Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

The cofactor nicotinamide adenine dinucleotide (NAD+) plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+ levels is an established approach to enhancing healthy aging. Recently, several classes of nicotinamide phosphoribosyl transferase (NAMPT) activators have been shown to increase NAD+ levels in vitro and in vivo and to demonstrate beneficial effects in animal models. The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors, however the basis for the switch from inhibitory activity to activation is not well understood. Here we report an evaluation of the structure activity relationships of NAMPT activators by designing, synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators. The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site, resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead, which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.

Trainee perceptions of a group-based standardized patient training for challenging behavioral health scenarios in the United States / 보건의료교육평가

No abstract available.

Measurement accuracy and reliability of tooth length on conventional and CBCT reconstructed panoramic radiographs

INTRODUCTION: This in vivo study assessed accuracy and reliability of tooth length measurements obtained from conventional panoramic radiographs and CBCT panoramic reconstructions to that of a digital caliper (gold standard). METHODS: The sample consisted of subjects who had CBCT and conventional panoramic radiographic imaging and who required maxillary premolar extraction for routine orthodontic treatment. A total of 48 teeth extracted from 26 subjects were measured directly with digital calipers. Radiographic images were scanned and digitally measured in Dolphin 3D software. Accuracy of tooth length measurements made by CBCT panoramic reconstructions, conventional panoramic radiographs and digital caliper (gold standard) were compared to each other by repeated measures one-way ANOVA with Bonferroni correction and by single measures intraclass correlation coefficient. RESULTS: Repeated root length measures with digital calipers, panoramic radiographs and CBCT constructed panoramic-like images were all individually highly reliable. Compared to the caliper (gold standard), tooth measurements obtained from conventional panoramic radiographs were on average 6.3 mm (SD = 2.0 mm) longer, while tooth measurements from CBCT panoramic reconstructions were an average of 1.7 mm (SD = 1.2 mm) shorter. CONCLUSIONS: In comparison to actual tooth lengths, conventional panoramic radiographs were relatively inaccurate, overestimating the lengths by 29%, while CBCT panoramic reconstructions underestimated the lengths by 4%. .

INTRODUÇÃO: este estudo in vivo avaliou a precisão e a confiabilidade de medições do comprimento dentário realizadas em radiografias panorâmicas convencionais e em reconstruções panorâmicas de tomografias computadorizadas de feixe cônico (TCFC), comparando-as com medições feitas com um paquímetro digital, consideradas o padrão-ouro. MÉTODOS: a amostra incluiu indivíduos que já tivessem realizado tanto exames imaginológicos de TCFC quanto radiografias panorâmicas, e cujo tratamento ortodôntico exigisse a extração de pré-molar superior. No total, 48 dentes extraídos, de 26 pacientes, foram mensurados diretamente com paquímetros digitais. As radiografias foram escaneadas e digitalmente avaliadas com a ajuda do software Dolphin 3D. Por meio da análise de variância simples com correção de Bonferroni e Coeficiente de Correlação Intraclasse simples, comparou-se a precisão das medições de comprimento dentário realizadas em reconstruções panorâmicas de TCFC, em radiografias panorâmicas convencionais e com paquímetro digital. RESULTADOS: medições repetidas de comprimento dentário feitas com o paquímetro digital, radiografias panorâmicas e reconstruções panorâmicas de TCFC foram todas consideradas, individualmente, altamente confiáveis. Em comparação ao paquímetro, as medidas obtidas por meio de radiografias panorâmicas convencionais foram, em média, 6,3 ± 2,0mm mais longas, enquanto as medidas obtidas por meio das reconstruções panorâmicas de TCFC foram, em média, 1,7 ± 1,2mm mais curtas. CONCLUSÕES: em comparação com o real comprimento dentário, as radiografias panorâmicas convencionais foram relativamente ...

