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ABSTRACT: Wie in der Erwachsenennephrologie stellt die Nierenbiopsie mittlerweile auch in der pädiatrischen Nephrologie ein Standardverfahren
dar. Es gibt aber in der Indikationsstellung und Durchführung einige Unterschiede zum Vorgehen beim Erwachsenen. Da die größten
Unterschiede im Vorgehen beim nephrotischen Syndrom im Kindes- und Jugendalter liegen, soll dies Schwerpunkt des nachstehenden
Artikels sein und hier näher erläutert werden.
As in adult nephrology, renal biopsy is now standard procedure in pediatric nephrology as well. Indication and technique of
kidney biopsy in children and adolescents however differ in some aspects from the procedure in adults. As the greatest such
differences exist in the management of nephrotic syndrome, this article concentrates particularly on descriptions and explanations
of that subject.
Der Nephrologe 05/2012; 3(3):178-181.
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ABSTRACT: Hintergrund. Der sekundäre Hyperparathyreoidismus ist zum großen Teil Folge des Kalzitriolmangels bei der chronischen Niereninsuffizienz.
Die Therapie mit Vitamin-D-Metaboliten soll insbesondere das Entstehen der renalen Osteopathie verhindern. Die Therapiesteuerung
erfordert jedoch eine exakte Kenntnis der Regulationsmechanismen des Kalzium-Phosphat-Stoffwechsels während der chronischen
Niereninsuffizienz.
Kasuistik. Wir stellen 2 terminal niereninsuffiziente Patienten mit ausgeprägter Hyperkalzämie und Hyperphosphatämie unter hoch dosierter
Vitamin-D-Therapie vor. In beiden Fällen fanden sich stark supprimierte Parathormonwerte.Besonders auffällig bei einer Patientin
waren kardiale Verkalkungen, die zu einem schrittmacherpflichtigen atrioventrikulärem Block Grad III führten.Bei beiden Patienten
kam es nach Aussetzen der Vitamin-D-Therapie,diätetischen Maßnahmen, Einsatz von Phosphatbindern und mit Beginn einer adäquaten
Nierenersatztherapie zur Normalisierung des Kalzium-Phosphat-Stoffwechsels.
Schlussfolgerung. Die Gabe von Vitamin-Dmetaboliten bei der chronischen Niereninsuffizienz stellt mittlerweile eine Standardtherapie dar.Die
Kasuistik demonstriert jedoch, dass aufgrund nicht sachgerechter Dosierung und Überwachung Entgleisungen des Kalzium-Phosphat-Stoffwechsels
auftreten können.Zur Ermittlung der optimalen Vitamin-D-Dosis empfiehlt sich daher eine sorgfältige Überwachung des Serumkalzium-
und -phosphatwerts sowie von Parathormon und alkalischer Phosphatase.
Background. Secondary hyperparathyroidism in chronic renal failure is due to the lack of calcitriol.Therapy with vitamin D prevents renal
osteopathy.However, the dosage and monitoring of vitamin D therapy requires profound knowledge of calcium-phosphate metabolism
in chronic renal failure.
Case report. We present two patients in end stage renal failure with substantial hypercalcemia and hyperphosphatemia following high dose
vitamin D therapy.Parathormone was suppressed in both cases.One patient showed cardiac calcifications leading to third degree
heart block. In both cases a temporary discontinuation of vitamin D therapy, dietetic instructions,phosphate binders and adequate
renal replacement therapy led to a normalized calcium-phosphate metabolism.
Discussion. The administration of vitamin D represents a standard therapy in chronic renal failure.However, this case demonstrates the
consequences of inadequate monitoring of vitamin D therapy.To determine the appropriate dose we recommend careful monitoring
of serum calcium,phosphate, parathormone and alkaline phosphatase in a paediatric nephrology department.
