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RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.
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Amicacina/administração & dosagem , Amicacina/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Fibrose Cística/fisiopatologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Adolescente , Adulto , Análise de Variância , Criança , Fibrose Cística/complicações , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Lipossomos , Masculino , Testes de Sensibilidade Microbiana , Nebulizadores e Vaporizadores , Qualidade de Vida , Escarro/microbiologia , Adulto JovemRESUMO
The predominant geometry for a neutron imaging experiment is that of a pinhole camera. This is primarily due to the difficulty in focusing neutrons due to the weak refractive index, which is also strongly chromatic. Proof of concept experiments demonstrated that neutron image forming lenses based on reflective Wolter mirrors can produce quantitative, high spatial resolution neutron images while also increasing the time resolution compared to the conventional pinhole camera geometry. Motivated by these results, we report the design of a neutron microscope where two Wolter mirrors replace condensing and objective lenses, in direct analogy with typical visible light microscopes. Ray tracing results indicate that this system will yield 3 µm spatial resolution images with an acquisition time of order <1 s (104 faster than currently possible at this spatial resolution) with a field of view of about 5 mm in diameter.
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BACKGROUND: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF. METHODS: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (nâ¯=â¯22); CF (nâ¯=â¯63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, nâ¯=â¯22), low length (CF LL, nâ¯=â¯23), and low weight (CF LW, nâ¯=â¯15). RESULTS: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins. CONCLUSIONS: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).
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Fibrose Cística/urina , Metabolômica , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Feminino , Humanos , Lactente , Masculino , Redes e Vias Metabólicas , Estado Nutricional , Estudos ProspectivosRESUMO
The need for a time-resolved monochromatic x-ray imaging diagnostic at photon energies >15 keV has motivated the development of a Wolter optic to study x-ray sources on the Z-machine at Sandia National Laboratories. The work is performed in both the LLNL's x-ray calibration facility and SNL's micro-focus x-ray lab. Characterizations and calibrations include alignment, measurement of throughput within the field of view (FOV), the point-spread function within the FOV both in and out of focus, and bandpass in the FOV. These results are compared with ray tracing models, showing reasonable agreement.
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Recent breakthroughs in the fabrication of small-radii Wolter optics for astrophysics allow high energy density facilities to consider such optics as novel x-ray diagnostics at photon energies of 15-50 keV. Recently, the Lawrence Livermore National Laboratory, Sandia National Laboratories (SNL), the Smithsonian Astrophysical Observatory, and the NASA Marshall Space Flight Center jointly developed and fabricated the first custom Wolter microscope for implementation in SNL's Z machine with optimized sensitivity at 17.5 keV. To achieve spatial resolution of order 100-200 microns over a field of view of 5 × 5 × 5 mm3 with high throughput and narrow energy bandpass, the geometry of the optic and its multilayer required careful design and optimization. While the geometry mainly influences resolution and the field of view of the diagnostic, the mirror coating determines the spectral response and throughput. Here we outline the details of the design and fabrication process for the first multilayer-coated Wolter I optic for SNL's Z machine (Z Wolter), including its W/Si multilayer, and present results of raytrace simulations completed to predict and verify the performance of the optic.
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A new Wolter x-ray imager has been developed for the Z machine to study the emission of warm (>15 keV) x-ray sources. A Wolter optic has been adapted from observational astronomy and medical imaging, which uses curved x-ray mirrors to form a 2D image of a source with 5 × 5 × 5 mm3 field-of-view and measured 60-300-µm resolution on-axis. The mirrors consist of a multilayer that create a narrow bandpass around the Mo Kα lines at 17.5 keV. We provide an overview of the instrument design and measured imaging performance. In addition, we present the first data from the instrument of a Mo wire array z-pinch on the Z machine, demonstrating improvements in spatial resolution and a 350-4100× increase in the signal over previous pinhole imaging techniques.
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X-ray microanalysis of freeze-dried labial gland cryosections revealed that Na concentration was doubled and the Ca/S concentration ratio was decreased in secretory granules of labial glands from patients with cystic fibrosis (CF) when compared with glands from normal subjects. Other results suggested that the decrease in the Ca/S concentration ratio resulted from an increase in S concentration. These findings imply that mucous granules in labial saliva showed a CF-related increase in Na and S content, and such changes would be expected to affect the rheology of the mucus after exocytosis. In contrast with a previous study in human parotid glands, no evidence was found for CF-related changes in cytoplasmic or nuclear Na, K, and Ca concentrations. Significant elemental differences were found between secretory granules and nuclei and cytoplasm of control cells.
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Fibrose Cística/metabolismo , Glândulas Salivares/metabolismo , Adolescente , Adulto , Cálcio/metabolismo , Núcleo Celular/metabolismo , Cloretos/metabolismo , Citoplasma/metabolismo , Grânulos Citoplasmáticos/metabolismo , Microanálise por Sonda Eletrônica , Feminino , Humanos , Masculino , Microscopia Eletrônica , Potássio/metabolismo , Sódio/metabolismo , Enxofre/metabolismoRESUMO
Cystic fibrosis (CF) is a common autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator gene. Recombinant adenoviruses have shown promise as vectors for transfer of CF transmembrane conductance regulator cDNA to airway epithelia and correction of the Cl- transport defect. However, because adenovirus-mediated gene transfer is transient, use of adenovirus as a vector for treatment of CF would require repeated administration. Therefore, we evaluated repeat administration of an adenovirus vector to the nasal epithelium of patients with CF with five escalating doses of up to 10(10) infectious units. There were no detectable adverse affects. All subjects were initially seropositive but developed additional humoral immune responses. The vector partially corrected the defect in airway epithelial Cl- transport in some subjects, although there was variability between subjects and there was less correction with subsequent administration, perhaps because the immune response limited gene transfer. Future work must focus on vectors with increased efficiency and with the ability to evade host defenses.
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Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Fibrose Cística/terapia , Mucosa Nasal/metabolismo , Adenoviridae , Adulto , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Sistemas de Liberação de Medicamentos , Epitélio/metabolismo , Feminino , Técnicas de Transferência de Genes , Terapia Genética , Vetores Genéticos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Human serum albumin was delipidated by solvent extraction or by treatment with charcoal. Progesterone complexes formed with these albumin preparations had higher association constants than those formed with the untreated samples. The charcoal method of delipidation resulted in somewhat higher affinity constants than extraction with chloroform/methanol. Addition of 5 mol lauric acid per mol albumin reduced the association constant of the progesterone complex by approx. 50%. Studies with lauric, myristic, and palmitic acid showed that the decrease of binding affinity for progesterone was proportional to the amount of fatty acid added to albumin, and to its chain length. These results confirm and extend our previous findings of inhibition of progesterone binding to human albumin by long-chain fatty acids.
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Ácidos Graxos/farmacologia , Progesterona/metabolismo , Albumina Sérica/metabolismo , Sítios de Ligação , Depressão Química , Humanos , Cinética , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.
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Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/terapia , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Pneumopatias/terapia , Adulto , Alelos , Células Cultivadas , Fibrose Cística/genética , Citocinas/metabolismo , DNA Complementar/metabolismo , Dependovirus/genética , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Feminino , Vetores Genéticos , Células HeLa , Humanos , Imuno-Histoquímica , Pulmão/fisiologia , Masculino , Mutação , Nebulizadores e Vaporizadores , Reação em Cadeia da Polimerase , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.
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Ensaios Clínicos como Assunto/tendências , Redes de Comunicação de Computadores/organização & administração , Fibrose Cística/terapia , Informática em Saúde Pública/organização & administração , Doenças Raras/terapia , Ensaios Clínicos como Assunto/história , Fibrose Cística/história , História do Século XX , História do Século XXI , Humanos , Internet , Estudos Multicêntricos como Assunto/história , Estudos Multicêntricos como Assunto/métodos , Doenças Raras/história , Projetos de Pesquisa , Estados UnidosRESUMO
Although androgens have myriad effects on the skeleton, the regulation of androgen action in bone is not well understood. Androgen receptors (ARs) are known to play an important role in mediating androgen action. We have examined the effects of androgens and other sex steroids on AR levels in osteoblastic cells in vitro using two clonal human cell lines, SaOS-2 and U-2 OS. AR protein levels were quantitated both by specific androgen binding studies and Western analyses, and AR messenger RNA was measured with RNase protection assays. Potential changes in AR functionality was assessed by reporter assays. Treatment of osteoblastic cells with the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT) increased specific androgen binding 2-to 4-fold. Similar increases in AR protein levels were documented by Western analysis in both cell lines. The androgen-mediated increase in receptor levels was time and dose dependent as well as androgen specific. Steady-state AR messenger RNA levels were also increased by DHT. When AR concentrations in osteoblastic cells were elevated with exogenous receptor, there was an enhancement of DHT responsiveness, measured by increased trans-activation of an androgen-responsive promoter. Thus, androgen exposure increased androgen receptor protein levels and specific androgen binding in osteoblastic cells. Androgen action as measured by androgen-mediated transcriptional activation is enhanced in the presence of elevated AR levels. Consequently, these studies have revealed an additional means by which androgens may modulate skeletal metabolism.
