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Biomedical subjects

F Schaefer

Publications and source records attributed to F Schaefer.

At least 19 recordsLinked to original sources
PubMed2006

Distinct roles of Mac-1 and its counter-receptors in neonatal obstructive nephropathy.

Urinary tract obstruction during renal development leads to tubular atrophy and interstitial fibrosis. Inflammatory macrophages are crucial in this process, and beta2-integrins play a major role in leukocyte recruitment. We investigated the role of beta2-integrins and their major counter-receptors (intercellular adhesion molecule-1 (ICAM-1), receptor for advanced glycation endproducts (RAGE), junctional adhesion molecule (JAM)-C) in obstructive nephropathy in neonatal mice. Two-day-old beta2-integrin-deficient mice (Mac-1-/- and LFA-1-/-(deficient for leukocyte function-associated antigen-1)) and wild-type mice (C57BL/6) underwent unilateral ureteral obstruction (UUO) or sham operation. After 1, 5 or 12 days of obstruction, renal macrophage infiltration and tubulointerstitial damage were quantitated. Tissue abundance of Mac-1 and its ligands ICAM-1, RAGE and JAM-C was examined by Western blot and immunoprecipitation. Deficiency of either integrin was associated with reduced early macrophage invasion into the obstructed kidney. After 12 days of UUO, macrophage infiltration and tubulointerstitial injury were reduced only in Mac-1-/- but not in LFA-1-/- mice. Besides ICAM-1, an upregulation of two novel Mac-1 ligands, RAGE and JAM-C were observed, however, with distinct time courses. We conclude that beta2-integrins mediate macrophage infiltration in UUO. Mac-1 is the predominant leukocyte integrin involved in leukocyte recruitment after obstruction. ICAM-1 and its new ligands RAGE and JAM-C are sequentially activated in UUO. Blocking of Mac-1 and its ligands may confer synergistic renoprotective effects in neonatal obstructive nephropathy.

Animals↗
PubMed2005

Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines.

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol(2)/l(2). The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

Algorithms↗
PubMed2005

Structural organization and biological relevance of oscillatory parathyroid hormone secretion.

Parathyroid gland secretory activity exhibits seasonal and circadian fluctuations, which are in synchrony with changes in serum calcium, phosphate, and bone turnover. In addition, an ultradian rhythm exists, which comprises seven pulses per hour, accounts for 30% of basal parathyroid hormone (PTH) release, and is highly sensitive to changes in ionized calcium. Acute hypocalcemia induces a selective, severalfold increase in pulse frequency and amplitude, whereas hypercalcemia suppresses the pulsatile secretion component, as does prolonged calcitriol therapy. Chronic renal failure is associated with a GFR dependent decrease in metabolic PTH clearance accounting for a two- to threefold increase in plasma PTH concentrations, a consistent increase of PTH burst mass and frequency, and a markedly reduced capacity to counteract changes in ionized calcium by modulation of pulsatile PTH release. Continuous PTH excess destroys bone, whereas intermittent administration of pharmacological doses of PTH improves bone morphology and strength in experimental and clinical settings. The molecular mechanisms of the exposure pattern dependent, contrasting biological effects of PTH may involve differential regulation of osteoblastic G protein signaling feedback circuits. In this context, calcimimetic and calcilytic agents are promising new therapeutic tools allowing for tight control of plasma PTH and restoration of circadian PTH rhythmicity.

Bone and Bones↗
PubMed2003

1,25(OH)2D3 and dihydrotestosterone interact to regulate proliferation and differentiation of epiphyseal chondrocytes.