Diagnóstico genético preimplantacional: análisis de aneuploidías únicas / Preimplantational genetic diagnosis: single aneuploidies analysis

Introducción: De las causas más conocidas en cuanto a la falta del éxito en el embarazo con tratamientos de reproducción asistida son aquellas relacionadas a las aneuploidías cromosómicas presentes en los embriones. El diagnóstico genético preimplantacional (PGD) es una técnica empleada en reproducción asistida para detectar estas anomalías, seleccionando aquellos que sean cromosómicamente normales, para luego transferirlos al útero de la paciente. Los embriones con aneuploidías únicas podrían tener la capacidad de sobrevivir y lograr la implantación, y por lo tanto, sin diagnóstico previo, estas podrían pasar desapercibidas. Objetivos: Determinar la incidencia de aneuploidías únicas en embriones de buena calidad embrionaria en el día 3 de desarrollo hasta blastocisto. Diseño: Estadístico y experimental. Instituciones: Reprogenetics Latinoamérica y Centro de Reproducción asistida, de la Clínica Concebir. Material Biológico: Muestras de biopsia embrionaria. Metodología: Análisis comparativo de resultados a partir de la evaluación de cada muestra obtenida por biopsia en el día tercero y día quinto de desarrollo embrionario, realizando el PGD por hibridación in situ (FISH) y genómica comparada (aCGH), respectivamente. Resultados: El 62,9% de embriones que presentaron monosomías únicas al tercer día de desarrollo embrionario resultaron ser de 8 células. Pero cuando se evaluó por aCGH en día cinco, 42,3% resultó anormal, y de estos 37,5% perteneció al estadio de 8 células. El índice de monosomías únicas en blastocisto resultó ser 57,9% de un total de 84,2% de aneuploidías únicas. Conclusiones: Los embriones de 8 células en el tercer día de desarrollo embrionario son los más probables de llegar al estadio de blastocisto, así como presentar aneuploidías únicas.

Background: Known causes of unsuccessful pregnancy in couples undergoing assisted reproduction treatment include embryo aneuploidies. Preimplantation genetic diagnosis (PGD) is a technique used in assisted reproduction in order to detect these abnormalities, select embryos chromosomally normal and subsequently transfer to the patients’ uterus. Embryos with single aneuploidies may have the ability to survive and achieve unnoticed implantation. Objectives: To determine incidence of single aneuploidies in good quality embryos in third day of development to blastocyst. Design: Statistical and experimental study. Setting: Reprogenetics Latin-America and Assisted Reproduction Center - Concebir. Biologic material: Samples of embryo biopsies. Methods: Comparative analysis of results from evaluation of each sample obtained by embryo biopsy on the third and fifth days of embryonic development, performing PGD by respectively in situ hybridization (FISH) and comparative genomics (aCGH). Results: On third day of embryonic development 62.9% of embryos with single monosomy had 8-cell morphology. Though when evaluated by aCGH in the blastocyst stage 42.3% were abnormal and 37.5% of these belonged to the 8-cell stage. Single monosomies index in the blastocyst stage was 57.9% in 84.2% of single aneuploidies. Conclusions: Eight-cell embryos on the third day of embryonic development are most likely to reach blastocyst stage and have single aneuploidies.

Cryoablation and cementoplasty of a pathologic fracture in the sternum

A 49-year-old man with metastatic melanoma and pathologic fracture of the sternum was deemed to be a poor candidate for general anaesthesia. He suffered severe pain and range of motion limitation that did not respond to narcotic therapy. Ultimately, the lesion was managed with computed tomography-guided cryoablation and subsequent cementoplasty, and saw good initial clinical results.

New Statistical Method to Analyze Three-Dimensional Landmark Configurations Obtained with Cone-Beam CT: Basic Features and Clinical Application for Rapid Maxillary Expansion

OBJECTIVE: To describe a statistical method of three-dimensional landmark configuration data and apply it to an orthodontic data set comparing two types of rapid maxillary expansion (RME) treatments. MATERIALS AND METHODS: Landmark configurations obtained from cone beam CT scans were used to represent patients in two types (please describe what were two types) of RME groups and a control group over four time points. A method using tools from persistent homology and dimensionality reduction is presented and used to identify variability between the subjects. RESULTS: The analysis was in agreement with previous results using conventional methods, which found significant differences between treatment groups and the control, but no distinction between the types of treatment. Additionally, it was found that second molar eruption varied considerably between the subjects, and this has not been evaluated in previous analyses. CONCLUSION: This method of analysis allows entire configurations to be considered as a whole, and does not require specific inter-landmark distances or angles to be selected. Sources of variability present themselves, without having to be individually sought after. This method is suggested as an additional tool for the analysis of landmark configuration data.

