RESUMO
In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.
Assuntos
Amidas/química , Antituberculosos/química , Tiazóis/química , Amidas/farmacocinética , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microssomos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/patologiaRESUMO
INTRODUCTION: To evaluate the prevalence of medial collateral ligament (MCL) injury of the knee among ankle-fracture patients and to determine the risk factors associated with MCL injury in this patient group. MATERIALS AND METHODS: 303 patients (303 affected ankles) who underwent surgical treatment for an ankle fracture were assessed. Supination versus pronation injury, Danis-Weber classification, age, sex, body mass index (BMI), limb dominance, and mechanism of injury were reviewed to identify factors related to MCL injury. RESULTS: Prevalence of MCL injury of the knee among the total number of patients with an ankle fracture was 3.96% (12 out of 303 injuries). Multivariable logistic and linear regression analysis with adjustment of possible confounding factors confirmed that female sex and pronation injury were associated significantly (p < 0.05) with MCL injury. CONCLUSIONS: The prevalence of MCL injury among females and the pronation type of ankle injury was 8.19% (10 out of 122 females) and 10.75% (10 out of 93 pronation injuries), respectively. More careful physical examination of the knee joint is strongly recommended in patients with ankle fractures, especially if the patient is female or the ankle-fracture pattern corresponds to the pronation type of injury.
Assuntos
Fraturas do Tornozelo/cirurgia , Traumatismos do Tornozelo/cirurgia , Traumatismos do Joelho/terapia , Ligamento Colateral Médio do Joelho/lesões , Adolescente , Adulto , Idoso , Fraturas do Tornozelo/complicações , Traumatismos do Tornozelo/complicações , Feminino , Humanos , Traumatismos do Joelho/complicações , Masculino , Ligamento Colateral Médio do Joelho/cirurgia , Pessoa de Meia-Idade , Prevalência , Pronação , Fatores de Risco , Supinação , Adulto JovemRESUMO
BACKGROUND: Both histologic chorioamnionitis (HCAM) and Ureaplasma infection are considered important contributors to perinatal lung injury. We tested the hypothesis that coexistence of maternal HCAM and perinatal Ureaplasma exposure increases the risk of prolonged mechanical ventilation in extremely low-birthweight (ELBW) infants. METHODS: A retrospective cohort study was carried out of all ELBW infants born between January 2008 and December 2013 at a single academic center. Placental pathology and gastric fluid Ureaplasma data were available for all infants. Culture and polymerase chain reaction were used to detect Ureaplasma in gastric fluid. Prolonged mechanical ventilation was defined as mechanical ventilation that began within 28 days after birth and continued. RESULTS: Of 111 ELBW infants enrolled, 84 survived beyond 36 weeks of postmenstrual age (PMA) and were included in the analysis. Eighteen infants (21.4%) had both HCAM and Ureaplasma exposure. Seven infants (8.3%) required mechanical ventilation beyond 36 weeks of PMA. Coexistence of HCAM and Ureaplasma in gastric fluid was significantly associated with prolonged mechanical ventilation after adjustment for gestational age, sex, mode of delivery, and use of macrolide antibiotics (OR, 8.7; 95%CI: 1.1-67.2). CONCLUSIONS: Coexistence of maternal HCAM and perinatal Ureaplasma exposure significantly increases the risk of prolonged mechanical ventilation in ELBW infants.
