RESUMEN
The development of insecticide resistance is a threat to the control of malaria in Africa. We report the findings of a national survey carried out in Tanzania in 2011 to monitor the susceptibility of malaria vectors to pyrethroid, organophosphate, carbamate and DDT insecticides, and compare these findings with those identified in 2004 and 2010. Standard World Health Organization (WHO) methods were used to detect knock-down and mortality rates in wild female Anopheles gambiae s.l. (Diptera: Culicidae) collected from 14 sentinel districts. Diagnostic doses of the pyrethroids deltamethrin, lambdacyhalothrin and permethrin, the carbamate propoxur, the organophosphate fenitrothion and the organochlorine DDT were used. Anopheles gambiae s.l. was resistant to permethrin in Muleba, where a mortality rate of 11% [95% confidence interval (CI) 6-19%] was recorded, Muheza (mortality rate of 75%, 95% CI 66-83%), Moshi and Arumeru (mortality rates of 74% in both). Similarly, resistance was reported to lambdacyhalothrin in Muleba, Muheza, Moshi and Arumeru (mortality rates of 31-82%), and to deltamethrin in Muleba, Moshi and Muheza (mortality rates of 28-75%). Resistance to DDT was reported in Muleba. No resistance to the carbamate propoxur or the organophosphate fenitrothion was observed. Anopheles gambiae s.l. is becoming resistant to pyrethoids and DDT in several parts of Tanzania. This has coincided with the scaling up of vector control measures. Resistance may impair the effectiveness of these interventions and therefore demands close monitoring and the adoption of a resistance management strategy.
Asunto(s)
Anopheles/efectos de los fármacos , Resistencia a los Insecticidas , Insecticidas/farmacología , Animales , DDT/farmacología , Femenino , Piretrinas/farmacología , TanzaníaRESUMEN
SETTING: During 2002-2003, a large outbreak of tuberculosis (TB) occurred among persons using multiple homeless facilities in King County, Washington. OBJECTIVE: To control the transmission of TB in multiple settings. DESIGN: In 2002, contacts exposed to patients in homeless facilities were screened using tuberculin skin tests (TSTs) and symptom review. Based on these screening results, sites of transmission were identified and prioritised, and exposed cohorts at these sites were offered intensive screening tests in 2003 (e.g., symptom review, TST, chest radiograph [CXR], sputum examination and culture). Mycobacterium tuberculosis isolates from patients were genotyped using PCR-based methods to identify outbreak-associated patients quickly. RESULTS: During 2002-2003, 48 (15%) of 313 patients diagnosed in King County were outbreak-associated; 47 culture-positive patients had isolates that matched the outbreak strain by genotyping. Three facilities visited by >12 patients in 2002 had a higher prevalence of TST positive results (approximately 30%) among clients compared with the background rate (7%) in the homeless community. Screening contacts with one sputum culture was as sensitive as CXR in detecting TB disease (77% vs. 62%, respectively). CONCLUSIONS: A comprehensive, resource-intensive approach likely helped to control transmission. This outbreak highlights the vulnerability of homeless populations and the need to maintain robust TB programs in urban settings.
Asunto(s)
Brotes de Enfermedades , Personas con Mala Vivienda , Tuberculosis Pulmonar/epidemiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tuberculosis Pulmonar/prevención & control , Washingtón/epidemiologíaRESUMEN
SETTING: Literature review for the process of contact tracing for sexually transmitted diseases (STD) and for tuberculosis (TB), focusing on articles that report results of studies or commentary. OBJECTIVE: To compare and contrast contact tracing in order to highlight emerging commonalities. DESIGN: A descriptive review, based on Medline search with augmentation from other published and unpublished sources. RESULTS: Contact tracing for STD and TB have some obvious differences because of differing routes of transmission, differing sensibilities required to work with the affected populations, a different potential for anonymous contacts, and a major difference in the epidemiologic value of biomarkers. Nonetheless, the convergence of these processes on disadvantaged populations where drug use and sexual activity are important social factors has engendered an increasing similarity. CONCLUSION: A broadened approach to both, with greater attention to how ancillary contacts and associates may be of use in interrupting deeply embedded endemic disease transmission, deserves further study. Some newer approaches in the use of network-informed methods to elicit contacts and investigate the community dynamics of transmission may be of particular value in TB case investigation. These strategies will be enhanced by the availability of DNA fingerprinting, a powerful biomarker of recent Mycobacterium tuberculosis transmission and case association (a technology not available for STD contact tracing).