El inicio del Ministerio Médico de HCJB y la creación del Hospital Vozandes Quito / The beginning of HCJB Medical Ministry and the creation of Vozandes Hospital

El Hospital Vozandes Quito se inauguró el 12 de octubre de 1955. La historia de su origen se remonta al comienzo del Ministerio Médico de HCJB en Ecuador, cuando Clarence Jones, Reuben Larson y Stuart Clark, fundadores de la radio estación, habían previsto la creación de un Albergue Indígena y Dispensario. En este manuscrito, el Dr. Paul W. Roberts, fundador del Hospital Vozandes, narra sus vivencias desde que en 1946 conoció a Clarence Jones y decidió ser médico misionero; pero con un sueño dado por Dios, mucho más grande y signifcativo: construir un hospital moderno, bien equipado, para atender a los necesitados en el nombre de Jesús.

Vozandes Quito Hospital opened on October 12, 1955. The history of its origin dates back to the beginning of the Medical Ministry of HCJB in Ecuador, when Clarence Jones, Reuben Larson and Stuart Clark, founders of the radio station had plans to create a small indigenous shelter and clinic. In this manuscript, Dr. Paul W. Roberts, founder of Vozandes Hospital, describes his experiences since 1946 when he met Clarence Jones and decided to become a medical missionary, but with a God-given dream, much larger and signifcant: to build a modern hospital, well equipped to take care of the poor people in the name of Jesus.

Assessment and management of asthma and chronic obstructive pulmonory disease [COPD] - converging approaches

This review compares the methods of assessment and treatment objectives used for asthma and COPD. There is now a significant amount of convergence between the two diseases in these areas. It is now well recognised that both are inflammatory diseases. Anti-inflammatory therapy with inhaled corticosteroids [ICS] forms the basis of asthma therapy [and are underused in many countries, including Pakistan], but there also is now very good evidence that ICS reduce bronchial inflammation in COPD, especially when used in combination with long-acting beta[2] -agonists. Guidelines recommend that asthma assessment in routine practice, is based upon an evaluation of the level of asthma control; COPD assessment is moving towards something very similar, but it is termed health status measurement. Simple standardised methods designed for use in routine practice are now available for both purposes. Treatment in both conditions also now has two objectives: 1. To reduce symptoms to achieve control [in asthma] and improved health status [in COPD]; 2. Preventative therapy to reduce the risk of exacerbations. In asthma, exacerbations are associated with a risk of hospital admissions and death and in COPD the same risks apply, but now with good evidence that exacerbations also speed disease progression. The treatments that are available for asthma can, if used properly, achieve high levels of control. Whilst new drugs are welcome, good application of existing drugs would very greatly reduce the burden of this disease on patients and healthcare systems. New treatments are steadily becoming available for COPD and there is now much that can be done to reduce the burden of this disease. Both diseases are eminently treatable

Condições higiênico-sanitárias da pimenta do reino em pó (Piper nigrum L) com o emprego de duas diferentes técnicas para detecção de sujidades leves / Assessment of hygienic conditions of ground pepper (Piper nigrum L) by means of two methodologies for detecting the light filth

A pimenta do reino deve ser colhida, processada, embalada em condições ideais para evitar a presença de matérias estranhas. Com o objetivo de avaliar as condições higiênicas da pimenta do reino em pó, comercializada em São Paulo, foram analisadas 22 amostras por meio de duas diferentes técnicas no período de maio a setembro de 2006. Para a análise de sujidades leves foi utilizada a técnica de flutuação segundo AOAC e ensaio imunoenzimático – ELISA. Observou-se que 100% das amostras continham fragmentos de insetos e em várias amostras foram demonstrados mais de um tipo de matéria estranha; e 23% das amostras mostraram ser impróprias ao consumo em virtude da presença de pelos de roedor. Para realizar o ELISA, foram adicionados os padrões constituídos de 1, 2, 4, 8 e 10 insetos para estimar o número de insetos nas amostras em análise, por meio de valores de densidade óptica (DO). Verificou-se que 36,4% das amostras apresentaram valores de DO próximos aos correspondentes ao do padrão 8 insetos, 40,9% ao do padrão 4 insetos, 18,2% ao do padrão 10 e 4,5% ao do padrão 2 insetos. A técnica descrita na AOAC mostra ser mais apropriada, em função de sua eficiência de detecção de insetos, bem como de outras matérias estranhas, enquanto que o ELISA detecta especificamente a miosina presente no músculo dos insetos, cuja degradação ocorre com o passar do tempo.

