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Biomedical subjects

O Mehls

Publications and source records attributed to O Mehls.

At least 109 records · Page 6Linked to original sources
PubMed1996

Effect of growth hormone treatment on pubertal growth in a boy with cystinosis and growth failure after renal transplantation.

Recombinant human growth hormone (rhGH) has proven effective in improving growth in short prepubertal children with chronic renal failure (CRF) before and after renal transplantation. However, its effect in pubertal patients is still doubtful. We report the case of a boy with nephropathic cystinosis and persistent growth failure despite successful renal transplantation who was treated with rhGH (30 i.u./m2 body surface area/week sc) from early puberty up to final height.

Child↗
PubMed1996

Predictors of the response to growth hormone in short prepubertal children post-renal transplant. German Study Group for Growth Hormone Treatment in Children Post Renal Transplantation Study Group Members.

The growth response to recombinant human growth hormone (rhGH) in post-renal transplantation children is variable. We sought to determine predictive factors of this variable effect of rhGH by analysis of a homogeneous group of 16 prepubertal children with a median age of 12.4 years (range 7.7-18.0 years). rhGH was given at 30 i.u./m2/week for at least one year. All children remained prepubertal during the study period. Height velocity increased from 2.5 +/- 0.4cm/year to 7.4 +/- 0.5cm/year after one year of treatment (p < 0.001). The growth response to rhGH (height velocity after one year of rhGH) was not significantly correlated with the dose of prednisolone administered (range 2.3-9.1mg/m2/day), graft function as estimated by creatinine clearances (range 19-88ml/min/1.73m2), the degree of stunting at baseline, baseline height velocity, or chronological age. However, a relatively tight inverse correlation was found between the growth response to rhGH and the degree of bone age delay (r = 0.73, p < 0.005). Hence, the degree of bone age delay appears to be a helpful clinical predictor of response to rhGH in short prepubertal children post-renal transplantation.

Adolescent↗
PubMed1995

Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia.

UNLABELLED: Three short prepubertal children with X-linked hypophosphataemia were treated with 1 IU recombinant human growth hormone (rhGH)/kg per week sc in addition to calcitriol and phosphate supplementation over a period of 3 years. Improvement of height standard deviation score (SDS) ranged from 1.0-1.7 SD based on an increase in sitting height of 1.5-2.9 SD, whereas subischial leg length improved only slightly by 0.3-0.9 SD. In all three patients, renal phosphate threshold concentration increased slightly and transient hyperparathyroidism was noted. CONCLUSION: Treatment of stunted children with X-linked hypophosphataemia is effective in improving growth velocity, but appears to aggravate the pre-existent disproportionate stature of such children.

Anthropometry↗
PubMed1995

Insulin-like growth factors (IGF) and IGF binding proteins in children with chronic renal failure.

The pathomechanism of growth retardation and catabolism in children with chronic renal failure (CRF) is multifactorial. Recent evidence indicates that in particular disturbances of the somatotropic hormone axis play an important pathogenic role. In preterminal CRF serum insulin-like growth factor (IGF)-I and IGF-II levels are normal, while in end-stage renal disease (ESRD), IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated growth hormone levels in ESRD, these serum IGF-I levels appear as inadequately low. Indeed, there is both clinical and experimental evidence for a decreased hepatic IGF-I production rate in CRF. This hepatic insensitivity to the action of GH is partially owing to a reduced GH receptor expression. The action and metabolism of IGFs are modulated by specific high-affinity IGF binding proteins (IGFBPs), which bind approximately 99% of circulating IGF. IGFBP-1, IGFBP-2, and low molecular weight IGFBP-3 fragments are increased in CRF serum in relation to the degree of renal dysfunction. Both decreased renal filtration, in particular of low molecular weight IGFBP-3 fragments, and increased hepatic production of IGFBP-1 and -2 contribute to high IGFBP serum levels. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action on target tissues by competition with the type 1 IGF receptor for IGF binding.

Child↗
PubMed1995

Calbindin-D28K and -D9K and 1,25(OH)2 vitamin D3 receptor immunolocalization and mineralization induction in long-term primary cultures of rat epiphyseal chondrocytes.

