Bladder exstrophy and Epstein type congenital macrothrombocytopenia: evidence for a common cause?
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Bladder Exstrophy↗
Biomedical subjects
Jörg Dötsch
Publications and source records attributed to Jörg Dötsch.
Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
OBJECTIVE: Children and adolescents with classical congenital adrenal hyperplasia have been shown to be at risk for obesity associated with higher insulin and leptin levels. Because these factors are also known to cause hypertension, the aim of this study was to analyze 24-h blood pressure profiles and their relation to different clinical and laboratory parameters. DESIGN: Fifty-five subjects, aged between 5.3 and 19.0 yr, were enrolled in a prospective, cross-sectional study. All patients had genetically proven 21-hydroxylase deficiency and underwent ambulatory 24-h blood pressure monitoring during a period off school/work. RESULTS (MEDIAN, RANGE): The median body mass index of the cohort was significantly elevated [1.09 sd score (SDS), -2.45 to 3.77]. Daytime and nighttime systolic blood pressures were also significantly elevated (0.67 SDS, -1.5-4.1; 0.63 SDS, -0.91 to 3.3), whereas daytime diastolic blood pressure was significantly lowered (-0.81 SDS, -2.6 to 3.2) and normal during the night (0.11 SDS, -2.0 to 2.0). Overall, there was a normal nocturnal drop of systolic (12.8%, 2.1-22.8) but not diastolic blood pressure (17.2%, 0.90-25.8). The different parameters of systolic and diastolic blood pressures were significantly correlated with body mass index and skinfold thickness (r(s) = 0.271-0.486). There was no correlation with equivalent hydrocortisone and fludrocortisone dosage and laboratory parameters except for serum leptin and insulin. CONCLUSIONS: Our data show altered 24-h blood pressure profiles with elevated systolic levels correlated with the degree of overweight and obesity, whereas normal-weight patients tended to diastolic hypotension.
Adolescent↗
Stable graft function after reduction of calcineurin inhibitor dosage in paediatric kidney transplant patients.
BACKGROUND: Chronic calcineurin inhibitor (CNI) toxicity contributes to the development and progression of chronic allograft nephropathy (CAN), which is still the major cause of transplant dysfunction and graft loss. Reduction in dosage of CNI may delay the development of CAN, leading to longer graft survival. METHODS: Therefore, 19 paediatric kidney transplant patients under immunosuppressive therapy with CNI (12/19 ciclosporin A, CSA, 7/19 tacrolimus, Tac), mycophenolat mofetil and some patients on steroids were included in a prospective study. Over a period of 9 months CNI dosage was stepwise reduced from CSA trough levels of 100-150 ng/ml to 50-70 ng/ml and Tac trough levels of 5-8 ng/ml to 2-3 ng/ml, respectively. RESULTS: Glomerular filtration rate was stabilized in patients after CSA and Tac reduction. One borderline rejection occurred in a patient prior to reduction of Tac. In patients on CSA, one interstitial cellular rejection (BANFF IA) was noted. Reduction of CNI had no significant effects on blood pressure, lipid status and the infection frequency. CONCLUSIONS: In paediatric kidney transplant patients, reduction of CNI down to low trough levels stabilizes renal function. However, the risk of acute rejection episodes may be increased. Therefore, further studies based on protocol biopsies within a randomized trial are warranted.
Adolescent↗
Hypertonic-hyperoncotic solutions improve cardiac function in children after open-heart surgery.
