach to the use of video as a tool to support

La enseñanza de las ciencias biomédicas o denominadas también básicas, en los programas de medicina de las Universidades de Colombia, es la base fundamental para el desarrollo continuo del razonamiento científico y clínico en los futuros profesionales facultativos para la evolución social y científica del país. La evaluación autónoma de la calidad interna, por parte de las instituciones educativas, se hace imprescindible para lograr, no sólo, la adquisición de conocimientos fácticos en forma significativa, sino también, la formación ética, estética y humanística de los estudiantes. La enseñanza y el aprendizaje de las ciencias Biomédicas implican aspectos teóricos, metodológicos e investigativos, así como una reflexión constante sobre el quehacer pedagógico, lo que implica la interdisciplinaridad, la integración básico-clínica y, por extensión, la didáctica y la aplicación de tecnologías de la información y la comunicación (TIC). En este escrito, se expone una experiencia pedagógica de tipo cualitativo fundamentada en Método de Caso Clínico (MdC), la cual se llevó a cabo dentro de la sección de Bioclínica de la Universidad El Bosque, se estructuró con el uso de TIC y se basó en un problema de impacto de morbilidad de Salud Pública para Colombia.

The teaching of biomedical sciences or also called basic medical programs at the Universities of Colombia, is the fundamental basis for the continued development of scientific reasoning and clinical professionals in future physicians, and therefore to the social and scientific the country. Therefore, the independent evaluation of internal quality by educational institutions is essential to achieve not only the acquisition of factual knowledge significantly, but also the ethical, aesthetic and humanistic students. Teaching and learning science involves Biomedical theoretical, methodological and research and a constant reflection on the pedagogical practice, which involves interdisciplinary, basic clinical integration, and by extension the teaching and application of new Information and Communication Technology (ICT). In this paper, presents a qualitative learning experience based on Clinical Case Method (MdC), which was held in the section Bioclinic of the University El Bosque, and was structured with the use of TICS and which was based on a problem of impact of disease of public health for Colombia.

Evaluation and computational characterization of the facilitated transport of Glc carbon C-1 oxime reactivators across a blood brain barrier model.

We are evaluating a facilitative transport strategy to move oximes across the blood brain barrier (BBB) to reactivate inhibited brain acetylcholinesterase (AChE). We selected glucose (Glc) transporters (GLUT) for this purpose as these transporters are highly represented in the BBB. Glc conjugates have successfully moved drugs across the BBB and previous work has shown that Glc-oximes (sugar-oximes, SOxs) can reduce the organophosphonate induced hypothermia response. We previously evaluated the reactivation potential of Glc carbon C-1 SOxs. Here we report the reactivation parameters for VX- and GB-inhibited human (Hu) AChE of the best SOx (13c) and our findings that the kinetics are similar to those of the parent oxime. Although crystals of Torpedo californica AChE were produced, neither soaked or co-crystallized experiments were successful at concentrations below 20mM 13c, and higher concentrations cracked the crystals. 13c was non-toxic to neuroblastoma and kidney cell lines at 12-18 mM, allowing high concentrations to be used in a BBB kidney cell model. The transfer of 13c from the donor side was asymmetric with the greatest loss of 13c from the apical- or luminal-treated side. There was no apparent transfer from the basolateral side. The 13cP(app) results indicate a 'low' transport efficiency; however, mass accounting revealed only a 20% recovery from the apical dose in which high concentrations were found in the cell lysate fraction. Molecular modeling of 13c through the GLUT-1 channel demonstrated that transport of 13c was more restricted than Glc. Selected sites were compared and the 13c binding energies were greater than two times those of Glc.

Bordetellas, más que solo pertussis: Genética, genómica, evolución y nuevos patógenos para la especie humana / Bordetella genus, more than only pertussis: Genetics, genomics, evolution and new human pathógens

La Bordetella pertussis es un reconocido patógeno gram negativo relacionado con enfermedad respiratoria aguda en la especie humana. Cada día hay un mayor reporte de cuadros infecciosos producidos por otras bacterias del género Bordetella. Los modelos teóricos actuales y la evidencia científica en relación con la evolución de las distintas bacterias del género, han abierto nuevas posibilidades de comprensión para descifrar los paradigmas en especiación bacteriana, así como los factores genéticos y genómicos involucrados en tal proceso. El objetivo de este artículo es explorar la genética, la genómica y los hallazgos en filogénesis del género Bordetella y difundir el conocimiento actual en relación con el papel nosológico para la salud humana de los nuevos patógenos del grupo...

