Protodeboronation of (Hetero)Arylboronic Esters: Direct versus Prehydrolytic Pathways and Self-/Auto-Catalysis.

The kinetics and mechanism of the base-catalyzed hydrolysis (ArB(OR)2 → ArB(OH)2) and protodeboronation (ArB(OR)2 → ArH) of a series of boronic esters, encompassing eight different polyols and 10 polyfluoroaryl and heteroaryl moieties, have been investigated by in situ and stopped-flow NMR spectroscopy (19F, 1H, and 11B), pH-rate dependence, isotope entrainment, 2H KIEs, and KS-DFT computations. The study reveals the phenomenological stability of boronic esters under basic aqueous-organic conditions to be highly nuanced. In contrast to common assumption, esterification does not necessarily impart greater stability compared to the corresponding boronic acid. Moreover, hydrolysis of the ester to the boronic acid can be a dominant component of the overall protodeboronation process, augmented by self-, auto-, and oxidative (phenolic) catalysis when the pH is close to the pKa of the boronic acid/ester.

Chronic kidney disease of nontraditional etiology in Central America: a provisional epidemiologic case definition for surveillance and epidemiologic studies / Enfermedad renal crónica de causas no tradicionales en Centroamérica: una definición de caso provisional para vigilancia y estudios epidemiológicos

Over the last two decades, experts have reported a rising number of deaths caused by chronic kidney disease (CKD) along the Pacific coast of Central America, from southern Mexico to Costa Rica. However, this specific disease is not associated with traditional causes of CKD, such as aging, diabetes, or hypertension. Rather, this disease is a chronic interstitial nephritis termed chronic kidney disease of nontraditional etiology (CKDnT). According to the Pan American Health Organization (PAHO) mortality database, there are elevated rates of deaths related to kidney disease in many of these countries, with the highest rates being reported in El Salvador and Nicaragua. This condition has been identified in certain agricultural communities, predominantly among male farmworkers. Since CKD surveillance systems in Central America are under development or nonexistent, experts and governmental bodies have recommended creating standardized case definitions for surveillance purposes to monitor and characterize this epidemiological situation. A group of experts from Central American ministries of health, the U.S. Centers for Disease Control and Prevention (CDC), and PAHO held a workshop in Guatemala to discuss CKDnT epidemiologic case definitions. In this paper, we propose that CKD in general be identified by the standard definition internationally accepted and that a suspect case of CKDnT be defined as a person age < 60 years with CKD, without type 1 diabetes mellitus, hypertensive diseases, and other well-known causes of CKD. A probable case of CKDnT is defined as a suspect case with the same findings confirmed three or more months later.

En los dos últimos decenios, los expertos han notificado un aumento del número de defunciones causadas por enfermedad renal crónica (ERC) a lo largo de la costa del Pacífico de Centroamérica, desde el sur de México hasta Costa Rica. Sin embargo, esta enfermedad específica no está asociada con las causas tradicionales de ERC, como envejecimiento, diabetes o hipertensión. En cambio, esta enfermedad es una nefritis intersticial crónica denominada enfermedad renal crónica de causas no tradicionales (ERCnT). Según la base de datos de mortalidad de la Organización Panamericana de la Salud (OPS), se registran tasas de mortalidad elevadas relacionadas con la enfermedad renal en muchos de estos países; las más elevadas se informaron en El Salvador y Nicaragua. Esta enfermedad ha sido identificada en algunas comunidades agrícolas, predominantemente en trabajadores agrícolas varones. Como los sistemas de vigilancia de la ERC en Centroamérica están en desarrollo o son inexistentes, los expertos y los organismos gubernamentales han recomendado elaborar definiciones de caso estandarizadas con fines de vigilancia, para monitorear y caracterizar esta situación epidemiológica. Un grupo de expertos de los ministerios de salud centroamericanos, los Centros para el Control y la Prevención de Enfermedades de los Estados Unidos (CDC) y la OPS se reunieron en un taller realizado en Guatemala para debatir posibles definiciones de caso epidemiológicas de ERCnT. En este artículo proponemos que, en general, la ERC se identifique mediante la definición normalizada internacionalmente aceptada y que un caso presunto de ERCnT se defina como: persona menor de 60 años con ERC, sin diabetes mellitus de tipo I, enfermedades hipertensivas ni otras causas conocidas de ERC; y un caso probable de ERCnT se defina como un caso presunto con los mismos resultados confirmados tres meses después o más.

Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection.

There is an urgent need for new antibiotics to treat multidrug-resistant Neisseria gonorrhoeae In this report, the microbiology, in vivo pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced N. gonorrhoeae infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.

Formaldehyde Levels in Traditional and Portable Classrooms: A Pilot Investigation.

The pilot study discussed in this article assessed formaldehyde levels in portable classrooms (PCs) and traditional classrooms the authors evaluated formaldehyde levels in day and overnight indoor air (TCs) and explored factors influencing indoor air quality (e.g., carbon dioxide, temperature, and relative humidity). In a cross-sectional design, samples from nine PCs renovated within three years previously and three TCs in a school district in metropolitan Atlanta, Georgia. Formaldehyde levels ranged from 0.0068 to 0.038 parts per million (ppm). In both types of classroom, overnight formaldehyde median levels (PCs = 0.018 ppm; TCs = 0.019 ppm) were higher than day formaldehyde median levels (PCs = 0.011 ppm; TCs = 0.016 ppm). Carbon dioxide levels measured 470-790 ppm at 7:00 a.m. and 470-1800 ppm at 4:00 p.m. Afternoon medians were higher in TCs (1,400 ppm) than in PCs (780 ppm). Consistent with previous studies, formaldehyde levels were similar among PCs and TCs. Reducing carbon dioxide levels by improving ventilation is recommended for classrooms.

Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV.

OBJECTIVES: The objective of this study was to characterize the in vitro and in vivo biological properties of a novel series of small-molecule bacterial type IIA topoisomerase inhibitors. METHODS: Bacterial susceptibility testing was performed by broth microdilution. Resistance frequencies were determined by plating bacteria onto agar containing test compound and enumerating mutants. Bacteria were passaged using subinhibitory concentrations of antibacterials to generate resistance. Target enzyme inhibition was determined by exposure to antibacterials and DNA; topoisomers were visualized by gel electrophoresis. Oral and intravenous pharmacokinetic profiles were determined in mice. In vivo efficacy was determined using a mouse model of septicaemia and thigh infection with MSSA and MRSA, respectively. RESULTS: Representative compounds REDX04139, REDX05604 and REDX05931 demonstrated in vitro potency against a range of Gram-positive and fastidious Gram-negative pathogens. Clinical isolate testing revealed REDX04139 and REDX05931 had MIC90 values of 0.25 and 0.5 mg/L, respectively, for MRSA and MIC90 values of 2 mg/L for streptococci. REDX04139 was bactericidal in vitro against Staphylococcus aureus at 8× MIC over 6 h. Pharmacokinetic profiling of REDX04139 and REDX05604 in mice revealed low clearance and excellent bioavailability (≥71%). REDX04139 provided 100% survival against S. aureus in a mouse septicaemia model, while REDX05604 reduced bacterial load by up to 3.7 log units in the MRSA mouse thigh infection model. CONCLUSIONS: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

Chronic kidney disease of nontraditional etiology in Central America: a provisional epidemiologic case definition for surveillance and epidemiologic studies.

SYNOPSIS Over the last two decades, experts have reported a rising number of deaths caused by chronic kidney disease (CKD) along the Pacific coast of Central America, from southern Mexico to Costa Rica. However, this specific disease is not associated with traditional causes of CKD, such as aging, diabetes, or hypertension. Rather, this disease is a chronic interstitial nephritis termed chronic kidney disease of nontraditional etiology (CKDnT). According to the Pan American Health Organization (PAHO) mortality database, there are elevated rates of deaths related to kidney disease in many of these countries, with the highest rates being reported in El Salvador and Nicaragua. This condition has been identified in certain agricultural communities, predominantly among male farmworkers. Since CKD surveillance systems in Central America are under development or nonexistent, experts and governmental bodies have recommended creating standardized case definitions for surveillance purposes to monitor and characterize this epidemiological situation. A group of experts from Central American ministries of health, the U.S. Centers for Disease Control and Prevention (CDC), and PAHO held a workshop in Guatemala to discuss CKDnT epidemiologic case definitions. In this paper, we propose that CKD in general be identified by the standard definition internationally accepted and that a suspect case of CKDnT be defined as a person age < 60 years with CKD, without type 1 diabetes mellitus, hypertensive diseases, and other well-known causes of CKD. A probable case of CKDnT is defined as a suspect case with the same findings confirmed three or more months later.