Chilli anthracnose disease caused by Colletotrichum species / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Anthracnose disease is one of the major economic constraints to chilli production worldwide, especially in tropical and subtropical regions. Accurate taxonomic information is necessary for effective disease control management. In the Colletotrichum patho-system, different Colletotrichum species can be associated with anthracnose of the same host. Little information is known concerning the interactions of the species associated with the chilli anthracnose although several Colletotrichum species have been reported as causal agents of chilli anthracnose disease worldwide. The ambiguous taxonomic status of Colletotrichum species has resulted in inaccurate identification which may cause practical problems in plant breeding and disease management. Although the management and control of anthracnose disease are still being extensively researched, commercial cultivars of Capsicum annuum that are resistant to the pathogens that cause chilli anthracnose have not yet been developed. This paper reviews the causal agents of chilli anthracnose, the disease cycle, conventional methods in identification of the pathogen and molecular approaches that have been used for the identification of Colletotrichum species. Pathogenetic variation and population structure of the causal agents of chilli anthracnose along with the current taxonomic status of Colletotrichum species are discussed. Future developments leading to the disease management strategies are suggested.

Links between the built environment, climate and population health: interdisciplinary environmental change research in New York City

Global climate change is expected to pose increasing challenges for cities in the following decades, placing greater stress and impacts on multiple social and biophysical systems, including population health, coastal development, urban infrastructure, energy demand, and water supplies. Simultaneously, a strong global trend towards urbanisation of poverty exists, with increased challenges for urban populations and local governance to protect and sustain the wellbeing of growing cities. In the context of these 2 overarching trends, interdisciplinary research at the city scale is prioritised for understanding the social impacts of climate change and variability and for the evaluation of strategies in the built environment that might serve as adaptive responses to climate change. This article discusses 2 recent initiatives of The Earth Institute at Columbia University (EI) as examples of research that integrates the methods and objectives of several disciplines, including environmental health science and urban planning, to understand the potential public health impacts of global climate change and mitigative measures for the more localised effects of the urban heat island in the New York City metropolitan region. These efforts embody 2 distinct research approaches. The New York Climate & Health Project created a new integrated modeling system to assess the public health impacts of climate and land use change in the metropolitan region. The Cool City Project aims for more applied policy-oriented research that incorporates the local knowledge of community residents to understand the costs and benefits of interventions in the built environment that might serve to mitigate the harmful impacts of climate change and variability, and protect urban populations from health stressors associated with summertime heat. Both types of research are potentially useful for understanding the impacts of environmental change at the urban scale, the policies needed to address these challenges, and to train scholars capable of collaborative approaches across the social and biophysical sciences.

Burden of diarrhea among children in Honduras, 2000-2004: estimates of the role of rotavirus

OBJECTIVES: To estimate the annual burden of diarrhea and of diarrhea that is associated with rotavirus (RV) in children who are treated at public clinics and hospitals in Honduras. METHODS: Data were collected from computerized records of all children < 5 years old treated for diarrhea at clinics and hospitals operated by the Secretary of Health for the period of 2000 through 2004. A review of studies of RV in Honduras and neighboring countries provided estimates of detection rates of RV among children treated for acute diarrhea as outpatients or as inpatients. From these data, we estimated the annual number of cases of diarrhea and of rotavirus-related diarrhea in Honduras, the cumulative incidence of diarrhea and of rotavirus-related diarrhea for a child from birth to age 5 years, and the number of fatalities due to RV among children hospitalized for diarrhea. RESULTS: From 2000 through 2004, a mean of 222 000 clinic visits, 4 390 hospitalizations, and 162 in-hospital deaths due to diarrhea were recorded annually among children < 5 years of age in the public health facilities in Honduras. From our review of scientific literature on Honduras and neighboring countries, an estimated 30 percent of outpatients and 43 percent of inpatients who were treated for diarrhea would be expected to have RV. Consequently, we estimated that 66 600 outpatient visits, 1 888 hospitalizations, and 70 in-hospital deaths among children < 5 years in Honduras could be attributed to RV each year. Therefore, a child in the first five years of life has a respective risk for consultation, hospitalization, and in-hospital death of 1:1, 1:46, and 1:1 235 for diarrhea. For an episode associated with RV, the respective risks are 1:3, 1:106, and 1:2 857. These values likely underestimate the true burden of diarrhea in Honduras, since some 51 percent of children with acute diarrhea do not receive formal care for the illness, 70 percent do not receive oral rehydration...

