RESUMEN
Increasing concern over air pollution has led to the development of low-cost sensors suitable for wide-scale deployment and use by citizen scientists. This project investigated the AirU low-cost particle sensor using two methods: (1) a comparison of pre- and post-deployment calibration equations for 24 devices following use in a field study, and (2) an in-home comparison between 3 AirUs and a reference instrument, the GRIMM 1.109. While differences (and therefore some sensor degradation) were found in the pre- and post-calibration equation comparison, absolute value changes were small and unlikely to affect the quality of results. Comparison tests found that while the AirU did tend to underestimate minimum and overestimate maximum concentrations of particulate matter, ~88% of results fell within ±1 µg/m3 of the GRIMM. While these tests confirm that low-cost sensors such as the AirU do experience some sensor degradation over multiple months of use, they remain a valuable tool for exposure assessment studies. Further work is needed to examine AirU performance in different environments for a comprehensive survey of capability, as well as to determine the source of sensor degradation.
RESUMEN
Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation.
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Ácidos Borónicos/química , Niacinamida/análogos & derivados , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Ácidos Borónicos/uso terapéutico , Biología Computacional , Diseño de Fármacos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/tratamiento farmacológico , Estructura Molecular , Niacinamida/química , Niacinamida/uso terapéutico , Ozono/toxicidad , Ratas , Ratas Sprague-Dawley , Receptores de Interleucina-8B/químicaRESUMEN
The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure-activity studies that examined the effect of a novel series of S-substituted 6-mercapto-N-phenyl-nicotinamides on CXCL1-stimulated Ca(2+) flux in whole human PMNs led to the discovery of 2-[5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic acid (SX-517), a potent noncompetitive boronic acid CXCR1/2 antagonist. SX-517 inhibited CXCL1-induced Ca(2+) flux (IC50 = 38 nM) in human PMNs but had no effect on the Ca(2+) flux induced by C5a, fMLF, or PAF. In recombinant HEK293 cells that stably expressed CXCR2, SX-517 antagonized CXCL8-induced [(35)S]GTPγS binding (IC50 = 60 nM) and ERK1/2 phosphorylation. Inhibition was noncompetitive, with SX-517 unable to compete the binding of [(125)I]-CXCL8 to CXCR2 membranes. SX-517 (0.2 mg/kg iv) significantly inhibited inflammation in an in vivo murine model. SX-517 is the first reported boronic acid chemokine antagonist and represents a novel pharmacophore for CXCR1/2 antagonism.
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Ácidos Borónicos/química , Niacinamida/farmacología , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Unión Competitiva , Ácidos Borónicos/farmacología , Quimiocina CXCL1/antagonistas & inhibidores , Técnicas Químicas Combinatorias , Células HEK293/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Interleucina-8/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones Endogámicos , Neutrófilos/efectos de los fármacos , Niacinamida/química , Fosforilación , Receptores de Interleucina-8B/metabolismo , Relación Estructura-ActividadRESUMEN
Solid phase synthetic methodology has been developed in our laboratory to incorporate an affinity label (a reactive functionality such as isothiocyanate or bromoacetamide) into peptides (Leelasvatanakij, L. and Aldrich, J. V. (2000) J. Peptide Res. 56, 80), and we have used this synthetic strategy to prepare affinity label derivatives of a variety of opioid peptides. To date side reactions have been detected only in two cases, both involving intramolecular cyclization. We have identified several peptide-based affinity labels for delta opioid receptors that exhibit wash-resistant inhibition of binding to these receptors and are valuable pharmacological tools to study opioid receptors. Even in cases where the peptide derivatives do not bind covalently to their target receptor, studying their binding has revealed subtle differences in receptor interactions with particular opioid peptide residues, especially Phe residues in the N-terminal "message" sequences. Solid phase synthetic methodology for the incorporation of other labels (e.g. biotin) into the C-terminus of peptides has also been developed in our laboratory (Kumar, V. and Aldrich, J. V. (2003) Org. Lett. 5, 613). These two synthetic approaches have been combined to prepare peptides containing multiple labels that can be used as tools to study peptide ligand-receptor interactions. These solid phase synthetic methodologies are versatile strategies that are applicable to the preparation of labeled peptides for a variety of targets in addition to opioid receptors.
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BACKGROUND: Oseltamivir is safe and effective in immunocompetent persons, and prophylactic use is recommended during influenza outbreaks. However, no data exist regarding the use of oseltamivir as prophylaxis among patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: In January 2002, an influenza A outbreak was identified when 4 cases occurred within 1 week at an outpatient residential facility for patients undergoing HSCT. Oseltamivir prophylaxis (75 mg per day) was initiated for all asymptomatic patients living in the housing facility. Retrospectively, 45 patients (25 of whom had undergone HSCT, and 20 of whom were pre-HSCT candidates) who received oseltamivir prophylaxis were evaluated for adverse events. These 45 patients were matched 1 : 1 with control subjects who received transplants during the period 1994-2003 and did not receive prophylaxis; they were matched according to donor type, conditioning regimen, cytomegalovirus serostatus, time after HSCT, and recipient age (+/-5 years). The frequency of clinical and laboratory adverse events was determined by chart review and graded using National Cancer Institute Common Terminology Criteria. RESULTS: Forty-five residents received oseltamivir for a median of 17 days (range, 10-81 days). No new cases of influenza A occurred in the facility. Seven weeks after initiation of prophylaxis, 1 resident who had been noncompliant to prophylaxis developed an influenza B infection, followed by an additional case of influenza B that occurred in a patient who had not received prophylaxis. No deaths occurred that were attributable to prophylaxis. The proportions of clinical and laboratory adverse events meeting common terminology criteria grades 2-4 or 3-4 were not significantly different between the case patients who received oseltamivir prophylaxis and control subjects. CONCLUSION: Oseltamivir prophylaxis appeared to be safe and well tolerated in managing an influenza outbreak in an HSCT outpatient residence.
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Antivirales/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Gripe Humana/prevención & control , Oseltamivir/uso terapéutico , Adolescente , Adulto , Anciano , Antivirales/efectos adversos , Estudios de Casos y Controles , Niño , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/inmunología , Humanos , Huésped Inmunocomprometido , Gripe Humana/inmunología , Masculino , Persona de Mediana Edad , Oseltamivir/efectos adversos , Probabilidad , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Resultado del TratamientoRESUMEN
The incidence of respiratory virus infection after hematopoietic cell transplantation (HCT) has probably been underestimated with conventional testing methods in symptomatic patients. This prospective study assessed viral infection episodes by testing weekly respiratory samples collected from HCT recipients, with and without symptoms reported by questionnaire, for 100 days after HCT. Samples were tested by culture and direct fluorescent antibody testing for respiratory syncytial virus (RSV), parainfluenza virus (PIV), and influenza A and B, and by quantitative reverse transcription-polymerase chain reaction for RSV, PIV, influenza A and B, and metapneumovirus (MPV). Of 122 patients, 30 (25%) had 32 infection episodes caused by RSV (5), PIV (17), MPV (6), influenza (3), RSV, or influenza (1). PIV, with a cumulative incidence estimate of 17.9%, was the only virus for which asymptomatic infection was detected. Lower virus copy number in patients with no or one symptom compared with 2 or more symptoms was found for all viruses in all patients (P < .001), with PIV infection having a similar virus-specific comparison (P = .004). Subclinical infection with PIV may help explain why infection-control programs that emphasize symptoms are effective against RSV and influenza but often not against PIV.
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Trasplante de Células Madre Hematopoyéticas , Infecciones por Paramyxoviridae/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Adolescente , Adulto , Anciano , Animales , Línea Celular , Niño , Preescolar , Chlorocebus aethiops , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virología , Humanos , Incidencia , Lactante , Control de Infecciones , Masculino , Persona de Mediana Edad , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/genética , Infecciones por Paramyxoviridae/virología , Estudios Prospectivos , Virus ARN/genética , ARN Viral/análisis , ARN Viral/genética , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/virología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vigilancia de Guardia , Trasplante Autólogo , Trasplante Homólogo , Cultivo de VirusRESUMEN
OBJECTIVES: To characterize illness and identify the etiology for two nursing home outbreaks of respiratory illness. DESIGN: Multisite outbreak investigations; cohort. SETTING: Two nursing homes in Pennsylvania. PARTICIPANTS: Facility A residents (n = 170), Facility B residents (n = 124), and employees (n = 91). MEASUREMENTS: Medical records for Facility A and B residents were reviewed, and employees from Facility B self-administered a questionnaire to identify risk factors for illness. Serological, oropharyngeal, and nasopharyngeal specimens were collected for both outbreaks, and testing for respiratory pathogens was performed. RESULTS: In Facility A, 40 (24%) of 170 residents were identified with respiratory illness; 13 (33%) case-patients had radiographically confirmed pneumonia, 15 (38%) were taken to a hospital, and two (5%) died. Of 10 specimens collected from symptomatic Facility A case-patients, four (40%) tested positive using reverse transcription polymerase chain reaction for rhinovirus. In Facility B, 77 (62%) of 124 residents had respiratory illness, and 40 (52%) had radiographically confirmed pneumonia; 12 (16%) case-patients were hospitalized, and five (6%) died. Of 19 respiratory specimens collected from symptomatic Facility B case-patients, six (32%) were positive for rhinovirus; one was from an employee. Five (50%) of 10 rhinovirus-positive cases in both outbreaks had clinical and radiographic evidence of pneumonia. CONCLUSION: These investigations suggest that rhinoviruses may be an underrecognized cause of respiratory outbreaks in nursing homes, capable of causing pneumonia and perhaps death.