Rat epiphyseal plat chondrocytes were grown on glass slides, as nonadhering monolayer cultures for up to 6 weeks. Chondrocyte growth, differentiation and maturation, matrix formation and mineralization, and the temporospatial distribution of the vitamin D-dependent calcium-binding proteins, calbindin-D9K and -D28K, and the 1,25(OH)2D3 receptor (VDR), were all monitored. Chondrocytes became confluent in 2.5 weeks, differentiated to acquire a chondrocyte (polygonal) morphology, produced extracellular matrix, and finally formed a true monolayer mineralizing cartilaginous tissue, with all the stages of chondrocyte development within a single culture. beta-Glycerophosphate promoted initial matrix mineralization in 4 weeks and accelerated cell differentiation. High nominal calcium and ascorbic acid were needed for abundant matrix formation. VDR occurred at all differentiation stages, in the nuclei and nucleoli and in the cytoplasm. Calbindin-D28K and -D9K were not coexpressed. Calbindin-D28K was found in prechondroblasts, chondroblasts, and in newly differentiated chondrocytes. It was cytoplasmic in prechondroblasts and subsequently also in the perinuclear region and in nuclei, suggesting migration to the nuclear chromatin. Calbindin-D28K was nuclear only in newly differentiated chondrocytes in vitro and was not found in mature chondrocytes. In contrast, calbindin-D9K was present in the cytoplasm of mature and hypertrophic chondrocytes only. It was first in the cell body and eventually migrated within and to the far end of long cell processes with a decreasing cytoplasmic concentration showed by decreased immunostaining intensity, and ultimately hypertrophy of chondrocytes in culture. These in vitro patterns of calbindins-D and VDR accurately reflect their in vivo distributions. The genomic action of vitamin D, in vitro, resulted in the synthesis of nuclear VDR and calbindins-D.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Vitamin D therapy in patients receiving dialysis.

Secondary hyperparathyroidism is found in a large proportion, but not all patients on dialysis. Calcitriol controls moderate hyperparathyroidism in most patients but only in a proportion of those with advanced hyperparathyroidism. Patients with nodular parathyroid hyperplasia respond less frequently, presumably because of monoclonal growth and diminished calcitriol-receptor expression by parathyroid cells. In patients with nodular parathyroid hyperplasia, parathyroidectomy is an important alternative to calcitriol treatment. A priori reasoning indicates that prophylactic administration of calcitriol (to prevent parathyroid hyperplasia) is a reasonable option, but currently no controlled evidence for long-term efficacy of this approach without side effects is available. Intermittent administration of calcitriol by intravenous or oral routes is effective and, at least in experimental studies, superior to continuous calcitriol. However, in clinical comparisons, no superiority of intravenous versus oral or daily versus intermittent calcitriol has been documented. Calcitriol treatment must be closely supervised to prevent hypercalcemia, hyperphosphatemia, and excessive suppression of parathyroid hormone. Because of an altered dose response relationship, parathyroid hormone levels should not be completely normalized so as to prevent low bone turnover (adynamic bone lesion).

Calcitriol↗
PubMed1995

Deconvolution analysis of spontaneous nocturnal growth hormone secretion in prepubertal children with preterminal chronic renal failure and with end-stage renal disease.

We sought to determine whether elevated circulating growth hormone (GH) concentrations in uremic prepubertal children are due to an increase in GH secretory activity by the pituitary gland or a decrease in the metabolic clearance of GH consequent to reduced GFR. Deconvolution analysis was applied to the nighttime plasma GH profiles of 1) 11 children with preterminal chronic renal failure, 2) 12 children with end-stage renal disease (ESRD), and 3) a control group of matched children with idiopathic short stature (n = 12). Mean (+/- SEM) half-life of endogenous GH in children with ESRD (27.5 +/- 2.7 min) and preterminal chronic renal failure (23.1 +/- 2.1 min) was significantly higher than in controls (14.8 +/- 1.6 min; p < 0.001). GH half-life correlated inversely with GFR (r = -0.65, p < 0.001). The number of GH secretory bursts/10 h in ESRD (8.1 +/- 0.4) was amplified compared with preterminal chronic renal failure (6.4 +/- 0.5) and with controls (5.9 +/- 0.4; p < 0.005). GH production rate varied over a broad range in the three groups: It was highest in ESRD (202 +/- 56.6 microgm/L/10 h; range 36-683), mainly as a result of an increased number of GH secretory bursts, and not statistically different in preterminal chronic renal failure (66.2 +/- 11.4 microgm/L/10 h; range 25-168) and in controls (129 +/- 27.7 microgm/L/10 h; range 39-392). Increased GH half-life, in concert with an increased GH production in some individuals with ESRD, leads to a 2.5-fold increase in the mean plasma GH concentration in ESRD compared with the two other groups (p < 0.005) [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Serum insulin-like growth factors (IGFs) and IGF binding proteins 1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood.

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, and IGF binding protein 1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured in 94 children with chronic renal failure (CRF). The results were compared with their respective age-dependent normal ranges, and the relationship with height and residual glomerular filtration rate (GFR) was examined. Each IGF and IGFBP was quantified by specific RIA. Serum IGF-I and IGF-II levels were in the normal range throughout their entire childhood in the vast majority of cases. The mean age-related IGF-I (0.07 +/- 0.14 SD score) and IGF-II levels (0.06 +/- 0.11 SD) were similar. Age-related IGF-II but not IGF-I levels showed a weak inverse linear correlation with residual GFRs (r = -0.24, P < 0.02). Mean age-related IGFBP-1 serum levels (1.04 +/- 0.09 SD) were slightly elevated, whereas mean age-related serum IGFBP-2 levels (3.25 +/- 0.20 SD) and serum IGFBP-3 levels (2.61 +/- 0.12 SD) were markedly elevated. Significant inverse correlations were found between GFRs and age-related IGFBP-1 (r = -0.42, P < 0.001), IG-FBP-2 (r = -0.56, P < 0.001), and IGFBP-3 (r = -0.28, P < 0.005), but the increase in IGFBP-2 with declining GFR was relatively more pronounced than the respective increase in IGFBP-1 and IGFBP-3. The correlation between age-related IGF-I and relative height in prepubertal children with CRF (n = 54, r = 0.43, P < 0.001) was lower than in prepubertal controls (n = 68, r = 0.67, P < 0.001), and the slope of the regression line was significantly less steep, indicating that the normal relationship between IGF-I and height is disturbed in CRF. The normal relationship between IGFBP-3 and height was disrupted in CRF. Forward stepwise regression analysis revealed that height in CRF is correlated with IGF-I and inversely correlated with IGFBP-2. We conclude that the imbalance between normal IGFs and excessive IGFBP serum levels in CRF plays a pathogenic role in the growth failure of these children.

Body Height↗
PubMed1995

Quantification of urinary insulin-like growth factors (IGFs) and IGF binding protein 3 in healthy volunteers before and after stimulation with recombinant human growth hormone.

We examined excretion of urinary insulin-like growth factors I and II (IGF-I and IGF-II) and their major binding protein IGFBP-3 in comparison to their respective serum concentration in nine healthy female volunteers (median age 25 years, range 22-27) under baseline conditions and after stimulation with recombinant human growth hormone (rhGH), 4.5 IU twice daily subcutaneously for a period of 3 days. The IGFs were measured in unconcentrated urine by use of recently developed, highly sensitive radioimmunoassays. The IGFBP-3 was measured by a specific radioimmunoassay. The mean (+/- SD) urinary concentrations of IGF-I (0.08 +/- 0.07 micrograms/l), IGF-II (1.02 +/- 0.47 micrograms/l) and IGFBP-3 (19.1 +/- 6.9 micrograms/l) were two to three orders of magnitude lower than in serum. The ratio of IGF-II over IGF-I concentration in urine (13:1) was five times higher than in serum (2.5:1), and the ratio of IGFBP-3 over the sum of IGF-I and IGF-II in urine (17:1) was four times higher than in serum (4:1). Urinary excretion was 63.3 +/- 46.6 ng.m-2.24h-1 for IGF-I, 1002 +/- 598 ng.m-2.24h-1 for IGF-II and 18039 +/- 4983 ng.m-2.24h-1 for IGFBP-3. Using fast protein liquid exclusion chromatography, only immunoreactive IGFBP-3 components of less than 60 kD were detected in urine, with a major peak at 20 kD. Urinary IGFBP-3 excretion correlated with serum IGFBP-3 (r = 0.61, p < 0.01) and the glomerular filtration rate (r = 0.56, p < 0.05) measured by steady-state inulin infusion clearances.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Treatment of peritoneal dialysis-associated peritonitis with continuous versus intermittent vancomycin/teicoplanin and ceftazidime in children: preliminary results of a prospective randomized trial. Members of APN Arbeitsgemeinschaft Paidiatrische Nephrologie.

A recent treatment update for continuous peritoneal dialysis (CPD)-associated peritonitis recommends first-line use of continuously or intermittently administered intraperitoneal vancomycin and ceftazidine. Teicoplanin has recently been introduced as a potentially less toxic alternative glycopeptide antibiotic. However, efficacy and safety have not been demonstrated for intermittent treatment schedules or for the use of teicoplanin in prospective studies. Therefore, a prospective trial on the treatment of CPD-associated peritonitis was started in 15 pediatric dialysis units using vancomycin or teicoplanin, in combination with ceftazidine. Vancomycin or teicoplanin was administered either continuously with each bag of dialysate for 10 days or as a single dose on days 1 and 8, and ceftazidime either continuously or in one bag of dialysate per day. Until December 31, 1994, 81 episodes of peritonitis including 16 relapses occurred in a cohort of 120 patients. The incidence of peritonitis was 1 episode/13.7 months, regardless of treatment modality [continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD)]. Thirty-six (57%) primary peritonitis episodes were caused by staphylococci (21 Staphylococcus aureus, 15 coagulase-negative), 12 (19%) by gram-negative bacteria, 7 by other germs, and in 8 (13%) cases cultures remained sterile. Primary treatment response was achieved in 43/46 (93%) gram-positive and 4/12 (33%) gram-negative peritonitis episodes. Relapses occurred only with gram-positive bacteria (16/63, 25%). In cases of gram-positive peritonitis, no differences in primary response (25/25 vs 15/18) or relapse rates (10/36 vs 6/27) were observed between groups on continuous and intermittent treatment, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Bacterial Agents↗
PubMed1994

Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia.