Growth plate chondrocytes are affected by 1,25(OH)2D3 and androgens, which may critically interact to regulate proliferation and differentiation during the male pubertal growth spurt. We investigated possible interactions of 1,25(OH)2D3 and the non-aromatizable androgen dihydrotestosterone (DHT) in primary chondrocyte cultures from young male rats. DHT and 1,25(OH)2D3 independently stimulated DNA synthesis and cell proliferation in a dose-dependent manner with maximally effective doses of [10(-8) M] and [10(-12) M], respectively. Both DHT and 1,25(OH)2D3 stimulated the expression and release of IGF-I, and the proliferative effects of each hormone were prevented by an IGF-I antibody. DHT and 1,25(OH)2D3 increased messenger RNAs (mRNAs) of their cognate receptors and of IGF-I receptor mRNA (IGF-I-R). 1,25(OH)2D3 also stimulated mRNA of the androgen receptor (AR), whereas DHT did not affect mRNA of the vitamin-D receptor (VDR). Coincubation with both steroid hormones did not stimulate receptor mRNAs more than either hormone alone. The proliferative effects of DHT and 1,25(OH)2D3 were completely inhibited by simultaneous incubation with both hormones, despite potentiation of IGF-I synthesis. In contrast, both hormones synergistically stimulated cell differentiation as judged by alkaline phosphatase activity, collagen X mRNA, and matrix calcification in long-term experiments. We conclude that DHT and 1,25(OH)2D3 interact with respect to chondrocyte proliferation and cell differentiation. The proliferative effects of both hormones are mediated by local IGF-I synthesis. Simultaneous coincubation with both hormones blunts the proliferative effect exerted by either hormone alone, in favor of a more marked stimulation of cell differentiation.

Androgens↗
PubMed2003

Vitamin D and dexamethasone inversely regulate parathyroid hormone-induced regulator of G protein signaling-2 expression in osteoblast-like cells.

The PTH/PTHrP receptor stimulates both adenylate cyclase- and phospholipase C-dependent signaling pathways via different G proteins. The biological actions of PTH on bone are modified by steroid hormones. PTH induces expression of regulator of G protein signaling (RGS)-2, a putative preferential inhibitor of G(q)-mediated phospholipase C activation. We investigated whether steroid hormones interfere with PTH signaling by modulating PTH-induced RGS-2 expression in osteoblast-like UMR 106-01 cells. PTH (1-34) rapidly and transiently induced expression of RGS-2 mRNA and protein via the cAMP/protein kinase A pathway within 30 min, with maximal protein abundance after 2 h. PTH-induced RGS-2 preferentially bound to Galpha(q), compared with Galpha(s) protein. 1,25-(OH)(2)D(3) pretreatment enhanced PTH-induced RGS-2 mRNA and protein accumulation, whereas dexamethasone preincubation had an attenuating effect. These effects were due to modulation of the RGS-2 gene transcription rate, which increased by 35% with 1,25-(OH)(2)D(3) and decreased by 63% with dexamethasone pretreatment. RGS-2 mRNA half-life was not affected by either steroid. The transcriptional effects of dexamethasone and 1,25-(OH)(2)D(3) were independent of PTH/PTHrP receptor activation and were not explained by effects on cAMP accumulation, cAMP response element-binding protein expression or phosphorylation, or the abundance of the osteoblast-specific transcription factor core-binding factor alpha (CBFa1/Runx2), a known activator of RGS-2 expression. In conclusion, glucocorticoids and 1,25-(OH)(2)D(3) inversely modulate PTH-induced RGS-2 gene transcription. Regulation of RGS-2 may constitute a novel mechanism by which steroids modulate signaling via the PTH/PTHrP receptor and other G protein-coupled receptors in bone.

Animals↗
PubMed2001

Measurement of nitric oxide metabolites in brain microdialysates by a sensitive fluorometric high-performance liquid chromatography assay.