Asunto(s)
Trazado de Contacto/métodos , Enfermedades de Transmisión Sexual/prevención & control , Enfermedades de Transmisión Sexual/transmisión , Tuberculosis/prevención & control , Tuberculosis/transmisión , HumanosRESUMEN
BACKGROUND: To elucidate networks of Mycobacterium tuberculosis transmission, it may be appropriate to characterize the types of relationships among tuberculosis (TB) cases and their contacts (with and without latent TB infection) in addition to relying on traditional efforts to distinguish 'close' from 'casual' contacts. SETTING: A TB outbreak in a US low incidence state. OBJECTIVE: To evaluate whether social network analysis can provide insights into transmission settings that might otherwise go unrecognized by routine practices. DESIGN: All adult outbreak-associated cases (n = 19) and a convenience sample of their contacts with and without latent TB infection (LTBI) (n = 26) were re-interviewed in 2001 using a structured questionnaire. Network analysis software was used to create diagrams illustrating important persons within the outbreak network, as well as types of activities TB cases engaged in with their contacts. RESULTS: Drug use and drug sharing were more commonly reported among cases and their infected contacts than among contacts without LTBI. TB cases central to the outbreak network used crack cocaine, uncovering the need to focus control efforts on specific sites and persons involved in illicit drug use. CONCLUSION: Outbreaks occur even in areas with low TB incidence, frequently among groups whose drug use or other illegal activities complicate control efforts. TB programs should consider the use of network analysis as a supplement to routine contact investigations to identify unrecognized patterns of M. tuberculosis transmission.
Asunto(s)
Redes Comunitarias , Trazado de Contacto/métodos , Brotes de Enfermedades , Tuberculosis/epidemiología , Tuberculosis/transmisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Kansas/epidemiología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Conducta Sexual , Conducta Social , Trastornos Relacionados con Sustancias/complicaciones , Tuberculosis/diagnósticoRESUMEN
BACKGROUND: Why asthma is rare in rural subsistence societies is not clear. We tested the hypotheses that the risk of asthma is reduced by intestinal parasites or hepatitis A infection, and increased by exposure to dust-mite allergen or organophosphorus insecticides in urban and rural areas of Jimma, Ethiopia. METHODS: From 12876 individuals who took part in a study of asthma and atopy in urban and rural Jimma in 1996, we identified all who reported wheeze in the previous 12 months, and a random subsample of controls. In 1999, we assessed parasites in faecal samples, Der p 1 levels in bedding, hepatitis A antibodies, serum cholinesterase (a marker of organophosphorus exposure), total and specific serum IgE, and skin sensitisation to Dermatophagoides pteronyssinus in 205 cases and 399 controls aged over 16 years. The effects of parasitosis, Der p 1 level, hepatitis A seropositivity, and cholinesterase concentration on risk of wheeze, and the role of IgE and skin sensitisation in these associations, were analysed by multiple logistic regression. FINDINGS: The risk of wheeze was independently reduced by hookworm infection by an odds ratio of 0.48 (95% CI 0.24-0.93, p=0.03), increased in relation to Der p 1 level (odds ratio per quartile 1.26 [1.00-1.59], p=0.05), and was unrelated to hepatitis A seropositivity or cholinesterase concentration. In the urban population, D pteronyssinus skin sensitisation was more strongly related to wheeze (9.45 [5.03-17.75]) than in the rural areas (1.95 [0.58-6.61], p for interaction=0.017), where D pteronyssinus sensitisation was common, but unrelated to wheeze in the presence of high-intensity parasite infection. INTERPRETATION: High degrees of parasite infection might prevent asthma symptoms in atopic individuals.
