Late effects of caffeine use on sleep of infants born prematurely / Efeitos tardios do uso de cafeína no sono de crianças nascidas prematuras

ABSTRACT Objective: This study aimed to evaluate whether the therapeutic use of caffeine for premature newborns is associated with changes in sleep habits and the presence of obstructive sleep apnea in childhood. Methods: This is a cross-sectional single-center study in which the caretakers of 87 children aged 5-10 years, born full-term or preterm, treated or not with caffeine in the neonatal period, answered questionnaires to screen for obstructive sleep apnea (Pediatric Obstructive Sleep Apnea Screening Tool [PosaST]) and to characterize the sleep habits (Children's Sleep Habits Questionnaire [CSHQ]) of their children. ANOVA and linear regression tests were performed to verify possible differences between the groups. Results: Children born prematurely who were treated with caffeine woke up significantly later on weekdays than those born at term (09h±00h58 and 07h43±1h15, respectively, p=0.022) and had longer total daily sleep time also compared to those born at term (10h24±1h08 and 09h29±1h08, respectively, p<0.001). There was no significant difference between the three groups in overall PosaST and CSHQ scores. Conclusions: Caffeine use in the neonatal period did not impair sleep habits later in life and did not lead to increased obstructive sleep apnea scores in prematurely born children compared to those born at term.

RESUMO Objetivo: Avaliar se o uso terapêutico de cafeína para recém-nascidos prematuros se associa a alterações nos hábitos de sono e à presença de apneia obstrutiva do sono na infância. Métodos: Este é um estudo unicêntrico transversal no qual os responsáveis por 87 crianças com idades entre cinco e dez anos, nascidas a termo ou pré-termo e tratadas ou não com cafeína no período neonatal responderam a questionários para triagem de apneia obstrutiva do sono (Pediatric Obstructive Sleep Apnea Screening Tool - PosaST) e para a caracterização dos hábitos de sono (Children's Sleep Habits Questionnaire - CSHQ) de seus filhos. Foram realizados testes de variância (ANOVA) e de regressão linear para verificar possíveis diferenças entre os grupos. Resultados: As crianças nascidas prematuras que foram tratadas com cafeína acordaram significativamente mais tarde nos dias de semana do que as nascidas a termo (09h±00h58 e 07h43±1h15, respectivamente, p=0,022) e tiveram maior tempo total de sono diário também comparadas às nascidas a termo (10h24±1h08 e 09h29±1h08, respectivamente, p<0,001). Não houve diferença significativa entre os três grupos na pontuação geral dos questionários PosaST e CSHQ. Conclusões: O uso de cafeína no período neonatal não prejudicou tardiamente os hábitos de sono e não levou ao aumento dos escores de apneia obstrutiva do sono de crianças nascidas prematuras quando comparadas com crianças nascidas a termo.

Neonatal performed echocardiography course: Can we face it?

OBJECTIVE: To evaluate students' qualification after a six-month basic course of Neonatal Performed Echocardiography (NPEcho), adjusted by the motivational profile. STUDY DESIGN: Prospective cohort of 16 neonatologists/neonatal fellows who underwent the basic NPEcho course in 2019 (18 h face-to-face theoretical classes; 36 h hands-on training) and 12 in 2020 (18 h online theoretical classes; 36 h hands-on training). Students' qualification was defined as ≥70% in post-test, video test, and practical evaluation in neonates. Academic Motivation Scale was applied. RESULTS: Scores in 2019 vs. 2020 were: pre-test -32% vs. 40% (p = 0.029), final theoretical score -78% vs. 69% (p = 0.007), and practical evaluation -88% vs. 65% (p = 0.003), resulting in 68.8% in 2019 vs. 33.3% in 2020 qualified students. Students' motivational profile were similar in 2019 and 2020. CONCLUSION: The NPEcho was successful in qualifying students with face-to-face theoretical classes, but the online format was inadequate to achieve the learning goals.

Echocardiography performed by the neonatologist: the impact on the clinical management.

BACKGROUND: The aim of this study was to assess whether neonatologist-performed echocardiography (NPE) changed the previously planned hemodynamic approach in critically ill newborn infants. METHODS: This prospective cross-sectional study included the first NPE of 199 neonates. Before the exam, the clinical team was asked about the planned hemodynamic approach and the answer was classified as an intention to change or not to change the therapy. After being informed about the NPE results, the clinical management was grouped as performed as previously planned (maintained) or modified. RESULTS: NPE modified the planned pre-exam approach in 80 cases (40.2%; 95% CI: 33.3-47.4%), and variables associated with an increased chance of this modification were exams to assess pulmonary hemodynamics (prevalent ratio (PR): 1.75; 95% CI: 1.02-3.00) and to assess systemic flow (PR: 1.68; 95% CI: 1.06-2.68) in relation to those requested for patent ductus arteriosus, pre-exam intention of changing the prescribed management (PR: 2.16; 95% CI: 1.50-3.11), use of catecholamines (PR: 1.68; 95% CI: 1.24-2.28) and birthweight (per kg) (PR: 0.81; 95% CI: 0.68-0.98). CONCLUSION: The NPE was an important tool to direct hemodynamic management in a different approach from the previous intention of the clinical team, mainly for critically ill neonates. IMPACT: This study shows that neonatologist-performed echocardiography guides the therapeutic planning in the NICU, mainly in the more unstable newborns, with lower birthweight and receiving catecholamines. Exams requested with the intention of modifying the current approach were more likely to change the management in a different way than planned pre-exam.

Maternal methionine supplementation in mice affects long-term body weight and locomotor activity of adult female offspring.

Methionine is a precursor of s-adenosylmethionine, the main donor of methyl radicals for methylation of DNA and other compounds. Previous studies have shown that reduced availability of methyl radicals during pregnancy/lactation decreased offspring perigonadal white adipose tissue (PWAT) and body weight. Therefore, we aimed to evaluate the effects of methionine supplementation during early development, a time of great ontogenic plasticity, by assessing the biometric, biochemical and behavioural parameters of the offspring of adult Swiss female mice supplemented with 1 % methionine in water 1 month before pregnancy, during pregnancy or pregnancy/lactation. After birth, the offspring were distributed into three groups: control (CT), methionine supplementation during pregnancy (SP) and methionine supplementation during pregnancy and lactation (SPL), and were followed until postnatal day (PND) 300. No changes were observed in offspring birth weight in both sexes. At PND 5, 28 and 90, no differences in body weight were found in females; however, at PND 300, SP and SPL females showed an increase in body weight when compared with the control group. This increase in body weight was accompanied by a total and relative increase in PWAT, and a decrease in locomotor activity in these groups. No differences in the body and organ weights were found in male offspring. In conclusion, the increased availability of methyl radicals during pregnancy and lactation impacted long-term body composition and locomotor activity in female offspring.

Hyperlipidic diet affects body composition and induces anxiety-like behaviour in intrauterine growth-restricted adult mice.

NEW FINDINGS: What is the central question of this study? What is the effect in male and female offspring of a protein-deficient diet producing intrauterine growth restriction (IUGR) in maternal mice on morphometric, metabolic and behavioural parameters before and after a challenge with a fat diet? What is the main finding and its importance? Male and female mice presented different growth trajectories after birth. IUGR favoured increased adiposity in male mice, and high-fat diet-induced anxiety-like behaviour in female mice. ABSTRACT: As there is sexual dimorphism in the response to maternal manipulations, we aimed to analyse the effects of intrauterine growth restriction (IUGR) in both sexes on morphometric, metabolic and behavioural parameters throughout postnatal development, and after challenge with a hyperlipidic diet. Female Swiss mice (n = 59) were distributed into two groups (SD: standard diet, n = 26; and PDD: isocaloric protein-deficient diet, n = 33), 2 weeks before mating and during the gestational period. After birth, offspring from SD and PDD dams were cross-fostered and nurtured by SD dams until postnatal day (PND) 28. At PND 60 all animals were challenged with a hypercaloric diet for 4 weeks. Offspring birth weight was significantly reduced in the PDD group compared to the SD group (P = 0.0001), but only male offspring presented a rapid catch-up during the first 21 days of development. Although no differences in body weight were observed between groups after the challenge with the hyperlipidic diet, an increase in the relative perigonadal white adipose tissue (P = 0.009) and a decrease in gross gastrocnemius muscle weight (P = 0.010) were observed in the PDD males. In relation to behavioural tests, there was an increase in locomotion in both sexes (P = 0.0001), and a decrease in female grooming (P = 0.006) in the PDD group. Additionally, females from the PDD group showed increased hyperlipidic food intake. In conclusion, IUGR affected both sexes, with females showing prominent behavioural modifications and males presenting altered body composition elicited by a hyperlipidic diet.

Gomez-López-Hernández syndrome: A case report with clinical and molecular evaluation and literature review.

Gomez-López-Hernández syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

Functional echocardiography training in the neonatal intensive care unit: comparing measurements and results with the pediatric cardiologist.

OBJECTIVES: Functional echocardiography is a valuable tool in the neonatal intensive care unit, but training programs are not standardized. The aim was to report an functional echocardiography training program for neonatologists and to describe the agreement of their measurements with the pediatric cardiologist. METHODS: Functional echocardiography training lasted 32h. After training program, the neonatologists performed functional echocardiography in the neonatal intensive care unit and were required to measure left cardiac chambers dimensions, left ventricle systolic function, right and left ventricular output, ductus arteriosus diameter, and flow pattern. Images were recorded by the equipment and reviewed offline by the pediatric cardiologist. The Bland-Altman test was used for quantitative variables and the kappa test, for qualitative variables. RESULTS: Twenty-two trained neonatologists performed 100 functional echocardiography exams. Ductus arteriosus identification and flow pattern had substantial agreement (kappa=0.91 and 0.88, respectively), as well as its diameter (mean difference=0.04mm). The mean difference for the aortic root was -1.2mm; left atrium, 0.60mm; left ventricle diastolic diameter, -0.90mm; left ventricle systolic diameter, -0.30mm. Shortening fraction and ejection fraction correlated well with broad limits of agreement, -2.96% (14.88; -20.82%) and --3.43% (15.54; -22.40%), respectively. Right and left ventricular output had broad limits of agreement, 16.69mL/kg/min (222.76; -189.37) and 23.57mL/kg/min (157.88; -110), respectively. There was good agreement between interpretations of normal or low cardiac output (76.7% for right ventricular output; 75.7% for left ventricular output). CONCLUSION: This functional echocardiography training program enabled neonatologists to obtain adequate skills in performing the images, obtaining good agreement with the cardiologist in simple hemodynamic measurements and ductus arteriosus evaluation.

Homocysteine and Psychiatric Disorders

Abstract Psychiatric disorders are highly prevalent all over the world with a great impact on public health. Altered homocysteine metabolism is implicated in the pathogenesis of many of these disorders, as it can interfere in normal methylation of subcellular components, promote neuroexcitotoxicity, and induce oxidative stress and inflammation. There are cumulative data implicating these mechanisms in the development of autism, schizophrenia, depression, bipolar disorder, and Alzheimer disease. Altered homocysteine metabolism is multifactorial in its origin. On one hand, genetic factors act as predisposing factors through brain development and function, and on the other hand, environmental factors give the opportunity for nutritional interventions improving metabolic status and possibly also clinical parameters. This article provides a review on the association of 1-carbon metabolism and autism, schizophrenia, depression, bipolar disorder, and dementia and goes through studies on the role of different cofactors and metabolites involved in this pathway.

Homocysteine and cysteine levels in prepubertal children: association with waist circumference and lipid profile.

OBJECTIVE: To evaluate homocysteine and total cysteine levels in prepubertal children and to determine the association between these levels and obesity, increased waist circumference, glucose levels, and lipid profile alterations. METHODS: Using a cross-sectional study, 677 prepubertal students 6 to 11 y old were assessed. The weight, height, and waist circumference of the students were measured. Laboratory analyses included triacylglycerols, total cholesterol and its fractions, glucose, vitamin B12, folate, homocysteine, and cysteine. Chi-square tests and logistic regression (forward-stepwise) were used for statistical analysis; the significance level was set at 5%. RESULTS: The median age of the students was 8.9 y (6.5-11.5), and the prevalences of overweight and obesity were 90 in 677 (13.3%) and 81 in 677 (12.0%), respectively. An increase in waist circumference was observed in 180 of 677 children (26.6%). Inadequate levels of low-density lipoprotein cholesterol, triacylglycerols, and high-density lipoprotein cholesterol were found in 95 (14.0%), 129 (19.1%), and 179 (26.4%) of the 677 students, respectively. The median homocysteine and total cysteine plasma levels were 5.6 µmol/L (0.1-11.7) and 365.7 µmol/L (191.5-589.2), respectively. A multivariate analysis showed that children with a waist circumference above the 90th percentile (7.3 µmol/L) were 2.4 times (95% confidence interval 1.4-4.0) more likely to have increased homocysteine levels and that children with increased waist circumferences and those with high low-density lipoprotein cholesterol levels were 2.7 (95% confidence interval 1.6-4.6) and 2.1 (95% confidence interval 1.1-4.0) times more likely, respectively, to have total cysteine levels above the 90th percentile (445.0 µmol/L). CONCLUSION: The association of abdominal obesity in prepuberty with levels of homocysteine and cysteine found in this study of a prepubertal population could be an early and independent predictor of cardiovascular risk.

