Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. ...We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.
In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.
Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 36%) did not differ significantly from the control group (54/180 30%; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).
Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.
Deutsche Forschungsgemeinschaft.
OBJECTIVE:--To investigate the growth of children from pregnancies with gestational diabetes mellitus (GDM) and its association with antenatal maternal, fetal, and recent anthropometric parameters of ...mother and father. RESEARCH DESIGN AND METHODS--In 324 pregnancies of Caucasian women with GDM, BMI before pregnancy, maternal glycemic values, and measurements of the fetal abdominal circumference were recorded. The weight and height of infants were measured at birth and at follow-up at 5.4 years (range 2.5-8.5). In addition, somatic data from routine examinations at 6, 12, and 24 months and the BMI of parents at follow-up were obtained. BMI standard deviation scores (SDSs) were calculated based on age-correspondent data. RESULTS:--At all time points, BMI was significantly above average (+0.82 SDS at birth; +0.56 at 6, +0.35 at 12, and +0.32 at 24 months; and +0.66 at follow-up; P < 0.001). BMI at birth was related to BMI at follow-up (r = 0.27, P < 0.001). The rate of overweight at follow-up was 37% in children with birth BMI >/=90th percentile and 25% in those with normal BMI at birth (P < 0.05). Abdominal circumference of third trimester and postprandial glucose values were related to BMI at follow-up (r = 0.22 and r = 0.18, P < 0.01). Recent maternal, paternal, and birth BMI were independent predictors of BMI at follow-up (r = 0.42, P < 0.001). Sixty-nine percent of children of parents with BMI >/=30 kg/m² were overweight at follow-up compared with 20% of those with parental BMI <30 kg/m² (P < 0.001). CONCLUSIONS:--Children of mothers with GDM have a high rate of overweight that is associated both with intrauterine growth and parental obesity.
Anticancer treatment with ifosfamide but not with its structural isomer cyclophosphamide is associated with development of renal Fanconi syndrome leading to diminished growth in children and bone ...problems in adults. Since both cytotoxics share the same principal metabolites, we investigated whether a specific renal uptake of ifosfamide is the basis for this differential effect. First we studied the interaction of these cytotoxics using cells transfected with organic anion or cation transporters and freshly isolated murine and human proximal tubules with appropriate tracers. Next we determined changes in membrane voltage in proximal tubular cells to understand their differentiated nephrotoxicity. Ifosfamide but not cyclophosphamide was significantly transported into cells expressing human organic cation transporter 2 (hOCT2) while both did not interact with organic anion transporters. This points toward a specific interaction of ifosfamide with hOCT2, which is the main OCT isoform in human kidney. In isolated human proximal tubules ifosfamide also interacted with organic cation transport. This interaction was also seen in isolated mouse proximal tubules; however, it was absent in tubules from OCT-deficient mice, illustrating the biological importance of this selective transport. Ifosfamide decreased the viability of cells expressing hOCT2, but not that of control cells. Coadministration of cimetidine, a known competitive substrate of hOCT2, completely prevented this ifosfamide-induced toxicity. Finally, ifosfamide but not cyclophosphamide depolarized proximal tubular cells. We propose that the nephrotoxicity of ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of cimetidine may be used to prevent ifosfamide-induced nephrotoxicity.
Background
Randomized controlled trials have indicated reduced mortality rates in very preterm infants assigned to high compared to low oxygen saturation (SpO
2
) target levels, accompanied by higher ...rates of retinopathy of prematurity and bronchopulmonary dysplasia. However, the benefit-to-harm ratio may depend on the local background mortality risk. We therefore aimed to quantify the risk–benefit ratios of different SpO
2
target ranges in 10 tertiary newborn intensive care units (NICUs) in East Germany.
Methods
In a retrospective multicenter study, 1,399 infants born between 2008 and 2012 at a gestational age between 24 0/7 and 27 6/7 weeks and with a birthweight below 1,250 g were grouped according to the hospital's target SpO
2
range high oxygen saturation group (HOSG) above 90%, low oxygen saturation group (LOSG) below 90% and the compliance of units with their target SpO
2
range. The association between neonatal morbidities, neurodevelopmental outcomes, selected treatment strategies, and target SpO
2
ranges was calculated using chi-squared and Mann Whitney
U
tests.
Results
Nine of the ten participating NICUs met their SpO
2
target ranges. Five units were considered as HOSG, and five units were considered as LOSG. Necrotizing enterocolitis and intraventricular hemorrhage grade ≥ 2 occurred significantly more frequently in the HOSG than in the LOSG (8.4% vs. 5.1%,
p
= 0.02; and 26.6% vs. 17.7%,
p
< 0.001). No significant differences in the mortality rate and the rate of retinopathy of prematurity were found.
Conclusion
In our patient population, a lower SpO
2
target range was not associated with increased safety risks in extremely preterm infants. We cannot be sure that our outcome differences are associated with differences in oxygen saturations due to the retrospective study design and the differences in site practices.