Nitric oxide (NO), formed from arginine by a specific neuronal NO synthase, is an important neurotransmitter in various regions of the central nervous system. While intracerebral microdialysis is an elegant technique to study local extracellular neurotransmitter concentrations in vivo, NO metabolites (nitrate, nitrite (NO(x))) are difficult to study at high temporal resolution because of low tissue concentrations and small sample volumes. We developed a sensitive fluorometric high-performance liquid chromatography (HPLC)-coupled NO(x) assay adapted for the use in brain microdialysate samples. The assay includes an initial enzymatic step in which nitrate is reduced to nitrite. Nitrite is acidified to N2O3, which reacts with 2,3-diaminonaphthalene to form 1-(H)-naphthotriazole. This reaction product can be readily isolated and quantitated by HPLC with fluorometric detection. The theoretical assay sensitivity is less than 1 nM, but numerous sources of contamination must be eliminated in the sampling and assaying process to reliably monitor brain NO(x) outflow by microdialysis.

Animals↗
PubMed2001

Impact of ACE I/D gene polymorphism on congenital renal malformations.

To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo-/dysplasia, obstructive uropathy, reflux nephropathy; n = 59), other congenital or hereditary diseases (n = 23), or acquired glomerular disorders (n = 13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal 'survival' analysis was performed, using a GFR loss of 10 ml/min per 1.73 m2 as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n = 163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P < 0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P < 0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P < 0.001) and gross proteinuria (RR 4.7, P < 0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria.

Adolescent↗
PubMed2001

Does recombinant growth hormone improve adult height in children with chronic renal failure?

During the past decade, the safety and efficacy of long-term treatment with recombinant human growth hormone (rhGH) in children with chronic renal failure before and after renal transplantation has been established. This article reviews the increasing evidence that rhGH treatment also results in a significant improvement of adult height in patients with childhood-onset chronic renal failure. The eventual height benefit of extended rhGH treatment appears to be 1.0 to 1.5 standard deviations on average. Whereas prepubertal rhGH treatment has a beneficial effect on final height, the efficacy of rhGH during puberty is less evident. The cumulative duration of rhGH treatment was found to be the most important positive, and the duration of dialysis treatment periods a negative predictor of rhGH efficacy, stressing the importance of prolonged rhGH treatment starting early in the course of chronic renal failure.

Adult↗
PubMed2001

Exercise induced hypoglycaemic hyperinsulinism.

BACKGROUND: Hyperinsulinism in childhood is often caused by genetic defects involving the regulation of insulin secretion leading to recurrent episodes of hypoglycaemia. We report two patients with exercise induced hypoglycaemia. METHODS: Standardised short exercise tests with frequent blood glucose and plasma insulin measurements were performed in the patients and young healthy controls. RESULTS: Short term exercise resulted in insulin induced hypoglycaemia 15 to 50 minutes after the end of exercise. A massive burst of insulin secretion was observed within a few minutes of the start of exercise in both patients. By contrast glucose and insulin concentrations remained unchanged in healthy controls. CONCLUSIONS: Hyperinsulinaemic hypoglycaemia after moderate physical exercise represents a rarely described phenotype of hyperinsulinism with an as yet unknown defect in the regulation of insulin secretion. It should be suspected in individuals with recurrent exercise related syncope or disturbance of consciousness.

Adolescent↗
PubMed2001

Bacterial keratitis: a prospective clinical and microbiological study.

AIM: To define the clinical and microbiological profile of bacterial keratitis at the Jules Gonin Eye Hospital and to test the in vitro bacterial resistance. METHODS: Patients presenting with bacterial keratitis were prospectively followed; clinical features (age, risk factors, visual acuity) and response to therapy were analysed. Bacteriological profile was determined and the sensitivity/resistance of isolated strains were tested towards 12 ocular antibiotics (NCCLS disc diffusion test). RESULTS: 85 consecutive patients (mean age 44.3 (SD 20.7) years) were prospectively enrolled from 1 March 1997 to 30 November 1998. The following risk factors were identified: contact lens wear, 36%; blepharitis, 21%; trauma, 20%; xerophthalmia, 15%; keratopathies, 8%; and eyelid abnormalities, 6%. The most commonly isolated bacteria were Staphylococcus epidermidis, 40%; Staphylococcus aureus, 22%; Streptococcus pneumoniae, 8%; others Streptococcus species, 5%; Pseudomonas, 9%; Moraxella and Serratia marcescens, 5% each; Bacillus, Corynebacterium, Alcaligenes xyloxidans, Morganella morganii, and Haemophilus influenza, 1% each. 1-15% of strains were resistant to fluoroquinolones, 13-22% to aminoglycosides, 37% to cefazolin, 18% to chloramphenicol, 54% to polymyxin B, 51% to fusidic acid, and 45% to bacitracin. Five of the 85 patients (5.8%) had a poor clinical outcome with a visual loss of one or more lines of visual acuity. CONCLUSION: Fluoroquinolones appear to be the therapy of choice for bacterial keratitis, but, based upon these in vitro studies, some strains may be resistant.

