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Importance: Resuscitation with lower fractional inspired oxygen (FiO2) reduces mortality in term and near-term infants but the impact of this practice on very preterm infants is unclear. Objective: To evaluate the relative effectiveness of initial FiO2 on reducing mortality, severe morbidities, and oxygen saturations (SpO2) in preterm infants born at less than 32 weeks' gestation using network meta-analysis (NMA) of individual participant data (IPD). Data Sources: MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov, and WHO ICTRP from 1980 to October 10, 2023. Study Selection: Eligible studies were randomized clinical trials enrolling infants born at less than 32 weeks' gestation comparing at least 2 initial oxygen concentrations for delivery room resuscitation, defined as either low (≤0.3), intermediate (0.5-0.65), or high (≥0.90) FiO2. Data Extraction and Synthesis: Investigators from eligible studies were invited to provide IPD. Data were processed and checked for quality and integrity. One-stage contrast-based bayesian IPD-NMA was performed with noninformative priors and random effects and adjusted for key covariates. Main Outcomes and Measures: The primary outcome was all-cause mortality at hospital discharge. Secondary outcomes were morbidities of prematurity and SpO2 at 5 minutes. Results: IPD were provided for 1055 infants from 12 of the 13 eligible studies (2005-2019). Resuscitation with high (≥0.90) initial FiO2 was associated with significantly reduced mortality compared to low (≤0.3) (odds ratio [OR], 0.45; 95% credible interval [CrI], 0.23-0.86; low certainty) and intermediate (0.5-0.65) FiO2 (OR, 0.34; 95% CrI, 0.11-0.99; very low certainty). High initial FiO2 had a 97% probability of ranking first to reduce mortality. The effects on other morbidities were inconclusive. Conclusions and Relevance: High initial FiO2 (≥0.90) may be associated with reduced mortality in preterm infants born at less than 32 weeks' gestation compared to low initial FiO2 (low certainty). High initial FiO2 is possibly associated with reduced mortality compared to intermediate initial FiO2 (very low certainty) but more evidence is required.
Assuntos
Metanálise em Rede , Oxigenoterapia , Oxigênio , Ressuscitação , Humanos , Recém-Nascido , Ressuscitação/métodos , Oxigenoterapia/métodos , Oxigênio/administração & dosagem , Recém-Nascido Prematuro , Idade Gestacional , Saturação de OxigênioRESUMO
PURPOSE: Feeding tolerance is extremely important in preterm infants. This study aimed to evaluate whether preterm infants receiving Lactobacillus reuteri DSM 17938 would develop fewer symptoms of feeding intolerance. Secondary outcomes were duration of parenteral nutrition, time to reach full feeding, length of hospital stay, sepsis, necrotizing enterocolitis (NEC), diarrhea, and mortality. METHODS: This double-blind randomized controlled trial of L. reuteri DSM 17938 versus placebo included 94 neonates with a gestational age of 28-34 weeks and birth weight of 1,000-1,800 g. RESULTS: Feeding intolerance (vomiting and/or distension) was less common in the probiotic group than in the placebo group (8.5% vs. 25.5%; relative risk, 0.33; 95% confidence interval, 0.12-0.96; p=0.03). No significant intergroup differences were found in proven sepsis, time to reach full feeding, length of hospital stay, or diarrhea. The prevalence of NEC (stages 2 and 3) was 6.4% in the placebo group vs. 0% in the probiotic group (relative risk, 1.07; 95% confidence interval, 0.99-1.15; p=0.24). Mortality rates were 2.1% in the probiotic group and 8.5% in the placebo group, p=0.36). CONCLUSION: The administration of L. reuteri DSM 17938 to preterm infants was safe and significantly reduced feeding intolerance. No significant differences were found in any other secondary outcomes.
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Autoimmune-mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T-cell activation. Our patient is a 28-month-old female who received a heart transplant at five wk of age. At 24 months post-transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid-induced remission, but long-term complications of this disease process are unknown.
