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ZusammenfassungIn Deutschland kommen rund 1,4 % aller Neugeborenen mit einem Gewicht unter 1500 g zur Welt. Im Jahr 2015 waren das 9484 Kinder, von denen 87 % lebend nach Hause entlassen werden konnten. Seit 2006 schreibt der Gemeinsame Bundesausschuss eine Nachuntersuchung dieser Kinder im Alter von 2 Jahren vor, etwa mit den Bayley Scales of Infant Development. In diesem Alter lassen sich Zerebralparesen relativ sicher diagnostizieren, Aussagen zur kognitiven Entwicklung sind aber erst mit etwa 4–5 Jahren einigermaßen verlässlich. Längsschnittdaten aus Niedersachsen der Jahrgänge 2004–2008 weisen nur in 73 % eine übereinstimmende Klassifizierung der gleichen Frühgeborenen (FG) im Alter von 2 und 5 Jahren auf. Die landesweiten Berliner Einschulungsuntersuchungen im Alter von 5–6 Jahren weisen bei 36 % der Kinder unter 750 g Geburtsgewicht und bei 22 % der Kinder zwischen 750 und 1500 g Geburtsgewicht auf einen sonderpädagogischen Förderbedarf hin (gegenüber 5 % bei normalgewichtigen Neugeborenen). Im Alter von 26 Jahren hatten ehemalige Frühgeborene der Bayerischen Entwicklungsstudie (Jahrgänge 1985/86) einen um 7–15 Punkte verringerten Intelligenzquotienten gegenüber Reifgeborenen (RG), sie neigten mehr zu sozialen Ängsten, hatten Schwierigkeiten, einen Partner bzw. eine Part-nerin zu finden und waren häufiger von ihren Eltern abhängig als Kontrollpersonen.

ZusammenfassungWährend effektive Präventionsstrategien zu einem deutlichen Rückgang der meisten vertikalen Infektionen geführt haben (Röteln, HIV, Hepatitis B, Lues, B-Streptokokken), dürften jedes Jahr in Deutschland mehrere Tau-send Kinder mit einer konnatalen Zytomegalie-Virus (CMV)-Infektion auf die Welt kommen, von denen schätzungsweise 90 % jedoch nicht diagnostiziert werden. Während in Mitteleuropa jeweils rund die Hälfte der konnatalen CMV-Infektionen Kinder betrifft, deren Mütter ihre CMV-Erstinfektion entweder in der Schwangerschaft oder bereits vor der Schwangerschaft durchgemacht haben, erreicht der Anteil fetaler CMV-Infektionen bei prägravider mütterliche CMV-Infektion in Ländern mit höheren durchschnittlichen Familiengrößen über 90 %. Die Transmissions-rate steigt mit der Schwangerschaftsdauer an, während die fetale Erkrankungsschwere abnimmt. Bei Erkrankungen vor allem im ersten und zweiten Trimenon kann es zu Hydrops fetalis, hämolytischer Anämie und Gehirnfehlbildungen kommen. Ist die Erkrankung bei Geburt noch in einem floriden Stadium, bietet sich das Bild eines „blueberry muffin“-Babys mit extramedullären Hämatopoiese-Herden in der Haut. Auch bei Geburt asymptomatisch erscheinende Kinder mit konnataler CMV-Infektion können im Laufe des ersten Lebensjahres einen sensorineuralen Hörverlust erleiden (zweithäufigste Ursache nicht syndromalen Hörverlustes nach Connexin-26-Mutationen). Der hypothetische Wert einer pränatalen spezifischen ImmunglobulinGabe wird gegenwärtig in zwei randomisierten Multicenterstudien geprüft, die Behandlung wird dennoch vielerorts von den Krankenkassen übernommen. Bei Neugeborenen mit symptomatischer CMV-Infektion lässt sich ein konsekutiver Hörverlust durch Behandlung mit Ganciclovir bzw. dem oral applizierbaren Valganciclovir in vielen Fällen verhindern, Aussagen zu Neugeborenen mit asymptomatischer konnataler CMV-Infektion sind mangels Screenings derzeit nicht möglich.

