When prevention is dangerous: perceptions of isoniazid preventive therapy in KwaZulu-Natal, South Africa.

SETTING: In 2011, the South African government began to offer isoniazid preventive therapy (IPT) through the public health system to presumptively treat latent tuberculous infection (LTBI) among people living with human immunodeficiency virus. OBJECTIVE: To describe IPT perceptions and experiences in three Zulu communities in KwaZulu-Natal Province, South Africa. DESIGN: Using a combination of community-based research and ethnographic methods, we undertook 17 individual and group interviews between October 2014 and May 2015. Interviews transcripts were analysed using qualitative content analysis and validated with grass-roots community advisors. RESULTS: Participants reported multiple ways in which IPT was perceived as dangerous: when costs related to pill collection or consumption were unsustainable, or when daily pill consumption resulted in stigma or was seen to introduce excess dirt or toxins, 'ukungcola', in the body. Theories on dirt are evoked to describe how IPT was perceived as 'matter out of place' when given to people who believed themselves to be healthy, suggesting that under the current TB aetiological model in Zulu culture, 'prevention as tablet' may not fit. CONCLUSION: Implementing IPT without understanding the realities of community stakeholders can unintentionally undermine TB control efforts by worsening the situation for people who already encounter numerous daily problems.

Impact of pre-pregnancy diabetes mellitus on congenital anomalies, Canada, 2002-2012.

OBJECTIVE: To examine the impact of pre-pregnancy diabetes mellitus (DM) on the population birth prevalence of congenital anomalies in Canada. METHODS: We carried out a population-based study of all women who delivered in Canadian hospitals (except those in the province of Quebec) between April 2002 and March 2013 and their live-born infants with a birth weight of 500 grams or more and/or a gestational age of 22 weeks or more. Pre-pregnancy type 1 or type 2 DM was identified using ICD-10 diagnostic codes. The association between DM and all congenital anomalies as well as specific congenital anomaly categories was estimated using adjusted odds ratios; the impact was calculated as a population attributable risk percent (PAR%). RESULTS: There were 118,892 infants with a congenital anomaly among 2,839,680 live births (41.9 per 1000). While the prevalence of any congenital anomaly declined from 50.7 per 1000 live births in 2002/03 to 41.5 per 1000 in 2012/13, the corresponding PAR% for a congenital anomaly related to pre-pregnancy DM rose from 0.6% (95% confidence interval [CI]: 0.4-0.8) to 1.2% (95% CI: 0.9-1.4). Specifically, the PAR% for congenital cardiovascular defects increased from 2.3% (95% CI: 1.7-2.9) to 4.2% (95% CI: 3.5-4.9) and for gastrointestinal defects from 0.8% (95% CI: 0.2-1.9) to 1.4% (95% CI: 0.7-2.6) over the study period. CONCLUSION: Although there has been a relative decline in the prevalence of congenital anomalies in Canada, the proportion of congenital anomalies due to maternal pre-pregnancy DM has increased. Enhancement of preconception care initiatives for women with DM is recommended.

TITRE: Influence du diabète antérieur à la grossesse sur les anomalies congénitales au Canada entre 2002 et 2012. OBJECTIF: Examiner l'influence du diabète antérieur à la grossesse sur la prévalence à la naissance des anomalies congénitales au Canada. MÉTHODOLOGIE: Nous avons réalisé une étude en population chez l'ensemble des femmes ayant accouché à l'hôpital au Canada (hors Québec) entre avril 2002 et mars 2013, ainsi que chez leurs enfants nés vivants ayant un poids à la naissance d'au moins 500 grammes ou un âge gestationnel d'au moins 22 semaines. On a attribué les codes de diagnostic de la CIM-10 au diabète de type 1 ou de type 2 antérieur à la grossesse. L'association entre le diabète et l'ensemble des anomalies congénitales ainsi qu'avec les diverses catégories prises séparément a été estimée à l'aide des rapports de cotes ajustés et son influence a été calculée sous forme de pourcentage de risque attribuable dans la population (%RAP). RÉSULTATS: Sur les 2 839 680 naissances vivantes, 118 892 nouveau-nés étaient atteints d'anomalies congénitales (41,9 pour 1 000). Même si la prévalence des anomalies congénitales est passée de 50,7 pour 1 000 naissances vivantes en 2002­2003 à 41,5 pour 1 000 en 2012­2013, le %RAP d'une anomalie congénitale liée au diabète antérieur à la grossesse est passé de 0,6 % (intervalle de confiance [IC] à 95 % : 0,4 à 0,8) à 1,2 % (IC à 95 % : 0,9 à 1,4). Plus précisément, le %RAP des cardiopathies congénitales est passé de 2,3 % (IC à 95 % : 1,7 à 2,9) à 4,2 % (IC à 95 % : 3,5 à 4,9) et celui des anomalies gastrointestinales de 0,8 % (IC à 95 % : 0,2 à 1,9) à 1,4 % (IC à 95 % : 0,7 à 2,6) au cours de la période étudiée. CONCLUSION: En dépit de la diminution relative de la prévalence des anomalies congénitales au Canada, la proportion d'anomalies congénitales pouvant être attribuées au diabète maternel antérieur à la grossesse a augmenté. On recommande l'amélioration des initiatives en matière de soins préconceptionnels destinées aux femmes diabétiques.