In uremia, reduced longitudinal growth and decreased hepatic insulin-like growth factor-I (IGF-I) secretion despite elevated GH serum levels point to an insensitivity to the action of GH. The molecular basis that accounts for this insensitivity could comprise decreased GH receptor expression in the target organs for GH or binding of GH in the circulation to substances that compete with the receptor. To address this hypothesis, the abundance of hepatic GH receptor mRNA was measured by solution hybridization RNase protection assay in uremic female Sprague-Dawley rats, following two-stage 5/6 nephrectomy, and in pair-fed and in ad libitum-fed sham-operated controls; rat GH binding protein (GHBP) plasma concentration was measured by a sensitive direct RIA. Uremia was associated with a 50% decrease of hepatic GH receptor expression compared to pair-fed controls, which themselves showed a 25% reduction of hepatic GH receptor mRNA abundance when compared to ad libitum-fed controls. Plasma GHBP levels in uremia were markedly higher than in both control groups. Treatment with recombinant human GH (rhGH) (10 IU/kg body wt per day s.c. for 10 days) led to a comparable induction of IGF-I plasma levels and weight gain in uremia and pair-fed controls, indicating that the insensitivity to GH in uremia can be overcome by large rhGH doses. Subcutaneous rhGH injections did not significantly alter the hepatic GH receptor transcript abundance or plasma GHBP levels in any of the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Growth response to recombinant human growth hormone in short prepubertal children with chronic renal failure with or without dialysis. The European/Australian Study Group.

The growth-promoting effect of recombinant human growth hormone (GH) in children with chronic renal failure was assessed in eight clinical trials. A total of 103 prepubertal children participated in the trials, 34 of whom were undergoing dialysis. The children were treated with GH, 30 IU/m2/week (approximately 1 IU/kg/week), for up to 2 years, and various growth parameters, bone age and renal function were assessed before and during treatment. In all trials, the children showed clear catch-up growth and an improved height SDS after treatment with GH, although the increase in height was less in dialysis patients than in those not receiving dialysis. GH maintained its growth-promoting effect during the second year of treatment; the effect, however, was less marked than during the first year of treatment. Bone age appeared to advance in parallel with chronological age. Median serum creatinine increased from 204 mumol/l to 230 and 262 mumol/l after 12 and 24 months of treatment, respectively, due to increased muscle mass and/or progression of the underlying renal disease. The loss of estimated glomerular filtration rate/year was not different before and during GH treatment.

Adolescent↗
PubMed1994

Outcome and prognostic determinants in the hemolytic uremic syndrome of children.

The late outcome in 89 children with the hemolytic-uremic syndrome (HUS) observed from 1971 to 1988 was analyzed up to 17 years after onset in relationship to various clinical and pathologic features at the onset of the disease. In the first 3 months after onset (acute phase) 69% of all children needed dialysis therapy. Fifteen children died, 9 during the acute phase and 6 subsequently. All surviving patients except 7 were reexamined and divided into five prognostic categories: recovery, residual renal symptoms with normal kidney function, moderate renal insufficiency, preterminal chronic renal failure (CRF) and end-stage renal disease (ESRD). The rate of recovery calculated by the life table method increased from 35% after 10 years in 1971-1979 to 68% in 1980-1988 (p < 0.001); it was lower in infants than in older children (44 vs. 63%; nonsignificant). Children with atypical HUS experienced more often preterminal CRF, ESRD or death than those with a typical (postenteropathic) form (33 vs. 17%; p < 0.05). If oliguria lasted < 7 days, 74% of patients recovered after 10 years versus 13% in the case of oliguria > 14 days or anuria > 7 days (p < 0.0005). The rate of recovery was also significantly smaller with the duration of dialysis treatment > 7 days, central nervous system involvement and requirement for antihypertensive therapy. In the entire series 7 patients developed preterminal CRF and 5 ESRD. Of 27 cases serially followed for 5-10 years after onset, a stable course was noted in 16, a subsequent improvement in 8 and deterioration in 3 leading to ESRD in 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Central Nervous System Diseases↗
PubMed1994

Metabolic clearance of recombinant human growth hormone in health and chronic renal failure.

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.

Adolescent↗