Bone marrow and peripheral white blood cells number is affected by sleep deprivation in a murine experimental model.

Sleep deficit and related disorders are becoming increasingly prevalent in modern life and an extensive literature has documented that acute or chronic sleep deprivation can lead to several physiological consequences. Here, we evaluated the effects of sleep deprivation on hematopoietic composition of either bone marrow or peripheral blood. Mice were subjected to paradoxical sleep deprivation (PSD) for 72 h by modified multiple platform method, with or without an additional sleep recovery (SR) period of 10 days. PSD decreased total cellularity of the bone marrow and peripheral blood concomitantly. Subsequent analysis of cell composition showed that absolute number of hematopoietic stem/progenitor cells and colony-forming units was decreased. Moreover, the absolute number of granulocytes and monocytes in bone marrow was reduced in PSD group. These alterations were paralleled by an accumulation of neutrophils and monocytes in peripheral blood. PSD also induced lymphopenia in the circulation. To the best of our knowledge, this is the first study that demonstrates the importance of sleep on the hematopoietic microenvironment and provides new insights into the relationship between sleep and the immune system.

Screening for inborn errors of metabolism among newborns with metabolic disturbance and/or neurological manifestations without determined cause

CONTEXT: Inborn Errors of Metabolism are hereditary affections resulting from incompetence in enzymatic reactions of intermediary metabolism. At present, several hundred hereditary metabolic disturbances are known, many of which correspond to severe life-threatening disorders. OBJECTIVE: The early detection of carriers has motivated the screening for these disturbances among newborns at the Neonatal Unit of Hospital Säo Paulo, in an attempt to initiate support treatment, when available, before clinical manifestations become evident. DESIGN: Prospective study of risk patients. SETTING: Laboratory for Inborn Errors of Metabolism at the Center for Medical Genetics of the Departments of Pediatrics and Morphology of Universidade Federal de Säo Paulo/Escola Paulista de Medicina.Newborn care unit at a tertiary care hospital. PARTICIPANTS: 101 children admitted into the Neonatal Unit were included in this study by presenting hypoglycemia, metabolic acidosis, jaundice, difficulty in gaining weight, diarrhea, vomiting, hepato- and/or splenomegaly, cataracts, apnea, convulsions, hypo- or hypertonia. DIAGNOSTIC TESTS: Tests routinely utilized, performed for qualitative research of abnormal substances excreted in the urine in situations of metabolic disorder. RESULTS: Children were included in the study mainly because of presenting hypoglycemia, jaundice and metabolic acidosis. Sixty-four newborns presented at least one positive test result. Most of the positivity was due to transitory metabolic alterations of the newborn, such as the case of Transitory Neonatal Tyrosinemia, presented by 29 patients. Nine infants were referred to the Center for Medical Genetics of Universidade Federal de Säo Paulo for continuation of the diagnostic investigation. For three of them, the tests applied permitted us to formulate a diagnostic hypothesis of mucopolysaccharidosis, tyrosinemia type I and non-ketotic hyperglycinemia, respectively. CONCLUSIONS: The high positivity observed in the tests reflects the newborn's own metabolic immaturity. The selection of 9 percent of the studied cases for outpatient follow-up confirms that Inborn Errors of Metabolism must be suspected whenever a patient presents metabolic disturbances or neurological manifestations without a determined cause. They should be researched in parallel with the other diagnostic possibilities and not just taken to be exceptional diagnoses