Role of RNase H1 in DNA repair: Removal of single ribonucleotide misincorporated into DNA in collaboration with RNase H2

Several RNases H1 cleave the RNA-DNA junction of Okazaki fragment-like RNA-DNA/DNA substrate. This activity, termed 3’-junction ribonuclease (3’-JRNase) activity, is different from the 5’-JRNase activity of RNase H2 that cleaves the 5’-side of the ribonucleotide of the RNA-DNA junction and is required to initiate the ribonucleotide excision repair pathway. To examine whether RNase H1 exhibits 3’-JRNase activity for dsDNA containing a single ribonucleotide and can remove this ribonucleotide in collaboration with RNase H2, cleavage of a DNA(8)-RNA(1)-DNA(9)/DNA(18) substrate with E. coli RNase H1 and H2 was analyzed. This substrate was cleaved by E. coli RNase H1 at the (5’)RNA-DNA(3’) junction, regardless of whether it was cleaved by E. coli RNase H2 at the (5’)DNA-RNA(3’) junction in advance or not. Likewise, this substrate was cleaved by E. coli RNase H2 at the (5’)DNA-RNA(3’) junction, regardless of whether it was cleaved by E. coli RNase H1 at the (5’)RNA-DNA(3’) junction in advance or not. When this substrate was cleaved by a mixture of E. coli RNases H1 and H2, the ribonucleotide was removed from the substrate. We propose that RNase H1 is involved in the excision of single ribonucleotides misincorporated into DNA in collaboration with RNase H2

Perception of pain and distress in intubated and mechanically ventilated newborn infants by parents and health professionals

Background: An understanding of perceptions of parents and health caregivers who assist critically ill neonates is necessary to comprehend their actions and demands. Therefore this study aim to analyze the agreement among parents, nurse technicians and pediatricians regarding the presence and intensity of pain and distress in mechanically ventilated and intubated newborn infants.Methods: Cross-sectional study comprising 52 infants and 52 trios of adults composed of one parent, one nurse technician, and one pediatrician who all observed the same infant. All infants were intubated and under mechanical ventilation and were not handled during the observations. Each newborn was simultaneously observed by the trio of adults for 1 minute to evaluate the presence of pain and distress. the intensity of pain and distress that the adults believed was felt by the infants was marked in a visual analogical scale. Adults' agreement about the simultaneous presence of pain and distress in each infant was analyzed by marginal homogeneity and Cochran tests. the agreement about the intensity of pain and distress in each infant was studied by Bland-Altman plot and intraclass correlation coefficient (ICC).Results: the assessments of pain and distress were heterogeneous in all three investigated groups of adults as determined by the results of a Bland-Altman plot. the presence of distress was more frequently reported compared with pain (marginal heterogeneity, p < 0.01). the pain and distress scores in each adult group were not correlated as shown by ICC [parents, 0.36 (95% CI: 0.01-0.63); nurses 0.47 (0.23-0.66); pediatricians, 0.46 (0.22-0.65)].Conclusions: Adults systematically underscore pain in comparison to distress in mechanically ventilated newborns, without recognizing the association between them.Universidade Federal de São Paulo, Catanduva, SP, BrazilFac Integradas Padre Albino, Fac Med Catanduva, Catanduva, SP, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Div Neonatal Med, BR-01410020 São Paulo, BrazilUniversidade Federal de São Paulo, Catanduva, SP, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Div Neonatal Med, BR-01410020 São Paulo, BrazilWeb of Scienc

Time above the MIC of piperacillin-tazobactam as a predictor of outcome in pseudomonas aeruginosa bacteraemia.

All rights reserved. Pseudomonas aeruginosa bacteremia is an infection associated with a high mortality rate. Piperacillin-tazobactam is a β-lactam-β-lactamase inhibitor combination that is frequently used for the management of Pseudomonas aeruginosa infections. The pharmacokinetic-pharmacodynamic index associated with in vitro maximal bacterial killing for piperacillin-tazobactam is the percentage of the time between doses at which the free fraction concentration remains above the MIC (%fT>MIC). However, the precise %>MICtarget associated with improved clinical outcomes is unknown. The aim of this study was to investigate the correlation between the survival of patients with Pseudomonas aeruginosa bacteremia and the threshold of the piperacillin-tazobactam %fT>MIC. This retrospective study included all adult patients hospitalized over an 82-month period with Pseudomonas aeruginosa bacteremia and treated with piperacillin-tazobactam. Patients with a polymicrobial infection or those who died within 72 h of the time of collection of a sample for culture were excluded. The %fT>MICof piperacillin-tazobactam associated with in-hospital survival was derived using classification and regression tree analysis. After screening 270 patients, 78 were eligible for inclusion in the study; 18% died during hospitalization. Classification and regression tree analysis identified a %fT>MICof >60.68% to be associated with improved survival, and this remained statistically significant after controlling for clinical covariates (odds ratio=7.74, 95% confidence interval=1.32 to 45.2). In conclusion, the findings recommend dosing of piperacillintazobactam with the aim of achieving a pharmacodynamic target %fT>MICof at least 60% in these patients

A DNA damage-induced phosphorylation circuit enhances Mec1ATR Ddc2ATRIP recruitment to Replication Protein A

The cell cycle checkpoint kinase Mec

Disagreement between parents and health professionals regarding pain intensity in critically ill neonates

OBJECTIVE: To verify whether parents and health professionals homogeneously evaluate presence and intensity of neonatal pain. METHODS: This cross-sectional study enrolled 52 neonates and 154 adults. Inclusion criteria for neonates were admission to neonatal intensive care unit, presence of gastric tube, tracheal tube, and venous lines. Each newborn was observed by a different group of three adults (parent, nurse assistant and pediatrician) for 1 minute at the same time to evaluate presence and intensity of infant's pain. Homogeneity of pain evaluation was analyzed by a modified Bland-Altman plot and by intraclass correlation coefficient (ICC). Multiple linear regression analysis was used to evaluate association of neonatal characteristics and heterogeneity of pain scores for adults. RESULTS: ICC showed disagreement of the pain scores given by the three groups of adults (ICC 0.066, agreement > 0.75). Bland-Altman analysis showed agreement among adults when they thought pain was absent. When they thought pain was present, there was heterogeneity of opinions regarding intensity of neonatal pain. Multiple regression analysis indicated that 10% of this disagreement could be explained by infant's gender and mode of delivery. CONCLUSIONS: Disagreement among adults about intensity of neonatal pain is a marker of the difficulty in deciding the need for analgesia in preverbal patients.OBJETIVO: Verificar se pais e profissionais de saúde que trabalham em unidades de terapia intensiva neonatal avaliam de maneira semelhante a presença e a magnitude da dor no recém-nascido (RN). MÉTODOS: Estudo transversal com 52 RN e 154 adultos. Os critérios de inclusão foram: internação em unidade de terapia intensiva neonatal, presença de sonda gástrica, cânula traqueal e acesso venoso. Cada RN foi observado de modo simultâneo por um trio diferente de adultos (pai/mãe, pediatra e auxiliar de enfermagem) durante 1 minuto para avaliar presença e intensidade da dor do paciente. A análise quanto à homogeneidade da avaliação de dor foi realizada por meio do gráfico de Bland-Altman modificado e do coeficiente de correlação intraclasses (CCI). A associação de fatores próprios do recém-nascido com a heterogeneidade da avaliação da dor do RN pelos adultos foi avaliada por meio de regressão linear múltipla. RESULTADOS: O CCI mostrou discordância entre os três grupos de adultos quanto à avaliação da dor (CCI 0,066, concordância > 0,75). A análise de Bland-Altman mostrou que houve concordância entre os adultos quanto à ausência de dor no RN. Porém, quando os adultos achavam que a dor estava presente, houve heterogeneidade na avaliação da intensidade de dor neonatal. A análise de regressão múltipla indicou que apenas 10% desta heterogeneidade foi explicada pelo sexo e via de parto do RN. CONCLUSÕES: A heterogeneidade na avaliação feita por adultos da intensidade da dor de RN é um marcador da dificuldade de se decidir a respeito da necessidade de analgesia em pacientes pré-verbais.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Divisão de Pediatria NeonatalUNIFESP-EPM Departamento de EpidemiologiaUNIFESP, EPM, Divisão de Pediatria NeonatalUNIFESP, EPM Depto. de EpidemiologiaSciEL

Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol’s adverse effects.Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects.Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects.Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18–11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84–9.28), and 3.25 (95% CI 1.78–5.93), respectively.Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes

Doença de Kawasaki: relato de caso

A Doença de Kawasaki (DK) é uma vasculite que afeta crianças menores de 5 anos, especialmente meninos e asiáticos. Predominantemente, ela envolve vasos de médio porte, com uma propensão para inflamar as artérias coronárias, podendo levar a aneurismas, tromboses e estenoses. O diagnóstico, geralmente clínico, é crucial para minimizar lesões e melhorar o prognóstico, sendo o ecocardiograma fundamental para identificar alterações cardíacas. O tratamento recomendado inclui imunoglobulinas e ácido acetilsalicílico. O objetivo desse trabalho é relatar o diagnóstico e evolução de um caso de Doença de Kawasaki moderada, em uma paciente do sexo feminino com dois anos de idade, sem acometimento cardíaco