OBJECTIVES: Hypertonic-hyperoncotic solutions are used for the improvement of micro- and macrocirculation in various types of shock. In pediatric intensive care medicine, controlled, randomized studies with hypertonic-hyperoncotic solutions are lacking. Hypertonic-hyperoncotic solutions may improve cardiac function in children. The primary objective of this controlled, randomized, blinded study was to evaluate the hemodynamic effects and safety of hypertonic-hyperoncotic solution infusions in children shortly after open-heart surgery for congenital cardiac disease. The secondary objective was to determine whether the administration of hypertonic-hyperoncotic solutions could be a potential and effective therapeutic option for preventing a probable capillary leakage syndrome that frequently occurs in children after open-heart surgery. METHODS: The children were randomly assigned to 2 groups of 25. The hypertonic-hyperoncotic solution group received Poly-(O-2)-hydroxyethyl-starch 60.0 g, with molecular weight of 200 kDa, Na+ 1232 mmol/L and osmolality of 2464 mOsmol/L (7.2% sodium chloride with 6% hydroxyethyl-starch 200 kDa). The isotonic saline solution group received isotonic saline solution (0.9% sodium chloride). Atrial and ventricular septal defects were corrected using a homograft patch. Monitoring consisted of an arterial, a central venous, and a thermodilution catheter (PULSIOCATH). Cardiac index, extravascular lung water index, stroke volume index, mean arterial blood pressure, and systemic vascular resistance index were measured (Pulse Contour Cardiac Output technique). Immediately after surgery, patients were loaded either with hypertonic-hyperoncotic solution or with isotonic saline solution (4 mL/kg). Blood samples (sodium concentration, osmolality, thrombocyte count, fibrinogen, and arterial blood gases) were drawn directly before; immediately after; 15 minutes after; and, 1, 4, 12, and 24 hours after the end of volume loading. Hemodynamic parameters were registered at the same time. The total amount of dobutamine required was documented, as well as the 24- and 48-hour fluid balances. RESULTS: In the hypertonic-hyperoncotic solution group, cardiac index was 3.6 +/- 0.26 L/min per m2 before volume administration and increased to 5.96 +/- 0.27 after the administration of the study solution (64%). Fifteen and 60 minutes after administration, the cardiac index remained significantly elevated (5.55 +/- 0.29 L/min per m2 and 4.65 +/- 0.18 L/min per m2, respectively) and returned to preadministration values after 4 hours. In the isotonic saline solution group, the cardiac index did not change during the entire observation period (3.39 +/- 0.21 before and 3.65 +/- 0.23 L/min per m2 after isotonic saline solution). The systemic vascular resistance index decreased in the hypertonic-hyperoncotic solution group after administration from 1396 +/- 112 to 868 +/- 63 dyn/sec per cm(-5)/m2. The decrease of systemic vascular resistance index in the hypertonic-hyperoncotic solution group was transiently significant within 60 minutes after administration but stayed lower than before volume load (999 +/- 70 dyn/sec per cm-(5)/m2). In the isotonic saline solution group, we found no statistically relevant change in systemic vascular resistance index. Stroke volume index significantly increased after hypertonic-hyperoncotic solution infusion (53.9 +/- 3.0 mL/m2 directly after, 48.8 +/- 2.46 mL/m2 15 minutes after, and 41.4 +/- 2.2 mL/m2 60 minutes after) when compared with stroke volume index before administration (32.4 +/- 2.6 mL/m2). In the hypertonic-hyperoncotic solution group, an increase in mean arterial blood pressure remained transiently significant within 60 minutes after administration when compared with the isotonic saline solution group, in which the mean arterial blood pressure remained unchanged. Both central venous pressure and heart rate were unchanged during the whole time of observation in both groups. In the hypertonic-hyperoncotic solution group, extravascular lung water index decreased from 10.6 +/- 1.2 to 5.6 +/- 1.2 mL/kg and remained significantly decreased 15 minutes after (6.5 +/- 1.2 mL/kg) when compared with before volume administration. In the isotonic saline solution group, extravascular lung water index increased from 12.3 +/- 1.1 mL/kg to 18.1 +/- 1.7 mL/kg directly after administration and remained elevated for 60 minutes after volume loading (15.6 +/- 1.5 mL/kg). In all patients, no hypoxia (Pa(O2)<60 mm Hg) or hypercapnia (Pa(CO2) >60 mm Hg) was observed. Arterial blood gas analysis showed pH and base excess within physiologic range, and this did not change throughout the whole period of observation. After infusion of hypertonic-hyperoncotic solution, sodium concentration increased from 139.2 +/- 0.7 to 147.5 +/- 0.7 mmol/L. The maximum sodium concentration was 153 mmol/L, measured immediately after hypertonic-hyperoncotic solution in 1 patient. The total amount of fluid infused was similar in both groups. The postoperative need for infused dobutamine in the patients in the hypertonic-hyperoncotic solution group was decreased compared with the isotonic saline solution group (46.9 +/- 8.8 microg/kg vs 308.2 +/- 46.6 microg/kg). No patient presented with severe bleeding. Short- and long-term cardiac and neurologic outcome was not reduced and all patients left the hospital in a clinically sufficient state. DISCUSSION: This study demonstrates a profound increase of cardiac index after the administration of hypertonic-hyperoncotic solution in children after uncomplicated open-heart surgery, suggesting a positive inotropic effect. The total amount of catecholamine was lower, assuming that hypertonic-hyperoncotic solution reduces the need for positive inotropic support. The observed positive cardiac effect of hypertonic-hyperoncotic solution may even be