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Androgênios/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Regulação para Cima/fisiologia , Linhagem Celular , DNA Complementar/genética , Di-Hidrotestosterona/farmacologia , Humanos , Concentração Osmolar , Osteoblastos/metabolismo , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Testosterona/farmacologia , Ativação Transcricional/fisiologia , Transfecção/fisiologiaRESUMO
We compared the pharmacokinetics of ticarcillin at a dose of 120 mg/kg in 11 patients with cystic fibrosis to 11 control subjects matched for age and sex. The mean elimination half-life of ticarcillin in serum was 70.8 minutes in the control subjects and 53.1 minutes in the patients with cystic fibrosis. The total body clearance of ticarcillin was significantly higher in cystic fibrosis patients (65.6 +/- 22.0 versus 46.2 +/- 10.9 ml/min/m2 in control subjects; p = 0.017). The nonrenal clearance of ticarcillin was also significantly higher in patients with cystic fibrosis (24.8 +/- 11.1 versus 13.3 +/- 6.0 ml/min/m2 for the control group; p = 0.006). There was no significant difference in volume of distribution between the two groups. We concluded that the shorter elimination half-life and the higher total body clearance of ticarcillin in patients with cystic fibrosis are a result of an increase in both renal and nonrenal elimination.
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Fibrose Cística/metabolismo , Penicilinas/farmacocinética , Ticarcilina/farmacocinética , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Estudos Prospectivos , Ticarcilina/sangue , Ticarcilina/urinaRESUMO
The disposition of sulfamethoxazole and trimethoprim, after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim for 1 hour), was investigated in adult patients with cystic fibrosis (n = 7) and in age-matched healthy subjects (control subjects, n = 8). The total plasma clearance of sulfamethoxazole was found to be increased in cystic fibrosis (0.0262 +/- 0.0064 L/hr/kg) when compared with that found in control subjects (0.0188 +/- 0.0043 L/hr/kg). This increase in clearance was found to be primarily attributable to an increase in the metabolic clearance of sulfamethoxazole to N4-acetylsulfamethoxazole (0.00903 +/- 0.00247 versus 0.00355 +/- 0.00049 L/hr/kg) with the renal clearance of sulfamethoxazole remaining unchanged. These conclusions were not altered when the pharmacokinetic parameters were computed for the unbound drug or when they were normalized with respect to body surface area. These data indicate that, in cystic fibrosis, the enzymes mediating the metabolism of sulfamethoxazole to N4-acetylsulfamethoxazole, N-acetyltransferase(s), may be induced, activated, or both, or that the uptake of sulfamethoxazole by cells that metabolize sulfamethoxazole to N4-acetylsulfamethoxazole is enhanced. The total plasma clearance of trimethoprim was also found to be increased in cystic fibrosis (0.1808 +/- 0.0440 L/hr/kg) when compared with that found in control subjects (0.1139 +/- 0.0193 L/hr/kg). In contrast to sulfamethoxazole, this increase in clearance was found to be primarily attributable to an increase in the renal clearance of trimethoprim (0.1240 +/- 0.0299 versus 0.0720 +/- 0.0166 L/hr/kg). These data indicate that the tubular secretion of trimethoprim may be enhanced in cystic fibrosis.
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Fibrose Cística/metabolismo , Sulfametoxazol/farmacocinética , Trimetoprima/farmacocinética , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Ligação Proteica , Sulfametoxazol/análogos & derivados , Sulfametoxazol/sangue , Sulfametoxazol/metabolismo , Trimetoprima/sangueRESUMO
To investigate the hypothesis that renal secretion of penicillins is enhanced in cystic fibrosis the maximal tubular secretion rate (Tmax) of ticarcillin and the serum concentration of ticarcillin at half-maximal secretion rate (TC50) were determined in patients with cystic fibrosis (n = 6) and control subjects (n = 6). Each subject received three consecutive constant-rate intravenous infusions of ticarcillin (4, 13, and 70 mg/kg/hr; 2 1/2 hours each) simultaneously with a constant-rate (30 mg/kg/hr) infusion of insulin. Urine samples were collected at 1/2-hour intervals and serum samples at the midpoint of the urine collections. Ticarcillin and inulin concentrations in serum and urine were determined by high-performance liquid chromatographic and a spectrophotometric method, respectively. Ticarcillin serum protein binding was determined by ultrafiltration. Steady-state ticarcillin serum concentrations were achieved at all three infusion rates. The TC50 was significantly lower (p < 0.05) in patients with cystic fibrosis (33.7 +/- 12.2 micrograms/ml) compared with that in control subjects (77.6 +/- 38.4 micrograms/ml). In contrast, the Tmax was similar (cystic fibrosis, 0.25 +/- 0.12 mg/min/kg; control, 0.22 +/- 0.14 mg/min/kg; p > 0.05). These data indicate that renal clearance of penicillins is enhanced in cystic fibrosis because of greater affinity of the renal secretory system for these drugs.
