Intensive Care Medicine

Carbamazepine intoxication is not uncommon and accounts for many cases of poisoning among anticonvulsive medications users. Since there is no specific antidote for carbamazepine overdose, management is limited to gastric decontamination and supportive therapy. With its high protein binding, the role of extracorporeal elimination in carbamazepine intoxication is still questionable. Here two cases of severe carbamazepine intoxication are presented; the cases were brought to the emergency department after the ingestion of 12,000 mg of controlled release carbamazepine for the first case, and unknown amounts of the same drug for the second case. Both cases were presented with altered mental status, convulsion, and high serum carbamazepine levels of more than 20 mcg/mL. They were intubated and treated with continuous venovenous hemofiltration, after which carbamazepine levels declined significantly along with subsequent clinical improvement and complete neurological recovery. Both cases were discharged home for further psychiatric care.

The intra-and interindividual variability of the oral glucose tolerance test (OGTT) and other risk factors was investigated in 237 subjects, aged 64-87, examined annually in the period 1971-1975. Coefficients of intraindividual variation (CV,) were calculated from individual regressions on time. The lowest CV, was found for the summary index including fasting glucose (area under the curve, AUC): 10.0 f 4.9%. For fasting and 30, 60, and 120 min glucose the values ranged from 12 to 18%. The CV,'s were not associated with age, gender, drug use, and disease prevalence, and may also be applied to other populations. The reliability coefficient depended on the prevalence of diabetes in the population and was higher than observed in younger populations. The highest reliability coefficient was observed for AUC: 0.81. For the combined information of OGTT, reflected by AUC or by classification according to WHO criteria, the variability was comparable to that of other cardiovascular risk factors such as serum total cholesterol.

Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of ∼5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two-NR2F2 and CHD2-are particularly intriguing gene candidates for CDH.

Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a ~19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.

Rationale: Disordered extracellular matrix production is a feature of bronchopulmonary dysplasia (BPD). The basis of this phenomenon is not understood. Objectives: To assess lysyl oxidase expression and activity in the injured developing lungs of newborn mice and of prematurely born infants with BPD or at risk for BPD. Methods: Pulmonary lysyl oxidase and elastin gene and protein expression were assessed in newborn mice breathing 21 or 85% oxygen, in patients who died with BPD or were at risk for BPD, and in control patients. Signaling by transforming growth factor (TGF-b) was preemptively blocked in mice exposed to hyperoxia using TGFb-neutralizing antibodies. Lysyl oxidase promoter activity was assessed using plasmids containing the lox or loxl1 promoters fused upstream of the firefly luciferase gene. Measurements and Main Results: mRNA and protein levels and activity of lysyl oxidases (Lox, LoxL1, LoxL2) were elevated in the oxygeninjured lungs of newborn mice and infants with BPD or at risk for BPD. In oxygen-injured mouse lungs, increased TGF-b signaling drove aberrant lox, but not loxl1 or loxl2, expression. Lox expression was also increased in oxygen-injured fibroblasts and pulmonary artery smooth muscle cells. Conclusions: Lysyl oxidase expression and activity are dysregulated in BPD in injured developing mouse lungs and in prematurely born infants. In developing mouse lungs, aberrant TGF-b signaling dysregulated lysyl oxidase expression. These data support the postulate that excessive stabilization of the extracellular matrix by excessive lysyl oxidase activity might impede the normal matrix remodeling that is required for pulmonary alveolarization and thereby contribute to the pathological pulmonary features of BPD.

Aim-To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two diVerent age groups. Methods-Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score. Results-Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T 1 ⁄2) could not be determined in all infants: T 1 ⁄2 was 11.0 ± 5.7 in 11 infants in group 1 and 4.8 ± 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 ± 0.09 (group 1) and 0.28 ± 0.35 (group 2). The pain score did not correlate with therapeutic concentrations. Conclusions-A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations. (Arch Dis Child Fetal Neonatal Ed 1999;80:F59-F63)

Background. Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available.