OBJETIVOS: Estimar la carga anual por diarrea y por diarrea asociada con la infección por rotavirus (RV) en niños atendidos en clínicas y hospitales públicos de Honduras. MÉTODOS: Los datos se obtuvieron a partir de los registros computarizados de todos los niños menores de 5 años atendidos por diarrea en clínicas y hospitales operados por la Secretaría de Salud de Honduras durante el período 2000-2004. Una revisión de los estudios realizados sobre RV en Honduras y los países vecinos ofreció estimados de las tasas de detección de RV en niños tratados por diarrea aguda hospitalizados o de forma ambulatoria. Con estos datos se estimó el número anual de casos de diarrea y de diarrea asociada con la infección por RV en Honduras, la incidencia acumulativa de diarrea y de diarrea asociada con la infección por RV en niños menores de 5 años y el número de muertes debido a RV en niños hospitalizados por diarrea. RESULTADOS: Entre los años 2000 y 2004 se registraron medias anuales de 222 000 visitas médicas, 4 390 hospitalizaciones y 162 muertes hospitalarias por diarrea en niños menores de 5 años en instalaciones sanitarias públicas de Honduras. A partir de la revisión de la literatura científica relativa a Honduras y los países vecinos se estimó que 30 por ciento de los casos de diarrea atendidos ambulatoriamente y 43 por ciento de los hospitalizados podrían deberse a RV. En consecuencia, se estimó que 66 600 visitas médicas ambulatorias, 1 888 hospitalizaciones y 70 muertes hospitalarias de niños menores de 5 años pueden atribuirse a la infección por RV anualmente en Honduras. Por lo tanto, los riesgos de un niño en sus primeros 5 años de vida de asistir a una consulta, de ser hospitalizado y de morir en un hospital por diarrea son de 1:1, 1:46 y 1:1 235, respectivamente. Los riesgos asociados con la infección por RV son de 1:3, 1:106 y 1:2 857, respectivamente. Posiblemente, estos valores subestiman la carga real por diarrea en Honduras, ya...

The safety of iodine supplementation for our children / 中华内分泌代谢杂志

The benefits of diet supplementation to prevent iodine deficiency disorders are understood, but adverse effects also occur, including thyrotoxicosis and thyroiditis causing hypothyroidism. Previous evidence iodine-induced thyroiditis has come from experimental studies, pathological series, and cross-sectional epidemiological surveys. In the current study of three Chinese populations in regions with mildly deficient, more than adequate, and excessive iodine intake, Teng et al. have identified small, but significantly higher incidences of thyroid autoimmunity and subclinical hypothyroidism with higher iodine intakes, but no higher incidence of overt hypothyroidism. These findings are reassuring from the clinical and public health perspectives, confirming that iodization programs yield great benefits with little risk to human health.

Posibles beneficios médicos de los tocotrienoles de la palma en la prevención y tratamiento del cáncer de mama / Potential health benefits of palm tocotrienols in the prevention and treatment of breast cancer

Tocoferoles y tocotrienoles representan los dos subgrupos en la familia de compuestos de la vitamina E, pero sólo los tocotrienoles presentan fuerte actividad anticancerosa en dosis que tienen muy poco o ningún efecto en el desarrollo o la función normales de las células. Los tocotrienoles son fuertes antioxidantes, pero la actividad antitumoral es independiente de la actividad antioxidante. No es del todo clara la razón por la que los tocotrienoles son más potentes que los tocoferoles, pero al menos eso se debe (en parte) a una mayor acumulación celular. Además, estudios realizados acerca de dosis-respuesta indican que las dosis de tocotrienoles inhibidoras del desarrollo son de 5 a 6 veces menores que sus correspondientes dosis letales, lo cual sugiere que en los efectos antiproliferantes y citotóxicos de los tocotrienoles intervienen diferentes mecanismos. Estudios recientes indican que la muerte celular programada inducida por tocotrienoles (apoptosis) se debe a la activación de proteasas cisteínicas intracelulares específicas (caspasas) asociadas con activación del receptor de muerte y la transducción de señales. Además, los inhibidores específicos de caspasa en tratamiento combinado bloquean los efectos citotóxicos de los tocotrienoles en las células epiteliales mamarias malignas. Por el contrario, la inhibición de muerte celular provocada por tocotrienol parece incluir la supresión de hormonas y de las vías de señalamiento mitógeno del factor-receptor de desarrollo. Aunque es preciso realizar estudios complementarios para esclarecer los mecanismos intracelulares que intervienen en los efectos anticancerosos de los tocotrienoles, la evidencia experimental sugiere firmemente que el suplemento dietético con tocotrienoles puede ofrecer beneficios médicos significativos, ya que disminuye en las mujeres el riesgo de cáncer de mama...