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Brotes de Enfermedades , Casas de Salud , Infecciones por Picornaviridae/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Rhinovirus , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/inmunología , ADN Viral/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pennsylvania/epidemiología , Infecciones por Picornaviridae/virología , Infecciones del Sistema Respiratorio/virología , Rhinovirus/genética , Rhinovirus/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVE: Lower respiratory tract infections (LRTIs) cause substantial childhood morbidity. This study characterizes and compares LRTI-associated morbidity among American Indian/Alaska Native (AI/AN) children and the general population of U.S. children. METHODS: Hospitalization and outpatient records with a diagnosis indicating LRTIs were evaluated for children aged younger than 5 years during 1990-2001. RESULTS: For 1999-2001, the LRTI-associated hospitalization rate was significantly higher for AI/AN children than for U.S. children (116.1 versus 63.2/1000, respectively), with the disparity being greater for infants than for 1- to 4-year-old children. Also the rate of LRTI-associated outpatient visits among AI/AN infants was higher than that for all U.S. infants (737.7 versus 207.2/1000, respectively). LRTI hospitalization and outpatient visit rates were highest in the Alaska and Southwest Indian Health Service regions. During 1990-2001, the LRTI hospitalization rate among AI/AN infants in the Alaska region and among the general U.S. infant population increased. Bronchiolitis-associated hospitalization rates increased for AI/AN and U.S. infants, whereas the pneumonia-associated hospitalization rate decreased among AI/AN infants and remained stable among U.S. infants. CONCLUSIONS: LRTIs continue to be an important cause of morbidity in children, especially among AI/AN infants in the Alaska and Southwest regions. Strategies to reduce LRTI hospitalizations and outpatient visits are warranted for all infants, but the greatest potential impact would be among AI/AN infants.
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Indígenas Norteamericanos/estadística & datos numéricos , Inuk/estadística & datos numéricos , Infecciones del Sistema Respiratorio/etnología , Infecciones del Sistema Respiratorio/epidemiología , Distribución por Edad , Alaska/epidemiología , Alaska/etnología , Bronquiolitis/epidemiología , Bronquiolitis/etnología , Niño , Preescolar , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Masculino , Pacientes Ambulatorios/estadística & datos numéricos , Neumonía/epidemiología , Neumonía/etnología , Distribución por Sexo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Delay of hematopoietic stem cell transplantation (HSCT) has been suggested if upper respiratory tract infection (URTI) due to respiratory syncytial virus (RSV) occurs in transplantation candidates, but the efficacy of this strategy in preventing posttransplantation RSV infection is unknown. METHODS: In a retrospective study, we reviewed charts of patients who underwent transplantation at Fred Hutchinson Cancer Research Center (Seattle, WA) during the period of June 1987 through December 2000 and evaluated the strategy of delaying HSCT in candidates with laboratory-confirmed RSV URTI. RESULTS: Thirty-one of 37 patients had RSV URTI before conditioning, 2 (6.5%) of whom developed RSV infection after HSCT. In 6 of 37 patients, symptoms of URTI were present during the start of conditioning, but RSV virologic confirmation occurred a median of 4.5 days (range, 2-5 days) into the conditioning regimen. Conditioning was aborted for 3 of 6 patients; none had progression to RSV pneumonia. Of the 3 patients in whom HSCT proceeded as scheduled, 2 developed RSV pneumonia. Overall, RSV pneumonia occurred in 1 of 34 patients for whom HSCT was delayed, compared with 2 of 3 patients for whom there was no delay (P=.01). CONCLUSIONS: In patients with pretransplantation RSV URTI, delay of HSCT was associated with a lower risk of pneumonia than was no delay. Because URTIs can progress to severe complications in patients receiving HSCTs, these results support Centers for Disease Control and Prevention/American Society of Blood and Marrow Transplantation recommendations that HSCT be delayed on the basis of symptoms of URTI rather than waiting for virologic confirmation.