A mechanistic proposal for the protodeboronation of neat boronic acids: boronic acid mediated reaction in the solid state.

A combined experimental and computational study suggests that a reduction in the entropy of activation in the solid state can lead to the protodeboronation of boronic acids.

Rhodium/phospholane-phosphite catalysts give unusually high regioselectivity in the enantioselective hydroformylation of vinyl arenes.

Using the phospholane-phosphite ligand, BOBPHOS, almost perfect regioselectivities and high enantioselectivities (up to 92% ee) are observed in Rh catalysed enantioselective hydroformylation of vinyl arenes. This can be achieved under solvent-free conditions.

Blood lead levels in children after phase-out of leaded gasoline in Bombay, India.

The objective of this study was to test for reduction in pediatric blood lead levels (BLLs) in Bombay, India, by comparing BLLs collected in 2002 (after use of leaded gasoline was phased out in Bombay) to those collected in a study conducted by the George Foundation in 1997 (when leaded gasoline was still used in Bombay). We analyzed BLL in a total of 754 children under 12 years of age in two separate sampling campaigns (276 from December 2002 to January 2003 [non-monsoon season]; 478 in June to August 2003 [monsoon season]). BLL was measured using an ESA Lead Care Portable Analyzer. We also measured lead in PM10 samples collected in the study region. These data were compared with a study done by the George Foundation in 1997 before the phase out of leaded gasoline. The George Foundation study reported that 61.8% of the 291 children tested in Bombay had elevated blood lead levels (BLL>or=10 microg/dL). In the present study, 33.2% of the 754 tested children had elevated blood lead levels. The average BLL for the current study population (Geometric Mean=8.36 microg/dL, SD=5.23 microg/dL) was lower than the CDC level of concern (10 microg/dL), with one child diagnosed with lead poisoning (BLL>65 microg/dL). A seasonal trend of BLLs was suggested, with BLL in monsoon season (Geometric Mean=9.1 microg/dL, SD=5.7 microg/dL) higher than that in the non-monsoon season (Geometric Mean=7.3 microg/dL, SD=4.0 microg/dL). A seasonal periodicity of lead in PM10 was found, with lead in monsoon season (Geometric Mean=0.04 microg/m3, SEM=0.000667 microg/m3) lower than that in the non-monsoon season (Geometric Mean=0.38 microg/m3, SEM=0.10 microg/m3). The overall level of airborne dust (PM10) in monsoon season (56.2 microg/m3) was lower than in the non-monsoon season (273.0 microg/m3), presumably due to precipitation. The comparatively higher BLLs in the monsoon season, in the presence of lower air lead levels, suggest ingestion of water or food, with greater lead contamination in the monsoon season, as a possible pathway contributing to elevated BLLs in these children in the monsoon season. These results demonstrate a significant success of the public health system in Bombay, India-achieved by the removal of lead from gasoline. The emphasis should shift in the study region towards sources of lead exposure other than leaded gasoline (lead in paints, lead in Herbal medicines and lead in Kohl).

Blood lead levels and risk factors for lead poisoning in children and caregivers in Chuuk State, Micronesia.

Lead poisoning is a preventable environmental disease. Children and developing fetuses are especially vulnerable; even low blood lead levels (BLLs) are linked with learning and behavioral problems. We assessed children's and their caregivers' BLLs and risk factors for lead exposure in Chuuk State, Federated States of Micronesia. Children aged 2-6 years were randomly selected within 20 randomly selected villages. Children and caregivers provided venous blood, and caregivers offered information about possible risk factors for lead exposure. Mean BLLs were 39 microg/l for children and 16 microg/l for caregivers. Children with BLLs of > or = 100 microg/l (elevated) were 22.9 (95% CI: 4.5-116.0) times more likely to have a caregiver with an elevated BLL, 6.2 (95% CI: 1.4-27.3) times more likely to live on an outer island, and 3.4 (95% CI: 1.7-6.9) times more likely to have a family member who made lead fishing weights than did other children even after controlling for age and sex. For children, 61% of elevated BLLs could be attributed to making fishing weights. Caregivers with elevated BLLs were 5.9 (95% CI: 1.5-23.7) times more likely to live in a household that melted batteries than other caregivers even after controlling for age and education. For caregivers, 37% of the elevated BLLs could be attributed to melting batteries. The association of elevated BLLs in children and their caregiver suggests a common environmental exposure. Melting batteries to make fishing sinkers is a preventable source of lead exposure for children and their caregivers in Chuuk. Published by Elsevier GmbH.

High-intensity targeted screening for elevated blood lead levels among children in 2 inner-city Chicago communities.

OBJECTIVES: We assessed the prevalence of elevated blood lead levels (> or = 10 micrograms of lead per deciliter of blood), risk factors, and previous blood lead testing among children in 2 high-risk Chicago, Ill, communities. METHODS: Through high-intensity targeted screening, blood lead levels were tested and risks were assessed among a representative sample of children aged 1 to 5 years who were at risk for lead exposure. RESULTS: Of the 539 children who were tested, 27% had elevated blood lead levels, and 61% had never been tested previously. Elevated blood lead levels were associated with chipped exterior house paint. CONCLUSIONS: Most of the children who lived in these communities--where the prevalence for elevated blood lead levels among children was 12 times higher than the national prevalence--were not tested for lead poisoning. Our findings highlight the need for targeted community outreach that includes testing blood lead levels in accordance with the American Academy of Pediatrics' recommendations.

Blood lead levels and risk factors for lead poisoning among children in a Mexican smelting community.

The authors evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs in children 1-6 yr of age living in Torreón, Mexico, and assessed risk factors for lead exposure in these children. The study involved a simple random sample of households in the area around a local smelter, as well as a 2-stage cluster sample of neighborhoods and households in the remainder of Torreón. The geometric mean BLL of children in this study (N = 367) was 6.0 microg/dl (95% confidence interval [CI] = 5.2, 6.8) (0.29 microM/l [95% CI = 0.25, 0.33]). Twenty percent of the children had BLLs > or = 10 microg/dl (0.48 microM/l), and 5% had BLLs > or = 20 microg/dl (0.97 microM/l). In multivariate analyses, distance from the smelter, amount of income, and education level of the primary caregiver predicted BLLs. In the environmental risk factor subsample (n = 124), dust and soil lead levels were associated with BLLs and distance from the smelter. BLLs in this study were moderately high, but the levels were lower than those in other smelting communities prior to remediation.

Use of isotope ratios to identify sources contributing to pediatric lead poisoning in Peru.

In 1998, a school-based blood lead level (BLL) survey of 2,510 children, conducted in Lima and Callao, Peru, revealed elevated BLLs in children from 2 Callao schools (mean BLL = 25.6 microg/dl; n = 314) and in children from Callao overall (mean BLL = 15.2 microg/dl; n = 898), compared with children from Lima (mean BLL = 7.1 microg/dl; n = 1,612). Public health officials at Peru's Direccion General de Salud Ambiental (DIGESA) hypothesized that a possible source of the elevated pediatric BLLs observed in Callao was a large depository near the port where mineral concentrates are stored prior to shipment. The U.S. Centers for Disease Control and Prevention worked with DIGESA to identify source(s) that contributed to the pediatric lead poisonings by comparing isotopic profiles of lead in blood, mineral, gasoline, and air filter samples. The lead isotope ratio (IR) observed in mineral samples from the depository in Callao differed from those in gasoline samples from Lima and Callao. The blood lead IRs of children living near the depository were similar to the IRs of the mineral samples and different from the IRs of the gasoline samples, suggesting that lead from the depository-and not gasoline-was the primary source of lead in these children. Lead IR analysis of regional air filter samples supported these findings.

Blood lead levels and risk factors for lead poisoning among children in Jakarta, Indonesia.