Congenital diaphragmatic hernia (CDH) occurs sporadically, with an incidence of 1 in 2500 to 1 in 5000 of newborns, depending on whether stillbirths are included. The embryology and molecular and genetic mechanisms behind this anomaly are beyond the scope of this article and can be found elsewhere. 1,2 CDH does not designate a single clinical entity, and outcomes are accordingly diverse. Most cases are left sided (LCDH); 13% are right sided (RCDH); and bilateral lesions, complete agenesis, and other rarities total up to less than 2% of cases. In around 40% of cases, there are associated anomalies, representing an independent predictor of neonatal death, with less than 15% of babies surviving in this group. 2,3 Most of these cases are thus apparently isolated, although they might still be part of a yet unidentified spectrum of a disease affecting multiple organs. Key to the problem is that CDH lungs display severe developmental arrest of airway and vessels, resulting in lung hypoplasia. 4,5

The vagal neural crest adjacent to the first seven somites gives rise to both ganglionic and ectomesenchymal derivatives. Ganglionic derivatives are the neurons and supportive cells of the enteric nervous system (ENS), cardiac, and dorsal root ganglia. Ectomesenchymal derivatives are cells in the cardiac outflow tract and the mesenchymal components of thymus and parathyroids. Ectomesenchymal derivatives are formed by a segment of the vagal neural crest, from the level of the otic vesicle down to the caudal boundary of the third somite, called the cardiac neural crest. We performed neural crest ablations to study regional differences within the avian vagal neural crest with regard to the formation of the ENS. Ablation of the entire vagal neural crest from the mid-otic vesicle down to the seventh somite plus the nodose placode resulted in the absence of ganglia in the midgut (jejunum and ileum) and hindgut (colon). The foregut (esophagus, proventriculus, gizzard, and duodenum) was normally innervated. After ablation of the vagal neural crest adjacent to somites 3-5, ganglia were absent in the hindgut. Ablations of vagal neural crest not including this segment had no effect on the formation of the ENS. We surmise that the innervation of the hindgut in vivo depends specifically on the neural crest adjacent to somites 3-5, whereas innervation of the midgut can be accomplished by all segments within the vagal neural crest. The foregut can also be innervated by a source outside the vagal neural crest.

In conditions associated with high serum iodothyronine sulfate concentrations, e.g. during fetal development, desulfation of these conjugates may be important in the regulation of thyroid hormone homeostasis. However, little is known about which sulfatases are involved in this process. Therefore, we investigated the hydrolysis of iodothyronine sulfates by homogenates of V79 cells expressing the human arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well as tissue fractions of human and rat liver and placenta. We found that only the microsomal fraction from liver and placenta hydrolyzed iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic reticulum-associated ARSC showed activity toward iodothyronine sulfates; the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as well as human placenta microsomes hydrolyzed iodothyronine sulfates with a substrate preference for 3,3-diiodothyronine sulfate (3,3-T 2 S) ϳ T 3 sulfate (T 3 S) Ͼ Ͼ rT 3 S ϳ T 4 S, whereas human and rat liver microsomes showed a prefer-ence for 3,3-T 2 S > T 3 S Ͼ Ͼ rT 3 S ϳ T 4 S. ARSC and the tissue microsomal sulfatases were all characterized by high apparent K m values (>50 M) for 3,3-T 2 S and T 3 S. Iodothyronine sulfatase activity determined using 3,3-T 2 S as a substrate was much higher in human liver microsomes than in human placenta microsomes, although ARSC is expressed at higher levels in human placenta than in human liver. The ratio of estrone sulfate to T 2 S hydrolysis in human liver microsomes (0.2) differed largely from that in ARSC homogenate (80) and human placenta microsomes (150). These results suggest that ARSC accounts for the relatively low iodothyronine sulfatase activity of human placenta, and that additional arylsulfatase(s) contributes to the high iodothyronine sulfatase activity in human liver. Further research is needed to identify these iodothyronine sulfatases, and to study the physiological importance of the reversible sulfation of iodothyronines in thyroid hormone metabolism.

Abbreviations: BPA, Bisphenol A; -OH, hydroxylated metabolite of; PAPS, 3Ј-phosphoadenosine-5Ј-phosphosulfate; PBDE, polybrominated diphenylether; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran; PHAH, polyhalogenated aromatic hydrocarbon; SULT1E1, estrogen sulfotransferase.