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Trasplante de Células Madre Hematopoyéticas/métodos , Complicaciones Posoperatorias/virología , Cuidados Preoperatorios/métodos , Infecciones por Virus Sincitial Respiratorio/terapia , Virus Sincitiales Respiratorios/aislamiento & purificación , Adolescente , Adulto , Niño , Preescolar , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/diagnóstico , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitiales Respiratorios/efectos de los fármacos , Estudios Retrospectivos , Ribavirina/uso terapéutico , Factores de Riesgo , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
Inhibition of the 90 kDa heat shock proteins (Hsp90) represents a promising new chemotherapeutic approach for the treatment of several cancers. Hsp90 is essential to the survival of cancer cells and is inhibited by members of the ansamycin family of antibiotics. In particular, the quinone-containing antibiotics geldanamycin (GDA) and herbimycin A inhibit Hsp90 function in vitro at low micromolar concentrations via interaction with an ATP binding domain. Many proteins bind ATP, and the discovery of selective Hsp90 inhibitors requires the identification of other proteins that bind GDA and may cause undesired effects. Biotinylated analogues of GDA with varying tether lengths have been synthesized to elucidate other proteins that competitively bind GDA. Analogues containing a photolabile tether have also been prepared as a complementary method for the removal of GDA-bound proteins from neutravidin-containing resin. Preliminary studies indicate several proteins other than Hsp90 are isolated with biotinylated GDA.
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Quinonas/síntesis química , Adenosina Trifosfato/metabolismo , Benzoquinonas , Biotinilación , Proteínas HSP90 de Choque Térmico/aislamiento & purificación , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Lactamas Macrocíclicas , Fotoquímica , Unión Proteica , Quinonas/química , Quinonas/metabolismo , Quinonas/farmacología , Rifabutina/análogos & derivadosRESUMEN
In early April 2003, severe acute respiratory syndrome (SARS) was diagnosed in a Pennsylvania resident after his exposure to persons with SARS in Toronto, Canada. To identify contacts of the case-patient and evaluate the risk for SARS transmission, a detailed epidemiologic investigation was performed. On the basis of this investigation, 26 persons (17 healthcare workers, 4 household contacts, and 5 others) were identified as having had close contact with this case-patient before infection-control practices were implemented. Laboratory evaluation of clinical specimens showed no evidence of transmission of SARS-associated coronavirus (SARS-CoV) infection to any close contact of this patient. This investigation documents that, under certain circumstances, SARS-CoV is not readily transmitted to close contacts, despite ample unprotected exposures. Improving the understanding of risk factors for transmission will help focus public health control measures.
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Síndrome Respiratorio Agudo Grave/transmisión , Trazado de Contacto , Factores Epidemiológicos , Humanos , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Pennsylvania/epidemiología , Salud Pública , Factores de Riesgo , Síndrome Respiratorio Agudo Grave/epidemiología , Factores de Tiempo , Viaje , Estados Unidos/epidemiologíaRESUMEN
To better assess the risk for transmission of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV), we obtained serial specimens and clinical and exposure data from seven confirmed U.S. SARS patients and their 10 household contacts. SARS-CoV was detected in a day-14 sputum specimen from one case-patient and in five stool specimens from two case-patients. In one case-patient, SARS-CoV persisted in stool for at least 26 days after symptom onset. The highest amounts of virus were in the day-14 sputum sample and a day-14 stool sample. Residual respiratory symptoms were still present in recovered SARS case-patients 2 months after illness onset. Possible transmission of SARS-CoV occurred in one household contact, but this person had also traveled to a SARS-affected area. The data suggest that SARS-CoV is not always transmitted efficiently. Routine collection and testing of stool and sputum specimens of probable SARS case-patients may help the early detection of SARS-CoV infection.
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Síndrome Respiratorio Agudo Grave/transmisión , Adolescente , Adulto , Niño , Trazado de Contacto , Brotes de Enfermedades , Composición Familiar , Heces/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/aislamiento & purificación , Síndrome Respiratorio Agudo Grave/epidemiología , Síndrome Respiratorio Agudo Grave/virología , Esputo/virología , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
Healthcare workers accounted for a large proportion of persons with severe acute respiratory syndrome (SARS) during the worldwide epidemic of early 2003. We conducted an investigation of healthcare workers exposed to laboratory-confirmed SARS patients in the United States to evaluate infection-control practices and possible SARS-associated coronavirus (SARS-CoV) transmission. We identified 110 healthcare workers with exposure within droplet range (i.e., 3 feet) to six SARS-CoV-positive patients. Forty-five healthcare workers had exposure without any mask use, 72 had exposure without eye protection, and 40 reported direct skin-to-skin contact. Potential droplet- and aerosol-generating procedures were infrequent: 5% of healthcare workers manipulated a patient's airway, and 4% administered aerosolized medication. Despite numerous unprotected exposures, there was no serologic evidence of healthcare-related SARS-CoV transmission. Lack of transmission in the United States may be related to the relative absence of high-risk procedures or patients, factors that may place healthcare workers at higher risk for infection.