Assuntos
Corioamnionite/microbiologia , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Complicações Infecciosas na Gravidez/microbiologia , Respiração Artificial/estatística & dados numéricos , Infecções por Ureaplasma/complicações , Ureaplasma/isolamento & purificação , Técnicas Bacteriológicas , Displasia Broncopulmonar/microbiologia , Displasia Broncopulmonar/terapia , Estudos de Coortes , DNA Bacteriano/genética , Feminino , Humanos , Recém-Nascido , Doenças do Prematuro/microbiologia , Doenças do Prematuro/terapia , Masculino , Reação em Cadeia da Polimerase , Gravidez , Estudos RetrospectivosRESUMO
OBJECTIVE: To describe the clinical course and risk factors for pulmonary arterial hypertension (PAH) after ibuprofen treatment to close patent ductus arteriosus. STUDY DESIGN: All neonates weighing < 1500 g at birth who received ibuprofen to close patent ductus arteriosus and were admitted to Seoul National University Children's Hospital's neonatal intensive care unit in 2010-2014 were eligible for this study. The study population was divided into the PAH and non-PAH groups, and medical records were retrospectively reviewed. RESULTS: Of the 144 eligible infants, 10 developed PAH (6.9%). Relative to the non-PAH group, the PAH group exhibited greater respiratory severity and more frequent severe bronchopulmonary dysplasia or death before 36 weeks postmenstrual age. Multivariable analysis demonstrated that lower gestational age, birth weight in less than the third percentile for age, maternal hypertension of pregnancy, and oligohydramnios were risk factors for developing PAH after ibuprofen treatment. CONCLUSION: A high incidence of PAH after ibuprofen treatment was observed in the study population. Furthermore, younger gestational age and several prenatal conditions were identified as risk factors for developing PAH after ibuprofen treatment. Additional large cohort studies are necessary to confirm our results.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Hipertensão Pulmonar/induzido quimicamente , Ibuprofeno/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVES: The aim of the present study was to report possible improvements in ventilator variables associated with a transition from synchronized intermittent mandatory ventilation to neurally adjusted ventilatory assist in preterm infants with bronchopulmonary dysplasia who required a high level of mechanical ventilatory support in a single center. DESIGN: Retrospective study. SETTING: Neonatal ICU. PATIENTS: Twenty-nine preterm infants with a median gestational age of 25.4 weeks (range, 23.4-30.3 wk) and a median birth weight of 680 g (range, 370-1,230 g) and who were supported with a mechanical ventilator for more than 4 weeks and had a respiratory severity score greater than four during conventional mechanical ventilation prior to conversion to neurally adjusted ventilatory assist. INTERVENTIONS: Comparison of ventilatory variables, work of breathing, and blood gas values during conventional ventilation and at various time intervals after the change to neurally adjusted ventilatory assist. MEASUREMENTS AND MAIN RESULTS: The values of various ventilatory variables and other measurements were obtained 1 hour before neurally adjusted ventilatory assist and 1, 4, 12, and 24 hours after conversion to neurally adjusted ventilatory assist. During neurally adjusted ventilatory assist, the peak inspiratory pressure (20.12 ± 2.93 vs 14.15 ± 3.55 cm H2O; p < 0.05), mean airway pressure (11.15 ± 1.29 vs 9.57 ± 1.27 cm H2O; p < 0.05), and work of breathing (0.86 ± 0.22 vs 0.46 ± 0.12 J/L; p < 0.05) were significantly decreased, and the blood gas values were significantly improved. Significantly lower FIO2 and improved oxygen saturation were observed during neurally adjusted ventilatory assist compared with conventional ventilation support. The RSS values decreased and sustained during neurally adjusted ventilatory assist (4.85 ± 1.63 vs 3.21 ± 1.01; p < 0.001). CONCLUSIONS: The transition from synchronized intermittent mandatory ventilation to neurally adjusted ventilatory assist ventilation was associated with improvements in ventilator variables, oxygen saturation, and blood gas values in infants with bronchopulmonary dysplasia in a single center. This study suggests the possible clinical utility of neurally adjusted ventilatory assist as a weaning modality for bronchopulmonary dysplasia patients in the neonatal ICU.
Assuntos
Displasia Broncopulmonar/terapia , Terapia Intensiva Neonatal/métodos , Suporte Ventilatório Interativo/métodos , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: There have been many studies supporting fluconazole prophylaxis in preterm infants for prevention of invasive fungal infections (IFIs). However, the routine use of fluconazole prophylaxis in neonatal intensive care units (NICUs) raises concerns with respect to resistance development, including the selection of resistant Candida species. We aimed to evaluate the efficacy and safety of fluconazole prophylaxis in extremely low birth weight (ELBW) infants. METHODS: An interventional pre-post cohort study at two tertiary NICUs was conducted. Data from two 5-year periods with and without fluconazole prophylaxis (Mar 2008-Feb 2013 and Mar 2003-Feb 2008) was compared. Prophylactic fluconazole was administered starting on the 3rd day at a dose of 3 mg/kg twice a week for 4 weeks during the prophylaxis period. RESULTS: The fluconazole prophylaxis group consisted of 264 infants, and the non-prophylaxis group consisted of 159 infants. IFI occurred in a total of 19 neonates (4.7 %) during the 10-year study period. Fluconazole prophylaxis lower the fungal colonization rate significantly (59.1 % vs. 33.9 %, P <0.001). However, the incidence of IFIs in ELBW infants was not reduced after fluconazole prophylaxis (4.4 % vs. 5.5 %, P = 0.80). Rather, although the increase did not reach statistical significance, fluconazole prophylaxis tended to increase the incidence of invasive infections involving fluconazole-resistant C. parapsilosis (0 % vs. 41.7 %, P = 0.11). CONCLUSIONS: Fluconazole prophylaxis was not efficacious in decreasing IFIs in ELBW infants. There is a need for targeting prophylaxis to greatest risk population and prospective studies to measure the long-term effect of fluconazole prophylaxis on the emergence of organisms with antifungal resistance.
Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/prevenção & controle , Fluconazol/uso terapêutico , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Doenças do Prematuro/prevenção & controle , Terapia Intensiva Neonatal/métodos , Candidíase Invasiva/epidemiologia , Candidíase Invasiva/microbiologia , Esquema de Medicação , Farmacorresistência Fúngica , Feminino , Humanos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/microbiologia , Unidades de Terapia Intensiva Neonatal , Modelos Logísticos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: We investigated changes in the admission patterns of neonatal intensive care units and the epidemiology of neonatal sepsis following the rapid expansion and improvements in neonatal intensive care. METHODS: Data on the admission of neonates with culture-proven sepsis between 1996 and 2013 (period I, 1996-2005; period II, 2006-2013) were collected retrospectively. RESULTS: The admission of extremely low-birthweight (ELBW) infants increased between periods I and II (11.1 vs 28.7 infants per 1000 live births, P < 0.001). The survival rate of the ELBW infants improved (57.5 vs 80.1%, P < 0.001), and duration of hospital stay increased (median, 64 vs 80 days, P = 0.001). The incidence of sepsis among all infants and ELBW infants increased (all infants, 5.9 vs 12.7 cases per 1000 live births; ELBW infants, 189.5 vs 290.1 cases per 1000 live births). In ELBW infants, the incidence of sepsis caused by coagulase-negative Staphylococcus (CONS), significantly increased during period II (8.8 vs 25.4%, P = 0.039). On multivariate analysis, central vascular catheters and prolonged hospitalization were independently associated with increased sepsis rate, particularly CONS in ELBW infants. CONCLUSIONS: The inborn admission rate for ELBW infants has increased significantly and is accompanied by improved survival and longer hospital stay. The incidence of neonatal sepsis, particularly in ELBW infants, has also increased, and CONS has emerged as a major pathogen. Central vascular catheters and prolonged hospitalization could be independent risk factors for the increased sepsis rate, particularly sepsis due to CONS.
Assuntos
Previsões , Hospitais Pediátricos/estatística & dados numéricos , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Sepse Neonatal/epidemiologia , Centros de Atenção Terciária/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Morbidade/tendências , República da Coreia/epidemiologia , Estudos RetrospectivosRESUMO
This study was done to evaluate respiratory syncytial virus (RSV) related readmission (RRR) and risk factors of RRR in preterm infants < 34 weeks gestational age (GA) within 1 yr following discharge from the neonatal intensive care unit (NICU). Infants (n = 1,140) who were born and admitted to the NICUs of 46 hospitals in Korea from April to September 2012, and followed up for > 1 yr after discharge from the NICU, were enrolled. The average GA and birth weight of the infants was 30(+5) ± 2(+5) weeks and 1,502 ± 474 g, respectively. The RRR rate of enrolled infants was 8.4% (96/1,140), and RSV accounted for 58.2% of respiratory readmissions of infants who had laboratory tests confirming etiological viruses. Living with elder siblings (odd ratio [OR], 2.68; 95% confidence interval [CI], 1.68-4.28; P < 0.001), and bronchopulmonary dysplasia (BPD) (OR, 2.95; 95% CI, 1.44-6.04; P = 0.003, BPD vs. none) increased the risk of RRR. Palivizumab prophylaxis (OR, 0.06; 95% CI, 0.03-0.13; P < 0.001) decreased the risk of RRR. The risk of RRR of infants of 32-33 weeks' gestation was lower than that of infants < 26 weeks' gestation (OR, 0.11; 95% CI, 0.02-0.53; P = 0.006). This was a nationwide study that evaluated the rate and associated risk factors of RRR in Korean preterm infants. Preterm infants with BPD or living with siblings should be supervised, and administration of palivizumab to prevent RRR should be considered.