The phase-out of leaded gasoline began in Jakarta, Indonesia on July 1, 2001. We evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs of Jakarta school children and assessed risk factors for lead exposure in these children before the beginning of the phase-out activities. The study involved a population-based, cross-sectional blood lead survey that included capillary blood lead sampling and a brief questionnaire on risk factors for lead poisoning. A cluster survey design was used. Forty clusters, defined as primary schools in Jakarta, and 15 2nd- and 3rd-grade children in each cluster were randomly selected for participation in the study. The average age of children in this study was 8.6 years (range 6-12) and the geometric mean BLL of the children was 8.6 microg/dl (median: 8.6 microg/dl; range: 2.6-24.1 microg/dl) (n=397). Thirty-five percent of children had BLLs > or =10 microg/dl and 2.4% had BLLs > or =20 microg/dl. Approximately one-fourth of children had BLLs 10-14.9 microg/dl. In multivariate models, level of education of the child's primary caregiver, water collection method, home varnishing and occupational recycling of metals, other than lead, by a family member were predictors of log BLLs after adjustment for age and sex. BLLs of children who lived near a highway or major intersection were significantly higher than those of children who lived near a street with little or no traffic when level of education was not included in the model. Water collection method was a significant predictor of BLLs > or =10 microg/dl after adjustment for age and sex. BLLs in children in this study were moderately high and consistent with BLLs of children in other countries where leaded gasoline is used. With the phase-out of leaded gasoline, BLLs of children in Jakarta are expected to rapidly decline as they have in other countries that have phased lead out of gasoline.

Determinants of blood-lead levels in children in Callao and Lima metropolitan area.

OBJECTIVES: To determine blood lead levels in urban populations of children (n = 2,510) and women (n = 874) in the early postpartum in certain districts of Lima and Callao, and to correlate those levels with particular exposures. MATERIAL AND METHODS: Between July 1998 and January 1999 cross sectional study was conducted. The study population was selected using three sampling strategies in the government operated school system and from public pediatric and maternity hospitals at Lima and Callao, Peru. Study personnel were trained to collect finger stick blood samples with a protocol that minimizes external lead contamination. Lead determinations in blood and environmental samples were performed at the study site using portable anodic striping voltamenters. To determine the simultaneous effects of different predictors on blood lead levels, multivariate regression models were used to estimate adjusted mean differences. RESULTS: The mean blood lead level in the children studied was 9.9 micrograms/dl ranging from 1 microgram/dl to 64 micrograms/dl with 29% of the children displaying values greater than 10 micrograms/dl and 9.4% at levels greater than 20 micrograms/dl. Among the women, the mean was 3.5 micrograms/dl (SD = 2.4 micrograms/dl), and 2.4% (n = 21) displayed levels greater than 10 micrograms/dl. Important differences were observed between the sample locations, and the highest levels were documented in the port region near Callao. The mean level of blood lead in this group was 25.6 micrograms/dl (SD = 4.6 micrograms/dl), while among the rest of the sample it was 7.1 micrograms/dl (SD = 5.1 micrograms/dl). The presence of a mineral storage area signified a difference in exposure in excess of 13 micrograms/dl for children living near the port area in contrast to the other children who were not as close to such fixed sources of lead exposure. For the participants in Lima, the risk of showing levels above 10 micrograms/dl was associated with exposure to high vehicular traffic. CONCLUSIONS: In metropolitan Lima, we conclude that the mean blood lead levels of the populations studied were not alarming and that a positive health impact can be made by a reduction of lead in gasoline. With regard to the port area, the study demonstrates that the presence of mineral storage areas pose a detrimental risk factor for the health of the children living in this area. The English version of this paper is available too at: http://www.insp.mx/salud/index.html.