Monatsschrift Kinderheilkunde 04/2012; 150(12):1508-1512. · 0.27 Impact Factor
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ABSTRACT: In male patients with congenital anomalies of the kidney and urinary tract, an increased incidence of a polymorphism in the angiotensin type 2 receptor gene (AT2R) has been identified. The AT2R has been shown to be involved in apoptosis, particularly during embryogenesis. The aim of this study was to examine the A-->1675G transition polymorphism in intron 1 of the AT2R gene that is located on the X chromosome in patients with coarctation of the aorta (CoA) with and without Ullrich-Turner syndrome (UTS). Screening of DNA samples was performed with restriction fragment length polymorphism analysis. Ninety-seven patients with CoA, 28 girls with UTS, 10 girls with UTS and CoA, and 96 control individuals were studied. There was no significant difference in the distribution of A and G-genotypes in any of the patient groups compared to controls. An A-->1675G transition in the AT2R gene seems not to be involved in the pathogenesis of aortic coarctation.
Pediatric Cardiology 04/2012; 27(5):636-9. · 1.30 Impact Factor
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ABSTRACT: Unter fetaler Programmierung versteht man die Induktion fixierter, epigenetischer Veränderungen durch ein ungünstiges intrauterines
Milieu. Folge ist im ungünstigen Fall eine erhöhte Morbidität des fetal programmierten Organismus im späteren Leben. Ein Beispiel
ist die intrauterine Wachstumsrestriktion (IUGR), die u.a. mit einem gehäuften Auftreten von Nierenfunktionsstörungen im
Verlauf des Lebens assoziiert ist. Zwei prinzipielle Entstehungswege konnten gezeigt werden: Einerseits ist eine höhere Prävalenz
von Hypertonie und Diabetes mellitus Typ2 nach IUGR belegt. Beide Erkrankungen prädisponieren ihrerseits für die Entwicklung
einer chronischen Niereninsuffizienz im Erwachsenenalter. Andererseits werden bei einem niedrigen Geburtsgewicht primär renale
Veränderungen beobachtet; so ist beispielsweise die Zahl funktionsfähiger Nephrone reduziert. Auch dies kann langfristig einen
vorzeitigen renalen Funktionsverlust begünstigen. Zudem ist bereits im Kindesalter ein schwererer Verlauf glomerulärer Erkrankungen
nach IUGR zu beobachten: So finden sich beim kindlichen nephrotischen Syndrom ein prognostisch ungünstigerer Verlauf und bei
der IgA-Nephropathie im Kindesalter ein höherer Anteil an Nephrosklerose. Tierexperimentell lassen sich eine erhöhte Entzündungsaktivität
und eine verminderte Regenerationsfähigkeit belegen. Nicht nur pränatale, auch postnatale Einflüsse, z.B. eine postnatale
Hyperalimentierung, können die Manifestation der renalen Schädigung begünstigen.
Fetal programming is the process of persistent, epigenetic alteration by an adverse intrauterine milieu. Such alteration may
lead to increased morbidity later in life. An example of a deranged intrauterine milieu is intrauterine growth restriction
(IUGR), which is associated with, among other conditions, an increased prevalence of renal dysfunction. Two principal pathogenetic
courses may be responsible: On one hand, nonrenal diseases such as hypertension and type2 diabetes, both associated with
a former state of IUGR, predispose to secondary renal damage. On the other hand, renal mechanisms are involved; for example,
the reduced number of nephrons in low birth weight children is a risk factor for future renal failure. In addition, glomerular
diseases show a more severe course in children who experienced IUGR. The course of nephrotic syndrome is less favorable, and
IgA nephropathy is associated with a higher prevalence of glomerular sclerosis. Data from animal experiments suggest an increased
susceptibility of the kidney to inflammatory stimuli and lower regenerative capacities. However, not only the prenatal environment
but also postnatal hyperalimentation appears to contribute to the manifestation of renal disease after IUGR.
Der Nephrologe 04/2012; 4(2):142-147.
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ABSTRACT: Große epidemiologische Untersuchungen lassen auf einen klaren Zusammenhang zwischen niedrigem Geburtsgewicht und gestörter
Nierenentwicklung schließen, deren Konsequenzen sich teilweise bereits im Kindesalter bemerkbar machen. Dies betrifft sowohl
die chronische Niereninsuffizienz wie v.a. auch entzündliche glomeruläre Erkrankungen. Einer der wichtigsten Mechanismen scheint
die Reduktion der Nephronenzahl zu sein, wenn auch weitere Mechanismen der fetalen Programmierung zunehmend aufgeklärt werden.