Assuntos
Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Antivirais/uso terapêutico , Peso ao Nascer , Displasia Broncopulmonar/tratamento farmacológico , Displasia Broncopulmonar/patologia , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Masculino , Razão de Chances , Palivizumab/uso terapêutico , Alta do Paciente , Readmissão do Paciente , República da Coreia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/virologia , Fatores de Risco , IrmãosRESUMO
Late-onset hyponatremia (LOH), hyponatremia occurring after two weeks of age with the achievement of full feeding, is the result of a negative sodium balance caused by inadequate salt intake or excessive salt loss due to immature renal or intestinal function in preterm infants. The aims of our study were to identify the risk factors for LOH and its influence on neonatal outcomes. This was a retrospective cohort analysis of 161 preterm infants born before 34 weeks of gestation between June 2009 and December 2010 at Seoul National University Hospital. LOH was defined as a sodium level ≤ 132 mEq/L or 133-135 mEq/L with oral sodium supplementation. LOH occurred in 49 (30.4%) of the studied infants. A lower gestational age, a shorter duration of parenteral nutrition, the presence of respiratory distress syndrome, the use of furosemide, and feeding with breast milk were significant risk factors for LOH. In terms of neonatal outcomes, the infants with LOH had longer hospital stays and higher risks of bronchopulmonary dysplasia and retinopathy of prematurity requiring surgery. LOH lasting at least 7 days significantly increased moderate to severe bronchopulmonary dysplasia, periventricular leukomalacia, and extra-uterine growth retardation. LOH is commonly observed in preterm infants; it may be a risk factor for bronchopulmonary dysplasia and retinopathy of prematurity or a marker of illness severity.
Assuntos
Hiponatremia/etiologia , Displasia Broncopulmonar/etiologia , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis.
Assuntos
Displasia Broncopulmonar/epidemiologia , Corioamnionite/epidemiologia , Recém-Nascido de muito Baixo Peso , Pré-Eclâmpsia/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Retinopatia da Prematuridade/epidemiologia , Adulto , Peso ao Nascer , Displasia Broncopulmonar/complicações , Corioamnionite/classificação , Corioamnionite/patologia , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Infiltração de Neutrófilos/imunologia , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Retinopatia da Prematuridade/complicações , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
OBJECTIVES: Remifentanil is an ultrashort-acting synthetic opioid, and the metabolism of which is not influenced by hepatic or renal function. This study aims to compare the efficacy of two remifentanil doses during procedures in ventilated preterm infants. DESIGN: Prospective, randomized, double-blind, noninferiority trial. SETTING: Neonatal ICU. PATIENTS: Preterm infants who were supported by a mechanical ventilator with tracheal tube and requiring central venous access. INTERVENTIONS: Two remifentanil dosages were administered in mechanically ventilated preterm infants during peripherally inserted central catheter insertion. Fourteen preterm infants were randomly assigned to low-dose (0.1 µg/kg/min) or high-dose (0.25 µg/kg/min) remifentanil infusion. The Premature Infant Pain Profile was used to score pain during the procedure, and changes in the Premature Infant Pain Profile score between needle puncture and baseline were analyzed to investigate the noninferiority of low-dose to high-dose remifentanil. Occurrence of cardiorespiratory complications was also recorded. MEASUREMENTS AND MAIN RESULTS: The median gestational age (minimum, maximum) was 26 weeks (24, 31), and the median birth weight was 825 g (610, 1,280). Changes in Premature Infant Pain Profile in the high-dose and low-dose groups were 1.43 ± 3.10 and -0.60 ± 5.32, respectively. The difference in changes in the Premature Infant Pain Profile score between the high-dose and low-dose groups was -2.03 ± 4.13. The corresponding lower limit of one-tailed 97.5% CI was -7.24, below the noninferiority margin. Apneic events and bradycardia did not occur in the low-dose group; however, there were three episodes of apnea (42.9%) and one of bradycardia (14.3%) in the high-dose group (p = 0.683 and 0.366, respectively). CONCLUSION: For mechanically ventilated preterm infants, the use of remifentanil at 0.25 µg/kg/min as an analgesic for short procedures represents a therapeutic option. Our pilot study suggests the need for larger randomized trials.