Bordetella pertussis is a well known Gram-negative organism that causes acute respiratory disease in humans. There is a trend of an increase in reported cases of infections caused by other bacteria of the Bordetella genus. Current theoretical models and scientific evidence related to the evolution of the various species of this genus have open new possibilities of understanding to solve the paradigms of bacterial speciation, as well as, the genetic and genomic factors involved in such process. The main objective of this article is to explore Bordetella genus genetics, genomics and phylogenetic findings and extend current knowledge on the role of the new strains of this group as human pathogens...

Synthesis of (±)-7-hydroxylycopodine.

A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether. The resulting product was converted to 7-hydroxydehydrolycopodine by heating with KO-t-Bu and benzophenone in benzene followed by acidic workup. During unsuccessful attempts to make optically pure starting material, we observed the selective Pt-catalyzed hydrogenation of the 5-phenyl group of a 4,5-diphenyloxazolidine under acidic conditions and the Pt-catalyzed isomerization of the oxazolidine to an amide under neutral conditions. In attempts to hydroxylate the starting material so that we could adapt this synthesis to the preparation of (±)-7,8-dihydroxylycopodine (sauroine) we observed the novel oxidation of a bicyclic vinylogous amide to a keto pyridine with Mn(OAc)(3) and to an amino phenol with KHMDS and oxygen.

Hydrolysis potential of recombinant human skin and kidney prolidase against diisopropylfluorophosphate and sarin by in vitro analysis.

Human prolidase (PROL), which has structural homology to bacterial organophosphate acid anhydrolase that hydrolyze organophosphates and nerve agents has been proposed recently as a potential catalytic bioscavenger. To develop PROL as a catalytic bioscavenger, we evaluated the in vitro hydrolysis efficiency of purified recombinant human PROL against organophosphates and nerve agents. Human liver PROL was purified by chromatographic procedures, whereas recombinant human skin and kidney PROL was expressed in Trichoplusia ni larvae, affinity purified and analyzed by gel electrophoresis. The catalytic efficiency of PROL against diisopropylfluorophosphate (DFP) and nerve agents was evaluated by acetylcholinesterase back-titration assay. Partially purified human liver PROL hydrolyzed DFP and various nerve agents, which was abolished by specific PROL inhibitor showing the specificity of hydrolysis. Both the recombinant human skin and kidney PROL expressed in T. ni larvae showed ∼99% purity and efficiently hydrolyzed DFP and sarin. In contrast to human liver PROL, both skin and kidney PROL showed significantly low hydrolyzing potential against nerve agents soman, tabun and VX. In conclusion, compared to human liver PROL, recombinant human skin and kidney PROL hydrolyze only DFP and sarin showing the substrate specificity of PROL from various tissue sources.

Acidemia propiónica neonatal con deterioro neurológico, rechazo al alimento y emesis reporte de caso y revisión de la literatura / Neonatal-onset propionic acidemia neurologic deficit, poor feeding and vomiting - a case report and literature review

Paciente pretérmino que reingresa a la unidad de recién nacidos de la Clínica Universitaria Colombia, Bogotá DC, por problemas en la alimentación y pobre ganancia ponderal, a quien se le diagnosticó acidemia propiónica mediante cromatografía de ácidos orgánicos en orina. Los errores innatos del metabolismo son entidades que a pesar de tener una baja incidencia, se deben considerar en todo neonato con encefalopatía, problemas en la alimentación o pobre ganancia ponderal, entre otras manifestaciones, ya que el diagnóstico temprano y tratamiento oportuno previenen la aparición de secuelas neurológicas con retardo del desarrollo psicomotor y muerte temprana.