Determinants of blood-lead levels in children in Callao and Lima metropolitan area

OBJETIVO: Determinar los niveles de plomo en sangre en una muestra compuesta por niños y mujeres en el posparto temprano, residentes en Lima y El Callao. Investigar los determinantes de estos niveles y algunas fuentes de exposición. MATERIAL Y MÉTODOS: Entre julio de 1998 y enero de 1999 se llevó a cabo una encuesta en el área metropolitana de Lima y en El Callao, Perú. La población de estudio fue identificada mediante tres estrategias de muestreo y con la cual se seleccionaron escuelas públicas y hospitales pediátricos y gineco-obstétricos. El personal que participó en el estudio recibió entrenamiento para la técnica de punción digital y puso especial énfasis en controlar la contaminación externa con plomo. Las determinaciones del metal en sangre y muestras ambientales se llevaron a cabo utilizando voltametría anódica. Para determinar los efectos simultáneos de diferentes predictores sobre los niveles de plomo en sangre se usaron modelos de regresión multivariada para estimar diferencias de media y ajustadas. RESULTADOS: Los niveles promedio de plomo en sangre fueron de 9.9 µg/dl de una variación entre 0 y 64 µg/dl. El 29 y 9.4% de los niños presentaron valores por encima de 10 µg/dl y 20 µg/dl,respectivamente. Para las mujeres el promedio de plomo en sangre fue de 3.5 µg/dl (DE=2.4) y 2.4% (n=2l) presentaron niveles superiores a 10 µg/dl. Se observaron diferencias importantes en relación con el sitio de residencia; los niveles más altos se documentaron en la zona de El Callao. Para este grupo la media de plomo en sangre fue de 25.6 µg/dl (DE=4.6) mientras que para el resto de la muestra el promedio de plomo en sangre fue de 7.1 µg/dl (DE=5.l). En esta zona se detectó un área de almacenamiento de minerales como una fuente importante de exposición. Los niños que viven cerca de esta área tenían en promedio un exceso de 13 µg/dl en sangre. Para los participantes de la zona de Lima el riesgo de presentar niveles por encima de 10 µg/dl se asoció con la exposición a tráfico vehicular. CONCLUSIONES: Para Lima Metropolitana se puede concluir que los niveles de plomo en sangre no representan un problema urgente, sin embargo, el reducir el plomo de la gasolina se acompaña de un beneficio importante. En contraste, para el área cercana al puerto de El Callao, nuestro estudio demuestra la presencia de sitios de almacenamiento de minerales que representan un riesgo importante para la salud de los niños que viven en esta zona.

Lead poisoning among young children in Russia: concurrent evaluation of childhood lead exposure in Ekaterinburg, Krasnouralsk, and Volgograd.

The Gore-Chernomyrdin Commission encouraged a binational collaboration to evaluate pediatric lead poisoning in Russia. The study evaluated children in three Russian cities: Krasnouralsk, a small city with minimal traffic centered around a copper smelter; and Ekaterinburg and Volgograd, both of which are large cities with multiple factories and heavy vehicular traffic. This project was the first international use of portable blood lead analysis instruments. In each city, at least 90% of children attending selected neighborhood kindergartens participated. We selected kindergartens on the basis of their proximity to industrial areas and major traffic corridors. We obtained capillary blood samples and analyzed for lead content and hemoglobin (Hgb) levels in the field, and collected environmental samples (i.e., indoor dust, tap water, play area soil, and interior and exterior paint) and analyzed for each participating school and in the homes of about 10% of the children who had elevated blood lead levels (BLLs; greater than or equal to 10 microg/dL). We calculated all age-, sex-, and city-specific geometric means using generalized estimating equations to account for covariance within kindergartens, and used multivariate logistic regression models to identify variables predictive of elevated BLLs. Overall, 23% of study children had elevated BLLs and 2% were anemic, defined as Hgb < 11 g/dL. Krasnouralsk had the highest geometric mean BLL (10.7 microg/dL), the highest percentage of children (60%) with elevated BLLs, and the highest percentage of anemic children (4%). All soil samples in Krasnouralsk had detectable lead levels. Volgograd was the only city that had paint samples with elevated lead levels. We found apparent city-specific differences in the percentages of children with elevated BLLs. Lead-contaminated soil and dust, which can result from lead-based automotive fuel and from lead-related industrial emissions, appear to be the most important routes of lead exposure of those evaluated in this study. Elevated lead levels found in paint samples from Volgograd may indicate old undercoats of lead-based paint that could represent a regionally rather than nationally important source of exposure.