Assuntos
Analgésicos Opioides/administração & dosagem , Dor/tratamento farmacológico , Piperidinas/administração & dosagem , Analgésicos Opioides/efeitos adversos , Apneia/induzido quimicamente , Peso ao Nascer , Bradicardia/induzido quimicamente , Cateterismo Venoso Central/efeitos adversos , Método Duplo-Cego , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Dor/etiologia , Medição da Dor , Piperidinas/efeitos adversos , Estudos Prospectivos , Remifentanil , Respiração ArtificialRESUMO
UNLABELLED: Congenital chloride diarrhea (CLD, OMIM#214700) is an autosomal recessive disorder caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene, which encodes an intestinal chloride/bicarbonate exchanger. While more than 50 mutations have been identified throughout the world, there have been no data on the genetic characteristics of the patients of East Asian ethnic origin. In this study, we performed genetic analysis by direct sequencing of the 20 exons and parts of exon-intron boundaries of the SLC26A3 gene in eight patients of Korean origin with non-consanguineous parents. We identified three novel mutations, including two splice-site mutations (c.2063-1G>T in intron 18, c.1047+3 A>C in intron 12) and one missense mutation (p.Ser134Asn in exon 5). One previously identified mutation was also found (p.Pro131Leu in exon 5). The most common mutation was c.2063-1G>T, which was found in at least one allele of all patients. CONCLUSION: This is the first report to demonstrate the genetic background of CLD in a single ethnic group of East Asian descent. The c.2063-1G>T mutation could be suggested as a founder mutation in Korean population so that the targeting sequencing for the mutation would be a cost-efficient screening method to confirm a diagnosis of CLD in patients of Korean descent.
Assuntos
Antiportadores de Cloreto-Bicarbonato/genética , Diarreia/congênito , Erros Inatos do Metabolismo/genética , Mutação , Povo Asiático , Pré-Escolar , Diarreia/genética , Feminino , Frequência do Gene , Humanos , Lactente , Recém-Nascido , Coreia (Geográfico) , Masculino , Reação em Cadeia da Polimerase/métodos , Análise de Sequência , Transportadores de SulfatoRESUMO
OBJECTIVE: To evaluate clinical applicability of noninvasive hemoglobin (Hb) measurement with a pulse CO-oximeter in neonates. DESIGN: Prospective comparison study. SETTING: Neonatal ICU. PATIENTS: Fifty-six preterm and term infants with median age = 20 days (range = 1-98 days) and median weight = 1,440 g (range = 530-4,230 g). INTERVENTIONS: Hb measurements by Pulse CO-Oximetry (Masimo Radical-7) were recorded immediately prior to venous samplings. MEASUREMENTS AND MAIN RESULTS: The collected data were compared with the corresponding venous Hb level obtained in laboratory testing, and a total of 137 data pairs were analyzed. Noninvasive Hb values measured with a pulse CO-oximeter were significantly correlated with the venous Hb levels (correlation coefficient, r = 0.758; p < 0.001). Hb values measured with a pulse CO-oximeter were higher than those measured with a laboratory hematology analyzer (13.3 ± 2.6g/dL vs. 12.5 ± 3.1g/dL). In terms of the agreement between the laboratory analyzer and the pulse CO-oximeter, 94.8% of the measurements fell within two standard deviations of the mean difference. CONCLUSION: Noninvasive Hb measurements with Pulse CO-Oximetry provide clinically acceptable accuracy, and they were significantly correlated with laboratory Hb measurement in neonates. In terms of the clinical applicability, noninvasive Hb monitoring with a pulse CO-oximeter could be useful in the early detection of Hb changes in neonates.
Assuntos
Hemoglobinas/análise , Oximetria , Feminino , Hemoglobinometria/métodos , Hemoglobinas/metabolismo , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Monitorização Fisiológica/métodos , Flebotomia , Estudos Prospectivos , Estatísticas não ParamétricasRESUMO
AIM: We investigated the combined effects of intra-amniotic lipopolysaccharide (LPS) and maternal betamethasone (BMZ) on alveolarization using a newborn rat model. METHODS: LPS (1.0 µg/sac) or vehicle was injected into the amniotic sacs of pregnant rats and BMZ (170 µg/kg) or vehicle was injected intramuscularly into the pregnant rats twice at 8-h intervals on gestation day 20. The rat pups were delivered spontaneously after 2-2.5 days and raised until the measurements were taken. Bronchoalveolar lavage was performed on days 2 and 5, and morphometric analyses of the lungs were performed on days 5 and 14. RESULTS: Intra-amniotic LPS significantly increased the neutrophils in the bronchoalveolar lavage fluid (BALF) on day 2, but double exposure to LPS and BMZ significantly alleviated the neutrophil increase in the BALF. On day 5, while the neutrophils in the BALF decreased in the animals exposed to LPS alone, the neutrophil numbers in the BALF were steady in the animals exposed to both LPS and BMZ. Morphometric analyses on days 5 and 14 revealed a significant disruption of alveolarization only in the animals exposed to both LPS and BMZ. CONCLUSIONS: Our results suggested that double exposure to maternal BMZ and intra-amniotic LPS induces sustained increase of neutrophils in the lungs and disrupts alveolarization.
Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Betametasona/administração & dosagem , Lipopolissacarídeos/administração & dosagem , Pulmão/patologia , Neutrófilos/efeitos dos fármacos , Alvéolos Pulmonares/crescimento & desenvolvimento , Âmnio , Animais , Betametasona/efeitos adversos , Líquido da Lavagem Broncoalveolar/citologia , Interações Medicamentosas , Feminino , Glucocorticoides/efeitos adversos , Contagem de Leucócitos , Lipopolissacarídeos/efeitos adversos , Gravidez , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-DawleyRESUMO
A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed 29f, a novel ENPP1 inhibitor with phthalazin-1(2H)-one as the core scaffold. 29f inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC50 = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. 29f demonstrated excellent metabolic stability and bioavailability (F = 65%). Orally administered 29f promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, 29f-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of 29f.
Assuntos
Neoplasias , Diester Fosfórico Hidrolases , Humanos , Diester Fosfórico Hidrolases/metabolismo , Neoplasias/terapia , Pirofosfatases , Imunoterapia , Microambiente TumoralRESUMO
OBJECTIVE: To determine whether neurally adjusted ventilatory assist (NAVA), a new method of mechanical ventilation that delivers pressure assistance that is proportional to the electrical activity of the diaphragm (EAdi), could lower the inspiratory pressure and respiratory muscle load in preterm infants supported with ventilators. STUDY DESIGN: Twenty-six mechanically ventilated preterm infants were randomized to crossover ventilation with NAVA and synchronized intermittent mandatory ventilation (SIMV) with pressure support (PS) for 4 hours each in a randomized order. A 1-hour interval for washout was provided between the 2 modes of ventilation. The ventilator settings were adjusted to maintain similar levels of end-tidal partial pressure of CO(2). The ventilator parameters, vital signs, and gas exchange effects under the 2 ventilatory modes were compared. RESULTS: Nineteen infants completed the 9-hour crossover comparison protocol. Peak inspiratory pressure (PIP), work of breathing, and peak EAdi with NAVA were lower than those in SIMV with PS. Calculated tidal volume to peak EAdi ratio and PIP to peak EAdi ratio were higher with NAVA. There were no significant differences in mean airway pressure, inspiratory oxygen fraction, and blood gas values. The measurements of vital signs did not differ significantly between the 2 modes. CONCLUSION: NAVA lowered PIP and reduced respiratory muscle load in preterm infants at equivalent inspiratory oxygen fraction and partial pressure of CO(2) of capillary blood in comparison with SIMV with PS.
Assuntos
Respiração Artificial/métodos , Estudos Cross-Over , Diafragma/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/terapia , Suporte Ventilatório Interativo , Ventilação com Pressão Positiva Intermitente/métodos , Masculino , Oxigênio/química , Projetos Piloto , Pressão , Estudos Prospectivos , Respiração , Transtornos Respiratórios/terapia , Volume de Ventilação Pulmonar , Ventiladores MecânicosRESUMO
The aim of our study was to investigate the differential effects of dexamethasone (DXM) and hydrocortisone (HCS) on somatic growth and postnatal lung development in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was induced by administering intra-amniotic lipopolysaccharide (LPS) and postnatal hyperoxia. The rats were treated with a 6-day (D1-D6) tapering course of DXM (starting dose 0.5 mg/kg/day), HCS (starting dose 2 mg/kg/day), or an equivalent volume of normal saline. DXM treatment in a rat model of BPD induced by LPS and hyperoxia was also associated with a more profound weight loss compared to control and LPS + O(2) groups not exposed to corticosteroid, whereas HCS treatment affected body weight only slightly. Examination of lung morphology showed worse mean cord length in both LPS + O(2) + DXM and LPS + O(2) + HCS groups as compared to the LPS + O(2) alone group, and the LPS + O(2) + DXM group had thicker alveolar walls than the LPS + O(2) group at day 14. The HCS treatment was not significantly associated with aberrant alveolar wall thickening and retarded somatic growth. The use of postnatal DXM or HCS in a rat model of BPD induced by intra-amniotic LPS and postnatal hyperoxia appeared detrimental to lung growth, but there was less effect in the case of HCS. These findings suggest that effect of HCS on somatic growth and pulmonary outcome may be better tolerated in neonates for preventing and/or treating BPD.
Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Hidrocortisona/farmacologia , Hiperóxia , Pneumopatias/patologia , Alvéolos Pulmonares/efeitos dos fármacos , Âmnio/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos/toxicidade , Oxigênio/metabolismo , Alvéolos Pulmonares/crescimento & desenvolvimento , Alvéolos Pulmonares/patologia , Ratos , Ratos Sprague-DawleyRESUMO
At chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.
Assuntos
Transporte Biológico , Caenorhabditis elegans/metabolismo , Ácido Glutâmico/metabolismo , Transmissão Sináptica/fisiologia , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Interneurônios/metabolismo , Locomoção , Neurônios , Alinhamento de Sequência , Sinapses/metabolismo , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Glutamato/metabolismoRESUMO
OBJECTIVES: To test the hypothesis that intrauterine inflammation increases prostaglandin production and may be a risk factor for persistent ductus arteriosus after therapy with indomethacin, a nonselective cyclooxygenase inhibitor. STUDY DESIGN: Indomethacin therapy was started after confirming ductus arteriosus within 24 hours after birth in extremely low birth weight infants. After one cycle of therapy, infants with closed ductus were classified as responders, and those with patent ductus were classified as nonresponders. Multiple logistic regression analysis was used to determine important perinatal factors associated with persistent ductus arteriosus. Immunohistochemistry with cyclooxygenase antibodies and radioimmunoassay by 6-keto prostaglandin F(1α) kit were used to determine the relationship between intrauterine inflammation and ductal patency. RESULTS: Forty-one infants were responders, and 37 infants were nonresponders. Responders were frequently small for gestational age; nonresponders frequently had lower gestational age, respiratory distress syndrome, and intrauterine inflammation. By multiple logistic regression analysis, respiratory distress syndrome and intrauterine inflammation were more frequent in nonresponders. Cyclooxygenase-1 expression in the umbilical arteries and plasma 6-keto prostaglandin F(1α) levels were higher in nonresponders. CONCLUSIONS: Respiratory distress syndrome and intrauterine inflammation were independent risk factors for persistent ductus arteriosus after indomethacin therapy in extremely low-birth weight infants. Intrauterine inflammation may have a negative influence on ductus arteriosus closure via increased cyclooxygenase-1 activity.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/etiologia , Doenças Fetais , Indometacina/uso terapêutico , Recém-Nascido de Peso Extremamente Baixo ao Nascer , Inflamação/complicações , Permeabilidade do Canal Arterial/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Projetos Piloto , Fatores de Risco , Falha de TratamentoRESUMO
Neonatal hypoxic-ischemic brain injury (HIE) remains a major cause of neurologic disabilities. However, many experimental therapies have shown limited successes. We assessed whether human mesenchymal stem cells (MSCs) could be transplanted in the HIE rat brain to improve neurologic disabilities. P7 SD rats were either subjected to left carotid artery ligation and hypoxic exposure [hypoxia-ischemia (HI)] or sham operation and normoxic exposure (sham). On P10, rat pubs received either PKH26-labeled MSCs or buffer via intracardial injection, resulting in four experimental groups: sham-buffer, sham-MSC, HI-buffer, and HI-MSC. Cylinder test and accelerating rotarod test were performed 14, 20, 30, and 40 d after injection. Six weeks after injection, cresyl violet and double immunofluorescence staining were performed. MSCs were transplanted to the whole brain mainly after HI. Glial fibrillary acidic protein and OX42 were more abundantly colocalized with MSC than neuronal specific nuclear protein or myelin basic protein. There were no significant differences in the total amounts and cell types between the lesioned and nonlesioned hemisphere. The lesioned hemispheric volume was decreased after HI (p = 0.012) but not restored by MSC. Neurologic performance was significantly impaired only on the cylinder test after HI (p = 0.034), and MSC transplants improved it (p = 0.010). These suggest MSC can be a candidate for the treatment of neonatal HIE.