Clarissa Gutierrez Carvalho

Identificação de medicamentos "não apropriados para crianças" em prescrições de unidade de tratamento intensivo pediátrica

Objective: To assess the extent of use of drugs not appropriate for children in prescriptions issued in a tertiary pediatric intensive care unit (PICU), according to FDA standards. Methods: Observational cross-sectional study. The prescriptions issued to all patients admitted to the PICU at Hospital de Clinicas de Porto Alegre, Brazil, over a six-week period were assessed. Patients’ age, sex, weight, prior disease, reason for admission to the PICU and pediatric index of mortality (PIM) were recorded, as were all drugs prescribed, their indications, presentations, doses, frequencies and means of administration. Adequacy for prescription of drugs in three pediatric age ranges was defined according to USA Food and Drug Administration (FDA) approval classification, based on the USP DI 2001 drug reference database. Results: Data were obtained in the months of July and August 2002, on different days, for six consecutive weeks, based on prescriptions issued to 51 patients in 54 admissions to the PICU. Median patient age was 10.5 months; 61% of patients were male. Two thirds of patients (65%) presented prior disease. 87% of admissions were due to clinical reasons, of which 57% were respiratory complaints. A total of 747 prescription items were registered, with prevalence of 10.5% for nonapproved uses and 49.5% for off-label uses. No statistically significant difference was found in the distribution of prevalence of irregular prescription either by the three age ranges or by level of severity of

Association of late-onset neonatal sepsis with late neurodevelopment in the first two years of life of preterm infants with very low birth weight

OBJECTIVE To establish the influence of late-onset sepsis on neurodevelopment of preterm infants with very low birth weight (VLBW), according to the etiologic agent. METHOD This was a cohort of newborns with birth weight<1,500 g and gestational age less than 32 weeks, admitted to the institutional intensive care unit (ICU) with up to 48 hours of life, and followed-up at the outpatient follow-up clinic for preterm infants with VLBW until 2 years of corrected age. EXCLUSION CRITERIA death within the first 72 hours of life, congenital malformations and genetic syndromes, children with congenital infection by the human immunodeficiency virus (HIV), congenital infection (STORCH), presence of early-onset sepsis and cases with more than one pathogen growth in blood cultures. Septic and non-septic infants were compared regarding neonatal outcomes and mortality. Neurodevelopment was assessed using the Bayley Scale (BSDI-II) at 18 to 24 months of corrected age. RESULTS 411 preterm infants with VLBW were eligible; the mean gestational age was 29 ± 2.2 weeks and mean birth weight was 1,041 ± 281 grams. Late-onset sepsis occurred in 94 preterm infants with VLBW (22.8%). VLBW infants with Gram-positive infection showed motor deficit when compared to the non-septic group, 68.8% vs. 29.3%, respectively (OR 6; 1.6-21.8, p=0.006); the cognitive development was similar between the groups. The overall mortality rate from infection was 26.7%; considering the pathogens, the rates were 18.7% for coagulase-negative Staphylococcus, 21.8% for Gram-positive bacteria, and 50% for Gram-negative bacteria and fungi. CONCLUSION Neonatal sepsis has a significant influence on late neurodevelopment at 2 years of corrected age in preterm infants with VLBW, and Gram-positive infections are associated with motor deficit.

Reported Calcium Intake is Reduced in Women with Preeclampsia

Objective: The purpose of this trial is to investigate the relationship between dietary calcium content and incidence of preeclampsia, comparing diet calcium content in normotensive and preeclampsia patients. Dietary calcium was measured by a dietary interview conducted at the day after delivery. Methods: This is a prospective cross-sectional study involving 1092 patients who delivered at Hospital de Clínicas de Porto Alegre – Brazil. Results: The average diet calcium content in the studied population was 1038 mg. The average calcium intake in the normotensive group was 1057 mg, in chronic hypertension group was 962 mg, in transient hypertension group was 963 mg, in mild preeclampsia was 902 mg and in severe preeclampsia group was 755 mg. The results of this study show that pregnant women who develop severe preeclampsia have a significant lower diet calcium intake when compared to normotensive women (P = 0.018). Conclusion: The results of the present study can provide the foundations for prospective trials, including randomised clinical trials involving only patients with a low content of calcium in their diet.

DNA damage in leukocytes from pretreatment mucopolysaccharidosis type II patients; protective effect of enzyme replacement therapy.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Enzyme replacement therapy reduces the storage of these substances in the lysosomes. Oxidative stress is related to the pathophysiology of many disorders, including inborn errors of metabolism. Oxidative damage to protein and lipid has been described in MPS types I and III. The aim of this study was to analyze DNA damage, as determined by the alkaline comet assay using silver staining, in peripheral leukocytes from MPS II patients before treatment and during the first six months of enzyme replacement therapy. We also correlated DNA damage with lipid and protein oxidative damages, analyzed by plasma malondialdehyde levels and carbonyl group content, respectively. We found a significant increase in lipid and protein damage in MPS II patients before treatment when compared to controls. Also, our results showed greater DNA damage in terms of damage index (DI) in pretreatment MPS II patients (DI=18.0 ± 2.4) when compared to controls (DI=66.0 ± 2.0). Enzyme replacement therapy led to a significant decrease in levels of malondialdehyde and DNA damage when compared to pretreatment, but did not reach control values. Significant positive correlations between DNA damage and malondialdehyde levels, as well as carbonyl group content, were observed. Our findings indicate that MPS II patients are subject to DNA damage and that enzyme replacement therapy is able to protect against this process.

UGT1A1, SLCO1B1 , and SLCO1B3 polymorphisms vs. neonatal hyperbilirubinemia: is there an association?