Brain mitochondrial ATP-insensitive large conductance Ca⁺²-activated K⁺ channel properties are altered in a rat model of amyloid-ß neurotoxicity.

Mitochondrial dysfunction is a hallmark of amyloid-beta (Aß)-induced neuronal toxicity in Alzheimer's disease (AD). However, the underlying mechanism of how Aß affects mitochondrial function remains uncertain. Because mitochondrial potassium channels have been involved in several mitochondrial functions including cytoprotection, apoptosis and calcium homeostasis, a study was undertaken to investigate whether the gating behavior of the mitochondrial ATP- and ChTx-insensitive-IbTx-sensitive Ca(2+)-activated potassium channel (mitoBKCa) is altered in a rat model of Aß neurotoxicity. Aß1-42 (4 µg/µl) was intracerebroventricularly injected in male Wistar rats (220-250 g). Brain Aß accumulation was confirmed two weeks later on the basis of an immunohistochemistry staining assay, and physiological impacts measured in passive avoidance task cognitive performance experiments. Brain mitochondrial inner membranes were then extracted and membrane vesicles prepared for channel incorporation into bilayer lipid. Purity of the cell fraction was confirmed by Western blot using specific markers of mitochondria, plasma membrane, endoplasmic reticulum, and Golgi. Our results first provide evidence for differences in mitoBKCa ion permeation properties with channels coming from Aß vesicle preparations characterized by an inward rectifying I-V curve, in contrast to control mitoBKCa channels which showed a linear I-V relationship under the same ionic conditions (200 mM cis/50mM trans). More importantly the open probability of channels from Aß vesicles appeared 1.5 to 2.5 smaller compared to controls, the most significant decrease being observed at depolarizing potentials (30 mV to 50 mV). Because BKCa-ß4 subunit has been documented to shift the BKCa channel voltage dependence curve, a Western blot analysis was undertaken where expression of mitoBKCa α and ß4 subunits was estimated using anti-α and ß4 subunit antibodies. Our results indicated a significant increase in mitoBKCa-ß4 subunit expression coupled to a decrease in the expression of α subunit. Our results thus demonstrate a modification in the mitoBKCa channel gating properties in membrane preparations coming from a rat model of Aß neurotoxicity, an effect potentially linked to a change in mitoBKCa-ß4 and -α subunits expression or increased ROS production due to an enhanced Aß mitochondrial accumulation. Our results may provide new insights into the cellular mechanisms underlying mitochondrial dysfunctions in Aß neurotoxicity.

Does chronic oxygen dependency in preterm infants with bronchopulmonary dysplasia at NICU discharge predict respiratory outcomes at 3 years of age?

OBJECTIVE: To determine whether chronic oxygen dependency at the time of discharge from the neonatal intensive care unit (NICU) in infants with bronchopulmonary dysplasia (BPD) predicts respiratory outcomes at 3 years. STUDY DESIGN: Preterm infants ⩽1250 g without BPD, BPD and BPD with chronic oxygen dependency were identified from the Southern Alberta Perinatal Follow-up clinic database (1995-2007). Respiratory outcomes at 4, 8, 18 and 36 months corrected age following NICU discharge were examined. Univariate analyses were done. RESULTS: Out of 1563 infants admitted to the NICU, 1212 survived. Complete follow-up data at 36 months were available for 1030 (85%) children. Children with BPD with or without chronic oxygen dependency had significantly (P<0.001) lower birth weights and gestational ages, and greater post-natal steroid use, compared with those with no BPD. At 4, 8 and 18 months follow-up, the use of respiratory medications and supplemental oxygen were both significantly higher in the BPD infants with chronic oxygen dependency group compared with the no-BPD group and BPD group. At 36 months, children in the BPD with chronic oxygen dependency group were more likely to use respiratory medications and supplemental oxygen vs the no-BPD or the BPD groups. At 4, 8 and 36 months of age, more children in the BPD with chronic oxygen dependency group had post-neonatal chronic lung disease (PNCLD) than children in the other groups, but at 36 months the difference was significant only for the BPD with chronic oxygen dependency vs no-BPD group (P<0.001). CONCLUSIONS: At 36 months, children diagnosed with BPD with chronic oxygen dependency at NICU discharge were more likely to need respiratory medications and supplemental oxygen in the previous 12 months, as compared with no-BPD or BPD groups. They were also more likely to require frequent physician visits and have PNCLD at 3 years, as compared with the no-BPD group.

Impairment of brain mitochondrial charybdotoxin- and ATP-insensitive BK channel activities in diabetes.

Existing evidence indicates an impairment of mitochondrial functions and alterations in potassium channel activities in diabetes. Because mitochondrial potassium channels have been involved in several mitochondrial functions including cytoprotection, apoptosis and calcium homeostasis, a study was carried out to consider whether the gating behavior of the mitochondrial ATP- and ChTx-insensitive Ca(2+)-activated potassium channel (mitoBKCa) is altered in a streptozotocin (STZ) model of diabetes. Using ion channel incorporation of brain mitochondrial inner membrane into the bilayer lipid membrane, we provide in this work evidence for modifications of the mitoBKCa ion permeation properties with channels from vesicles preparations coming from diabetic rats characterized by a significant decrease in conductance. More importantly, the open probability of channels from diabetic rats was reduced 1.5-2.5 fold compared to control, the most significant decrease being observed at depolarizing potentials. Because BKCa ß4 subunit has been documented to left shift the BKCa channel voltage dependence curve in high Ca(2+) conditions, a Western blot analysis was undertaken where the expression of mitoBKCa α and ß4 subunits was estimated using of anti-α and ß4 subunit antibodies. Our results indicated a significant decrease in mitoBKCa ß4 subunit expression coupled to a decrease in the expression of α subunit, an observation compatible with the observed decrease in Ca(2+) sensitivity. Our results thus demonstrate a modification in the mitoBKCa channel gating properties in membrane preparations coming from STZ model of diabetic rats, an effect potentially linked to a change in mitoBKCa ß4 and α subunits expression and/or to an increase in reactive oxygen species production in high glucose conditions.

Stillbirth in twins, exploring the optimal gestational age for delivery: a retrospective cohort study.

OBJECTIVE: To evaluate the optimal gestational age at delivery for twins. DESIGN: Retrospective cohort study. SETTING: Database containing demographic, delivery, and pregnancy outcome data for over 600,000 births from 81 hospitals in Alberta, Canada. POPULATION: All twin births in Alberta, Canada, during 1992-2007, as recorded in the databases of the Alberta Perinatal Health Project (www.aphp.ca). METHODS: The case files were reviewed for cause of death and any information regarding the gestational age at diagnosis of stillbirth. Multivariate logistic regression was used to examine the impact of potentially confounding factors. The 'fetus at risk' approach was used to evaluate the prospective risk of stillbirth. Competing risks of stillbirth and neonatal death were evaluated with a perinatal risk ratio. RESULTS: Of a total of 17,724 twin births there were 236 antepartum stillbirths, 26 intrapartum stillbirths, and 244 neonatal deaths. The rate of stillbirth peaked at 7.0/1000 fetuses at risk at 38 weeks of gestation. On multivariate analysis, small for gestational age (odds ratio, OR 2.2; 95% confidence interval, 95% CI 1.35-3.59), birthweight discrepancy >20% (OR 2.67, 95% CI 1.42-5.03), and an interaction between these two variables (OR 2.94, 95% CI 1.31-6.59), were significant. The perinatal risk ratio suggested that the risks of delivery and expectant management were balanced at 36 weeks of gestation (RR 0.6, 95% CI 0.1-5.4), but the confidence interval included one, the null value, until 38 weeks of gestation (RR 0.1, 95% CI 0.02-0.40). The majority of stillbirths at term (14/25) occurred in monochorionic diamniotic twins. The estimated risk of stillbirth in this group was 2.3/1000 fetuses at risk at 37 weeks of gestation, and 17.4/1000 fetuses at risk at 38 weeks of gestation. CONCLUSIONS: The balance of risk between neonatal death/intrapartum stillbirth and antepartum stillbirth begins to favour delivery at 36 weeks of gestation, particularly in monochorionic diamniotic twins.

Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome.

OBJECTIVE: The objective of this study was to examine the impact of Coagulase-negative staphylococcus (CoNS) sepsis in preterm infants on the neurodevelopmental outcomes at 30 to 42 months corrected age (CA). STUDY DESIGN: This is a retrospective cohort study. All preterm infants born at <29 weeks gestational age between 1995 and 2008 and had a neurodevelopmetnal assessment at 30 to 42 months CA were eligible. The neurodevelopmetnal outcomes of infants exposed to CoNS sepsis were compared with infants unexposed to any type of neonatal sepsis. RESULT: A total of 105 eligible infants who were exposed to CoNS sepsis were compared with 227 infants with no neonatal sepsis. In univariate analysis, infants with CoNS sepsis were more likely to have total major disability (odds ratio (OR)=1.9; 95% CI: 1.07 to 3.38) and cognitive delay (OR=2.53; 1.26 to 5.14).There was no significant difference in the incidence of cerebral palsy, blindness and deafness between the two groups. After correcting for potential confounders, CoNS sepsis was associated with increased risk of cognitive delay (adjusted odds ratio (aOR)= 2.23; 95% CI 1.01 to 4.9), but not with the total major disability (aOR=1.14; 95% CI: 0.55 to 2.34). CONCLUSION: Our study suggests that CoNS sepsis in preterm infants might be associated with increased risk for cognitive delay at 36 months CA.

Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: systematic review and meta-analysis.

OBJECTIVE: To study the impact of neonatal sepsis on the long-term neurodevelopmental outcome in very low birth weight (VLBW) infants. STUDY DESIGN: Systematic review and meta-analysis of observational studies comparing neurodevelopmental outcomes in VLBW infants exposed to culture-proven sepsis in the neonatal period with similar infants without sepsis. RESULT: Seventeen studies involving 15,331 infants were included in the meta-analysis. Sepsis in VLBW infants was associated with an increased risk of one or more long-term neurodevelopmental impairments (odds ratio (OR) 2.09; 95% confidence interval (CI) 1.65 to 2.65) including cerebral palsy (CP; OR 2.09; 95% CI 1.78 to 2.45). Heterogeneity (I(2)=36.9%; P=0.06) between the studies was significant and related to variations in patient characteristics, causative pathogens and follow-up methods. Sensitivity analyses based on study design, follow-up rate and year of birth were not significantly different from the overall analysis. CONCLUSION: The meta-analysis suggests that sepsis in VLBW infants is associated with a worse neurodevelopmental outcome including higher incidence of CP.

Histological chorioamnionitis and neurodevelopmental outcome in preterm infants.

OBJECTIVE: The objective of this study is to examine the neurodevelopmental outcome at 30 to 42 months corrected age of preterm infants with histological chorioamnionitis (HCA). STUDY DESIGN: The study design is a retrospective cohort study with a prospective follow-up. All surviving infants with birth gestational age <29 weeks, born between 2000 and 2006, who had a neurodevelopmental assessment at 30 to 42 months corrected age were included. We compared the neurodevelopmental outcomes of infants with or without HCA. RESULT: Of the 384 infants, 197 (51%) were born to mothers with evidence of HCA. Infants with HCA were of lower gestational age (26 weeks vs 26.6 weeks) and more likely to have intraventricular hemorrhage (27.9% vs 14.4%), periventricular leukomalacia (2.5% vs 0%) and retinopathy of prematurity ≥ stage 3 (31.4% vs 22.4%). On univariate analysis, infants with HCA were more likely to have cerebral palsy (12.6% vs 6.4%, P=0.04). There was no significant difference in the incidence of cognitive delay, deafness, blindness, or total major disabilities between the two groups. After adjusting for perinatal variables, HCA was associated with increased risk of cerebral palsy (odds ratio (OR): 2.45; 95% confidence interval (CI) 1.11 to 5.40), but not for total major disabilities (OR: 1.22; 95% CI: 0.64 to 2.34). There was a trend towards increased risk of cerebral palsy with HCA with funisitis. CONCLUSION: HCA is associated with increased risk of cerebral palsy at 30 to 42 months corrected age in preterm infants.

Prophylactic theophylline for the prevention of severe renal dysfunction in term and post-term neonates with perinatal asphyxia: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To examine the effect of prophylactic theophylline for the prevention of severe renal dysfunction in post-asphyxiated term and post-term infants. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing prophylactic theophylline vs placebo in term infants following perinatal asphyxia. RESULT: Four RCTs involving 197 infants were included in the meta-analysis. Compared with placebo, prophylactic theophylline was associated with a significant reduction in the incidence of severe renal dysfunction (pooled relative risk) using fixed-effects model was 0.38 (95% confidence interval, 0.25 to 0.57; P<0.001). CONCLUSION: The meta-analysis provides evidence that prophylactic theophylline significantly reduce the incidence of severe renal dysfunction. However, because of the lack of information on the long-term renal and neurodevelopmental outcome and measured theophylline levels with relation to adverse effects observed, prudence with the clinical use of prophylactic theophylline is required. Additionally, the included trials were prior to the era of therapeutic hypothermia and thus inference of renal benefit in an infant undergoing hypothermia therapy cannot be made.

Histological chorioamnionitis and bronchopulmonary dysplasia: a retrospective cohort study.

OBJECTIVE: To examine the association between histological chorioamnionitis (HC) with or without fetal inflammatory response (FIR) and bronchopulmonary dysplasia (BPD) in preterm infants. STUDY DESIGN: We conducted a retrospective cohort study of infants born at <29 weeks gestation admitted to the neonatal intensive care unit from 2000 to 2006, who had placental histology. We compared the incidence of BPD among three groups: No HC group, HC without FIR group and HC with FIR group. The multivariable model based on generalized estimating equation was fitted to estimate the adjusted risk ratios (aRR) and 95% confidence intervals (CIs) for BPD and combined outcome of BPD or death. RESULT: Of 529 infants, 84 (16%) had HC without FIR, 186 (35%) had HC with FIR and 259 (49%) had no HC. Compared with the no HC group, HC with and without FIR group infants were of lower gestational age and singleton births. Multivariable modeling based on generalized estimating equation revealed that HC with FIR is associated with decreased risk of both BPD (aRR 0.88, 95% CI 0.81 to 0.95) and the combined outcome of BPD or death (aRR 0.91, 95% CI 0.86 to 0.97). HC without FIR showed a trend toward reduction in BPD (aRR 0.93, 95% CI 0.86 to 1.00). CONCLUSIONS: HC with FIR is associated with decreased risk of both BPD and the combined outcome of BPD or death in preterm infants.

Electro-pharmacological profile of a mitochondrial inner membrane big-potassium channel from rat brain.

Recent studies have indicated a calcium-activated large conductance potassium channel in rat brain mitochondrial inner membrane (mitoBK channel). Accordingly, we have characterized the functional and pharmacological profile of a BK channel from rat brain mitochondria in the present study. Brain mitochondrial inner membrane preparations were subjected to SDS-PAGE analysis and channel protein reconstitution into planar lipid bilayers. Western blotting and antibodies directed against various cellular proteins revealed that mitochondrial inner membrane fractions did not contain specific proteins of the other subcellular compartments except a very small fraction of endoplasmic reticulum. Channel incorporation into planar lipid bilayers revealed a voltage dependent 211 pS potassium channel with a voltage for half activation (V(1/2)) of 11.4±1.1mV and an effective gating charge z(d) of 4.7±0.9. Gating and conducting behaviors of this channel were unaffected by the addition of 2.5mM ATP, and 500 nM charybdotoxin (ChTx), but the channel appeared sensitive to 100 nM iberiotoxin (IbTx). Adding 10mM TEA at positive potentials and 10mM 4-AP at negative or positive voltages inhibited the channel activities. These results demonstrate that the mitoBK channel, present in brain mitochondrial inner membrane, displays different pharmacological properties than those classically described for plasma membrane, especially in regard to its sensitivity to iberiotoxin and charybdotoxin sensitivity.

The risk of unexplained antepartum stillbirth in second pregnancies following caesarean section in the first pregnancy.

