RESUMO
We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non-neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non-telomerase-mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra-bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus-positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human-specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra-bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus-positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus-positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus-positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina.
Assuntos
Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Homeostase do Telômero/genética , Telômero/genética , Fatores Etários , Envelhecimento/genética , Animais , DNA , Retinopatia Diabética/genética , Retinopatia Diabética/fisiopatologia , Feminino , Glaucoma/genética , Glaucoma/fisiopatologia , Humanos , Masculino , Fenótipo , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/fisiologia , Retina/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Telômero/fisiologiaRESUMO
A 57-year-old woman presented with a 3-year history of a progressive firm plaque on the right cheek. Skin biopsies revealed a bland, storiform, spindle-cell proliferation involving the deep dermis and subcutaneous fat. By immunohistochemistry, the tumor cells were diffusely positive for CD34 and caldesmon with multifocal reactivity for epithelial membrane antigen and focal, weak staining for smooth muscle actin. Retinoblastoma protein expression was not detectable in tumor cells by immunohistochemistry. An interphase fluorescence in situ hybridization analysis for platelet-derived growth factor B (PDGFB) gene rearrangement was negative. A single-nucleotide polymorphism array study detected 1) a gain of chromosome segment 17q21.33-q25.3 which overlapped the entire COL1A1 gene with a breakpoint at 17q21.33, approximately 250 Kb centromeric to the 3' end of COL1A1 gene, 2) several segmental gains on chromosome 11, and 3) an RB1 gene locus with normal copy number and allele frequency. Although the current case resembles dermatofibrosarcoma protuberans, it is unique in that it demonstrates a copy number gain of chromosome 17q in the absence of fusion of COL1A1 and PDGFB genes and an unusual immunohistochemical staining profile. The morphologic and molecular findings suggest a novel molecular variant of dermatofibrosarcoma protuberans not detectable with standard fluorescence in situ hybridization for PDGFB rearrangement. This variant appears to respond to imatinib after 9 months of follow-up.
Assuntos
Cromossomos Humanos Par 17 , Colágeno Tipo I/genética , Dermatofibrossarcoma/genética , Dosagem de Genes , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/análise , Cadeia alfa 1 do Colágeno Tipo I , Dermatofibrossarcoma/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologiaRESUMO
We present a 57-year-old man with erosive lichen sclerosus isolated to the infraorbital area.
Assuntos
Doenças Palpebrais/patologia , Pálpebras/patologia , Líquen Escleroso e Atrófico/patologia , Humanos , Hipopigmentação , Masculino , Pessoa de Meia-IdadeRESUMO
In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis.
Assuntos
Antibióticos Antituberculose/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/análogos & derivados , Rifampina/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antibióticos Antituberculose/uso terapêutico , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Etambutol/farmacologia , Etambutol/uso terapêutico , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Testes de Sensibilidade Microbiana , Pirazinamida/farmacologia , Pirazinamida/uso terapêutico , Distribuição Aleatória , Rifampina/farmacologia , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose Pulmonar/microbiologiaRESUMO
RATIONALE: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown. OBJECTIVES: To determine the length of treatment with rifapentine-isoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice. METHODS: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (± 1 mo of cortisone) and nude mice. MEASUREMENTS AND MAIN RESULTS: All rifapentine-treated mice were lung culture-negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin-treated nude mice harbored more than 4 log(10) lung cfu at Month 2 and approximately 6 log(10) cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did. CONCLUSIONS: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.
Assuntos
Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Pirazinamida/uso terapêutico , Rifampina/análogos & derivados , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Antibióticos Antituberculose/uso terapêutico , Cortisona/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Farmacorresistência Bacteriana , Quimioterapia Combinada , Feminino , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mycobacterium tuberculosis/efeitos dos fármacos , Prevenção Secundária , Fatores de TempoRESUMO
RATIONALE: Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less. OBJECTIVES: To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens. METHODS: Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment. MEASUREMENTS AND MAIN RESULTS: M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide. CONCLUSIONS: In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.
Assuntos
Antibióticos Antituberculose/uso terapêutico , Rifampina/análogos & derivados , Tuberculose/tratamento farmacológico , Animais , Antibióticos Antituberculose/administração & dosagem , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/administração & dosagem , Rifampina/uso terapêutico , Resultado do Tratamento , Tuberculose/microbiologiaRESUMO
RATIONALE: Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens. OBJECTIVES: We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily. METHODS: Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure. MEASUREMENTS AND MAIN RESULTS: After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment. CONCLUSIONS: These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.
Assuntos
Antibióticos Antituberculose/uso terapêutico , Antituberculosos/uso terapêutico , Compostos Aza/uso terapêutico , Isoniazida/uso terapêutico , Quinolinas/uso terapêutico , Rifampina/análogos & derivados , Tuberculose/tratamento farmacológico , Animais , Antibióticos Antituberculose/administração & dosagem , Antituberculosos/administração & dosagem , Compostos Aza/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoroquinolonas , Isoniazida/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Moxifloxacina , Pirazinamida/administração & dosagem , Pirazinamida/uso terapêutico , Quinolinas/administração & dosagem , Recidiva , Rifampina/administração & dosagem , Rifampina/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens. METHODS AND FINDINGS: Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice. CONCLUSIONS: Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.
Assuntos
Antibióticos Antituberculose/administração & dosagem , Antituberculosos/administração & dosagem , Compostos Aza/administração & dosagem , Pulmão/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Quinolinas/administração & dosagem , Rifampina/análogos & derivados , Tuberculose/tratamento farmacológico , Animais , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Fluoroquinolonas , Isoniazida/administração & dosagem , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Moxifloxacina , Mycobacterium tuberculosis/crescimento & desenvolvimento , Pirazinamida/administração & dosagem , Rifampina/administração & dosagem , Prevenção Secundária , Fatores de Tempo , Tuberculose/microbiologiaRESUMO
RATIONALE: Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin. METHODS: To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus isoniazid-based regimens to those of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined. RESULTS: After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg). CONCLUSIONS: By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation.
Assuntos
Antituberculosos/administração & dosagem , Compostos Aza/administração & dosagem , Isoniazida/administração & dosagem , Pirazinamida/administração & dosagem , Quinolinas/administração & dosagem , Rifampina/análogos & derivados , Rifampina/administração & dosagem , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/farmacocinética , Compostos Aza/farmacocinética , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fluoroquinolonas , Isoniazida/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Moxifloxacina , Pirazinamida/farmacocinética , Quinolinas/farmacocinética , Rifampina/farmacocinética , Tuberculose Pulmonar/metabolismoRESUMO
RATIONALE: Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens. METHODS: To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy. RESULTS: After 2 mo of treatment, lung colony-forming unit counts were 1 log(10) lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly isoniazid plus rifapentine (15 mg/kg) and the Denver regimen. CONCLUSIONS: These results suggest that the efficacy of the once-weekly isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg.