RESUMO
BACKGROUND: Uncertainties about the pathophysiological processes resulting in cardiac surgery-related acute kidney injury (AKI) in infants concern the relative impact of the most prominent risk factors, the clinical relevance of changes in glomerular filtration rate vs tubular injury, and the usefulness of available diagnostic tools. Structural equation modelling could allow for the assessment of these complex relationships. METHODS: A structural model was specified using data from a prospective observational cohort of 200 patients <1 year of age undergoing cardiopulmonary bypass surgery. It included four latent variables: AKI, modelled as a construct of perioperative creatinine variation, of oliguria and of urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations; the cardiopulmonary bypass characteristics; the occurrence of a post-operative low cardiac output syndrome and the post-operative outcome. RESULTS: The model showed a good fit, and all path coefficients were statistically significant. The bypass was the most prominent risk factor, with a path coefficient of 0.820 (95 % CI 0.527-0.979), translating to a 67.2 % explanation for the risk of AKI. A strong relationships was found between AKI and early uNGAL excretion, and between AKI and the post-operative outcome, with path coefficients of 0.611 (95 % CI 0.347-0.777) and 0.741 (95 % CI 0.610-0.988), respectively. The path coefficient between AKI and a >50 % increase in serum creatinine was smaller, with a path coefficient of 0.443 (95 % CI 0.273-0.596), and was intermediate for oliguria, defined as urine output <0.5 ml kg(-1) h(-1), with a path coefficient of 0.495 (95 % CI 0.250-0.864). A path coefficient of -0.229 (95 % CI -0.319 to 0.060) suggested that the risk of AKI during the first year of life did not increase with younger age at surgery. CONCLUSIONS: These findings suggest that cardiac surgery-related AKI in infants is a translation of tubular injury, predominately driven by the cardiopulmonary bypass, and linked to early uNGAL excretion and to post-operative outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01219998 . Registered 11 October 2010.
Assuntos
Injúria Renal Aguda/fisiopatologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Injúria Renal Aguda/etiologia , Biomarcadores/análise , Biomarcadores/urina , Procedimentos Cirúrgicos Cardíacos/mortalidade , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Ponte Cardiopulmonar/efeitos adversos , Ponte Cardiopulmonar/estatística & dados numéricos , Creatinina/análise , Creatinina/urina , Oxigenação por Membrana Extracorpórea/métodos , Feminino , França , Humanos , Recém-Nascido , Lipocalina-2/análise , Lipocalina-2/urina , Masculino , Pediatria/estatística & dados numéricos , Pediatria/tendências , Diálise Peritoneal/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Fatores de RiscoRESUMO
During the 2009 H1N1 influenza pandemics, the concentrations of oseltamivir (O) and its active metabolite (oseltamivir carboxylate [OC]) were determined in 11 children (1 month to 16 years of age) admitted to intensive care units for presumed severe H1N1 infection. They received oseltamivir phosphate (OP) nasogastrically at doses between 1.5 and 6.8 mg/kg of body weight. High OC concentrations were found, with a mean level of 678 ± 535 µg/liter. The mean OP concentration was 27 ± 52 µg/liter. No marked side effect was reported.
Assuntos
Antivirais/efeitos adversos , Antivirais/sangue , Estado Terminal , Oseltamivir/análogos & derivados , Adolescente , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Influenza Humana/tratamento farmacológico , Unidades de Terapia Intensiva , Intubação Gastrointestinal , Masculino , Oseltamivir/administração & dosagem , Oseltamivir/efeitos adversos , Oseltamivir/sangue , Oseltamivir/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVES: To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA). METHODS: A multicentre, randomised, double-blind, placebo-controlled trial was conducted. The primary objective was to compare the efficacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA. Response was defined by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline. After month 1 (M1), patients taking placebo were switched to anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months, and analyses of treatment effect on blood gene expression profiling. RESULTS: At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003). Ten patients from the placebo group switched to anakinra; nine were responders at M2. Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of efficacy (n=2) or a disease flare (n=2). Blood gene expression profiling at enrollment and at 6 months' follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra. CONCLUSIONS: Anakinra treatment is effective in SJIA, at least in the short term. It is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature. TRIAL REGISTRATION NUMBER: NCT00339157.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Adolescente , Anticorpos Antibacterianos/biossíntese , Antirreumáticos/efeitos adversos , Artrite Juvenil/sangue , Artrite Juvenil/genética , Artrite Juvenil/imunologia , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Masculino , Vacinas Pneumocócicas/imunologia , Polissacarídeos Bacterianos/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE: Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. OBJECTIVES: To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. METHODS: Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. MEASUREMENTS AND MAIN RESULTS: The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. CONCLUSIONS: In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.
Assuntos
Códon sem Sentido/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/biossíntese , Fibrose Cística/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Oxidiazóis/uso terapêutico , Adolescente , Criança , Códon sem Sentido/genética , Códon sem Sentido/fisiologia , Estudos Cross-Over , Fibrose Cística/genética , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Mucosa Nasal/metabolismo , Mucosa Nasal/fisiopatologia , Oxidiazóis/administração & dosagem , Oxidiazóis/farmacologiaRESUMO
PURPOSE: We characterized the innate immune response to intravesical bacillus Calmette-Guerin therapy using a systems approach based on proteomic and cytometric screens. MATERIALS AND METHODS: Blood and urine were collected from patients receiving intravesical bacillus Calmette-Guerin therapy before, and 2 and 4 hours after bacillus Calmette-Guerin treatment, at the first and third instillation. Proteomic and cytometry based screens were performed. RESULTS: Molecular analyte profiling revealed a prime/boost pattern to the innate response to intravesical bacillus Calmette-Guerin. We identified 36 statistically significant changes in the proteins induced during the third instillation compared to the initial treatment. These analytes were classified into 3 categories of 1) plasma proteins that leaked into the urine, 2) cytokines/chemokines produced locally during the first hours of inflammation and 3) other innate molecules that modulate the bladder microenvironment. To characterize the marked increase in the inflammatory response after multiple treatments we evaluated the cells present in the urine and again a prime/boost response was revealed. For the locally produced analytes it was possible to define the cell source(s) and, thus, provide a first generation map of what occurs during the initial phase of bacillus Calmette-Guerin therapy. CONCLUSIONS: This study provides in vivo information concerning the ability of bacillus Calmette-Guerin to sensitize the tissue microenvironment to enhance innate responses and establishes a framework for improving vaccination strategies while decreasing adverse events.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacina BCG/administração & dosagem , Citometria de Fluxo , Proteômica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/urinaRESUMO
BACKGROUND: Thiazide doses equivalent to 1 to 2 mg/kg/d of hydrochlorothiazide (HCTZ) have been proposed to correct hypercalciuria and prevent kidney failure in patients with Dent disease. However, they can cause adverse metabolic effects in the long term. In treating hypertension in children, lower thiazide doses have been shown to be as effective and well tolerated. STUDY DESIGN: Uncontrolled trial, with forced-titration sequential open-label study design. SETTING & PARTICIPANTS: 7 boys with genetically confirmed Dent disease and mild phenotype (neither overt sodium wasting nor kidney failure). INTERVENTION: After a 1-month run-in period, patients sequentially received amiloride (5 mg/d) alone (1 month) and then for 3 periods of 2 months in association with increasing doses of HCTZ (<0.2, 0.2 to 0.4, and 0.4 to 0.8 mg/kg/d). OUTCOMES: Urinary calcium excretion and extracellular volume indicators. MEASUREMENTS: At the end of each period, 2 daily 24-hour urinary collections were performed on the days preceding admission. Blood and spot urine samples also were collected. RESULTS: A greater HCTZ dose increased renin, aldosterone, and plasma protein concentrations. Amiloride alone had no effect on calcium excretion. The greatest HCTZ doses decreased spot urinary calcium excretion by 42% compared with baseline (median, 0.3; minimum, maximum, 0.2, 0.8 versus median, 0.8; minimum, maximum, 0.4, 1.1, respectively; P = 0.03). However, patients developed adverse reactions, including muscle cramps (n = 2), biological (n = 7) or symptomatic hypovolemia (n = 1), hypokalemia (n = 4), and hyponatremia (n = 1), which all corrected after treatment withdrawal. LIMITATION: Small sample size and absence of a control group. CONCLUSION: HCTZ doses greater than 0.4 mg/kg/d decreased calcium excretion, but were associated with significant adverse events. Thiazide diuretic therapy should be considered with caution in children with Dent disease.
Assuntos
Cálcio/urina , Diuréticos/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipercalciúria/tratamento farmacológico , Hipercalciúria/urina , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia/urina , Proteinúria/tratamento farmacológico , Proteinúria/urina , Aminoacidúrias Renais/tratamento farmacológico , Aminoacidúrias Renais/urina , Adolescente , Criança , Humanos , Masculino , SíndromeRESUMO
The objective of this study was to determine i) if Camembert cheese micro-organisms could be detected in fecal samples after regular consumption by human subjects and ii) the consequence of this consumption on global metabolic activities of the host colonic microbiota. An open human protocol was designed where 12 healthy volunteers were included: a 2-week period of fermented products exclusion followed by a 4-weeks Camembert ingestion period where 2x40 g/day of Camembert cheese was consumed. Stools were collected from the volunteers before consumption, twice during the ingestion period (2nd and 4th week) and once after a wash out period of 2 weeks. During the consumption of Camembert cheese, high levels of Lactococcus lactis and Leuconostoc mesenteroides were measured in fecal samples using real-time quantitative PCR, reaching median values of 8.2 and 7.5 Log(10) genome equivalents/g of stool. For Ln. mesenteroides, persistence was observed 15 days after the end of Camembert consumption. The survival of Geotrichum candidum was also assessed and the fecal concentration reached a median level of 7.1 Log(10) CFU/g in stools. Except a decreasing trend of the nitrate reductase activity, no significant modification was shown in the metabolic activities during this study.
Assuntos
Queijo/microbiologia , Colo/microbiologia , Fezes/microbiologia , Lactobacillus/crescimento & desenvolvimento , Streptococcus thermophilus/crescimento & desenvolvimento , Adulto , Contagem de Colônia Microbiana , Estudos Cross-Over , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Fúngico/química , DNA Fúngico/genética , Feminino , Microbiologia de Alimentos , Geotrichum/crescimento & desenvolvimento , Geotrichum/isolamento & purificação , Geotrichum/metabolismo , Humanos , Lactobacillus/isolamento & purificação , Lactobacillus/metabolismo , Masculino , Nitrato Redutase/metabolismo , Reação em Cadeia da Polimerase/métodos , Streptococcus thermophilus/isolamento & purificação , Streptococcus thermophilus/metabolismo , Fatores de TempoRESUMO
The aim of the study was to define the minimal effective dose (MED) of granulocyte colony-stimulating factor (G-CSF) among five daily doses following chemotherapy for peripheral blood stem cell (PBSC) collection. Twenty-five patients were included in this double-blind dose-finding phase II study conducted according to a two-stage Bayesian design. The estimated probabilities of success for PBSC collection for the G-CSF doses of 50, 75, 100, 125 and 150 microg/m2/day were 84%, 87.7%, 91%, 93.9 and 96.4%, respectively. Low G-CSF doses may be used with a similar probability of success as conventional doses and could allow significant savings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Adulto , Antígenos CD34 , Teorema de Bayes , Método Duplo-Cego , Sobrevivência de Enxerto , Humanos , Leucaférese/métodos , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante AutólogoRESUMO
Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted.
Assuntos
Anemia Falciforme/sangue , Hidroxiureia/sangue , Hidroxiureia/farmacocinética , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Cápsulas , Química Farmacêutica , Criança , Pré-Escolar , Estudos Cross-Over , Humanos , Hidroxiureia/uso terapêutico , Pessoa de Meia-Idade , Comprimidos com Revestimento EntéricoRESUMO
To date, there is significant controversy as to the survival of yogurt bacteria (namely, Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus) after passage through the human gastrointestinal tract. Survival of both bacterial species in human feces was investigated by culture on selective media. Out of 39 samples recovered from 13 healthy subjects over a 12-day period of fresh yogurt intake, 32 and 37 samples contained viable S. thermophilus (median value of 6.3 x 10(4) CFU g(-1) of feces) and L. delbrueckii (median value of 7.2 x 10(4)CFU g(-1) of feces), respectively. The results of the present study indicate that substantial numbers of yogurt bacteria can survive human gastrointestinal transit.
Assuntos
Trato Gastrointestinal/microbiologia , Lactobacillus delbrueckii/fisiologia , Streptococcus thermophilus/fisiologia , Iogurte/microbiologia , Adulto , Contagem de Colônia Microbiana , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Urine neutrophil gelatinase-associated lipocalin (uNGAL) has been shown to accurately predict and allow early detection of AKI, as assessed by an increase in serum creatinine in children and adults. The present study explores the accuracy of uNGAL for the prediction of severe AKI-related outcomes in neonates and infants undergoing cardiac surgery: dialysis requirement and/or death within 30 days. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective, observational cohort study conducted in a tertiary referral pediatric cardiac intensive care unit, including 75 neonates and 125 infants undergoing surgery with cardiopulmonary bypass between August 1, 2010, and May 31, 2011. Urine samples were collected before surgery and at median of five time points within 48 hours of bypass. Urine NGAL was quantified as absolute concentration, creatinine-normalized concentration, and absolute excretion rate, and a clusterization algorithm was applied to the individual uNGAL kinetics. The accuracy for the prediction of the outcome was assessed using receiver-operating characteristic areas, likelihood ratios, diagnostic odds ratios, net reclassification index, integrated reclassification improvement, and number needed to screen. RESULTS: A total of 1176 urine samples were collected. Of all patients, 8% required dialysis and 4% died. Three clusters of uNGAL kinetics were identified, including patients with significantly different outcomes. The uNGAL level peaked between 1 and 3 hours of bypass and remained high in half of all patients who required dialysis or died. The uNGAL levels measured within 24 hours of bypass accurately predicted the outcome and performed best after normalization to creatinine, with varying cutoffs according to the time elapsed since bypass. The number needed to screen to correctly identify the risk of dialysis or death in one patient varied between 1.5 and 2.6 within 12 hours of bypass. CONCLUSIONS: uNGAL is a valuable predictive tool of dialysis requirement and death in neonates and infants with AKI after cardiac surgery.
Assuntos
Injúria Renal Aguda/terapia , Injúria Renal Aguda/urina , Proteínas de Fase Aguda/urina , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Lipocalinas/urina , Proteínas Proto-Oncogênicas/urina , Diálise Renal , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/mortalidade , Fatores Etários , Área Sob a Curva , Biomarcadores/urina , Procedimentos Cirúrgicos Cardíacos/mortalidade , Distribuição de Qui-Quadrado , Análise por Conglomerados , Creatinina/urina , Mortalidade Hospitalar , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica , Funções Verossimilhança , Lipocalina-2 , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Sistema de Registros , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Fatores de Risco , Índice de Gravidade de Doença , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento , UrináliseRESUMO
We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5µL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5µm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The ß-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin.
Assuntos
Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Mastocitose Sistêmica/tratamento farmacológico , Estaurosporina/análogos & derivados , Estabilidade de Medicamentos , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estaurosporina/sangue , Estaurosporina/química , Espectrometria de Massas em Tandem/métodosRESUMO
The aim of this study was to evaluate the survival of Lactobacillus rhamnosus R11 and Lactobacillus acidophilus R52 in the human digestive tract and their effects on the microbiota homeostasis. We designed an open human trial including 14 healthy volunteers. A 3-week exclusion period of fermented products was followed by a 12-day consumption period of 4 capsules daily containing 2 x 10(9)L. rhamnosus R11 and 1 x 10(8)L. acidophilus R52, and a 12-day wash-out period. The 2 strains and dominant bacterial groups of the microbiota were quantified by real-time polymerase chain reaction. At the end of the capsule consumption period, high levels of L. rhamnosus R11 were detected in faecal samples from all volunteers, reaching a mean value of 7.1 log(10) colony-forming unit (CFU) equivalents/g of stool. L. acidophilus R52 was detected in the stools of only 1 volunteer, reaching a maximum level of 6.1 log(10) CFU equivalents/g of stool. Dilution plating enumerations performed in parallel provided less consistent and generally lower levels. No significant effect of capsule consumption was observed on microbiota homeostasis for the dominant faecal populations. Mean values of 8.8, 9.2, 9.9 and 10.6 log(10) CFU equivalents/g of stool were obtained for the Clostridium coccoides, Bifidobacterium sp., Bacteroides sp. and Clostridium leptum groups, respectively.
Assuntos
Trato Gastrointestinal/microbiologia , Lacticaseibacillus rhamnosus/crescimento & desenvolvimento , Probióticos/administração & dosagem , Administração Oral , Adolescente , Adulto , Bacteroides/crescimento & desenvolvimento , Bifidobacterium/crescimento & desenvolvimento , Clostridium/crescimento & desenvolvimento , Contagem de Colônia Microbiana , Fezes/microbiologia , Feminino , Humanos , Lacticaseibacillus rhamnosus/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Ribossômico 16S/genética , Resultado do TratamentoRESUMO
The survival of Bifidobacterium animalis strain DN-173 010 was assessed after its ingestion in a fermented product or in a lyophilised form. Twelve healthy subjects were included in a randomised, open study with 2 parallel groups. The composition and activities of the faecal microbiota were monitored before (10-day baseline step), during (1-week product administration step) and after (10-day follow-up step) the ingestion of 1 of the 2 products. A colony immunoblotting method, fluorescent in situ hybridisation with group-specific DNA probes, and temporal temperature gradient gel electrophoresis using group-specific primers were carried out to compare survival of B. animalis strain DN-173 010 after ingestion of the 2 products, together with analyses of enzyme activities and faecal metabolites. At the end of the supplementation step, the mean number of B. animalis DN-173 010 quantified by immunodetection in the faeces of 5 of 6 subjects in each treatment group was >/=10(8) colony-forming units/g faeces. These numbers corresponded to an average survival of 22% for the lyophilised form and 20% for the fermented product. At the same step, the PCR temporal temperature gradient gel electrophoresis profiles showed a double band corresponding to the B. animalis DN-173 010 pattern for 11 subjects. No major modification was observed during the trial in either the dominant members of the faecal microbiota assessed by fluorescent in situ hybridisation or their activities. In conclusion, we show that the lyophilised form of B. animalis DN-173 010 survives transit and could represent a more convenient form to administer for long-term clinical trials.
Assuntos
Bifidobacterium/crescimento & desenvolvimento , Produtos Fermentados do Leite/microbiologia , Fezes/microbiologia , Liofilização/métodos , Probióticos/administração & dosagem , Adulto , Bifidobacterium/isolamento & purificação , Contagem de Colônia Microbiana , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVES: Autism (MIM#209850) and schizophrenia (MIM#181500) are both neurodevelopmental psychiatric disorders characterized by a highly genetic component. Homeogenes and forkhead genes encode transcription factors, which have been involved in brain development and cell differentiation. Thus, they are relevant candidate genes for psychiatric disorders. Genetic studies have reported an association between autism and DLX2, HOXA1, EN2, ARX, and FOXP2 genes whereas only three studies of EN2, OTX2, and FOXP2 were performed on schizophrenia. Interestingly, most of these candidate genes contain trinucleotide repeats coding for polyamino acid stretch in which instability can be the cause of neurodevelopmental disorders. Our goal was to identify variations of coding trinucleotide repeats in schizophrenia, autism, and idiopathic mental retardation. METHODS: We screened the coding trinucleotide repeats of OTX1, EN1, DLX2, HOXA1, and FOXP2 genes in populations suffering from schizophrenia (247 patients), autism (98 patients), and idiopathic mental retardation (56 patients), and compared them with control populations (112 super controls and 202 healthy controls). RESULTS: Novel deletions and insertions of coding trinucleotide repeats were found in the DLX2, HOXA1, and FOXP2 genes. Most of these variations were detected in controls and no difference in their distribution was observed between patient and control groups. Two different polymorphisms in FOXP2 were, however, found only in autistic patients and the functional consequences of these variations of repeats have to be characterized and correlated to particular clinical features. CONCLUSION: This study did not identify specific disease risk variants of trinucleotide repeats in OTX1, EN1, DLX2, HOXA1, and FOXP2 candidate genes in neurodevelopmental psychiatric disorders.
Assuntos
Genes Homeobox , Transtornos Mentais/genética , Polimorfismo Genético , Repetições de Trinucleotídeos , Feminino , Humanos , MasculinoRESUMO
A human trial was carried out to assess the ileal and fecal survival of Lactobacillus casei DN-114 001 ingested in fermented milk. Survival rates were up to 51.2% in the ileum and 28.4% in the feces. The probiotic bacterium has the capacity to survive during its transit through the human gut.
Assuntos
Dieta , Fermentação , Trato Gastrointestinal/microbiologia , Lacticaseibacillus casei/crescimento & desenvolvimento , Leite/metabolismo , Probióticos , Adulto , Animais , Contagem de Colônia Microbiana , Fezes/microbiologia , Feminino , Humanos , Íleo/microbiologia , Lacticaseibacillus casei/isolamento & purificação , Masculino , Leite/microbiologia , Resultado do TratamentoRESUMO
The composition and activities of the faecal microbiota in twelve healthy subjects analysed in a single open study were monitored before (1-week baseline step), during (10 d supplementation step) and after (10 d follow-up step) the ingestion of a fermented milk containing Lactobacillus casei DN-114 001. Fluorescent in situ hybridisation with group-specific DNA probes, real-time PCR using L. paracasei group-specific primers and temporal temperature gradient gel electrophoresis (TTGE) using group-specific primers were carried out, together with bacterial enzyme activity and metabolite analyses to monitor the structure and activities of the faecal microbiota. L. casei DNA was detected in the faeces of all of the subjects by TTGE after 10 d supplementation. Its quantification by real-time PCR showed a 1000-fold increase during the test step compared with initial levels. No major modification in either the dominant members of the faecal microbiota or their activities was observed during the trial. In conclusion, the short-term consumption of a milk product containing L. casei DN-114 001 was accompanied by a high, transient increase in the quantity of this strain in the faeces of all of the subjects without markedly affecting biochemical or bacteriological factors.
Assuntos
Produtos Fermentados do Leite , Fezes/microbiologia , Lacticaseibacillus casei , Probióticos/administração & dosagem , Administração Oral , Adulto , DNA Bacteriano/análise , Fezes/química , Feminino , Humanos , Lacticaseibacillus casei/enzimologia , Lacticaseibacillus casei/isolamento & purificação , MasculinoRESUMO
Long-term glucocorticoid treatment contributes to the growth retardation in children after renal transplantation. We investigated whether determination of prednisone (PN) and prednisolone (PL) in plasma and PN, PL, and 6-beta-hydroxyprednisolone (betaOH-PL) in urine could help to predict growth. PN and PL pharmacokinetics were studied in 36 children, from 5 to 15 years of age, receiving daily (D) or alternate-day (AD) oral PN treatment. Statural growth velocity was evaluated over a 1-year period. We compared three groups of children according to the growth kinetics during the study year (catch-up, stable, or decline) for clinical and pharmacokinetic parameters. A multiple linear regression analysis was performed in order to determine pharmacokinetic parameters able to explain height 1 year after inclusion. Height at the beginning of the study, creatinine clearance, and type of D or AD treatment explained 94.2% of height variance 1 year after inclusion. Only PL clearance was associated with growth evolution, but introduction of PL clearance in the multivariate model did not improve the variance of height accounted for by the previous model. We, therefore, do not recommend using glucocorticoid pharmacokinetics to predict growth retardation in children with renal transplantation.