OBJECTIVE: To determine if a previous caesarean section increases the risk of unexplained antepartum stillbirth in second pregnancies. STUDY DESIGN: Retrospective cohort study. SETTING: Large Canadian perinatal database. POPULATION: 158 502 second births. METHODS: Data were obtained from a large perinatal database, which supplied data on demographics, pregnancy complications, maternal medical conditions, previous caesarean section and pregnancy outcomes. MAIN OUTCOME MEASURES: Total and unexplained stillbirth. RESULTS: The antepartum stillbirth rate was 3.0/1000 in the previous caesarean section group compared with 2.7/1000 in the previous vaginal delivery group (P= 0.46). Multivariate logistic regression modelling, including terms for maternal age (polynomial), weight >91 kg, smoking during pregnancy, pre-pregnancy hypertension and diabetes, did not document an association between previous caesarean section and unexplained antepartum stillbirth (OR 1.27, 95% CI 0.92-1.77). CONCLUSION: Caesarean section in the first birth does not increase the risk of unexplained antepartum stillbirth in second pregnancies.

Using the LMS method to calculate z-scores for the Fenton preterm infant growth chart.

OBJECTIVES: The use of exact percentiles and z-scores permit optimal assessment of infants' growth. In addition, z-scores allow the precise description of size outside of the 3rd and 97th percentiles of a growth reference. To calculate percentiles and z-scores, health professionals require the LMS parameters (Lambda for the skew, Mu for the median, and Sigma for the generalized coefficient of variation; Cole, 1990). The objective of this study was to calculate the LMS parameters for the Fenton preterm growth chart (2003). DESIGN: Secondary data analysis of the Fenton preterm growth chart data. METHODS: The Cole methods were used to produce the LMS parameters and to smooth the L parameter. New percentiles were generated from the smooth LMS parameters, which were then compared with the original growth chart percentiles. RESULTS: The maximum differences between the original percentile curves and the percentile curves generated from the LMS parameters were: for weight; a difference of 66 g (2.9%) at 32 weeks along the 90th percentile; for head circumference; some differences of 0.3 cm (0.6-1.0%); and for length; a difference of 0.5 cm (1.6%) at 22 weeks on the 97th percentile. CONCLUSION: The percentile curves generated from the smoothed LMS parameters for the Fenton growth chart are similar to the original curves. These LMS parameters for the Fenton preterm growth chart facilitate the calculation of z-scores, which will permit the more precise assessment of growth of infants who are born preterm.

Higher versus lower protein intake in formula-fed low birth weight infants.

BACKGROUND: The ideal quantity of dietary protein for formula-fed low birth weight infants < 2.5 kilograms is still a matter of controversy and debate. In premature infants, the protein intake must be sufficient to achieve normal growth without negative effects such as acidosis, uremia, and elevated levels of circulating amino acids (e.g. phenylalanine levels). This systematic review evaluates the benefits and risks of higher (>= 3.0 g/kg/day) versus lower (< 3.0 g/kg/day) protein intakes during the initial hospital stay of formula-fed preterm infants < 2.5 kilograms. OBJECTIVES: To determine whether higher (>= 3.0 g/kg/day) versus lower (< 3.0 g/kg/day) protein intakes during the initial hospital stay of formula-fed preterm infants < 2.5 kilograms result in improved growth and neurodevelopmental outcomes without evidence of short and long-term morbidity. SEARCH STRATEGY: Two review authors searched MEDLINE (1966 - May 2005), CINAHL (1982 - May 2005), PubMed (1966 - May 2005), EMBASE (1980 - May 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005), abstracts, conferences and symposia proceedings from Society of Pediatric Research, and American Academy of Pediatrics. Cross references were reviewed independently for additional relevant titles and abstracts for articles up to fifty years old. SELECTION CRITERIA: Randomized controlled trials contrasting levels of formula protein intakes as low (< 3.0 g/kg/day), high (=> 3.0 g/kg/day but < 4.0 g/kg/day), or very high protein intake (=> 4.0 g/kg/day) during hospitalization of neonates less than 2.5 kilograms at birth who were formula-fed. Studies were not included if infants received partial parenteral nutrition during the study period or were fed formula as a supplement to human milk. Given the small number of studies that met all inclusion criteria, studies in which nutrients other than protein also varied (> 10% relative difference) were added in a post-facto analysis. DATA COLLECTION AND ANALYSIS: Two review authors used standard methods of the Cochrane Collaboration and of the Cochrane Neonatal Review Group to independently assess trial eligibility and quality, and extracted data. In a 3-arm trial where two groups fell within the same predesignated protein intake group, weighted means and pooled standard deviations were calculated. MAIN RESULTS: The literature search identified 37 studies, of which five met all the inclusion criteria. All five studies compared low (< 3.0 g/kg/day) to high protein intakes (=> 3.0 g/kg/day but < 4.0 g/kg/day). The overall analysis revealed an improved weight gain (WMD 2.36 g/kg/day, 95% CI 1.31, 3.40) and higher nitrogen accretion (WMD 143.7 mg/kg/day, 95% CI 128.7, 158.8) in infants receiving formula with higher protein content while other nutrients were kept constant. None of the studies reported IQ or Bayley scores at 18 months or later. No significant differences were seen in rates of necrotizing enterocolitis, sepsis or diarrhea. Of three studies included in the post-facto analysis, only one could be included in the meta-analysis. The post-facto analysis revealed further improvement in all growth parameters in infants receiving formula with higher protein content (weight gain: WMD 2.53 g/kg/day, 95% CI 1.62, 3.45, linear growth: WMD 0.16 cm/week, 95% CI 0.03, 0.30, and head growth: WMD 0.23, 95% CI 0.12, 0.35). There was no significant difference (WMD 0.25, 95% CI -0.20, 0.70) in the concentration of plasma phenylalanine between the high and low protein intake groups. One study (Goldman 1969) in the post-facto analysis documented a significantly increased incidence of low IQ scores, below 90, in infants of birth weight less than 1300 grams who received a very high protein intake (6 to 7.2 g/kg/day). AUTHORS' CONCLUSIONS: This systematic review suggests that higher protein intake (=> 3.0 g/kg/day but < 4.0 g/kg/day) from formula accelerates weight gain. Based on increased nitrogen accretion rates, this most likely indicates an increase in lean body mass. Although accelerated weight gain is considered to be a positive effect, increase in other outcome measures examined may represent a negative or ambivalent effect. These include elevated blood urea nitrogen levels and increased metabolic acidosis. Limited information was available regarding the impact of higher formula protein intakes on long term outcomes such as neurodevelopmental abnormalities. As determined in this review, existing research literature on this topic is not adequate to make specific recommendations regarding the provision of very high protein intake (> 4.0 g/kg/day) from formula.

GI complications in pediatric patients post-BMT.

This retrospective study comprehensively examined hepatic and gastrointestinal complications post-bone marrow transplant (BMT) in a heterogeneous group of 132 pediatric patients that underwent 142 transplants. Hyperbilirubinemia occurred in 28% of this population with clinically evident jaundice in 16%. Acute graft-versus-host disease (GVHD) occurred in 46% of the population, with liver involvement in 39% and intestinal involvement in 60% of those with acute GVHD. Veno-occlusive disease (VOD) occurred in 18% of the population. A greater increase in hepatic transaminases was noted in GVHD and VOD than nonspecific liver injury. Serum bilirubin may help to differentiate between VOD and hepatic GVHD. Biliary sludging occurred in 20% of patients and was associated with increased morbidity. Common post transplant gastrointestinal complications included mucositis in 90%, vomiting in 85% and abdominal pain in 71%. TPN support post transplant was required in 91%. Diarrhea occurred in 67% with the most common identified etiologies reported as GVHD (27%), viral (6%), Clostridium difficile (8%) infections and unknown (28%). Typhilitis developed in 3.5%. Melena or hematochezia occurred in 11 patients (8%). However, gastrointestinal bleeding was disproportionately represented in intensive care unit admissions (5/27) and 100 day mortality (5/21). Gastrointestinal and hepatic complications represent a major cause of morbidity and mortality in pediatric BMT recipients.

Maternal haemolysis, elevated liver enzymes and low platelets syndrome: perinatal and neurodevelopmental neonatal outcomes for infants weighing less than 1250 g.

OBJECTIVES: To study mortality and short-term morbidity of infants born to women with HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome and to compare the long-term neurodevelopmental morbidity of a subgroup with birth weight (BWT) less than 1250 g (study group) with weight matched controls. METHODS: Retrospective chart review and prospective neurodevelopmental follow-up through a Perinatal Follow-up clinic. Analysis of perinatal and neonatal data for women diagnosed with HELLP from 1993 to 1996. Neurodevelopmental outcome for the study group was compared to a group of weight matched controls. RESULTS: A total of 109 infants (mean gestational age 32.6 weeks, mean BWT 1766 g) were born to 104 women with HELLP syndrome. There was a significant decrease in mortality (P = 0.002) and morbidity (P < 0.05) with increasing gestational age and birthweight. No significant differences in neonatal mortality and morbidity were present between the infants weighing less than 1250 g study and weight matched control group. However, at 3 years, the study group had fewer children with cerebral palsy (P = 0.024) and mental disability (P trend = 0.07). Mean cognitive index was 99 versus 91 in the controls (P = 0.101). CONCLUSION: Improved health outcomes occur with increased gestational age. Infants with BWT less than 1250 g born to women with HELLP syndrome were not at risk of increased neurodevelopmental disability compared to controls.