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Fibrose Cística/metabolismo , Rim/metabolismo , Ticarcilina/farmacocinética , Adolescente , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Infusões Intravenosas , Inulina/metabolismo , Túbulos Renais/metabolismo , Masculino , Modelos Biológicos , Análise de Regressão , Ticarcilina/administração & dosagemRESUMO
OBJECTIVE: To determine whether the activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin is enhanced in cystic fibrosis. DESIGN: Six adult subjects with cystic fibrosis and six healthy control subjects, matched by age and sex, were administered (R)-warfarin as a single intravenous bolus dose (0.375 mg/kg), and urine and plasma samples were collected for 192 hours. The concentration of (R)-warfarin in plasma and the concentration of (R)-warfarin and its metabolites in urine were determined by HPLC and GC/MS, respectively. Plasma protein binding of (R)-warfarin was measured by ultrafiltration. RESULTS: The unbound plasma clearance of (R)-warfarin was not significantly (p > 0.05) different between the cystic fibrosis and the control groups (cystic fibrosis, 997 +/- 483 ml/hr/kg; control, 788 +/- 219 ml/hr/kg). The unbound metabolic clearances of (R)-warfarin to its oxidative metabolites--6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin, and 10-hydroxywarfarin (mediated by P450 3A4)--were also similar (p > 0.05) in the two groups (6-hydroxywarfarin: cystic fibrosis: 124.2 +/- 72.8 ml/hr/kg, control: 99.4 +/- 37.3 ml/hr/kg; 7-hydroxywarfarin: cystic fibrosis: 43.8 +/- 32.2 ml/hr/kg, control: 34.5 +/- 10.6 ml/hr/kg; 8-hydroxywarfarin: cystic fibrosis: 80.4 +/- 85.4 ml/hr/kg, control: 69.5 +/- 39.5 ml/hr/kg; 10-hydroxywarfarin: cystic fibrosis: 4.38 +/- 2.72 ml/hr/kg, control: 16.28 +/- 13.71 ml/hr/kg). CONCLUSION: The in vivo activity of cytochrome P450 isoforms involved in the metabolism of (R)-warfarin, including P450 3A4, is not enhanced in cystic fibrosis.
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Fibrose Cística/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Varfarina/metabolismo , Adulto , Proteínas Sanguíneas/metabolismo , Fibrose Cística/enzimologia , Feminino , Humanos , Masculino , Ligação Proteica , Estereoisomerismo , Varfarina/farmacocinéticaRESUMO
This report is a summary of a meeting convened by the Cystic Fibrosis Foundation to develop a consensus among nutrition specialists and cystic fibrosis care givers regarding optimal nutritional management of patients with cystic fibrosis. The first section of the report provides a rationale for emphasizing nutritional management of this genetic disorder. The multiple factors causing malnutrition and a negative energy balance are outlined. The second section provides guidelines for routine assessment of nutrition in these patients. Five categories of nutritional status are defined based on ideal weight for height, age, and gender. These categories are used to formulate a graded response for nutritional intervention. Recommendations are provided for routine dietary supplements, vitamin supplements, and pancreatic enzyme replacement. The primary aim of this report is to educate clinicians as to the importance of frequent assessments and early intervention.
