Gerd M. Lackmann

Parental Smoking and Neonatal Serum Levels of Polychlorinated Biphenyls and Hexachlorobenzene

Polychlorinated biphenyls (PCB) and hexachlorobenzene (HCB) are ubiquitous compounds that have tumor-promoting properties if applied together with tobacco-specific carcinogens. It was the purpose of the present study to investigate whether parental smoking by itself will increase the prenatal uptake of such organochloric compounds. With the informed consent of the parents, blood samples were taken from 80 full-term neonates before the first oral feeding. Six PCB congeners (PCB 28, 52, 101, 138, 153, and 180) and HCB were analyzed with capillary gas chromatography. Information about parental smoking behavior, the geographic origin of the parents, and their actual and previous working places was recorded. We composed three study groups for statistical analyses: active smoking mothers (n = 12), passive smoking mothers (n = 33), and nonsmoking families (n = 35). Neonates born to active smoking mothers had the highest PCB and HCB concentrations compared with children of passive or nonsmoking mothers. These differences were statistically significant (p < 0.01) in the cases of PCB 138, total PCB, and HCB. Newborns of passive smoking mothers had higher PCB and HCB concentrations than children of nonsmoking families but lower values than those of active smoking mothers. These differences were statistically significant for all compounds with the exception of PCB 180. It is concluded that active and passive maternal smoking increases the neonatal burden with PCB and HCB.

Influence of Maternal Age and Duration of Pregnancy on Serum Concentrations of Polychlorinated Biphenyls and Hexachlorobenzene in Full-Term Neonates

Polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) are ubiquitous carcinogenic and teratogenic compounds that are transplacentally transferred from mother to fetus during pregnancy. It was the aim of the present study to evaluate the possible influence of maternal age and duration of pregnancy on the neonatal burden with these substances. Blood samples were taken from 80 full-term German neonates within the first 12 h of life, before the first oral feeding. The serum concentrations of six PCB congeners (28, 52, 101, 138, 153, and 180) and HCB were determined with capillary gas chromatography with electron capture detection. The concentrations of the lower chlorinated PCB congeners (28, 52, and 101) were below the detection limit. PCB 153 showed the highest serum concentration (median 0.42 μg/l), followed by PCB 138 (0.34 μg/l) and PCB 180 (0.17 μg/l). Total PCB concentration was 0.96 μg/l, HCB concentration 0.61 μg/l. All detectable PCB congeners and the total PCB concentration correlated significantly with the gestational age of the newborns (r = 0.2639; p < 0.01), with 50–140% higher serum levels in children born at 42 weeks of gestation as compared with neonates born in the 38th week. HCB concentration correlated with maternal age (r = 0.249; p < 0.01), with 2.7-fold higher serum levels in offspring of 40-year-old as compared with 20-year-old women. It is concluded that the neonatal burden with organochlorine compounds depends on maternal age and duration of pregnancy, thereby reflecting the increase in body pollution with these substances during human life as well as a continuous transplacental transfer from mother to fetus during pregnancy.

Serum enzyme activities in full-term asphyxiated and healthy newborns : enzyme kinetics during the first 144 hours of life

Little is known about the kinetics of most serum enzymes during the first hours of life, and even less about the effect on such enzyme activities of perinatal hypoxia-ischaemia. It was the aim of the present study to evaluate the serum kinetics of seven differently located cell enzymes in healthy and asphyxiated newborns during the 1st week of life. The serum activities of cytoplasmic and mitochondrial [aspartate aminotransferase (ASAT), creatine kinase (CK), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), and hydroxybutyrate dehydrogenase (HBDH)] and membrane-bound (gamma-glutamyl-transferase and leucine arylaminidase) enzymes were prospectively measured in full-term asphyxiated (n = 49) and healthy (n = 87) newborns during the first 144 h of life. The blood samples were taken serially at five fixed times: 0 (cord), 12, 24, 72, and 144 h postpartum. The asphyxiated newborns had significantly increased serum activities of ASAT, LDH, and HBDH up to 72 h postpartum, whereas healthy newborns showed higher CK and GLDH activities. Only the activities of ASAT, LDH, and HBDH seemed to depend on the oxygen supply of the fetus or newborn. If other causes of increased serum enzyme activities, e.g. liver diseases, haemolytic disorders, tumours, or inborn errors of metabolism, are excluded, elevated serum activities of ASAT, LDH, and HBDH should draw ones attention to a perinatal hypoxic-ischaemic insult of the newborn.