In den letzten Jahren mehren sich die Indizien, dass die gestörte fetale Programmierung durch postnatale Interventionen wie
die Vermeidung von Hyperalimentation zumindest teilweise revidiert werden kann. Ob diese Interventionen möglicherweise auch
den aggravierten Verlauf von Nierenerkrankungen nach niedrigem Geburtsgewicht positiv beeinflussen kann, muss abgewartet werden.
Large epidemiological studies suggest that a clear relationship exists between low birth weight and adverse renal outcomes,
which may begin as early as childhood. Such outcomes include renal failure as well as glomerular disease. One of the most
important mechanisms is a reduction in the number of nephrons, although further mechanisms of fetal programming must also
be considered. It appears likely that fetal programming may be altered postnatally, such as by avoiding hyperalimentation.
Whether such interventions could potentially alter the adverse course of renal disease after a small-for-gestational-age birth
remains to be seen.
Der Nephrologe 04/2012; 4(4):306-311.
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ABSTRACT: Borsäure wird heute sehr selten benutzt. Entsprechend sind die Erfahrungen mit Borsäureintoxikationen in den letzten Jahren
gering. Akutes Nierenversagen und desquamative Hauterosionen sind bekannte Intoxikationserscheinungen. Ein 14jähriges Mädchen
entwickelte 12h nach der Ingestion von etwa 4g Borsäure in suizidaler Absicht ein akutes Hämodialyse-pflichtiges Nierenversagen
mit Anurie über 14Tage. 25Tage nach der Ingestion kam es zu einem desquamativen Exanthem (Boiled-lobster-Syndrom) sowie
zu einer ausgeprägten Eosinophilie von 5184/µl bei einer Gesamtleukozytenzahl von 10800/µl. Unter symptomatischer Therapie
kam es zu einer schnellen und vollständigen Remission der klinischen Symptomatik sowie der Eosinophilie.
Diskussion: Das späte Auftreten des typischen Exanthems sowie die ausgeprägte Eosinophilie sind bemerkenswert und in diesem Ausmaß bisher
noch nicht beschrieben.
Today borate is a rarely used agent. Only few reports about borate intoxication have been published within the last few years.
Acute renal failure and skin-lesions are well-known symptoms of an acute borate intoxication. We report on a 14year old girl
with a suicidal ingestion of about 4g borate. Twelve hours later the girl developed an acute renal failure, which was compensated
by hemodialysis. Twenty five days later an allergic-toxic erythema appeared (”boiled lobster syndrome”) in parallel with an
eosinophilia of 50% (5184 eosinophiles/µl) in the peripheral blood smear. Under symptomatic therapy eosinophilia and other
symptoms resolved completely.
Discussion: The very late development of the typical erythema is as remarkable as the unusual, enormous eosinophilia, which has not
been reported before in this context. Mostly, mild courses are seen. Our patient recovered completely.
Monatsschrift Kinderheilkunde 04/2012; 148(2):127-130. · 0.27 Impact Factor
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ABSTRACT: Autoimmunthyreopathien im Kindes- und Jugendalter sind selten, die Hashimoto-Thyreoiditis (HT) ist insgesamt häufiger als
der Morbus Basedow. Das klinische Erscheinungsbild der HT ist unspezifisch und sehr variabel. Es gibt kein typisches Leitsymptom.
Erhöhte Antikörper gegen die thyreoidale Peroxidase werden oft nachgewiesen. Die Stoffwechsellage ist bei den meisten Patienten
euthyreot, bei etwa 20–40% hypothyreot. Sowohl die latente als auch die manifeste Hypothyreose werden mit Levothyroxinsubstitution
behandelt. Das klinische Bild des manifesten Morbus Basedow dagegen ist eindeutig. Mittel der 1. Wahl ist bei Kindern und
Jugendlichen die thyreostatische Therapie, die aber wegen potenziell schwerer Nebenwirkungen engmaschig überwacht werden muss.
Sie sollte aufgrund einer dauerhaften Remissionsrate von nur 20–40% nicht beständig fortgeführt werden. Der chirurgische Erfolg
ist weitgehend von der Erfahrung des Operateurs abhängig. Daher sollten operative Eingriffe bei Kindern und Jugendlichen mit
Morbus Basedow spezialisierten Zentren vorbehalten bleiben. Die Radiojodtherapie hat geringere Erfolgschancen, geht jedoch
nach heutigem Wissen bei Kindern und Jugendlichen nicht mit einem erhöhten Malignitätsrisiko einher.