Background:Jaundice is a physiological phenomenon; however, severe hyperbilirubinemia occurs in only 5 to 6% of the healthy newborn population. It has been suggested that genetic variation could enhance the risk of hyperbilirubinemia when coexpressed with other icterogenic conditions.Methods:The study included newborns with a gestational age of greater than 35 wk and weights greater than 2,000 g with indications for phototherapy. The polymorphisms from UGT1A1 (rs8175347), SLCO1B1 (rs4149056 and rs2306283), and SLCO1B3 (rs17680137 and rs2117032) were analyzed by capillary electrophoresis and hydrolysis probes.Results:A total of 167 hyperbilirubinemic infants and 247 control subjects were enrolled. The gender, ABO incompatibility, birth weight, and gestational age differed between the groups, but the allelic and genotypic frequency of the polymorphisms from SLCO1B genes did not. In logistic regression, the ABO incompatibility, gestational age, and polymorphic T allele of rs2117032 remained in the model. The presence of this polymorphism seemed to provide protection from hyperbilirubinemia. The individuals who were homozygous for the G allele of rs2306283 and who were glucose 6-phosphate-dehydrogenase deficient were more frequent among the cases.Conclusion:Although genetic variation accounts for a good part of this condition, the association between different polymorphisms and environmental factors has yet to be explained.

Glucose-6-phosphate-dehydrogenase deficiency and its correlation with other risk factors in jaundiced newborns in Southern Brazil.

OBJECTIVE To evaluate the correlation between glucose-6-phosphate-dehydrogenase (G6PD) deficiency and neonatal jaundice. METHODS Prospective, observational case-control study was conducted on 490 newborns admitted to Hospital de Clínicas de Porto Alegre for phototherapy, who all experienced 35 or more weeks of gestation, from March to December 2007. Enzymatic screening of G6PD activity was performed, followed by PCR. RESULTS There was prevalence of 4.6% and a boy-girl ratio of 3:1 in jaundiced newborns. No jaundiced neonate with ABO incompatibility presented G6PD deficiency, and no Mediterranean mutation was found. A higher proportion of deficiency was observed in Afro-descendants. There was no association with UGT1A1 variants. CONCLUSIONS G6PD deficiency is not related to severe hyperbilirubinemia and considering the high miscegenation in this area of Brazil, other gene interactions should be investigated.

Polymorphic variants of UGT1A1 in neonatal jaundice in southern Brazil.

Alterations in the hepatic conjugation of bilirubin due to uridyl-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms have been proposed as risk factors to neonatal jaundice. Herein, we estimated the frequency of genotypes of the promoter region of UGT1A1 gene in newborns and evaluated its association with severe hyperbilirubinemia. Prospective study of cases and controls including all newborns admitted for phototherapy at HCPA, Brazil, during 9 months; 490 babies were enrolled and PCR was performed. Polymorphic genotypes were detected in 16% of the patients and 7 of the 10 possible genotypes were identified with higher prevalence of polymorphisms in Afro-descendants. In this sample, the variants of UGT1A1 were not associated to severe hyperbilirubinemia; other genic factors should be sought in this high miscegenation area of Brazil.

Immune tolerance induction for laronidase treatment in mucopolysaccharidosis I.

Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose laronidase infusions (0.058–0.29 mg/kg/week) was followed by an immune-challenge period with laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving laronidase treatment. Clinical Trial Registration: NCT00741338.

Preterm Neonates with Respiratory Distress Syndrome: Ventilator-Induced Lung Injury and Oxidative Stress

Ventilator-induced lung injury is well recognized, and appropriate arterial saturation target is unknown, so gentle modes of ventilation and minimizing oxidative stress have been well studied. Our objective was to analyze any association between the oxygen levels at blood sampling and plasma levels of the interleukins IL-6, IL-1β, IL-10, and IL-8 and TNF-α in preterm newborns under mechanical ventilation (MV) in their first two days. Methods. Prospective cohort including neonates with severe respiratory distress. Blood samples were collected right before and 2 hours after invasive MV. For analysis purposes, newborns were separated according to oxygen requirement: low oxygen (≤30%) and high oxygen (>30%) groups. Interleukins were measured using a commercially available kit. Results. 20 neonates (gestational age 32.2 ± 3 weeks) were evaluated. Median O2 saturation levels pre-MV were not different in both oxygen groups. In the high oxygen group, IL-6, IL-8, and TNF-α plasma levels increased significantly after two hours under MV. Conclusions. Despite the small sample studied, data showed that there is a relationship between VILI, proinflammatory cytokines, and oxygen-induced lung injury, but a study considering oxidative marker measurements is needed. It seems that less oxygen may keep safer saturation targets playing a less harmful role.

Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer

Increases in nuclear calcium concentration generate specific biological outcomes that differ from those resulting from increased cytoplasmic calcium. Nuclear calcium effects on tumor cell proliferation are widely appreciated; nevertheless, its involvement in other steps of tumor progression is not well understood. Therefore, we evaluated whether nuclear calcium is essential in other additional stages of tumor progression, including key steps associated with the formation of the primary tumor or with the metastatic cascade. We found that nuclear calcium buffering impaired 4T1 triple negative breast cancer growth not just by decreasing tumor cell proliferation, but also by enhancing tumor necrosis. Moreover, nuclear calcium regulates tumor angiogenesis through a mechanism that involves the upregulation of the anti-angiogenic C-X-C motif chemokine 10 (CXCL10-IP10). In addition, nuclear calcium buffering regulates breast tumor cell motility, culminating in less cell invasion, likely due to enhanced vinculin expression, a focal adhesion structural protein. Together, our results show that nuclear calcium is essential for triple breast cancer angiogenesis and cell migration and can be considered as a promising strategic target for triple negative breast cancer therapy.