Gestational Age-Dependent Reference Values for Iron and Selected Proteins of Iron Metabolism in Serum of Premature Human Neonates

The diagnosis and treatment of fetal and neonatal diseases requires knowledge of gestational age-dependent reference ranges for most laboratory values. It was the aim of the present study to establish reference values for serum iron, transferrin, ferritin and ceruloplasmin concentrations in premature neonates, thereby paying attention to the possible changes with gestational age. Blood samples were taken from 100 premature neonates within the first hour of life. Total serum iron, transferrin, ferritin and ceruloplasmin concentrations were determined, transferrin saturation was calculated. Newborns who developed a presumed oxygen radical disease of prematurity were excluded from the study (n = 37), because previous investigations could demonstrate significantly lower serum transferrin and ceruloplasmin concentrations in prematures suffering one of these disorders. Related to gestational age, only serum transferrin concentration showed a statistically significant increase and correlation (r = 0.47; p < 0.0001) with rising age. Although statistically not significant, even serum ferritin concentration increased with rising age of the neonates. None of the investigated laboratory values correlated with birth weight. Only ferritin showed a slight, but statistically not significant increase with higher body mass. We conclude that gestational age-dependent changes of serum transferrin levels must be considered in the judgement of fetal and neonatal diseases, whereas total serum iron and ceruloplasmin concentrations remain rather constant at least during the last weeks of gestation.

Polychlorinated biphenyls and hexachlorobenzene in full-term neonates. Reference values updated.

Objective: To determine actual reference values of polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) in full-term neonates. Patients and Methods: Cord blood samples were taken from 200 healthy, full-term neonates in 1998. Blood specimens were immediately centrifuged, and serum was stored in glass tubes at –20°C up to analysis. Six PCB congeners (IUPAC No. 28, 52, 101, 138, 153, and 180) and HCB were determined with capillary gas chromatography with electron capture detection. Study groups were tested on mean differences with Wilcoxon’s test of independent samples. The 95th percentiles by rank were calculated as reference values. Results: One sample was excluded from further evaluation because of unusually high PCB concentrations. Personal data of the remaining 199 newborns showed 106 male and 93 female neonates. Mean gestational age was 40 weeks (range 38–43 weeks), mean birth weight was 3,450 g (2,300–5,060 g). The concentrations of the lower-chlorinated PCB congeners 28, 52, and 101 were below the detection limit with exception of two probes. Reference values (95th percentile by rank) of the higher-chlorinated PCB congeners and HCB were as follows: PCB 138, 0.5 µg/l; PCB 153, 0.5 µg/l; PCB 180, 0.4 µg/l; and HCB, 0.5 µg/l. Conclusions: The results of the present study clearly demonstrate a further decline in the prenatal uptake of PCBs and HCB since 1994–1995. During the past 15 years, a 75% decline in the prenatal burden with PCBs and a 90% reduction in the burden with HCB could be demonstrated.

Rapid Progressive Subacute Sclerosing Panencephalitis in a 2-Year-Old Child with Congenital Athyreosis

We present the unique case of a 2-year-old girl with congenital athyreosis who acquired primary measles virus infection at the age of 18 months, coincidentally with an Epstein-Barr virus infection. First neurologic symptoms of subacute sclerosing panencephalitis appeared 5 months later, and the girl died within 6 months after a rapid progressive illness. Factors possibly predisposing to this extraordinary disease course-primary measles virus infection at an early age and lack of evidence for immunodeficiency-are discussed.

Tabakspezifische transplazentare Kanzerogene, Nikotin und Cotinin im Urin von Neugeborenen rauchender Mütter