Although autoimmune thyroid diseases are generally rare in children and adolescents, Hashimoto’s thyroiditis is more common
than Graves’ disease. The clinical appearance of Hashimoto’s thyroiditis is nonspecific and highly variable; there is no typical
cardinal symptom. Antibodies against thyroidal peroxidase are verifiably increased by a high percentage. The metabolic situation
is euthyroidism in most patients and hypothyroidism in approximately 20–40% of the patients. For treatment of both subclinical
and apparent hypothyroidism, L-T4 substitution therapy is used.In contrast, the clinical appearance of Graves’ disease is
clear. Antithyroid drug therapy is the first-choice treatment for children and adolescents, but it must be closely monitored
because of potential serious side effects. It should not be continued on a long-standing basis due to a long-term remission
rate of only 20–40%. Surgical success largely depends on the surgeon’s skill and experience. Hence, surgical intervention
in children and adolescents with Graves’ disease should be limited to specialised centres. Radioiodine therapy holds little
prospect of success, but – based on today’s standards – does not cause an increased risk of malignancy in children and adolescents.
Monatsschrift Kinderheilkunde 04/2012; 156(10):987-993. · 0.27 Impact Factor
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ABSTRACT: The placenta is a major barrier that prevents potentially infectious agents from causing fetal diseases or related complications during pregnancy. Therefore, we postulated that the placenta might express a broad repertoire of antimicrobial proteins as well as inflammatory chemokines and cytokines to combat invading microorganisms. Here we demonstrate that placental cells indeed express a wide range of AMPs (antimicrobial peptides and proteins) including bactericidal/permeability-increasing protein (BPI), secretory leukocyte protease inhibitor (SLPI), human β-defensin 2 (hBD2), acyloxyacyl hydrolase (AOAH), and cathelicidin (CAP18). In addition, these cells also secrete pro-inflammatory cytokines and chemokines upon stimulation with bacterial ligands. Notably, we show that BPI expression by placental cells could be completely attributed to granulocytes while highly purified placental trophoblasts expressed only a subset of the AMPs like SLPI. Unexpectedly, trophoblast AMPs did not exhibit inducible secretion in response to various TLR ligands and further investigations showed that the unresponsiveness of trophoblasts to lipopolysaccharide (LPS) was due to a lack of TLR4 expression. In summary, we have shown that the expression of different AMPs can be allocated to various cells in the placenta and the repertoire of the AMPs expressed by placental cells is a result of a cooperation of leukocytes as well as cells from embryonic origin.
Placenta 09/2011; 32(11):830-7. · 3.69 Impact Factor
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ABSTRACT: Intrauterine growth restriction seems to be a risk factor for an aggravated course of secondary renal diseases in children. Catch-up growth after birth may play a critical role. We tested if there is an association between an aggravated course of nephritis in Henoch-Schönlein Purpura (PSHN) and low birth weight or early weight gain during infancy.
We retrospectively analysed the clinical course of 34 children with PSHN.
Patients were sorted according their birth weight standard deviation score (SDS) in tertiles. Early weight gain was defined as gain of weight standard deviation score >0.67 between birth and 2 years of age.
Patients with higher birth weight needed Cyclophosphamide in a higher rate than low birth weight children. In the high weight gain group (SDS gain >0.67) 9 of the 11 patients compared to 7 of 22 patients in the low weight gain group (SDS gain <0.67) presented with arterial hypertension during the initial manifestation of PSH nephritis (p=0.01). Median systolic blood pressure SDS in the high weight gain group was 1.54 (-1.39-4.71) versus 0.29 (0.52-4.05) in the low weight gain group (p=0.008). Nevertheless, other clinical parameters during first manifestation and follow-up were not relevantly different.
In contrast to the data of children with idiopathic nephrotic syndrome or IgA nephropathy, this study does neither provide evidence for an association between low birth weight nor early weight gain and the later course of PSHN. Interestingly, early weight gain was associated with a higher systolic blood pressure during the initial manifestation of PSHN.
Klinische Pädiatrie 12/2010; 222(7):455-9. · 1.77 Impact Factor
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Ultrasound in Obstetrics and Gynecology 10/2010; 36(S1):44. · 3.01 Impact Factor
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ABSTRACT: The mechanisms relating being born small for gestational age (SGA) and the later risk of metabolic disorders are not yet fully understood. Adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity and expression have been positively associated with metabolic syndrome. In humans, no in vivo studies have explored 11beta-HSD1 activity and gene expression in sc adipose tissue of SGA subjects.
Thirty-nine subjects SGA (birth weight<10th percentile) were matched on gender and age with 36 subjects born appropriate for gestational age (AGA) (25th percentile<birth weight<75th percentile); the two groups were stratified according to body fat content into low-fat-mass (20 SGA and 18 AGA) and high-fat-mass (19 SGA and 18 AGA) subjects. Basal and stimulated activities of the 11beta-HSD1 enzyme were assessed in the effluent of microdialysis performed in the abdominal sc wall in vivo. mRNA expression was measured by real-time quantitative PCR.
Basal 11beta-HSD1 activity was comparable in both groups, whereas stimulated activity was lower in SGA subjects. A significant effect of body fat content on the stimulated 11beta-HSD1 activity was found in AGA but not in SGA subjects. 11beta-HSD1 expression was associated with body fat but not with birth weight.
The in vivo stimulated 11beta-HSD1 activity was decreased in subjects born SGA as compared with adults born AGA. 11beta-HSD1 gene expression was not associated with birth weight. It is therefore unlikely that local glucocorticoid metabolism in sc fat plays a major role in the development of the metabolic complications associated with being born SGA.
The Journal of clinical endocrinology and metabolism 08/2010; 95(8):3949-54. · 6.50 Impact Factor
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ABSTRACT: The human placenta as part of the feto-placental unit may influence fetal endocrine systems and may therefore represent a very important link between intrauterine growth restriction (IUGR) and metabolic disorders in later life. We aimed to analyze the effect of sample origin on gene expression of placental factors potentially involved in fetal programming in IUGR versus appropriate for gestational age growth (AGA) to standardize sample collection procedure for a multicenter approach.
Placental gene expression of insulin-like growth factor-binding protein (IGFBP)-1, prolactin, corticotropin releasing hormone (CRH) and leptin was measured and compared between proximal, intermediate and peripheral region of the placenta in 22 IUGR (proven by anomalous placental Doppler velocimetry) and 19 AGA neonates.
Whereas no difference in gene expression was seen in the proximal portion, in the intermediate placental region mRNA expression of IGFBP-1 (p = 0.01), prolactin (p = 0.04), CRH (p = 0.01) and leptin (p = 0.04) was increased in IUGR samples compared to controls. At the placental periphery, gene expression of these placental transcripts showed a higher expression level in IUGR placentas without statistical significance, except for leptin (p = 0.03).
Placental sampling site seems to be relevant for detecting differences in gene expression between IUGR and AGA neonates.
Placenta 03/2010; 31(3):178-85. · 3.69 Impact Factor
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ABSTRACT: In paediatric peritoneal dialysis patients, pre-emptive omentectomy is discussed controversially and literature provides only little data concerning this issue. Our aim was to evaluate the rate of omentum-majus-related problems in our patients, in whom omentectomy was generally not performed. Furthermore, we were interested in the success rates of laparoscopic adhesiolysis.
Between 09/2006 and 03/2008, we regularly saw 18 peritoneal dialysis patients in whom we retrospectively analysed medical records to determine the rate of catheter-related complications. In addition, we evaluated the success rates of laparoscopic adhesiolysis.
During 355 dialysis months in 18 patients, we observed 7 omentum-majus-related obstructions in 6 patients (1/50.7 PM). The median age of the patients affected was 9 years, median filling volume at the time of the obstruction was 671 ml/m (2). Laparoscopic adhesiolysis was successful in 4 out of 7 episodes. In 3 cases, the catheter lumen was plugged by necrotic portions of the omentum and the catheters had to be replaced.
Our data confirm omentum-majus-related catheter obstruction as a major cause of catheter dysfunction. However, in comparison to literature, it remains unclear to which extent omentectomy can reduce the incidence of catheter obstruction in general (including e. g. obstruction due to coagulation). Thus, the decision to perform an omentectomy should be taken individually after careful consideration. In case of omentum-majus-associated obstruction, early but not late laparoscopic intervention proved to be a successful, minimally invasive technique to restore catheter function.
Klinische Pädiatrie 03/2010; 222(4):252-4. · 1.77 Impact Factor
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ABSTRACT: Maintenance therapy of severe pediatric systemic lupus erythematosus (SLE) usually consists of azathioprine and prednisone . In adult SLE patients mycophenolate mofetil (MMF) is successfully used, superiority to azathioprine has not been shown yet. We hypothesized that a maintenance therapy with MMF is able to decrease disease activity as well as the dose of glucocorticoid needed in children and adolescents with SLE. Five girls with a mean age of 13.9 (range 12-15) years were treated with 1.2+/-0.20 g/m (2) MMF daily on individual medical decision. Three patients had severe renal (WHO IV) and one severe cerebral involvement. Three patients with frequent flares on azathioprine maintenance therapy were switched to MMF, two patients with severe renal and cerebral manifestation received MMF additionally after induction therapy. Flares, steroid dosage, and disease activity (SLEDAI) were monthly registered in all patients. The number of flares decreased from 1.28 to 0.25 episodes per patient year during a mean follow-up period of 39 (range 36-42) months after MMF initiation. In parallel prednisone dose could be reduced from 10.80+/-5.25 to 3.25+1.18 mg/d (p<0.01). SLEDAI score dropped from 15.20+/-2.8 before MMF to 3.60+/- 0.9 at the last visit under MMF (p<0.001). No severe adverse event occurred. In our cohort of five pediatric patients MMF was effective and safe for maintenance therapy of SLE over a period of 3.5 years. MMF seems to be successful in preventing flares even in adolescents having unfavorable course on azathioprine treatment before. This observation should be confirmed by a randomized multicenter clinical trial.
Klinische Pädiatrie 12/2009; 221(7):425-9. · 1.77 Impact Factor
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Ultrasound in Obstetrics and Gynecology 10/2009; 34(S1):29. · 3.01 Impact Factor
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E Struwe,
G Berzl,
R Schild,
H Blessing,
L Drexel,
B Hauck,
A Tzschoppe,
M Weidinger,
M Sachs,
C Scheler,
E Schleussner, J Dötsch
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ABSTRACT: Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro- and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder.
Placental tissues of 20 IUGR and control neonates were analysed by microarray technique. Four of the regulated genes with possible relevance in the pathogenesis of IUGR and its consequences were further studied in placentas of 27 IUGR and 35 control newborns.
Elevated gene expression of leptin, corticotrophin-releasing hormone (CRH), and IGF-binding protein-1 (IGFBP-1) in IUGR placentas could be confirmed in the larger group by real-time PCR, whereas prolactin showed no significant difference. Accordingly, protein expression of leptin and IGFBP-1 depicted by Western blot was elevated in IUGR, prolactin was not different. Birthweight standard deviation score (SDS) correlated negatively to leptin, IGFBP-1, and CRH, whereas placental weight correlated only to IGFBP-1. Leptin correlated negatively to gestational age of IUGR patients and positively to placental score, a marker of severity of impaired foeto-placental circulation.
As confirmed in a large group of IUGR and control samples, the up-regulated factors leptin, IGFBP-1, and CRH may serve as candidate genes for the prediction of subsequent metabolic consequences in IUGR newborns. These three factors may not only influence growth of the foetus, but might also interact with programming of its metabolic functions, which has to be determined in an ongoing study.
Clinical Endocrinology 07/2009; 72(2):241-7. · 3.17 Impact Factor
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B Utsch,
I Brun-Heath,
G Staatz,
C Gravou-Apostolatou,
S Karle,
U Jacobs,
M Ludwig,
M Zenker,
H-G Dörr,
W Rascher,
E Mornet, J Dötsch
[show abstract]
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ABSTRACT: Infantile hypophosphatasia (IH) is an inherited disorder characterized by defective bone mineralization and a deficiency of alkaline phosphatase activity.
The aim of the study was to evaluate a new compound heterozygous TNSALP mutation for its residual enzyme activity and localization of the comprised amino acid residues in a 3D-modeling.
We report on a 4-week old girl with craniotabes, severe defects of ossification, and failure to thrive. Typical clinical features as low serum alkaline phosphatase, high serum calcium concentration, increased urinary calcium excretion, and nephrocalcinosis were observed. Vitamin D was withdrawn and the patient was started on calcitonin and hydrochlorothiazide. Nonetheless, the girl died at the age of 5 months from respiratory failure.
Sequence analysis of the patient's TNSALP gene revealed two heterozygous mutations [c.653T>C (I201T), c.1171C>T (R374C)]. Transfection studies of the unique I201T variant in COS-7 cells yielded a mutant TNSALP protein with only a residual enzyme activity (3.7%) compared with wild-type, whereas the R374C variant was previously shown to reduce normal activity to 10.3%. 3D-modeling of the mutated enzyme showed that I201T resides in a region that does not belong to any known functional site.
We note that I201, which has been conserved during evolution, is buried in a hydrophobic pocket and, therefore, the I>T-change should affect its functional properties. Residue R374C is located in the interface between monomers and it has been previously suggested that this mutation affects dimerization. These findings explain the patient's clinical picture and severe course.
Experimental and Clinical Endocrinology & Diabetes 01/2009; 117(1):28-33. · 1.69 Impact Factor
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ABSTRACT: Hypoxia-inducible transcription factor-1 (HIF-1) is the most important component of cellular and molecular adaptive responses to hypoxia. We aimed to analyze effects of systemic hypoxia and CO exposure on the oxygen-regulated alpha-subunit of HIF-1 and HIF-1-dependent vasoactive target genes in rat brain. Brains of adult Sprague-Dawley rats were investigated after incubation for 3 and 12 h under normoxia, hypoxia (8% O(2)) and CO 0.1% (n = 10 per group). Upon 3 h of exposure, hypoxia and CO-induced accumulation of HIF-1alpha protein in brain homogenates assessed by Western blot analysis. In contrast to hypoxia HIF-1alpha signals decreased markedly during 12 h-exposure to CO. By immunohistochemistry, intensive HIF-1alpha-positive staining was found in neurons of the cortex and hippocampus. Cerebral expression of vasoactive target genes adrenomedullin (ADM) and vascular endothelial growth factor (VEGF) showed up-regulation during both hypoxia and CO exposure indicating functional activation of HIF-1. Hypoxia increased ADM (P < 0.05) and VEGF mRNA levels within 3 h (P < 0.01) which persisted up to 12 h of exposure (ADM, P < 0.05; VEGF, P < 0.001). Similarly, CO inhalation led to early up-regulation of VEGF (3 h: P < 0.05; 12 h: P < 0.01), but a more delayed increase of ADM mRNA levels (3 h: n.s., 12 h: P < 0.01). We suggest that CO-induced oxygen deprivation is a potent stimulus to cerebral HIF-1-regulated hypoxic stress responses even though its effects are more transient than exposure to hypoxia.
Arbeitsphysiologie 09/2008; 104(1):95-102. · 2.15 Impact Factor
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ABSTRACT: The objective of our study was to evaluate hemodynamic effects and the cardiac function after very early extubation within the first 6 hours after open-heart surgery in children. During a 12-month period, we performed a retrospective study of 50 children (ages 3 months to 7 years) admitted to the pediatric intensive care unit immediately after minor cardiac surgery. All children were extubated within the first 6 hours after their arrival. Arterial blood and central venous pressure were monitored, and arterial blood gas analysis was performed. Cardiac index, stroke volume index, systemic vascular resistance index, and extravascular lung water index were measured by thermodilution. Early extubation of children after minor open-heart surgery with cardiopulmonary bypass is safe and does not affect cardiac functions. A slight decrease of arterial oxygen tension not resulting in respiratory or metabolic acidosis or reintubation was noted. Very early extubation in children after open-heart surgery does not promote cardiodepressive effects. It is a safe procedure that helps to reduce the unnecessary and prolonged mechanical ventilation of children after cardiopulmonary bypass surgery.
Pediatric Cardiology 04/2008; 29(2):317-20. · 1.30 Impact Factor
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European Journal of Pediatrics 01/2008; 166(12):1285-8. · 1.88 Impact Factor