Asunto(s)
Asma/epidemiología , Heces/parasitología , Glicoproteínas/inmunología , Enfermedades Intestinales/parasitología , Ruidos Respiratorios , Adolescente , Adulto , Antígenos Dermatofagoides , Asma/inmunología , Estudios de Casos y Controles , Estudios Transversales , Etiopía/epidemiología , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Población Rural , Población UrbanaRESUMEN
A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene, with a guanine to adenine nucleotide change at position -308, TNF2 is associated with increased TNF-alpha production. TNF2 homozygotes have a higher risk of severe disease and/or death due to cerebral malaria and other infectious diseases. We investigated the impact of this allele on malaria morbidity and mortality in young children who participated in an immuno-epidemiologic cohort study of malaria in an area of intense perennial Plasmodium falciparum transmission in western Kenya. A total of 1,048 children were genotyped. Poisson regression and Cox proportional hazards models were used to determine the relationship between TNF-308 variants and morbidity and mortality. The gene frequencies of the TNF1 and TNF2 alleles were 0.90 and 0.10, respectively. TNF2 homozygosity was associated with pre-term birth when compared with TNF1 homozygotes [relative risk (RR) 7.3, 95% CI, 2.85-18.9, P = 0.002) and heterozygotes (RR 6.7, 95% CI 2.0-23.0, P = 0.008). Among children born prematurely, the TNF2 allele was significantly associated with a higher risk of death in infancy compared with TNF1 (RR 7.47, 95% CI 2.36-23.6). The risk of death was higher among TNF2 homozygotes than among heterozygotes. The TNF2 allele was significantly associated with high density P. falciparum parasitemia (RR 1.11, 95% CI 1.0-1.24). Among low birth weight children, the TNF2 allele was associated with severe anemia (RR 2.16, 95% CI 1.17-4.01) and showed a trend toward a risk for severe malaria anemia (RR 1.99, 95% CI 0.89-4.46). These data suggest that TNF2 is a risk factor for pre-term birth and early childhood mortality and malaria morbidity in children in this region. Further understanding of the pathogenic mechanisms underlying this association is required.
Asunto(s)
Predisposición Genética a la Enfermedad , Mortalidad Infantil , Malaria Falciparum/genética , Trabajo de Parto Prematuro/genética , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/genética , Alelos , Femenino , Genotipo , Humanos , Recién Nacido , Recien Nacido Prematuro , Kenia/epidemiología , Malaria Falciparum/epidemiología , Masculino , Distribución de Poisson , Polimorfismo Genético , Embarazo , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
In vitro studies have shown that inhibition of Plasmodium falciparum blood-stage parasite growth by antibody-dependent cellular inhibition is mediated by cooperation between malaria-specific IgG1 and IgG3, but not IgG2, and monocytes via the Fcgamma receptor II (FcgammaRII). A single amino acid substitution at position 131 in FcgammaRIIa is critical in the binding of human IgG subclasses. The hypothesis that the FcgammaRIIa-Arg/Arg131 genotype, which does not bind to IgG2, is a host genetic factor for protection against high-density P. falciparum infection was tested. One hundred eighty-two infants from a large community-based birth cohort study in western Kenya were selected for an unmatched case-control study. Results showed that the infants with the FcgammaRIIa-Arg/Arg131 genotype were significantly less likely to be at risk for high-density falciparum infection, compared with infants with the FcgammaRIIa-His/Arg131 genotype (adjusted odds ratio, 0.278; 95% confidence interval, 0.123-0.627; P=.0021). This finding supports the hypothesis.
Asunto(s)
Malaria Falciparum/inmunología , Receptores de IgG/genética , Sustitución de Aminoácidos/genética , Animales , Arginina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Genotipo , Humanos , Inmunoglobulina G/inmunología , Lactante , Kenia , Malaria Falciparum/genética , Monocitos/inmunología , Plasmodium falciparum , Polimorfismo Genético , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Although all-cause mortality has been used as an indicator of the health status of childhood populations, such data are sparse for most rural areas of sub-Saharan Africa, particularly community-based estimates of infant mortality rates. The longitudinal follow-up of more than 1,500 children enrolled at birth into the Asembo Bay Cohort Project (ABCP) in western Kenya between 1992 and 1996 has provided a fixed birth cohort for estimating all-cause mortality over the first 5 yr of life. We surveyed mothers and guardians of cohort children in early 1999 to determine survival status. A total of 1,260 households were surveyed to determine the survival status of 1,556 live births (99.2% of original cohort, n = 1,570). Most mothers (66%) still resided but 27.5% had migrated, and 5.5% had died. In early 1999, the overall cumulative incidence of all-cause mortality for the entire 1992-1996 birth cohort was 26.5% (95% confidence interval, 24.1-28.9%). Neonatal and infant mortality were 32 and 176 per 1,000 live births, respectively. These community-based estimates of mortality in the ABCP area are substantially higher than for Kenya overall (nationally, infant mortality is 75 per 1,000 live births). The results provide a baseline description of all-cause mortality among children in an area with intense Plasmodium falciparum transmission and will be useful in future efforts to monitor changes in death rates attributable to control programs for specific diseases (e.g., malaria and HIV/AIDS) in Africa.
Asunto(s)
Protección a la Infancia/estadística & datos numéricos , Estado de Salud , Mortalidad , Adolescente , Adulto , Distribución por Edad , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Infecciones por VIH/prevención & control , Humanos , Lactante , Mortalidad Infantil , Recién Nacido , Kenia/epidemiología , Estudios Longitudinales , Malaria/prevención & control , Masculino , Mortalidad Materna , Embarazo , Salud Rural/estadística & datos numéricosRESUMEN
Therapeutic use of recombinant human cytokines in humans can result in the generation of drug-specific antibodies. To predetermine the maximum potential effects of a granulocyte colony-stimulating factor (G-CSF) neutralizing auto-immunoglobulin G (auto-IgG) response during recombinant human G-CSF therapy, we developed a mouse model of mouse G-CSF (mG-CSF) neutralizing auto-IgG response. Mice were immunized and boosted with mG-CSF chemically conjugated to either keyhole limpet hemocyanin or ovalbumin on an alternating schedule. Sera were analyzed for mG-CSF-specific titers and full blood counts were performed on a Technicon H-1E. On day 252, tissues were collected for histology. IgG was protein A affinity purified from pooled mG-CSF autoimmune sera. Mice immunized with mG-CSF conjugates produced mG-CSF-specific auto-IgG responses that lasted for the length of the study. Significant neutropenia (p(max) < 0.004) was concurrent with the rise in mG-CSF-specific IgG titers. However, neutrophil counts remained at approximately 20% of preimmunization levels through day 252. Endogenous mG-CSF neutralizing auto-IgG had no significant effect on hemoglobin, erythrocyte, lymphocyte, eosinophil, basophil, and platelet counts, and had minor, transient, or no effects on monocyte counts. Bone marrow colony assays from mG-CSF autoimmune mice demonstrated no significant effect of G-CSF neutralization on the numbers or proliferative capacity of preneutrophil lineage progenitors. Purified IgG from mG-CSF autoimmune mice neutralized mG-CSF in vitro. High-titer G-CSF neutralizing auto-IgG in adult mice partially inhibited steady-state granulopoiesis and had little or no effect on steady-state levels of other hematopoietic cells.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedades Autoinmunes/etiología , Factor Estimulante de Colonias de Granulocitos/inmunología , Inmunoglobulina G/inmunología , Neutropenia/etiología , Animales , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/inmunología , Ensayo de Unidades Formadoras de Colonias , Femenino , Factor Estimulante de Colonias de Granulocitos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos/fisiología , Hematopoyesis/inmunología , Movilización de Célula Madre Hematopoyética/efectos adversos , Hemocianinas/inmunología , Inmunización , Ratones , Modelos Animales , Neutropenia/inmunología , Ovalbúmina/inmunología , Proteínas Recombinantes/farmacología , Reproducibilidad de los Resultados , Organismos Libres de Patógenos EspecíficosRESUMEN
OBJECTIVE: Glucocorticoid sensitivity varies between individuals and between tissues in the same individual. Although some of this variation is explained by the activity of the 11 beta-hydroxysteroid dehydrogenase enzymes, the possibility that glucocorticoid receptor sensitivity is modulated remains unexplored. This study examined glucocorticoid receptor binding in leucocytes and assessed the effects of seasonal hormonal variation on receptor binding. PATIENTS AND MEASUREMENTS: Two populations were studied. In the first, 318 healthy subjects were studied over 2 years with a single measurement of receptor binding made on each. In the second study nine healthy male subjects each had receptor binding measurements made at 3-week intervals over 1 year. RESULTS: In both populations there was significant seasonal variation in receptor binding. In the first population Kd for dexamethasone was highest in November and lowest in July (8.37 +/- 0.5 nmol/l vs. 1.58 +/- 0.7, mean +/- SEM P < 0.00001) and the number of receptor sites per leucocyte was highest in January and lowest in June (10 440 +/- 580 vs. 4969 +/- 302, P < 0.00001). In multivariate analysis, climate was the main determinant for both Kd and the number of receptor sites per cell: increases in day length and environmental temperature reduced Kd and the number of receptor sites per cell. Co-incubation with physiological concentrations of melatonin raised Kd without affecting receptor number. Co-incubation with forskolin lowered Kd suggesting that melatonin might act through the ML1 receptor class by inhibiting adenylyl cyclase. No correlations were found with 0900 h plasma cortisol. CONCLUSIONS: The results suggest that the glucocorticoid receptor might be modulated by season. Melatonin might mediate part of these effects. The lack of correlation with cortisol suggests that it is not an important determinant of receptor binding and that leucocyte receptors are regulated differently from central receptors.
Asunto(s)
Dexametasona/metabolismo , Leucocitos Mononucleares/metabolismo , Receptores de Glucocorticoides/metabolismo , Estaciones del Año , Inhibidores de Adenilato Ciclasa , Adulto , Análisis de Varianza , Células Cultivadas , Colforsina/farmacología , Dexametasona/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Hidrocortisona/sangre , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Melatonina/farmacología , Unión ProteicaRESUMEN
SETTING: Baltimore, Maryland. OBJECTIVE: To describe a tuberculosis (TB) outbreak among a highly mobile population and the efforts required to control it. DESIGN: Epidemiologic outbreak investigation. RESULTS: Between June 1998 and January 2000, 20 TB outbreak cases were identified, of which 18 were culture-confirmed. Seventeen isolates of Mycobacterium tuberculosis had an identical 11-band DNA fingerprint; another isolate had one additional band and was considered a match. Two cases were diagnosed in New York City; another patient lived primarily in Atlanta, but was diagnosed in Baltimore. Persons in the outbreak were predominantly young (median age 24 years), black, male, infected with the human immunodeficiency virus (HIV), and gay, transvestite or transsexual. Activities common among many TB cases included attending two nightclubs, membership in one of three social 'Houses', attending balls or pageants in East Coast cities, marijuana use, and prostitution. Community outreach, extended contact tracing, DNA fingerprinting, directly-observed therapy, and expanded use of preventive therapy were utilized to assess and control the outbreak. During the outbreak period the Baltimore City TB rate declined by 10%. However, additional public health personnel were required to control the outbreak, resulting in a 17% increase in TB clinic staff. CONCLUSION: As TB rates decline, remaining cases are likely to occur in difficult-to-reach populations. Increased resources per case of TB treated will be required to eliminate TB.
Asunto(s)
Brotes de Enfermedades , Tuberculosis/epidemiología , Infecciones Oportunistas Relacionadas con el SIDA/epidemiología , Infecciones Oportunistas Relacionadas con el SIDA/prevención & control , Adulto , Cromosomas Bacterianos/genética , Trazado de Contacto , Dermatoglifia del ADN , Femenino , Georgia/epidemiología , Humanos , Masculino , Maryland/epidemiología , Mycobacterium tuberculosis/genética , New York/epidemiología , Polimorfismo de Longitud del Fragmento de Restricción , Tuberculosis/prevención & controlRESUMEN
The relative importance of acute high-density versus persistent low-density Plasmodium falciparum parasitemia in contributing to the public health problem of malarial anemia remains unclear. The Asembo Bay Cohort Project in western Kenya collected monthly hemoglobin (Hb) and parasitologic measurements and biweekly assessments of antimalarial drug use among 942 singleton live births between 1992 and 1996. A mixed-model analysis appropriate for repeated measures data was used to study how time-varying parasitemia and antimalarial drug exposures influenced mean Hb profiles. Incidence of World Health Organization-defined severe malarial anemia was 28.1 per 1,000 person-years. Among children aged less than 24 months, concurrent parasitemia was significantly associated with lower mean Hb, especially when compared to children with no concurrent parasitemia. Increased densities of the 90-day history of parasitemia preceding Hb measurement was more strongly associated with mean Hb levels than concurrent parasitemia density. While the highest quartile of 90-day parasitemia history was associated with lowest mean Hb levels, children in the lowest 90-day exposure quartile still experienced significantly lower Hb levels when compared to children who remained parasitemia-free for the same 90-day period. The results highlight the importance of collecting and analyzing longitudinal Hb and parasitologic data when studying the natural history of malarial anemia.
Asunto(s)
Anemia/etiología , Hemoglobinas/análisis , Malaria Falciparum/sangre , Parasitemia/sangre , Anemia/epidemiología , Antimaláricos/uso terapéutico , Preescolar , Estudios de Cohortes , Humanos , Incidencia , Lactante , Recién Nacido , Kenia/epidemiología , Estudios Longitudinales , Malaria Falciparum/complicaciones , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Parasitemia/complicaciones , Parasitemia/tratamiento farmacológico , Parasitemia/epidemiologíaRESUMEN
Drawing from an institutional-theory perspective on innovations in organizations, this paper examines the use of human immunodeficiency virus (HIV) prevention practices by the nation's outpatient substance abuse treatment units during a critical period from 1988 to 1995. An institutional perspective argues that organizations adopt new practices not only for technical reasons, but also because external actors actively promote or model the use of particular practices. We examine the extent to which treatment units use several practices to prevent HIV infection among their clients and among drug-users not in treatment. Results from random-effects regression analyses of national survey data show that treatment units significantly increased their use of HIV prevention practices from 1988 to 1995. Further, the results show that treatment units' use of prevention practices was related to clients' risk for HIV infection, unit resources available to support these practices, and organizational support for the practices. Implications are discussed for an institutional view of organizational innovation as well as for research on HIV prevention.
Asunto(s)
Infecciones por VIH/prevención & control , Centros de Tratamiento de Abuso de Sustancias , Abuso de Sustancias por Vía Intravenosa/rehabilitación , Estudios Transversales , Humanos , Funciones de Verosimilitud , Modelos Lineales , Política Organizacional , Estados UnidosRESUMEN
Immmoglobulin E-rich plasma from patients from Papua New Guinea infected with Necator americanus has been used to probe an adult N. americanus cDNA library for the presence of hookworm allergens. Using this approach, one hookworm allergen has been identified as calreticulin, which was subsequently expressed in Escherichia coli. Little serological cross reactivity was seen between the recombinant calreticulins of this hookworm and its host. Prospective roles for hookworm calreticulin in the host-parasite relationship are discussed in depth.
Asunto(s)
Alérgenos/inmunología , Antígenos Helmínticos/inmunología , Proteínas de Unión al Calcio/inmunología , Necator americanus/inmunología , Ribonucleoproteínas/inmunología , Alérgenos/química , Alérgenos/genética , Secuencia de Aminoácidos , Animales , Anticuerpos Antihelmínticos/sangre , Anticuerpos Antihelmínticos/inmunología , Antígenos Helmínticos/química , Antígenos Helmínticos/genética , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/genética , Calreticulina , Clonación Molecular , Reacciones Cruzadas/inmunología , Escherichia coli/genética , Biblioteca de Genes , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Datos de Secuencia Molecular , Necator americanus/genética , Necator americanus/crecimiento & desarrollo , Necatoriasis/sangre , Necatoriasis/inmunología , Necatoriasis/parasitología , Papúa Nueva Guinea , Filogenia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34+ cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/análogos & derivados , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética , Animales , Filgrastim , Humanos , Ratones , Proteínas RecombinantesRESUMEN
Anemia is an important public health problem. During very early childhood numerous factors affect hemoglobin (Hb) concentration over time, making single cross-sectional measurements difficult to interpret when studying the natural history of anemia or evaluating anemia control strategies. We analyzed repeated Hb measures contributed by 942 Kenyan children between birth and 48 months of life using a mixed effects model, with a regression spline used to describe the population mean Hb profile, and random intercepts and slopes and first-order autoregressive correlation structure to accommodate the within-individual correlation among the repeated Hb measures. The approach facilitates the study of time-stationary and time-varying covariates that influence Hb in early life. The fitted mean Hb profile obtained from the analytic model is consistent with the observed mean Hb of the study population. Village of residence was associated with greatest difference in mean Hb at time of birth (16 versus 19 g/dL; P < 0.0001). Monthly weight-for-age was also associated with mean Hb after 3 months of age. This is the first description of an analysis strategy specifically for repeated Hb measures collected in a longitudinal field study in Africa. The strategy will facilitate improved study of time-varying covariates thought to influence pediatric anemia.
Asunto(s)
Anemia/epidemiología , Anemia/prevención & control , Hemoglobinas/análisis , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Adolescente , Adulto , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Kenia/epidemiología , Estudios Longitudinales , Masculino , Modelos Estadísticos , Embarazo , Valores de Referencia , Factores de TiempoRESUMEN
We have evaluated the durability of engraftment and the potential of remobilization in mice reconstituted with mobilized peripheral blood progenitor cells (PBPC). Female mice which had been reconstituted with cytokine-mobilized PBPC from male donors were serially transplanted into second, third, fourth and fifth lethally irradiated female recipients at intervals of 6-10 months. Male-derived hematopoiesis was determined in recipient mice at each serial transplantation. Male-positive CFCs were detected after 5 passages for 45 months, but declined from >95% at passage 1 to 74% at passage 2, 33% at passage 4, and 28% at passage 5. Long-term survival also declined from 97% at passage 2 to 53% at passage 4, and 27% at passage 5. The results demonstrated that mobilized PBPC were able to provide engraftment for more than 45 months, but the engraftment provided by mobilized PBPC decreased at each serial passage. In addition, mice reconstituted with mobilized PBPC (at 1 year post transplantation) were treated with the same cytokines as in the primary mobilization (remobilization). The remobilized PBPC were harvested and transplanted into lethally irradiated secondary recipients. Male-derived CFCs were evaluated at 20 months post transplantation. Mice transplanted with PBPC remobilized with rhG-CSF or rhG-CSF plus rrSCF-PEG showed 70% and 89% male-positive CFCs respectively, demonstrating that mice reconstituted with mobilized PBPC could be remobilized and that the remobilized PBPC were also capable of providing long-term hematopoietic reconstitution. Our studies demonstrated that mobilized PBPC have extensive proliferative or self-renewal capacity to provide durable engraftment and that marrow repopulating cells in PBPC reconstituted mice can be remobilized, suggesting that patients who relapse after PBPC transplantation may be remobilized for a second transplantation to support additional chemotherapy.
Asunto(s)
Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Proteínas Recombinantes , Factor de Células Madre/farmacologíaRESUMEN
The effect of chronic expression of flt3 ligand (FL) on in vivo hematopoiesis was studied. Retroviral vector-mediated gene transfer was used in a mouse model of bone marrow transplantation to enforce expression of mouse FL cDNA in hematopoietic tissues. As early as 2 weeks posttransplantation, peripheral blood white blood cell counts in FL-overexpressing recipients were significantly elevated compared with controls. With the exception of eosinophils, all nucleated cell lineages studied were similarly affected in these animals. Experimental animals also exhibited severe anemia and progressive loss of marrow-derived erythropoiesis. All of the FL-overexpressing animals, but none of the controls, died between 10 and 13 weeks posttransplantation. Upon histological examination, severe splenomegaly was noted, with progressive fibrosis and infiltration by abnormal lymphoreticular cells. Abnormal cell infiltration also occurred in other organ systems, including bone marrow and liver. In situ immunocytochemistry on liver sections showed that the cellular infiltrate was CD3+/NLDC145+/CD11c+, but B220- and F4/80-, suggestive of a mixed infiltrate of dendritic cells and activated T lymphocytes. Infiltration of splenic blood vessel perivascular spaces resulted in vascular compression and eventual occlusion, leading to splenic necrosis consistent with infarction. These results show that FL can affect both myeloid and lymphoid cell lineages in vivo and further demonstrate the potential toxicity of in vivo treatment with FL.