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Fibrose Cística/dietoterapia , Avaliação Nutricional , Distúrbios Nutricionais/prevenção & controle , Fibrose Cística/complicações , HumanosRESUMO
Two immunochemical methods were used to identify Haemophilus influenzae and Streptococcus pneumoniae capsular antigens in the urine and serum of 162 children with acute lower respiratory tract infection. These methods were compared with standard bacterial blood culture. Viral and mycoplasma cultures of respiratory secretions were obtained simultaneously to determine the frequency of antigenuria at the time of nonbacterial acute lower respiratory tract infection. Urine from groups of well children and children with acute otitis media was tested for capsular antigens to determine the incidence of antigenuria. Antigenuria was found in 24% of children 2 months to 18 years of age with acute lower respiratory tract infection compared with a 2% incidence of bacteremia. Antigenuria was found in 4% of asymptomatic children and 16% of children with acute otitis media. One third of children with symptoms of acute lower respiratory tract infection and viral isolates from the oropharynx had bacterial antigenuria. The sixfold increase in frequency of bacterial antigenuria in children at the time of lower respiratory symptoms suggests that bacterial acute lower respiratory tract infection may be more common than identified by traditional culture techniques. Because bacterial antigen may come from other sites such as the middle ear, further studies are needed to determine the role of antigen detection in the diagnosis of pediatric acute lower respiratory tract infection.
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Antígenos de Bactérias/imunologia , Haemophilus influenzae/imunologia , Infecções Respiratórias/diagnóstico , Streptococcus pneumoniae/imunologia , Doença Aguda , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Testes de Fixação do Látex , Masculino , Otite Média/microbiologia , Infecções Respiratórias/imunologia , Estações do Ano , Fatores SexuaisRESUMO
This study was conducted to determine the prevalence of mycobacterial disease in an adult cystic fibrosis (CF) population and to determine if there were any patients at higher risk for this disease within the group. Sixty-four patients (28 women, 36 men), ranging in age from 17 to 50 years were screened. One-step purified protein derivative skin testing with controls was performed and sputum was taken for examination. Eight of 64 had positive sputum culture for nontuberculous Mycobacterium. The CF patients with positive mycobacterial sputum cultures tended to be older and to have lower clinical scores than those who did not have Mycobacterium organisms in sputum. Guidelines to determine whether mycobacterial disease or colonization is present should be pursued for the CF population.
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Fibrose Cística/complicações , Infecções por Mycobacterium não Tuberculosas/complicações , Tuberculose Pulmonar/complicações , Adolescente , Adulto , Estudos Transversais , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/fisiopatologia , Micobactérias não Tuberculosas/isolamento & purificação , Estudos Prospectivos , Escarro/microbiologia , Teste Tuberculínico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/fisiopatologia , Capacidade VitalRESUMO
STUDY OBJECTIVE: To determine whether adequate concentrations of a new formulation of tobramycin could be delivered to the lower respiratory tract of patients with cystic fibrosis (CF) using a jet nebulizer delivery system. DESIGN: A multicenter, open-label, randomized, crossover study. SETTING: Ten tertiary care, university-affiliated, teaching hospitals in the United States. PATIENTS AND CONTROL SUBJECTS: Sixty-eight patients recruited from 10 CF Foundation centers and who were at least 8 years of age, had a diagnosis of CF, and expectorated daily sputum. No control subjects enrolled. INTERVENTIONS: Each patient received one administration of aerosolized tobramycin from each of the three nebulizer systems in random order. Each administration was separated by a minimum of 48 h. The two jet nebulizer systems tested were the Sidestream (Medic-Aid; Sussex, UK), and the Pari LC (Pari Respiratory Equipment; Richmond, Va), with a DeVilbiss Pulmoaide compressor (DeVilbiss Health Care; Somerset, Pa), both administering 300 mg tobramycin in 5 mL of 1/4 normal saline solution (NS). Patients were also administered 600 mg tobramycin in 30 mL of 1/2 NS with the UltraNeb 99/100 (DeVilbiss). MEASUREMENTS: Sputum and serum tobramycin concentration and pulmonary function were monitored. An adequate peak sputum tobramycin concentration was defined as > 128 microg/g sputum at any of three time points (10, 60, or 120 min) after completion of treatments. RESULTS: The peak tobramycin concentrations in expectorated sputum were 687+/-663 microg/g (mean+/-SD) with the Pari LC and 489+/-402 microg/g with the Sidestream. Adequate peak sputum tobramycin concentration was achieved in 93% of the patients with the Sidestream, and in 87% of the patients with the Pari LC. Peak sputum concentrations were found to be substantially higher when patients received tobramycin administered with the UltraNeb 99/100, 1,498+/-1,331 microg/g with 30% of patients having levels exceeding 2,000 microg/g. Serum tobramycin concentrations were < or = 4 microg/mL for all patients following administration with each nebulizer. CONCLUSIONS: Adequately high sputum tobramycin concentrations were documented in sputum in > 85% of patients following the administration of 300 mg/5 mL formulation of tobramycin aerosolized by the two jet nebulizer delivery systems, Sidestream and Pari LC. The single tobramycin administration delivered by these two systems is well-tolerated.