Preterm infant readmitted to the neonatal unit at ClínicaUniversitaria Colombia, Bogotá DC, presenting poor feeding and delays in normal growth velocity, who was diagnosed with propionic acidemiaby means of a urine organic acid profiling by chromatography. Although its low incidence, inborn metabolic disorders must be considered in any newborn presenting with encefalopathy, poor feeding or delays in normal growth velocity, among other manifestations for early diagnosisandprompt treatment preventneurological sequellae including psychomotor retardation and early neonatal death.

Biotina y regulación transcripcional (génica) y epigenética en la especie humana / Biotin and transcriptional (genetic) and epigenetic regulation in humans

La biotina es una vitamina hidrosoluble del complejo B que se conoce como una coenzima para carboxilasas en la especie humana. Es evidente que está ligada en forma covalente con distintos residuos de lisina en las histonas, afectando así la estructura cromatínica, muy estudiada mediante la regulación génica y la herencia no-mendeliana transgeneracional, denominada epigenética. Esta nueva ciencia estudia las modificaciones de ADN y de las proteínas unidas a él (sobre todo histonas), que alteran la estructura de la cromatina sin modificar la secuencia nucleotídica del ADN. El objetivo de esta revisión es presentar una breve actualización sobre la biotina desde el punto de vista de regulación genética y epigenética, los roles derivados en la patogénesis de ciertas enfermedades y el entendimiento de los potenciales usos farmacológicos futuros.

Biotin is a water-soluble B-complex vitamin known as a coenzyme for carboxylases in humans. It is evident that it covalently attaches to various lysine residues in histones, thus affecting the chromatin structure which is widely studied by means of genetic regulation and non-Mendelian transgenerational inheritance termed epigenetics. This new science, studies the modifications of DNA binding proteins (mainly histones), which alter the chromatin structure without modifying the nucleotide sequence of DNA. The objective of this review is to present a short update on biotin from the genetic and epigenetic perspective; the derived roles played in the pathogenesis of certain diseases; and the understanding of potential future pharmacological uses.

Multicentric oncologic outcomes of high-intensity focused ultrasound for localized prostate cancer in 803 patients.

BACKGROUND: High-intensity focused ultrasound (HIFU) is an emerging treatment for select patients with localized prostate cancer (PCa). OBJECTIVES: To report the oncologic outcome of HIFU as a primary care option for localized prostate cancer from a multicenter database. DESIGN, SETTING, AND PARTICIPANTS: Patients with localized PCa treated with curative intent and presenting at least a 2-yr follow-up from February 1993 were considered in this study. Previously irradiated patients were excluded from this analysis. In case of any residual or recurrent PCa, patients were systematically offered a second session. Kaplan-Meier analysis was performed to determine disease-free survival rates (DFSR). MEASUREMENTS: Prostate-specific antigen (PSA), clinical stage, and pathologic results were measured pre- and post-HIFU. RESULTS AND LIMITATIONS: A total of 803 patients from six urologic departments met the inclusion criteria. Stratification according to d'Amico's risk group was low, intermediate, and high in 40.2%, 46.3%, and 13.5% of patients, respectively. Mean follow-up was 42+/-33 mo. Mean PSA nadir was 1.0+/-2.8 ng/ml with 54.3% reaching a nadir of < or =0.3 ng/ml. Control biopsies were negative in 85% of cases. The overall and cancer-specific survival rates at 8 yr were 89% and 99%, respectively. The metastasis-free survival rate at 8 yr was 97%. Initial PSA value and Gleason score value significantly influence the DFSR. The 5- and 7-yr biochemical-free survival rates (Phoenix criteria) were 83-75%, 72-63%, and 68-62% (p=0.03) and the additional treatment-free survival rates were 84-79%, 68-61%, and 52-54% (p<0.001) for low-, intermediate-, and high-risk patients, respectively. PSA nadir was a major predictive factor for HIFU success: negative biopsies, stable PSA, and no additional therapy. CONCLUSIONS: Local control and DFSR achieved with HIFU were similar to those expected with conformal external-beam radiation therapy (EBRT). The excellent cancer-specific survival rate is also explained by the possibility to repeat HIFU and use salvage EBRT.

Novel oximes as blood-brain barrier penetrating cholinesterase reactivators.