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Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Transplante de Coração , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Doenças Autoimunes/etiologia , Basiliximab , Pré-Escolar , Feminino , Humanos , Doenças Inflamatórias Intestinais/etiologiaRESUMO
BACKGROUND: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. PATIENTS AND METHODS: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. RESULTS: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G-->A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%),
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Linfo-Histiocitose Hemofagocítica/etnologia , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Mutação , Perforina/genética , Adolescente , Adulto , Criança , Pré-Escolar , Etnicidade , Feminino , Mutação da Fase de Leitura , Genótipo , Humanos , Lactente , Recém-Nascido , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Mutação de Sentido Incorreto , FenótipoAssuntos
Substituição de Aminoácidos/genética , Linfo-Histiocitose Hemofagocítica/genética , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Proteínas Citotóxicas Formadoras de Poros/genética , Alanina/genética , Saúde da Família , Triagem de Portadores Genéticos , Genótipo , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Perforina , Valina/genéticaRESUMO
In women, chronically elevated androgens have been associated with polycystic ovarian syndrome and infertility. Recently, we described transgenic mice with elevated serum LH secondary to targeted expression of a transgene encoding a chimeric LH beta-subunit. Mature transgenic females exhibit elevated androgens, anovulation, and a range of ovarian phenotypes including cysts, widespread luteinization, and tumors. In the present study we have examined serum levels of LH and testosterone and the concurrent development of the reproductive system in prepubertal mice. Serum LH in prepubertal females was elevated despite increased serum testosterone and estradiol, indicating a relative insensitivity to steroid negative feedback. Elevated serum LH and hyperandrogenemia resulted in accelerated vaginal opening and ovarian follicular development in transgenic females. Precocious antral follicle formation and conspicuous hypertrophy of the theca-interstitium preceded the development of large cysts with marked hemorrhage. Based on these studies we conclude that chronic prepubertal elevation of serum LH results in gonadotropin-dependent hyperandrogenemia, leading to abnormal sexual development and significant ovarian pathology.
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Envelhecimento/sangue , Hiperandrogenismo/etiologia , Hormônio Luteinizante/sangue , Hormônio Luteinizante/fisiologia , Doenças Ovarianas/etiologia , Ovário/patologia , Maturidade Sexual/fisiologia , Androgênios/sangue , Animais , Estradiol/sangue , Feminino , Hiperandrogenismo/patologia , Hipertrofia/patologia , Masculino , Camundongos , Camundongos Transgênicos , Doenças Ovarianas/patologia , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/patologia , Radioimunoensaio , Testosterona/sangue , Útero/patologia , Vagina/patologiaRESUMO
The intracellular hydrophilic region of the cystic fibrosis transmembrane conductance regulator (CFTR), the R domain, has been postulated to be a regulator of the Cl-channel. Under basal conditions R blocks the channel, but when phosphorylated, R undergoes conformational change to open the channel. Overexpression of R in 9/HTEo- cells, a human tracheal epithelial cell line with adenosine 3',5' -cyclic monophosphate (cAMP)-regulated Cl- conductance due to CFTR, caused reduced basal Cl- conductance and elimination of its response to isoproterenol, but ionomycin-stimulated Cl- efflux was preserved. Cells which overexpressed R showed no downregulation of endogenous CFTR mRNA and had normal cAMP production and protein kinase A (PKA) activity, so R did not act at these levels. Although the precise mechanism by which R affects CFTR conductance is undetermined, these cell lines could be useful in separating the cell biological consequences of impaired Cl- transport from those of mutant CFTR per se.
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Cloretos/metabolismo , AMP Cíclico/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Expressão Gênica , Traqueia/fisiologia , Sequência de Bases , Cálcio/fisiologia , Linhagem Celular , Cloretos/fisiologia , AMP Cíclico/biossíntese , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Condutividade Elétrica , Corantes Fluorescentes , Humanos , Dados de Sequência Molecular , Sondas de Oligonucleotídeos/genética , Compostos de Quinolínio/metabolismo , Traqueia/citologiaRESUMO
Hypersecretion of luteinizing hormone (LH) is implicated in infertility and miscarriages in women. A lack of animal models has limited progress in determining the mechanisms of LH toxicity. We have recently generated transgenic mice expressing a chimeric LH beta subunit (LH beta) in gonadotropes. The LH beta chimera contains the C-terminal peptide of the human chorionic gonadotropin beta subunit. Addition of this peptide to bovine LH beta resulted in a hormone with a longer half-life. Furthermore, targeted expression of the LH beta chimera led to elevated LH levels and infertility in female transgenics. These mice ovulated infrequently, maintained a prolonged luteal phase, and developed pathologic ovarian changes such as cyst formation, marked enlargement of ovaries, and granulosa cell tumors. Testosterone and estradiol levels were increased compared to nontransgenic littermates. An unusual extragonadal phenotype was also observed: transgenic females developed hydronephropathy and pyelonephritis. The pathology observed demonstrates a direct association between abnormal secretion of LH and infertility and underscores the utility of the transgenic model for studying how excess LH leads to cyst formation, ovarian tumorigenesis, and infertility.