Acute Disease↗
PubMed2001

Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia.

Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.

Animals↗
PubMed2000

Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure.

BACKGROUND: Growth hormone treatment stimulates growth in short children with chronic renal failure. However, the extent to which this therapy increases final adult height is not known. METHODS: We followed 38 initially prepubertal children with chronic renal failure treated with growth hormone for a mean of 5.3 years until they reached their final adult height. The mean (+/-SD) age at the start of treatment was 10.4+/-2.2 years, the mean bone age was 7.1+/-2.3 years, and the mean height was 3.1+/-1.2 SD below normal. Fifty matched children with chronic renal failure who were not treated with growth hormone served as controls. RESULTS: The children treated with growth hormone had sustained catch-up growth, whereas the control children had progressive growth failure. The mean final height of the growth hormone-treated children was 165 cm for boys and 156 cm for girls. The mean final adult height of the growth hormone-treated children was 1.6+/-1.2 SD below normal, which was 1.4 SD above their standardized height at base line (P< 0.001). In contrast, the final height of the untreated children (2.1+/-1.2 SD below normal) was 0.6 SD below their standardized height at base line (P<0.001). Although prepubertal bone maturation was accelerated in growth hormone-treated children, treatment was not associated with a shortening of the pubertal growth spurt. The total height gain was positively associated with the initial target-height deficit and the duration of growth hormone therapy and was negatively associated with the percentage of the observation period spent receiving dialysis treatment. CONCLUSIONS: Long-term growth hormone treatment of children with chronic renal failure induces persistent catch-up growth, and the majority of patients achieve normal adult height.

Adolescent↗
PubMed2000

A case of Perlman syndrome: fetal gigantism, renal dysplasia, and severe neurological deficits.

We report on a neonate presenting with polyhydramnios; macrosomia; macrocephaly; visceromegaly including bilateral nephromegaly, hepatomegaly, cardiomegaly; thymus hyperplasia; cryptorchidism; generalized muscle hypotonia; and a distinctive facial appearance. The clinical course was marked by severe neurodevelopmental deficits combined with progressive respiratory decompensation leading to death at the age 6 months. Magnetic resonance imaging (MRI) disclosed a generalized cerebral atrophy with a marked deficit of the white matter. Renal ultrasound and MRI showed markedly enlarged kidneys with multiple small cystic lesions, a pattern indistinguishable from polycystic kidney disease. The postmortem kidney biopsy revealed dysplastic changes, microcysts, and a focal nephrogenic rest, characteristic features of the Perlman syndrome. In children with fetal gigantism, renal abnormalities, and neurological deficits, Perlman syndrome should be considered and may be confirmed by kidney biopsy.

Abnormalities, Multiple↗
PubMed2000

Malignant osteopetrosis obscured by maternal vitamin D deficiency in a neonate.

UNLABELLED: A neonate presented with clinical, biochemical, endocrine and radiographic features consistent with vitamin D deficiency rickets of maternal origin. Persistent hypocalcemia and subsequent development of pancytopenia, hemolysis and hepatosplenomegaly prompted further studies that led to the diagnosis of infantile osteopetrosis. CONCLUSION: Osteopetrosis is an important differential diagnosis of neonatal rickets and is not excluded by low vitamin D levels.