The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates were utilized. These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar-oximes, as well as six novel sugar-oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar-oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar-oxime 8b had low toxicity with a LD(50) of 1,590 mg/kg from a single IM dose in the guinea pig and >2,000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar-oximes can be effective reactivators and suggest that high treatment doses may be possible.

Estado del arte: biología, patobiología y bioclínica de la homocisteína en la especia humana / State of the art: biology, pathobiology and bioclinical aspects of homocysteine in the human species

La homocistinuria fue descrita en 1962 en niños con dificultades de aprendizaje y en 1969 McCully informó la evidencia en autopsias de trombosis arterial extensa y aterosclerosis en niños con elevadas concentraciones de homocisteína plasmática y homocistinuria. La homocisteína, un aminoácido de azufre, es un metabolito intermedio de la metionina, y sobre la base de estos hallazgos bioquímicos, ellos propusieron que la homocisteína plasmática elevada puede causar lesión neural y enfermedad vascular aterosclerótica. Hoy se considera un factor de riesgo independiente para esta última. La hiperhomocistinemia leve es bastante prevalente en la población general. Puede deberse a defectos genéticos en las enzimas que participan en el metabolismo de la homocisteína, carencias nutricionales de vitaminas y cofactores, ciertos medicamentos, ingesta rica en metionina o enfermedad renal. La alta concentración puede reducirse con folato, y es así que la suplementación vitamínica ha sido propuesta en individuos con hiperhomocistinemia con el fin de reducir su riesgo de enfermedad cardiovascular. En este artículo hacemos una revisión de la biología, la patobiología y la bioclínica del metabolismo de la homocisteína.

Homocystinuria was firstly described in 1962 en children with learning difficulties, and in 1969 McCully reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in children with elevated plasma homocysteine concentrations and homocystinuria. Homocysteine, a sulfur amino acid, is an intermediate metabolite of methionine, and in the both cases mentioned, on the basis of these finding biochemical, they proposed that elevated plasma homocysteine (hyperhomocysteinemia) can cause neural injury and atherosclerotic vascular disease. Hyperhomocysteinemia is now well established as an independent risk factor for atherosclerotic vascular disease. Mild hyperhomocysteinemia is quite prevalent in the general population. It can be caused by genetic defects in the enzymes involved in homocysteine metabolism or nutritional deficiencies in vitamin cofactors, certain medications, high methionie intake or renal disease. The homocysteine concentration can be lowered with folate, and it's so vitamin supplementation has thus been proposed in individuals with hyperhomocysteinemia in order to reduce their cardiovascular disease risk. In this article, we review the biology, pathobiology and bioclinic of the metabolism of homocysteine.

TCEP treatment reduces proteolytic activity of BoNT/B in human neuronal SHSY-5Y cells.

The light chain (LC) of botulinum neurotoxin B (BoNT/B) is unable to enter target neuronal cells by itself. It is brought into the cell in association with the BoNT/B heavy chain (HC) through endocytosis. The BoNT HC-LC subunits are held together by a single disulfide bond. Intracellular reduction of this bond and separation of the two subunits activates the endopeptidase activity of the LC. This requirement suggests a strategy to prevent uptake by prophylactic reduction to disrupt the disulfide bond prior to endocytosis of the complex. We examined the utility of tris-(2-carboxyethyl)-phosphine hydrochloride (TCEP), a relatively non-toxic, non-sulfur containing disulfide bond reducing agent that lacks the undesirable properties of mercapto-containing reducing agents. We found that TCEP was as effective as DTT with maximal LC endopeptidase activation occurring at 1 mM, a concentration not toxic to the human neuronal cell line, SHSY-5Y. In these cells, 1 mM TCEP maximally protected against BoNT/B inhibition of [(3)H]-NA release, achieving 72% of the release from un-intoxicated controls. This effect appears to be due to the sparing of SNARE proteins as the levels of VAMP-2, the specific target of BoNT/B, were protected. These results show that TCEP disrupts the structure of BoNT/B by reduction of the LC and HC bridging disulfide bond and prevents neuronal intoxication. Since disulfide bond coupling between toxin subunits is a general motif for many toxins, e.g., ricin, snake venom, and all BoNT serotypes, this suggests that TCEP is a promising means to protect against these toxins by preventing cell penetration.