RESUMEN

Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.

Asunto(s)

Autofagia , Encéfalo/metabolismo , Estrés del Retículo Endoplásmico , Inestabilidad Genómica , Proteínas Supresoras de Tumor/genética , Proteínas de Transporte Vesicular/genética , Animales , Apoptosis , Encéfalo/citología , Células Cultivadas , Ratones de la Cepa 129 , Ratones Transgénicos , Mitosis , Células-Madre Neurales/fisiología , Cultivo Primario de Células , Células de Purkinje/fisiología , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Transporte Vesicular/metabolismo

RESUMEN

The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma.

Asunto(s)

Metilación de ADN/genética , Epigénesis Genética , Meduloblastoma/genética , Proteínas Proto-Oncogénicas c-vav/genética , Animales , Proliferación Celular , Transformación Celular Neoplásica/genética , Islas de CpG/genética , Humanos , Meduloblastoma/patología , Ratones , Neuronas/metabolismo , Neuronas/patología , Proteínas Proto-Oncogénicas c-vav/biosíntesis , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The aim of this systematic review was to determine if eccentric exercise is superior to concentric exercise in stimulating gains in muscle strength and mass. Meta-analyses were performed for comparisons between eccentric and concentric training as means to improve muscle strength and mass. In order to determine the importance of different parameters of training, subgroup analyses of intensity of exercise, velocity of movement and mode of contraction were also performed. Twenty randomised controlled trials studies met the inclusion criteria. Meta-analyses showed that when eccentric exercise was performed at higher intensities compared with concentric training, total strength and eccentric strength increased more significantly. However, compared with concentric training, strength gains after eccentric training appeared more specific in terms of velocity and mode of contraction. Eccentric training performed at high intensities was shown to be more effective in promoting increases in muscle mass measured as muscle girth. In addition, eccentric training also showed a trend towards increased muscle cross-sectional area measured with magnetic resonance imaging or computerised tomography. Subgroup analyses suggest that the superiority of eccentric training to increase muscle strength and mass appears to be related to the higher loads developed during eccentric contractions. The specialised neural pattern of eccentric actions possibly explains the high specificity of strength gains after eccentric training. Further research is required to investigate the underlying mechanisms of this specificity and its functional significance in terms of transferability of strength gains to more complex human movements.

Asunto(s)

Fuerza Muscular/fisiología , Músculo Esquelético/anatomía & histología , Entrenamiento de Fuerza/métodos , Adaptación Fisiológica/fisiología , Adolescente , Adulto , Humanos , Persona de Mediana Edad , Músculo Esquelético/fisiología , Adulto Joven

RESUMEN

Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

Asunto(s)

Roturas del ADN de Doble Cadena , Reparación del ADN , Mamíferos/embriología , Recombinación Genética , Animales , Humanos , Mamíferos/fisiología

RESUMEN

The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.

Asunto(s)

Transformación Celular Neoplásica/genética , Genes Letales , Predisposición Genética a la Enfermedad , Meduloblastoma/genética , Proteínas Represoras/fisiología , Rabdomiosarcoma/genética , Animales , Apoptosis , Transformación Celular Neoplásica/metabolismo , Perfilación de la Expresión Génica , Genes Supresores de Tumor/fisiología , Pérdida de Heterocigocidad , Meduloblastoma/patología , Ratones , Ratones Noqueados , Receptores Patched , Receptor Patched-1 , Receptor Patched-2 , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Proteínas Represoras/genética , Rabdomiosarcoma/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiología

RESUMEN

Within the nervous system appropriate responses to DNA damage are required to maintain homeostasis and prevent disease. In this tissue, DNA double-strand breaks (DSBs) initiate a molecular response to repair DNA, or in many cases, activate apoptosis. The repair of DNA DSBs occurs via nonhomologous end-joining (NHEJ) or homologous recombination (HR). These mechanistically distinct pathways are critical for maintenance of genomic integrity. During nervous system development there are discrete requirements for each DNA DSB repair pathway at different stages of development. For example, in the nervous system HR is particularly important for proliferating cells, while NHEJ is critical for differentiating cells. Inactivation of either of these pathways can lead to embryonic lethality, neurodegeneration or brain tumors. Human syndromes that result from defective responses to DNA damage often feature overt neuropathology. A prime example is the neurodegenerative syndrome ataxia telangiectasia (A-T), which results from inactivation of the ATM kinase, a crucial nexus for the cellular response to DNA DSBs. This type of DNA damage activates ATM via the Mre11-Rad50-NBS1 (MRN) complex, which leads to selective phosphorylation of ATM substrates resulting in apoptosis or cell cycle arrest and DNA repair. Furthermore, DNA DSBs resulting from chronic genotoxic stress can also result in tumorigenesis, as inactivation of either HR or NHEJ can lead to certain types of brain tumors. Thus, there are distinct requirements for each DNA DSB repair pathway during neural development, which have important implications for understanding diseases of the nervous system.

Asunto(s)

Roturas del ADN de Doble Cadena , Daño del ADN/genética , Enfermedades del Sistema Nervioso/genética , Sistema Nervioso/metabolismo , Animales , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/fisiopatología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Reparación del ADN/genética , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Humanos , Sistema Nervioso/fisiopatología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/fisiopatología

RESUMEN

BACKGROUND: Patients with advanced renal failure are increasingly opting for conservative treatment, yet little is known of their palliative care needs. METHODS: We performed a cross-sectional study, examining symptom burden and quality of life in patients with advanced renal failure (estimated GFR < 17 mL/min; n = 11). A contemporary cohort with terminal malignancy acted as comparators (n = 11). Symptom burden was scored using an extended Memorial Symptom Assessment Scale Short Form questionnaire. Quality of life was assessed using the Euroqol-5Q questionnaire. Demographic and pathological data, performance status and co-morbidity were also recorded. RESULTS: Baseline characteristics were similar for the two groups. Symptom burden (renal 17; cancer 15; P =NS) and quality of life scores (renal 60; cancer 60; P =NS) were remarkably similar. Both groups reported high levels of psychological distress. CONCLUSIONS: Patients with advanced renal failure experience a symptom burden and impairment of quality of life similar to that of patients with terminal malignancy.

Asunto(s)

Fallo Renal Crónico/complicaciones , Neoplasias/complicaciones , Calidad de Vida , Enfermo Terminal , Anciano , Estudios Transversales , Femenino , Humanos , Fallo Renal Crónico/psicología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Calidad de Vida/psicología , Índice de Severidad de la Enfermedad , Estrés Psicológico/etiología , Enfermo Terminal/psicología

RESUMEN

This review outlines some of the many factors a clinician must consider when selecting an antimicrobial dosing regimen for the treatment of infection. Integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient provides the most comprehensive assessment of the interactions between pathogen, host, and antibiotic. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Disease states with special considerations for antimicrobial use are reviewed, as are situations in which pathophysiologic changes may alter the pharmacokinetic handling of antimicrobial agents.

Asunto(s)

Antibacterianos , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Bacteriana Múltiple , Quimioterapia Combinada/farmacocinética , Quimioterapia Combinada/uso terapéutico , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Infecciones Bacterianas/diagnóstico , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad

Asunto(s)

Antibacterianos/farmacocinética , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Humanos , Micosis/tratamiento farmacológico , Enfermedades Parasitarias/tratamiento farmacológico , Sensibilidad y Especificidad , Distribución Tisular

RESUMEN

HYPOTHESIS: Risk factors for Candida infection in surgical intensive care units (SICUs) change over time. Risk factor progression may influence Candida colonization and infection. DESIGN: Multicenter cohort survey. SETTING: Three urban teaching institutions. PATIENTS: A total of 301 consecutively admitted patients in SICUs for 5 or more days. MAIN OUTCOME MEASURES: Assessment of patients on SICU days 1, 3, 4, 6, and 8 and SICU discharge for risk factors, Candida colonization, and antifungal use. Candida colonization status was categorized as noncolonized (NC), locally colonized (LC) if 1 site was involved, and disseminated infection (DI) if 2 or more sites or candidemia were involved. RESULTS: The most frequent risk factors in the 301 patients enrolled were presence of peripheral and central intravenous catheters, bladder catheters, mechanical ventilation, and lack of enteral or intravenous nutrition. Early risk factors included total parenteral nutrition or central catheter at SICU day 1 and previous SICU admissions or surgical procedures. Peak number of risk factors (mean +/- SD) were as follows: 7.2 +/- 2.6 in NC (n = 229), 9.2 +/- 2.3 in LC (n = 45), and 9.2 +/- 2.6 in DI (n = 27). These numbers were reached at day 8 in the NC and LC groups and day 4 in the DI group. The LC and DI groups had more risk factors on each SICU day than the NC group and longer median SICU length of stay (28 days in the DI group vs 11 and 19 days in the NC and LC groups, respectively). Antifungal therapy, while used most frequently in the DI group, was initiated later for this group than in NC and LC groups. CONCLUSIONS: Risk factors for Candida infection in SICU patients change over time. Patients with DI demonstrate a greater number of and more rapid increase in risk factors than patients in the LC and NC groups. Presence of early risk factors at the time of SICU admission, a high incidence of risk factors, or a rapid increase in risk factors should prompt clinicians to obtain surveillance fungal cultures and consider empirical antifungal therapy.

Asunto(s)

Candidiasis/epidemiología , Infección Hospitalaria/epidemiología , Unidades de Cuidados Intensivos , APACHE , Antifúngicos/uso terapéutico , Estudios de Cohortes , Humanos , Tiempo de Internación/estadística & datos numéricos , Modelos Logísticos , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo

Asunto(s)

Confidencialidad/legislación & jurisprudencia , Health Insurance Portability and Accountability Act , Formulario de Reclamación de Seguro/legislación & jurisprudencia , Administración de la Práctica Médica/legislación & jurisprudencia , Adhesión a Directriz/legislación & jurisprudencia , Gestión de la Información/legislación & jurisprudencia , Administración de Consultorio/legislación & jurisprudencia , Administración de la Práctica Médica/economía , Estados Unidos

Asunto(s)

Satisfacción en el Trabajo , Lealtad del Personal , Administración de Personal/métodos , Administración de la Práctica Médica/organización & administración , Adulto , Humanos , Perfil Laboral , Medio Social , Estados Unidos , Lugar de Trabajo/psicología

RESUMEN

Ataxia-telangiectasia (A-T) is a neurodegenerative syndrome resulting from dysfunction of ATM (ataxia telangiectasia mutated). The molecular details of ATM function in the nervous system are unclear, although the neurological lesions in A-T are probably developmental because they appear during childhood. The nervous systems of Atm-null mice show a pronounced defect in apoptosis that is induced by DNA damage, suggesting that ATM may function to eliminate DNA-damaged neurons. Here we show that Atm-dependent apoptosis occurs at discrete stages of neurogenesis. Analysis of gamma-irradiated mouse embryos showed that Atm-dependent apoptosis occurred only in the postmitotic populations that were present in the neuroepithelial subventricular zone of the developing nervous system. Notably, Atm deficiency did not prevent radiation-induced apoptosis in multipotent precursor cells residing in the proliferating ventricular zone. Atm-dependent apoptosis required p53 and coincided with the specific phosphorylation of p53 and caspase-3 activation. Thus, these data show that Atm functions early in neurogenesis and underscore the selective requirement for Atm in eliminating damaged postmitotic neural cells. Furthermore, these data demonstrate that the differentiation status of neural cells is a critical determinant in the activation of certain apoptotic pathways.

Asunto(s)

Apoptosis/efectos de la radiación , Rayos gamma , Sistema Nervioso/citología , Sistema Nervioso/efectos de la radiación , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Apoptosis/fisiología , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Caspasa 3 , Caspasas/metabolismo , Proteínas de Ciclo Celular , Diferenciación Celular/fisiología , Diferenciación Celular/efectos de la radiación , División Celular/genética , División Celular/efectos de la radiación , Daño del ADN , Reparación del ADN , Proteínas de Unión al ADN , Embrión de Mamíferos/citología , Embrión de Mamíferos/efectos de la radiación , Femenino , Ratones , Ratones Noqueados , Mitosis/efectos de la radiación , Sistema Nervioso/embriología , Sistema Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de la radiación , Fosforilación/efectos de la radiación , Embarazo , Efectos Tardíos de la Exposición Prenatal , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Retina/citología , Retina/crecimiento & desarrollo , Retina/efectos de la radiación , Células Madre/citología , Células Madre/efectos de la radiación , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor

RESUMEN

Despite the rarity of the human autosomal recessive disease ataxia telangiectasia (A-T) (affecting approximately 1/40000-1/100000), interest in the function of the mutated gene product (ATM) in this syndrome is intense. Mutation of this single gene can lead to a diverse array of features, including cancer, immune defects, infertility and radiosensitivity. However, it is the pronounced and debilitating neurodegeneration that is the hallmark of this disease. Thus, from a clinical perspective, it is ATM function in the nervous system that, arguably, is the most important to understand. Although the case for DNA damage as a causative factor for neurodegeneration in A-T is compelling, new data point to a possible link to defects in neurogenesis. Thus, whereas ATM is important for nervous system development, it could also be important for adult neurogenesis.

Asunto(s)

Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patología , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Encéfalo/metabolismo , Proteínas de Ciclo Celular , Supervivencia Celular , Daño del ADN , Proteínas de Unión al ADN , Humanos , Ratones , Ratones Noqueados , Mutación , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Células Madre/metabolismo , Proteínas Supresoras de Tumor

RESUMEN

STUDY OBJECTIVE: To evaluate epidemiology, resistance, and treatment outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam for 72 hours or longer. DESIGN: Retrospective analysis. SETTING: University teaching hospital. PATIENTS: Forty-eight patients with A. baumannii bacteremia. INTERVENTION: Evaluation of susceptibility and clinical data from 48 patients treated with either ampicillin-sulbactam or imipenem-cilastatin from 1987-1999. MEASUREMENTS AND MAIN RESULTS: Comparing ampicillin-sulbactam and imipenem-cilastatin, there were no differences between days of bacteremia (4 vs 2 days, p=0.05), days to resolution of temperature or white blood cell count, success or failure during or at end of treatment, or intensive care unit total or antibiotic-related length of stay (13 vs 10 days, p=0.05). Patients treated with ampicillin-sulbactam had significantly decreased antibiotic treatment costs (1500 dollars vs 500 dollars, p=0.004). CONCLUSION: Ampicillin-sulbactam is at least as effective as imipenem-cilastatin based on clinical response at days 2, 7, and end of treatment and is a cost-effective alternative for treatment of A. baumannii infections.

Asunto(s)

Infecciones por Acinetobacter/tratamiento farmacológico , Ampicilina/uso terapéutico , Bacteriemia/tratamiento farmacológico , Cilastatina/uso terapéutico , Quimioterapia Combinada/uso terapéutico , Imipenem/uso terapéutico , Sulbactam/uso terapéutico , Infecciones por Acinetobacter/economía , Infecciones por Acinetobacter/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ampicilina/economía , Bacteriemia/economía , Bacteriemia/epidemiología , Distribución de Chi-Cuadrado , Cilastatina/economía , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Farmacorresistencia Microbiana , Quimioterapia Combinada/economía , Femenino , Humanos , Imipenem/economía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estadísticas no Paramétricas , Sulbactam/economía , Resultado del Tratamiento

RESUMEN

A continued increase in the expression of resistance among bacterial pathogens has prompted the development of a variety of new compounds directed against resistant strains of bacteria. Recently, the most dramatic increase in resistance has been among gram-positive organisms, and the predominant areas of development have been within a few classes of agents. Expanded spectrum fluoroquinolones offer advantages against many resistant gram-positive organisms, including S. pneumoniae and S. aureus. Newly developed classes of antimicrobials offer some unique activity against resistant staphylococci and enterococci. The first classes approved for use in the US are the streptogramins, specifically quinupristin/dalfopristin (Synercid), and the oxazolidinone linezolid (Zyvox). Other new classes of agents, including the ketolides, everninomycins, and newer glycopeptides, such as LY-333328, are in the early stages of development.

Asunto(s)

Antibacterianos/farmacología , Antiinfecciosos/farmacología , Virginiamicina/farmacología , Antiinfecciosos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Farmacorresistencia Microbiana , Fluoroquinolonas , Humanos , Virginiamicina/uso terapéutico

RESUMEN

Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously formed DNA double-strand breaks during nervous system development. Here we report that Atm is required for apoptosis in all areas of the DNA ligase IV-deficient developing nervous system. However, Atm deficiency failed to rescue deficits in immune differentiation in DNA ligase IV-null mice. These data indicate that ATM responds to endogenous DNA lesions and functions during development to eliminate neural cells that have incurred genomic damage. Therefore, ATM could be important for preventing accumulation of DNA-damaged cells in the nervous system that might eventually lead to the neurodegeneration observed in ataxia telangiectasia.

Asunto(s)

ADN Ligasas/deficiencia , Neuronas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Animales Recién Nacidos , Antígenos Nucleares , Apoptosis/fisiología , Ataxia Telangiectasia , Proteínas de la Ataxia Telangiectasia Mutada , Encéfalo/anatomía & histología , Encéfalo/crecimiento & desarrollo , Caspasa 3 , Caspasas/metabolismo , Proteínas de Ciclo Celular , Daño del ADN , ADN Ligasa (ATP) , ADN Ligasas/genética , Proteínas de Unión al ADN , Embrión de Mamíferos/patología , Ratones , Ratones Noqueados , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/patología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor

RESUMEN

Once-daily administration of aminoglycosides (ODA) is effective and safe for many indications. By optimizing pharmacodynamic principles, it enhances bactericidal activity and minimizes toxicity. Its use for the treatment of enterococcal infection is controversial, however, and results of in vitro studies and animal models of endocarditis are conflicting. To date, no case reports or clinical trials have examined its utility in human enterococcal endocarditis. A patient with right-sided endocarditis caused by Enterococcus faecalis was managed by once-daily gentamicin. Clinical and bacteriologic cures of this patient raise questions as to whether enterococcal endocarditis should be regarded as contraindication to ODA. The clinical utility of ODA in this disease deserves further investigation.

Asunto(s)

Antibacterianos/administración & dosificación , Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus faecalis/efectos de los fármacos , Gentamicinas/administración & dosificación , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Adulto , Anciano , Ampicilina/administración & dosificación , Animales , Endocarditis Bacteriana/sangre , Femenino , Infecciones por Bacterias Grampositivas/sangre , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Masculino , Persona de Mediana Edad , Penicilinas/administración & dosificación

RESUMEN

Many human pathological conditions with genetic defects in DNA damage responses are also characterized by neurological deficits. These neurological deficits can manifest themselves during many stages of development, suggesting an important role for DNA repair or processing during the development and maintenance of the nervous system. Although the molecular neuropathology associated with such deficits is largely unknown, many of the responsible gene defects have been identified. The current rapid progress in elucidation of molecular details following gene identification should provide further insight into the importance of DNA processing in nervous system function.

Asunto(s)

Daño del ADN/fisiología , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Trastornos Heredodegenerativos del Sistema Nervioso/fisiopatología , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Ataxia Telangiectasia/fisiopatología , Síndrome de Bloom , Reparación del ADN , Anemia de Fanconi/fisiopatología , Humanos , Síndrome Rothmund-Thomson/fisiopatología , Síndrome de Werner/fisiopatología , Xerodermia Pigmentosa/fisiopatología

RESUMEN

STUDY OBJECTIVE: Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cp(min)) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function. DESIGN: Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages. SETTING: University-affiliated hospital. PATIENTS: Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Cl(cr); ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30. INTERVENTIONS: Ceftizoxime serum concentrations were obtained at steady state. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment. The Cp(min) and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups. CONCLUSION: Our dosing guidelines achieved similar Cp(min) among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.

Asunto(s)

Ceftizoxima/farmacocinética , Cefalosporinas/farmacocinética , Guías de Práctica Clínica como Asunto , Insuficiencia Renal/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Infecciones Bacterianas/tratamiento farmacológico , Ceftizoxima/sangre , Ceftizoxima/uso terapéutico , Cefalosporinas/sangre , Cefalosporinas/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estadísticas no Paramétricas