Female↗
PubMed2000

Assessment of body composition in children with chronic renal failure.

In children with chronic renal failure treated conservatively by dialysis or by transplantation, various alterations of the nutritional, metabolic and fluid homeostasis may occur that may critically affect the patients' acute and chronic well-being. In the past, the assessment of body composition in children was hampered by insufficient precision, standardization and/or availability of appropriate anthropometric tools. Recently, there have been several methodological advances that may facilitate close and precise monitoring of body composition in this population. Specifically, the use of body mass index (BMI) data in children has become possible by the introduction of pediatric reference values processed for the calculation of standard deviation scores accounting for the skewed distribution of BMI. Skewness-adapted reference data have also been provided for percentage fat mass as assessed by multisite skinfold measurements. In addition, bioelectrical impedance analysis has been validated in healthy children as well as in pediatric dialysis and renal transplant populations. This novel auxological technique provides a highly reproducible, non-invasive and inexpensive way of assessing changes in total body water content in dialysed patients, as well as changes in fat and fat-free mass prior to dialysis and after renal transplantation.

Body Composition↗
PubMed2000

Experience with deflazacort in children and adolescents after renal transplantation.

Deflazacort (DFZ) has been proposed as an alternative drug for immunosuppression after renal transplantation (TX), with fewer side effects than conventional glucocorticoids. We investigated renal function, body growth, body fat, and bone mineral density (BMD) after switching from oral methylprednisolone (MPR) to equivalent doses of DFZ 1-9 years after TX in 20 patients aged 5-20 years, selected because of severe adverse effects from previous steroid therapy. At conversion the patients received a mean dose of 7.4 +/- 2.4 mg DFZ/m2 per day. The drug was continued for a mean of 3.7 (1.2-5.5) years. Under DFZ, the glomerular filtration rate dropped slightly (NS). A single rejection episode occurred. Growth velocity significantly improved in the 1st year on DFZ treatment and height standard deviation score (SDS) increased steadily after introduction of DFZ (from -2.64 to -1.96 after 4 years, P = 0.06). However, in 10 prepubertal children the height gain (+0.20 SDS in 2 years on DFZ) was not significant and the overall mean annual growth rate after TX was similar to that in 10 matched prepubertal TX children on continued MPR treatment. Relative obesity, estimated from mean body mass index corrected for height, was reduced from +1.11 SDS at the start of DFZ to +0.71 SDS after 2 years (P = 0.03) and to +0.39 SDS after 4 years (NS). BMD-SDS of the lumbar spine (L2-4) increased after 1 year on DFZ (P = 0.005). In conclusion, DFZ is well tolerated and safe in pediatric patients after TX. It improves relative obesity and bone mineralization. However, body growth is not significantly influenced pre puberty.

Adipose Tissue↗
PubMed2000

Comparison of electrodermal constant voltage and constant current recording techniques using the phase angle between alternating voltage and current.

If electrodermal activity is recorded with direct current, constant voltage and constant current measurements result in different dependencies of electrodermal reactions on the actual electrodermal level. The present study demonstrates empirically that such a problem does not exist when instead the phase angle changes between alternating current and voltage are obtained. Forty subjects were subjected to a 20-trial habituation series on two different occasions, in which electrodermal level variations were induced by room temperature changes. A multiplexing system was used to enable quasi-simultaneous constant current and constant voltage recording under both direct and alternating current measurement conditions. If the alternating current technique was applied and electrodermal responses were expressed as changes of phase angle between voltage and current, electrodermal recordings with constant voltage and with constant current provided equivalent results, even if electrodermal levels were considerably different. Therefore, using the phase angle method instead of the conventional direct current methods will finally resolve the problem of differential level dependency in electrodermal recording. A further advantage will be that electrode and skin polarization are prevented by the use of alternating current.

Acoustic Stimulation↗