The risk of stillbirth in pregnancies before and after the onset of diabetes.

AIMS: There is significant controversy as to whether or not stillbirth is increased in pregnancies prior to the onset of diabetes. An observed increase may be indicative of risks associated with untreated gestational diabetes. It is generally accepted that the risk of stillbirth in pregnancies that occur after the onset of diabetes has been diminished by modern obstetric care. However, the degree of residual risk is not well quantified. This study sought to examine the rates of stillbirth before and after the onset of diabetes compared with the general population. METHODS: Retrospective cohort and nested case-control study. The study population was drawn from the UK-based General Practice Research Database, comprising some 300 practices, with data collection from the late 1980s until September 1999. From the base population, 913 diabetic women who had had a pregnancy were identified and 10,000 subjects without diabetes were randomly chosen as controls. Stillbirth was defined as death in utero after 20 weeks or with birth weight >500 g. RESULTS: The stillbirth rates were higher in prediabetic pregnancies (19.7/1000), and in those occurring after the diagnosis of diabetes (33.7/1000), compared with the non-diabetic population (5.5/1000). Stillbirths were matched to four live births by maternal age and year of birth. Prediabetic pregnancy and pregnancy after the onset of diabetes were strongly associated with stillbirth: odds ratio (OR)=4.68 (1.67, 13.08) and OR=4.39 (2.22, 8.64), respectively. CONCLUSIONS: The risk of stillbirth was increased in both prediabetic and post-diabetic pregnancy.

Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients.

The incidence, risk factors and mortality of veno-occlusive disease (VOD) were identified for 142 pediatric hematopoietic stem cell (HSC) transplant recipients with hematological malignancies (83), solid tumors (41) and nonmalignant diseases (18). This historical cohort of 142 HSC transplant patients, from January 1993 through June 2000, was assessed by chart review. Risk factors for the development of VOD and mortality were assessed by multiple logistic regression and Kaplan-Meier survival curves respectively. The incidence of VOD was 18.3% (26/142 transplants). Multivariate analysis reconfirmed the known pretransplant risk factors of induction therapy with busulfan and transplantation with matched unrelated donor cells as significant risk factors for the development of VOD. In addition, two new risk factors, positive CMV serology in the recipient and TPN provided in the 30 days prior to transplant, were identified. Mortality in transplant patients at 100 days was greater in the VOD-positive group (10/26 (38.5%)) compared to the VOD-negative group (11/116 (9.5%) (P=0.001)). The risk of death was 4.97 times higher with 95% CIs (2.11, 11.71) for the VOD-positive group. Decreasing the risk factors for VOD may decrease mortality in this patient population.

Contribution of cytosolic cysteine residues to the gating properties of the Kir2.1 inward rectifier.

The topological model proposed for the Kir2.1 inward rectifier predicts that seven of the channel 13 cysteine residues are distributed along the N- and C-terminus regions, with some of the residues comprised within highly conserved domains involved in channel gating. To determine if cytosolic cysteine residues contribute to the gating properties of Kir2.1, each of the N- and C-terminus cysteines was mutated into either a polar (S, D, N), an aliphatic (A,V, L), or an aromatic (W) residue. Our patch-clamp measurements show that with the exception of C76 and C311, the mutation of individual cytosolic cysteine to serine (S) did not significantly affect the single-channel conductance nor the channel open probability. However, mutating C76 to a charged or polar residue resulted either in an absence of channel activity or a decrease in open probability. In turn, the mutations C311S (polar), C311R (charged), and to a lesser degree C311A (aliphatic) led to an increase of the channel mean closed time due to the appearance of long closed time intervals (T(c) >or= 500 ms) and to a reduction of the reactivation by ATP of rundown Kir2.1 channels. These changes could be correlated with a weakening of the interaction between Kir2.1 and PIP(2), with C311R and C311S being more potent at modulating the Kir2.1-PIP(2) interaction than C311A. The present work supports, therefore, molecular models whereby the gating properties of Kir2.1 depend on the presence of nonpolar or neutral residues at positions 76 and 311, with C311 modulating the interaction between Kir2.1 and PIP(2).