Tocopherols and tocotrienol represent the two subgroups within the vitamin E family of compounds, but only tocotrienols display potent anticancer activity at doses that have no effect on normal cell growth or function. Tocotrienols are potent antioxidants, but antitumor activity is independent of antioxidant activity. The exact reason why tocotrienols are more potent than tocopherols is not completely understood, but at least part of the reason is because of greater cellular accumulation. Furthermore, dose response studies show that growth inhibitory doses of tocotrienols are 5-6 times lower than their corresponding lethal doses, suggesting that the antiproliferative and cytotoxic effects of tocotrienols are mediated by different mechanisms. Recent studies show that tocotrienol-induced programmed cell death (apoptosis) results from the activation of specific intracellular cysteine proteases (caspases) associated with death receptor activation and signal transduction. Furthermore, combined treatment specific caspase inhibitors block the cytotoxic effects of tocotrienols in malignant mammary epithelial cells. In contrast, tocotrienol inhibition of cell death appears to involve the suppression of hormone - and growth factor-receptor mitogenic signaling pathways. Although additional studies are required to clarify the intracellular mechanisms mediating the anticancer effects of tocotrienols, experimental evidence strongly suggests that dietary supplementation of tocotrienols may provide significant health benefits in lowering the risk of breast cancer in women...

Theophylline Increases the Uptake of Radioiodine by Mouse Thyroid

Diagnostic and therapeutic use of radioiodine in the management of thyroid disorders depends on the ability of thyroid cells to concentrate radioiodine, a process that is regulated by the intracellular increase in cAMP. We hypothesized that theophylline, a drug known to increase intracellular cAMP via inhibition of phosphodiesterase, could increase thyroidal radioiodine uptake. We tested this effect in vivo, using C57BL/6j mice, and in vitro, using Fisher rat thyroid (FRTL-5) cells. One mouse received 2.5mg theophylline i.p., whereas a control mouse received only saline. Twenty-hours after theophylline, mice were injected with 10mu Ci Na(125)I in 0.1 mL saline through the tail vein. Mean thyroidal (125)I activity was 3.3-fold higher in theophylline-treated mice than in their respective controls. Radioiodine uptake and intracellular cAMP production of FRTL-5 cells were increased by a relatively low concentration of theophylline (1mu M). Intracellular cAMP increased up to 30 min and then declined in response to 1mu M theophylline. Sera from theophylline-treated mice stimulated (125)I uptake and intracellular cAMP production by FRTL-5 cells. These findings show that theophylline can enhance radioiodine uptake by thyrocytes in vivo and in vitro. The in vitro effects of theophylline on both radioiodine uptake and cAMP production in a dose-dependent manner are consistent with an action mediated by phosphodiesterase inhibition.

Evolutionary control of infectious disease: prospects for vectorborne and waterborne pathogens

Evolutionary theory may contribute to practical solutions for control of disease by identifying interventions that may cause pathogens to evolve to reduce virulence. Theory predicts, for example, that pathogens transmitted by water or arthropod vectors should evolve to relatively high levels of virulence because such pathogens can gain the evolutionary benefits of relatively high levels of host exploitation while paying little price from host illness. The entrance of Vibrio cholerae into South America in 1991 has generated a natural experiment that allows testing of this idea by determining whether geographic and temporal variations in toxigenicity correspond to variation in the potencial for waterborne transmission. Preliminary studies show such correspondences: toxigenicity is negatively associated with access to uncontaminated water in Brazil; and in Chile, where the potential for waterborne transmission is particularly low, toxigenicity of strains declined between 1991 and 1998. In theory vector-proofing of houses should be similarly associated with benignity of vectorborne pathogens, such as the agents of dengue, malaria, and Chagas'disease. These preliminary studies draw attention to the need for definitive prospective experiments to determine whether interventions such as provisioning of uncontaminated water and vector -proofing of houses cause evolutionary reductions in virulence.

The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro

We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P> 0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, N G -nitro L-arginine methyl ester (L-NAME; 50 µM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect