RESUMEN
Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.
RESUMEN
OBJECTIVES: To determine the prevalence of the carrier state in household contacts in children with tinea capitis, the duration of the carrier state, factors associated with carriage, and the proportion of carriers who develop clinical disease. DESIGN: Cross-sectional, cohort, prevalence study. SETTING: General pediatric clinic serving an indigent, inner-city, African American population. PATIENTS: Household contacts in children with tinea capitis. Index cases and carriers (no clinical evidence of infection) were identified by culture. Carriers were monitored until the results of their culture became negative, they developed clinical disease, or a 6-month period had elapsed. RESULTS: Fifty-six index cases and 114 contacts (50 adults and 64 children) were evaluated. Ninety-eight percent of the dermatophytes identified in index cases and 100% in carriers were Trichophyton tonsurans. At the initial visit, 18 (16%) of 114 (95% confidence interval [95% CI], 10-24) of contacts were carriers and 14 (32%) of 44 of the families studied had at least 1 carrier. At the 2-, 4-, and 6-month visits, the carrier state persisted in 7 (41%) of 17 (95% CI, 19-67), 3 (20%) of 15 (95% CI, 4-48), and 2 (13%) of 15 (95% CI, 2-40), respectively. Three of the carriers were lost to follow-up. Of the carriers, 1 (7%) of 15 (95% CI, 0.2-32) developed tinea capitis. Univariate and multivariate analysis showed no association of carrier state to age, sex, comb sharing, or cosleeping. However, cosleeping and comb sharing were common among the contacts, occurring 75% and 78% of the time, respectively, making statistical correlation difficult with our sample size. CONCLUSIONS: Initial prevalence of asymptomatic carriage of dermatophytes among household contacts of a child with tinea capitis was 16%, with 41% of carriers persisting up to 2 months. Thirty-two percent of families had at least 1 member who was a carrier. Seven percent of the carriers developed an active infection. Treatment of carriers with sporicidal shampoo should be considered since they may act as a reservoir for infection or develop active disease. The high prevalence of cosleeping and comb sharing may be important factors in the spread of the disease.
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Negro o Afroamericano/estadística & datos numéricos , Composición Familiar , Tiña del Cuero Cabelludo/transmisión , Adulto , Arthrodermataceae , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Indigencia Médica , Prevalencia , Tiña del Cuero Cabelludo/epidemiología , Salud Urbana , Wisconsin/epidemiologíaRESUMEN
Lymphomas and leukemias account for a large portion of orbital tumors. Orbital lymphoma accounts for 55% of malignant orbital tumors in adults. Idiopathic orbital inflammatory pseudotumors are pathologic entities that often challenge ophthalmologists and radiologists. This article describes the MR and CT features of orbital lymphoma, leukemia, and some other lymphoproliferative disorders.
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Diagnóstico por Imagen , Trastornos Linfoproliferativos/diagnóstico , Enfermedades Orbitales/diagnóstico , Adulto , Humanos , Leucemia/diagnóstico , Infiltración Leucémica , Linfoma no Hodgkin/diagnóstico , Imagen por Resonancia Magnética , Neoplasias Orbitales/diagnóstico , Seudotumor Orbitario/diagnóstico , Tomografía Computarizada por Rayos XAsunto(s)
Antineoplásicos/síntesis química , Compuestos de Mostaza Nitrogenada/síntesis química , Tiazoles/síntesis química , Animales , Derivados del Benceno/síntesis química , Compuestos de Bencilo/síntesis química , Carcinoma 256 de Walker/tratamiento farmacológico , Cloro , Éteres/síntesis química , Etilaminas/síntesis química , Leucemia/tratamiento farmacológico , Leucemia L1210/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Relación Estructura-Actividad , Tiazoles/uso terapéutico , Tolueno/síntesis químicaAsunto(s)
Aldehídos/síntesis química , Antineoplásicos/síntesis química , Compuestos de Mostaza Nitrogenada/síntesis química , Bases de Schiff/síntesis química , Animales , Antineoplásicos/uso terapéutico , Benzaldehídos/síntesis química , Benzaldehídos/uso terapéutico , Carcinoma 256 de Walker/tratamiento farmacológico , Leucemia L1210/tratamiento farmacológico , Leucemia Experimental/tratamiento farmacológico , Ratones , Compuestos de Mostaza Nitrogenada/uso terapéutico , Bases de Schiff/uso terapéutico , Relación Estructura-ActividadAsunto(s)
Antineoplásicos , Aldehídos/síntesis química , Aminas , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Carcinoma 256 de Walker/tratamiento farmacológico , Fenómenos Químicos , Química , Leucemia L1210/tratamiento farmacológico , Leucemia Experimental/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada , Tiazoles/síntesis químicaAsunto(s)
Antineoplásicos/síntesis química , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/síntesis química , Animales , Antineoplásicos/uso terapéutico , Carcinoma 256 de Walker/tratamiento farmacológico , Leucemia Experimental/tratamiento farmacológico , Métodos , Compuestos de Mostaza Nitrogenada/uso terapéutico , RatasRESUMEN
BACKGROUND: The opioid meperidine induces spinal anesthesia and blocks nerve action potentials, suggesting it is a local anesthetic. However, whether it produces effective clinical local anesthesia in peripheral nerves remains unclear. Classification as a local anesthetic requires clinical local anesthesia but also blockade of voltage-dependent Na+ channels with characteristic features (tonic and phasic blockade and a negative shift in the voltage-dependence of steady-state inactivation) involving an intrapore receptor. The authors tested for these molecular pharmacologic features to explore whether meperidine is a local anesthetic. METHODS: The authors studied rat skeletal muscle mu1 (RSkM1) voltage-dependent Na+ channels or a mutant form heterologously coexpressed with rat brain Na+ channel accessory beta1, subunit in Xenopus oocytes. Polymerase chain reaction was used for mutagenesis, and mutations were confirmed by sequencing. Na+ currents were measured using a two-microelectrode voltage clamp. Meperidine and the commonly used local anesthetic lidocaine were applied to oocytes in saline solution at room temperature. RESULTS: Meperidine and lidocaine produced tonic current inhibition with comparable concentration dependence. Meperidine caused phasic current inhibition in which the concentration-response relationship was shifted to fivefold greater concentration relative to lidocaine. Meperidine and lidocaine negatively shifted the voltage dependence of steady-state inactivation. Mutation of a putative local anesthetic receptor reduced phasic inhibition by meperidine and lidocaine and tonic inhibition by lidocaine, but not meperidine tonic inhibition. CONCLUSIONS: Meperidine blocks Na+ channels with molecular pharmacologic features of a local anesthetic. The findings support classification of meperidine as a local anesthetic but with less overall potency than lidocaine.
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Analgésicos Opioides/farmacología , Anestésicos Locales/farmacología , Lidocaína/farmacología , Meperidina/farmacología , Bloqueadores de los Canales de Sodio , Algoritmos , Animales , Electrofisiología , Técnicas In Vitro , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Oocitos , Técnicas de Placa-Clamp , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Canales de Sodio/genética , XenopusRESUMEN
OBJECTIVES: To determine 1) the frequency of missed vaccine opportunities (VOs) in inner city children =3 years of age; 2) whether the recommended vaccine(s) were given within 6 months of the missed opportunity (MO); 3) whether these vaccinations were age-appropriate according to the guidelines of the Advisory Committee on Immunization Practices; and 4) variables associated with MOs. DESIGN: Retrospective chart review with a nested retrospective cohort of children with MOs. SETTING: Two inner city practice settings in Milwaukee: a community health center and an academic continuity care practice. PATIENTS/SELECTION PROCEDURE: A consecutive sample of 710 visits of inner city children =3 years of age with VOs, seen between January 1 and March 31, 1995. A VO was defined as any encounter when the child was vaccine-eligible according to Advisory Committee on Immunization Practices guidelines. RESULTS: MOs occurred in 47% (330/710) of the VOs. Only 40% of the children with MOs received age-appropriate immunizations within 6 months; 30% received the vaccinations beyond the age-appropriate time. The remaining 30% either did not return or were not vaccinated on return. The variables significantly associated with MOs were 1) age: children with MOs were older than those without, with a mean age of 15.5 months vs 10.9 months; 2) minor febrile illness; 3) moderate/severe illness; 4) acute illness encounters; and 5) patient's being seen at the community health center. Only 15.5% of all MOs were justified by the presence of moderate/severe illness. CONCLUSIONS: VOs are frequently missed in inner city children. Most of the MOs were not justified by the valid contraindication of moderate/severe illness. Sixty percent of the children with MOs did not receive age-appropriate immunizations within 6 months. These children are vulnerable to vaccine-preventable diseases such as measles and pertussis.