Objectives
Post-measles increased susceptibility to subsequent infections seems particularly relevant in low-resource settings. We tested the hypothesis that measles causes a specifically increased ...rate of infections in children, also in a high-resource setting.
Methods
We conducted a retrospective cohort study on a large measles outbreak in Berlin, Germany. All children with measles who presented to hospitals in Berlin were included as cases, children with non-infectious and children with non-measles infectious diseases as controls. Repeat visits within 3 years after the outbreak were recorded.
Results
We included 250 cases, 502 non-infectious, and 498 infectious disease controls. The relative risk for cases for the diagnosis of an infectious disease upon a repeat visit was 1.6 (95% CI 1.4–2.0,
p
< 0.001) vs. non-infectious and 1.3 (95% CI 1.1–1.6,
p
= 0.002) vs. infectious disease controls. 33 cases (27%), 35 non-infectious (12%) and 57 (18%) infectious disease controls presented more than three times due to an infectious disease (
p
= 0.01, and
p
= 0.02, respectively). This results in a relative risk of more than three repeat visits due to an infection for measles cases of 1.8 (95% CI 1.3–2.4,
p
= 0.01), and 1.4 (95% CI 1.0–1.9,
p
= 0.04), respectively.
Conclusion
Our study demonstrates for the first time in a high-resource setting, that increased post-measles susceptibility to subsequent infections in children is measles-specific—even compared to controls with previous non-measles infections.
MECP2
(methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We ...describe for the first time the detailed infectious and immunological phenotype of
MECP2
duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (
S.pneumoniae
,
H.influenzae
) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG
2
-deficiency was detected – in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG
1
-levels were detected in 11/21 patients and supra-normal IgG
3
-levels were seen in 8/21 patients – in 6 of the patients as combined elevation of IgG
1
and IgG
3
. Three of the four patients with IgA/IgG
2
-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in
MECP2
duplication syndrome is associated with IgA/IgG
2
-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with
MECP2
duplication syndrome and low IgA/IgG
2
may benefit from prophylactic substitution of sIgA and IgG.
Tufting enteropathy (TE) is caused by recessive
mutations, and is characterized by intractable diarrhea of congenital onset and disorganization of enterocytes. TE generally requires parenteral ...nutrition (PN) during childhood or intestinal bowel transplantation. We report three unrelated families with six children with TE. We highlight the high rate of disease-related mortality. We observe adequate weight gain with PN, but low to normal and stunted body length, supporting the recent notion that a short stature might be intrinsic to TE. The diagnosis of TE in the index patients from each family was delayed for months to years, even when clinical data, duodenal biopsies, or exome sequencing data were obtained early on. We identified three novel pathogenic EPCAM variants: a deletion of exon 1 that removes the ATG initiation codon, a missense variant c.326A > G (p.Gln109Arg), and nonsense mutation c.429G > A (p.Trp143*) in a compound heterozygous state with the Mediterranean splice site variant c.556-14A > G (Tyr186Phefs*6). Homozygosity for p.Gln109Arg was associated with absent EPCAM staining, and compound heterozygosity for p.Trp143*/Tyr186Phefs*6 was associated with reduced EPCAM staining in duodenal biopsies; such observations might contribute to a genotype-phenotype correlation in larger cohorts of TE patients. This study extends the clinical and molecular spectrum of TE.
The causation of diseases involving the deficiency of more than one enzyme involved in the process of mitochondrial oxidative phosphorylation is unclear. This study suggests one potential cause. The ...authors identified mutation of a gene encoding a component of the mitochondrial translation machinery in two siblings with early fatal hepatoencephalopathy.
The authors identified mutation of the mitochondrial translation machinery in two siblings with early fatal hepatoencephalopathy.
Oxidative phosphorylation drives the synthesis of ATP and takes place through a series of reactions mediated by complexes I, II, III, IV, and V, which are integral to the inner mitochondrial membrane. Each complex is made up of several or many proteins.
1
,
2
For example, complex I is made up of 7 proteins encoded by mitochondrial genes and at least 39 proteins encoded by nuclear genes. Some diseases result from a deficit in a single complex. For example, Leigh's syndrome is caused by a single mutation in one of several mitochondrial and nuclear genes encoding proteins that make up, assemble, . . .
Objective To characterize a new lethal fetal and early postnatal variant of adenylosuccinate lyase (ADSL) deficiency. Study design This was a retrospective analysis of 6 patients with very early ...presentation of ADSL deficiency. Results Most of the 6 patients had impaired intrauterine growth, microcephaly, fetal hypokinesia, and a lack of fetal heart rate variability. Postnatally, they shared severe muscular hypotonia necessitating mechanical ventilation, intractable seizures, and early death. All 6 patients had biochemical evidence of severe (type 1) disease and low residual ADSL activities. All were compound heterozygous for mutations that, based on expression studies, have a pronounced effect on ADSL activity and/or stability. Conclusions ADSL deficiency may present with prenatal growth restriction, fetal and neonatal hypokinesia, and rapidly fatal neonatal encephalopathy. This clinical presentation is associated with genotypes resulting in very low residual enzyme activity.
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