Asunto(s)
Regulación de la Expresión Génica , Leucocitos/patología , Proteínas de la Membrana/genética , Bazo/patología , Animales , Recuento de Células Sanguíneas , Diferenciación Celular/genética , Linaje de la Célula , Movimiento Celular/genética , Fibrosis/genética , Fibrosis/patología , Expresión Génica , Masculino , Proteínas de la Membrana/biosíntesis , Ratones , Ratones EndogámicosRESUMEN
Blood-stage level Plasmodium falciparum infection (parasitemia density) is generally elevated prior to, or at the time of, clinical presentation of severe pediatric malaria episodes. Intensity of exposure to infective Anopheles mosquito bites is a suspected determinant of higher density parasitemia. Analyses of entomologic and parasitologic data collected in 1986-1987 were conducted to investigate whether the dose of infective bites predicted the incidence or degree of P. falciparum parasitemia in Kenyan children < 6 years old. At 21 consecutive 30-day intervals, a new cohort (n approximately 50 each) was enrolled, cured of malaria parasites, and monitored over 84 days for recurrent parasitemia. Outcomes included time to parasitemia, time to parasitemia > or = 5,000/microliter, and parasitemia density. Ecologic and individual-level analyses were conducted. The mean infective bite exposure experienced by each cohort was significantly associated with the incidence of parasitemia (age-adjusted r2 = 0.38, p = 0.022) and more strongly associated with the incidence of parasitemia > or = 5,000/microliter (age-adjusted r2 = 0.72, p < 0.001). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia > or = 5,000/microliter among children exposed to > or = 1 infective bite per day as compared with the referent (rate ratio (RR) = 2.82, 95% confidence interval (CI) 2.24-3.56). Cumulative infective bite exposure, exposure duration, and age were significant predictors of recurrent parasitemia density in multiple linear regression analyses. The results support the contention that reductions in P. falciparum transmission intensity, in the absence of complete elimination, will reduce higher level parasitemia among African children.
PIP: Elevated numbers of asexual erythrocytic-stage Plasmodium falciparum parasites in the peripheral blood circulation is a known risk factor of the clinical severity of malaria episodes. The interrelationships among a continuum of sporozoite dose, duration of exposure, age, level of parasitemia at enrollment, village of residence, sex, and recurrent P. falciparum parasitemia were investigated in a 2-year (1986-87) study of 862 children 6 months to 6 years of age from six contiguous villages in Western Kenya. At 21 consecutive 30-day intervals, a new cohort was enrolled, cured, and monitored over 84 days for recurrent parasitemia. The mean cumulative dose was 23 inoculations, and there was a significant linear correlation between this variable and the incidence rate of first recurrent parasitemia, with even stronger associations for the incidence of higher density parasitemia. The overall 70-day cumulative incidence of first recurrent parasitemia was 88.5% (22.5% for high-density P. falciparum). The infective bite dose, analyzed as a time-dependent covariate, was associated with a 2.8 times higher rate of parasitemia equal to or above 5000/mcl among children exposed to one or more bites per day compared to the referent. Each one unit increase in the mean dose was associated with a 24% higher rate of recurrent parasitemia and a 26% higher rate of recurrent high-density parasitemia after adjustment for covariates. Multiple linear regression analyses indicated that parasitemia density was significantly positively associated with cumulative dose and inversely associated with duration of exposure and age. Approximately 36% of the variance in malaria incidence rates was explained by the mean cumulative dose of infective bites.
Asunto(s)
Anopheles/parasitología , Mordeduras y Picaduras de Insectos/complicaciones , Malaria Falciparum/parasitología , Plasmodium falciparum/parasitología , Animales , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Kenia , Modelos Lineales , Malaria Falciparum/tratamiento farmacológico , Masculino , Estudios Prospectivos , Recurrencia , Estaciones del Año , Factores de TiempoRESUMEN
Recently, an association was described between the density of Plasmodium falciparum asexual parasitemia in Kenyan children and the entomologic inoculation rate (EIR) measured prior to measurement of asexual parasitemia. This study examined whether transmission pressure, as represented by the EIR, was associated with the prevalence or density of gametocytemia in Kenyan children. Each month for 19 months, a cohort of approximately 50 children was given a radical cure and enrolled in the study. Blood films were taken on days 0, 7, and 14. The EIR was calculated for the 28-day period ending 14 days prior to enrollment: the relationship between blood film data from day 7 and exposure variables was explored. We found that younger children were more likely to be gametocytemic than older children and, if gametocytemic, were more likely to have a dense gametocytemia. There was an inverse relationship between the number of infective bites per night received and prevalence but not density of gametocytemia, even after age adjustment. Concordance of gametocytemia prevalence on days 0 (64%), 7 (66%), and 14 (52%) was poor; 84% of the children were positive on at least one day. This indicates that in many subjects the detectable gametocytemia varied over the 14 days. Under these holoendemic transmission conditions, the EIR is inversely correlated with prevalence of gametocytemia, and point measurements of gametocytemia by conventional microscopy underestimate the number of infective donor hosts.