ZusammenfassungHintergrund: Obwohl viele Frauen während der Schwangerschaft rauchen und so der sich entwickelnde Fetus transplazentaren Kanzerogenen ausgesetzt werden kann, ist bislang wenig über die fetale Aufnahme solcher Verbindungen bekannt. Ziel der vorliegenden Untersuchung war es, den Urin von Neugeborenen rauchender und nichtrauchender Mütter auf Metaboliten des tabakspezifischen Kanzerogens 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanon (NNK) sowie Nikotin und Cotinin zu untersuchen. Methode: Die erste Urinprobe reifer Neugeborener wurde gesammelt und auf die NNK-Metaboliten 4-(Methylnitrosamino)- 1-(3-Pyridyl)-1-Butanol (NNAL) und dessen Glukuronid, NNAL-Gluc, untersucht. Die Analysen erfolgten mittels Gaschromatographie mit einem Nitrosamin-selektiven Detektor und wurden durch Massenspektrometrie bestätigt. Nikotin und Cotinin wurden gaschromatografisch-massenspektrometrisch analysiert. Ergebnisse: NNAL-Gluc wurde in 22 von 31 Urinproben (71%) von Neugeborenen rauchender Mütter nachgewiesen. In 4 Fällen wurde zusätzlich NNAL entdeckt. Keine dieser Verbindungen war in den 17 Proben von Neugeborenen nichtrauchender Mütter nachweisbar. Die mittlere Konzentration von NNAL plus NNAL-Gluc betrug in den quantifizierbaren Proben 0,19±0,14 pmol/ml Urin, ungefähr 10% des Werts, den man bei erwachsenen Aktivrauchern findet. Die Konzentration von NNAL plus NNAL-Gluc korrelierte mit der Anzahl der Zigaretten, die pro Tag während der Schwangerschaft geraucht worden waren (r=0,55; P<0,005). Auch die Nikotin- und Cotininkonzentrationen waren bei den Neugeborenen rauchender Mütter signifikant gegenüber der Kontrollgruppe erhöht und korrelierten mit den NNAL- und NNAL-Gluc-Konzentrationen. Schlußfolgerung: Die Ergebnisse zeigen, daß 2 Metaboliten des tabakspezifischen, transplazentaren Kanzerogens NNK im Urin von Neugeborenen rauchender Mütter nachweisbar sind.SummaryBackground: Cigarette smoking is common during pregnancy and can expose the developing fetus to transplacental carcinogens, but relatively little information is available on fetal uptake of such compounds. It was the aim of the present study to analyze the first urine of newborns of mothers who did or did not smoke for metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as nicotine and cotinine. Methods: First urine of newborns was collected and analyzed for two metabolites of NNK. The metabolites are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide, NNAL-Gluc. The analyses were carried out by gas chromatography and nitrosamine-selective detection with confirmation by mass spectrometry. Nicotine and cotinine were analyzed by gas chromatography-mass spectrometry. Results: NNAL-Gluc was detected in 22 of 31 (71%) of the urine samples from newborns of smoking mothers; in 4 cases, NNAL was also detected. Neither of these analytes was detected in the 17 samples from newborns of mothers who did not smoke. NNAL plus NNAL-Gluc levels in the positive quantified newborn urine samples were 0.19±0.14 pmol/ml urine, about 10% of that seen in adult smokers. NNAL plus NNAL-Gluc levels correlated with the number of cigarettes smoked per day during pregnancy (r=0.55; p<0.005). Nicotine and cotinine levels in the urine of newborns of smoking mothers were also significantly higher than in the urine of newborns of non-smoking mothers and correlated well with levels of NNAL plus NNAL-Gluc. Conclusions: The results demonstrate that two metabolites of the tobacco-specific transplacental carcinogen NNK are present in the urine of newborns born to mothers who smoke cigarettes.

An unspecific immunostimulating agent and juvenile dermatomyositis: enhanced T-cell proliferation and reverse immunosuppression as a severe adverse drug reaction

We report the case of an 8-year-old girl with juvenile dermatomyositis, whose disease course rapidly worsened under treatment with an unspecific immunostimulating agent containing large amounts of inosine. An 8-year-old girl had suffered from flat-topped papules over the dorsal interphalangeal joints for 1.5 years. As these papules were considered to be of viral origin, treatment with Delimmun, an unspecific immunostimulating agent containing 379.75 mg dimepranole4-acetoamidobenzoate and 120.25 mg inosine per tablet, was initiated 2 months previously. Under this therapy, the girl developed erythematous, scaling patches on the upper anterior chest and the extensor surfaces of her arms and legs as well as a violaceous erythema of the face in a ‘‘butterfly’’ distribution and purple-red discolouration of the upper eyelids. On admission to hospital, the papules on her hands were recognised as typical, so-called Gottron papules (Fig. 1), which are pathognomonic for dermatomyositis. Laboratory investigations were normal with the exception of slightly elevated transaminases (ASAT 29 U/l, reference range <20 U/l; GPT 16 U/l, reference range <12 U/l) and muscle enzymes (LDH 373 U/l, reference range <200 U/l; CK 157 U/l, reference range <70 U/l). Immunological investigations showed normal values for immunoglobulins, complement factors, and most auto-antibodies, with the exception of elevated anti-nuclear antibodies (1:320, normal <1:160). HLA-class 1 typing showed type A3 A-B7 B15 (62) Cw3 Cw7; HLA b27 was negative. Serological investigations revealed negative titres against most bacteria and viruses. T2-weighted, Gadolinium-enhanced MRI of the thighs showed a pathological, inhomogeneous signal enhancement of all muscles, especially of the subsartorial canal. We started treatment with prednisolone (2 mg per kg body weight). Under this therapy, the skin lesions disappeared immediately. Pathological MRI findings completely normalised after 6 months of therapy. Juvenile dermatomyositis, a systemic vasculopathy, is the most common of the idiopathic inflammatory myopathies of childhood with unknown aetiology. The cutaneous signs of dermatomyositis may precede, like in our patient, or follow myositis by weeks to years. An interplay with host genetic factors, viral infection of muscle, and autoimmune mechanisms is probably contributory [3]. Deposition of immunoglobulins and the C5b-9 complement membrane attack complex has been demonstrated on intramuscular blood vessels suggesting that humorally mediated damage initiates the angiopathy that precedes muscle destruction. The final pathway for muscle fibre damage may be T-cell-dependent stimulation of B-cells, with resultant antibody-mediated cytotoxicity [4]. Whether the immunostimulating agent Delimmun, that our patient received for treatment of the papules on her hands, worsened the course of the Fig. 1 Gottron papules on our patient’s hand, pathognomonic for juvenile dermatomyositis Eur J Pediatr (2003) 162: 725–726 DOI 10.1007/s00431-003-1290-z