Records of the only children's hospital equipped to perform exchange transfusions in West Berlin were used to identify all 29 non-hemolytic healthy term newborns with total serum bilirubin between 20 and 30 mg/dL, 16 of whom were available for follow-up neurological examination according to Touwen. Compared to 18 case controls with bilirubin

L-selectin, a cell surface glycoprotein expressed on lymphocytes, granulocytes, and monocytes, has been implicated in lymphocyte homing and extravasation of phagocytic leukocytes into areas of inflammation. Considerable differences of L-selectin expression among various individuals has been reported, with clinical correlations to perinatal events, maturation, and circadian rhythm. In this study, L-selectin expression of various white blood cells was found to be differentially sensitive to ficoll-hypaque or percoll density gradient centrifugation. After density gradient centrifugation, a significant loss of median monocyte L-selectin expression was observed when compared to time and temperature-matched controls or results obtained by whole blood incubation with anti-L-selectin monoclonal antibodies followed by simultaneous leukocyte fixation and red cell lysis. Mock treatment itself was associated with a variable L-selectin loss of monocytes but not lymphocytes or granulocytes. Ficoll-hypaque or percoll density gradient centrifugation resulted in significant L-selectin down-regulation of lymphocytes while granulocytes separated from lymphocytes and monocytes by ficoll-hypaque or percoll retained full L-selectin surface reactivity. L-selectin downregulation was seen also after colloid sedimentation with hydroxy-ethyl starch. It is concluded that unseparated blood should be used for measuring L-selectin expression.

Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has been studied in adults for the treatment of opioid-induced constipation in advanced illness. Here, the authors document the first neonate to receive methylnaltrexone in an attempt to resolve morphine-induced urinary retention. An asphyxiated term newborn infant underwent induced hypothermia and received morphine by continuous intravenous infusion. After 36 h, the patient developed progressive urinary retention (calculated bladder volume 63 ml), followed by venous congestion of the lower extremities. Attempted bladder catheterisation was unsuccessful. Voiding occurred within 20 min after intravenous administration of methylnaltrexone (0.15 mg/kg body weight). A relapse of urinary retention 24 h later responded well to a second dose of methylnaltrexone. There were no adverse effects and no opioid withdrawal symptoms. The neonate had normal findings in cranial MRI that was performed after elective cessation of induced hypothermia.

Directed migration of lymphocytes from blood into lymph nodes and gut-associated lymphatic tissue, also referred to as homing, is subject to change following activation. Lymphocyte migration into lymphoid organs in vivo and binding to high endothelial venules in vitro is largely suppressed after short-term stimulation with phorbol esters. The observed functional alterations were correlated with changes in the expression of three putative homing receptors, LECAM-1 (MEL-14 antigen), LPAM-1/2 (alpha 4-integrin) and the murine CD44 (Pgp-1, H-CAM, Hermes-antigen equivalent) upon different modes of cellular activation. Expression of LECAM-1 (gp90 MEL-14), a lymphocyte adhesion molecule implicated in targeting extravasation into lymph nodes, was found to be lost almost completely within minutes after protein kinase C activation. LECAM-1 re-expression occurred within less than 24 h. Rapid loss of LECAM-1 was also observed after calcium ionophores whereas anti-CD3 or concanavalin A elicited a gradual and heterogeneous loss of LECAM-1 becoming detectable after several hours only. A number of cytokines tested were not able to induce alterations in LECAM-1 expression. In contrast, expression of LPAM-1/2 (alpha 4-integrin) and CD44 (Pgp-1, H-CAM), two adhesion molecules supposed to direct extravasation into Peyer's patches, remained stable for hours after every stimulus tested; CD44 expression gradually increased 24 h after mitogenic activation, whereas a small reduction only was observed for the expression of the alpha 4-chain under certain conditions. Thus, reduced extravasation of lymphocytes into Peyer's patches after activation is not due to a decline in the surface density of LPAM-1/2 alpha-chain or CD44 whereas alterations in migration into lymph nodes parallel the expression of LECAM-1.

Animal models for morphological investigations of anorectal malformations are barely known to pediatric surgeons. In this study the morphological characteristics of a spontaneous mutation of the house mouse, the so-called SD-mouse, are described. The semidominant gene SD exerts its influence on the anorectum, the urogenital system and the axial skeleton. Many heterozygous (SD/+) and all homozygous (SD/SD) animals die shortly after birth due to their malformations. Surviving heterozygotes, identified by their short and deformed tails, may be used for breeding purposes. According to Mendel's laws, mating of such heterozygous yields 75% more or less malformed animals which may be used for morphological investigations. The morphological features of these animals were investigated in 61 neonatal SD-mice (33 SD/SD, 28 SD/+) and in 10 normal controls by microdissection and in 49 animals (25 SD/SD, 20 SD/+ and four normal controls) by serial sections. Of these, all homozygous and 10 heterozygous SD mice had anorectal malformations. The spectrum of these malformations is wide: very complex malformations in SD/SD mice and high anorectal malformations in SD/+ mice. These are comparable to morphological features found in humans and piglets. Hence the SD mouse represents an animal model for morphologic and embryonic investigations of complex anorectal malformations.

The high mortality of newborn infants with congenital diaphragmatic hernia (CDH) can be partly attributed to pulmonary hypertension causing extrapulmonary right-to-left shunting with subsequent severe hypoxemia. Inhaled nitric oxide (NO) may reduce elevated pulmonary artery pressure and has been successfully improve arterial oxygenation in some newborns with CDH. However, it is not clear whether inhaled NO will actually improve survival of newborns with CDH. We therefore investigated the effect of inhaled NO on the survival rate of newborn rats with CDH following intrauterine exposure to nitrofen. A total of 151 newborn rats (9 litters) were exposed to nitrofen on day 11 of pregnancy, After spontaneous delivery, 63 newborn rats (4 litters) were allowed to spontaneously breathe air containing NO (80 parts per million), while 88 newborn rats (5 litters) were given air without NO. Survival was checked 15 min after birth and then hourly until the animals were sacrificed at 24 h of age to verify the absence or presence of CDH. The 2 groups of newborn rats breathing air with or without NO did not differ significantly with respect to the presence or size of CDH. Twenty-four of 63 (38%) newborn rats breathing air with NO survived for 24 h, compared to 12 of 88 (14%) rats breathing air alone (p < 0.01). Of newborn rats that were actually found to have CDH (n = 113), 8 of 42 (19%) animals breathing air with NO survived for 24 h, compared to 2 of 71 (2.8%) animals breathing air alone (p < 0.01). In animals with CDH confirmed by autopsy, the median survival time was significantly longer with NO (p < 0.001) ( 2 h, interquartile range 2h-15h), than those breathing or without NO (median/interquartile range 15 min). We conclude that in the nitrofen rat CDH model, significantly improved survival rates occur with inhaled NO as a sole intervention. The combined impact of inhaled NO and mechanical ventilation remains to be determined.

Canavan disease (CD) is a rare leukodystrophy which is lethal in infancy or early childhood. The underlying biochemical abnormality in CD is a hereditary deficiency of N-aspartoacylase transmitted in an autosomal recessive fashion. We report on the ultrasound (US), CT, and MRI findings of three unrelated boys with biochemically confirmed CD. At 6 and 9 months of age, two CD patients with rapid neurological deterioration showed markedly enhanced acoustic attenuation of the white matter with the exception of the corpus callosum, giving the appearance of a reversed pattern of echogenicity of cortical gray and subcortical white matter. While gyri and sulci had an almost normal US appearance, the periventricular gray matter featured prominently with increased echogenicity. In contrast another CD patient with a more protracted course had ventricular enlargement when examined by US at 5 and 9 months but no alteration in white matter echogenicity. MRI showed impaired myelinization in all three patients with Canavan disease.

To clarify conflicting claims of altered serum concentrations of soluble L-selectin (sCD62L) in recent-onset IDDM, sCD62L was measured in 89 children and adolescents with IDDM (35 recent-onset, 12 during the first year of insulin treatment, and 42 with long-standing (1 yr) treatment) alongside 124 controls. Children14 yr of age both with and without IDDM (n = 160) had grossly elevated sCD62L concentrations (20.2 +/- 4.9 nmol/l), as compared with adolescents (14-18 yr, n = 23; 15.9 +/- 3.9 nmol/l) and adults (18 yr, n = 30; 11.2 +/- 2.3 nmol/l) (p0.0001). Multivariate analysis confirmed the strong inverse association between age and sCD62L (p0.001) while revealing that sCD62L concentrations were slightly elevated in recent-onset IDDM, as compared with insulin-treated IDDM patients or nondiabetic controls (p = 0.028). Actual sCD62L concentrations in the 35 recent-onset IDDM patients were 22.2 +/- 4.9 nmol/L vs 19.6 +/- 3.6 nmol/l in 35 non-diabetic controls matched for age (p = 0.022). While this significant but small rise of systemic sCD62L reflects leukocyte activation, it is obscured by the inverse association between sCD62L and chronological age in children and adolescents. Therefore, determining sCD62L serum concentrations appears to be of limited value for clinical investigators caring for children and adolescents with IDDM.

In children with acute lymphoblastic leukemia (ALL), relapse in the CNS is still a major limiting factor for cure [1]. CNS relapse prevention by cranial irradiation plus intrathecal methotrexate [2], while adequately protective for most patients, is stigmatized by considerable neurological and other sequelae [3]. For standard-risk ALL children (60% of all patients), the BFM study group has addressed the necessity of cranial irradiation in a risk-adapted and randomized fashion in trials ALL-BFM 81 and 83. Together with the historical controls of the preceding trials ALL-BFM 70, 76, and 79, the overall as well as the CNS relapse incidence in these trials is presented here.

Dose-dependent reduction of auditory function mainly in the high frequency range has been described as a common adverse side effect of cis-platinum. Here we report on a 4-year-old girl with osteosarcoma of the right distal femur who developed acute bilateral deafness 3 days after a single infusion of high-dose cis-platinum (150 mg/m2) during preoperative chemotherapy. Sudden disabling ototoxicity should be considered when administering high-dose cis-platinum to young children.

Background: In the developing human brain, periventricular leukomalacia (PVL) is the predominant white matter injury underlying the development of cerebral palsy. PVL has its peak incidence in the premature infant during a well-defined period in human brain development (23–32 weeks, postconceptional age) characterized by extensive oligodendrocyte migration and maturation. We hypothesized that the dramatic rise of oxygen tissue tension associated with mammalian birth may be harmful to immature oligodendrocytes. We therefore investigated the effects of hyperoxia on cultured rat premature, immature and mature oligodendroglia cells. Methods: Flow cytometry was used to assess apoptosis via annexin-V, anti-active caspase-3 antibody, and propidium iodide staining, while cell viability was measured by metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT). Results: Apoptosis was detected at various stages (early: annexin-V, effector: caspase-3) after 24–48 h incubation with hyperoxia (80% O2) in preoligodendrocytes, immature oligodendrocytes (OLN-93) but not in mature oligodendrocytes. These results were confirmed in MTT assays. Conclusion: Hyperoxia directly initiates the apoptotic cascade in immature oligodendrocytes and pre-oligodendroglia cells. This mechanism may contribute to the white matter damage observed in PVL.

Nonspecific cytotoxic cells provide a major line of defense against tumor. While natural killer (NK) cells display spontaneous, non-MHC-restricted killing activity, both NK and non-NK lymphocytes can be induced by lymphokines to exhibit enhanced nonspecific cytotoxicity against tumor, including NK-resistant targets [1–3]. The latter activity is mediated by a heterogeneous cell population commonly termed lymphokine-activated killer (LAK) cells [2–4]. According to the initial concept, nonspecific LAK killing is generated via exposure to interleukin 2 (IL-2) of peripheral blood lymphocytes [5, 6]. Most of the LAK activity appears to be mediated by NK cells stimulated with IL-2; however, recent studies suggest that induction of MHC-unrestricted lymphokine-activated killing is a more complex phenomenon requiring a multitude of cellular and noncellular signals [2–4, 7-10].