intensified by the decreased afterload (decreased systemic vascular resistance index). According to the Frank-Starling relation, an effective tool in the treatment of low cardiac output are an elevated preload while afterload is diminished. Therefore, we postulate that hypertonic-hyperoncotic solution may be helpful in preventing or attenuating low cardiac output failure in childhood. Capillary leakage syndrome also is a frequent problem after cardiopulmonary bypass. For quantification of edema formation, extravascular lung water index measurement is a useful tool. Using this approach, we provided evidence that the infusion of hypertonic-hyperoncotic solution is transiently able to reduce extravascular lung water index. This reduction was transient but might prevent the triggering of a clinically relevant capillary leakage syndrome. This is in line with in vitro studies demonstrating that hypertonic-hyperoncotic solution improves microcirculation by reducing vascular permeability. The single administration of hypertonic-hyperoncotic solution infusion was safe, and no adverse effects, such as hemostatic disturbances, were observed. CONCLUSIONS: A single infusion of hypertonic-hyperoncotic saline solution after cardiac surgery is safe despite the hypertonicity and the colloid component of the hypertonic-hyperoncotic saline solution. In children after cardiopulmonary bypass surgery, the administration of hypertonic-hyperoncotic saline solution increased cardiac index by elevating stroke volume index in combination with a lowered systemic vascular resistance index. Extravascular lung water index transiently decreased, suggesting that hypertonic-hyperoncotic saline solution effectively counteracts the capillary leakage that often occurs after cardiac surgery in children. Additional investigations might elucidate whether the temporary effects of hypertonic-hyperoncotic saline solution are beneficial in the treatment of severe capillary leakage after complicated cardiac surgery. It has to be shown that hypertonic-hyperoncotic saline solution is a long-lasting, effective treatment strategy for low cardiac output failure in children that is caused by sepsis, multiorgan failure, and endothelial edema. We have provided evidence to pediatric intensive care clinicians that the single administration of hypertonic-hyperoncotic saline solution might be a useful and safe treatment in the amelioration of contractility, inotropy, and the possible treatment of early-onset capillary leakage.
Capillary Leak Syndrome↗
Is tacrolimus for childhood steroid-dependent nephrotic syndrome better than ciclosporin A?
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Child↗
Transient insulin-dependent diabetes mellitus in children with steroid-dependent idiopathic nephrotic syndrome during tacrolimus treatment.
Despite the availability of immunosuppressive drugs such as prednisone, cyclophosphamide, cyclosporine A (CyA) and mycophenolate mofetil for the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS), medication-free remission is not achieved in a number of patients. To avoid excessive steroid toxicity, the use of tacrolimus (Tac) has been discussed. We report on five children diagnosed with SDNS on the histological basis of minimal change glomerulopathy or focal segmental glomerulosclerosis. Following the failure of other medications to achieve sustained remission, Tac was administered to these patients who varied in age from 10.5 to 13.5 years. Only one patient showed a substantial reduction in the number of relapses with the Tac treatment. Two boys, after 9 and 44 months on therapy, respectively, developed insulin-dependent diabetes mellitus (IDDM), necessitating the withdrawal of Tac and the daily use of insulin for 3 and 6 months. In both patients hyperglycemia had occurred during prednisone-based relapse therapy of SDNS. The patients had low serum protein concentrations, presumably increasing the free active Tac fraction, while trough levels of the drug remained unchanged. Both of the affected patients had additional risk factors for impaired glucose tolerance, such as morbid obesity (patient 1; BMI: 41.6 kg/m(2)) and African American origin (patient 2). Our case reports demonstrate that the use of Tac in patients with SDNS may be associated with an increased risk for IDDM, especially during relapse of NS, and particularly if additional risk factors are present. Moreover, Tac does not appear to substantially increase the success of treatment.
Adolescent↗
Hydrochlorothiazide in CLDN16 mutation.
BACKGROUND: Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation. However, the short-term efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial. METHODS: Four male and four female patients with FHHNC and CLDN16 mutation, under long-standing HCT therapy (0.4-1.2 mg/kg, median 0.9 mg/kg, dose according to calciuria), aged 0.7-22.4 years, were included in a clinical study to investigate the effect of HCT on calciuria. The study design consisted of three periods: continued therapy for 4 weeks, HCT withdrawal for 6 weeks and restart of therapy at the same dose for 4 weeks. Calciuria and magnesiuria were assessed weekly as Ca/creat and Mg/creat ratio, every 2 weeks in 24 h urine, and serum Mg, K and kaliuria (s-Mg, s-K and K/creat) at weeks 0, 6, 10 and 14. The data of each study period were averaged and analysed by Friedman and Wilcoxon test. RESULTS: Ca/creat was significantly reduced by HCT (median before/at/after withdrawal 0.76/1.24/0.77 mol/mol creat; n = 8, P<0.05). The reduction of Ca/24 h by HCT was not statistically significant (0.13/0.19/0.13 mmol/kg x 24 h; n = 5). Serum Mg (0.51/0.64/0.56 mmol/l; n = 8, P<0.05) and Serum K (3.65/4.35/3.65 mmol/l; n = 8, P<0.05) were significantly higher during withdrawal. However, Mg/creat (0.98/0.90/0.90 mol/mol creat; n = 8), Mg/24 h (0.14/0.12/0.18 mmol/kg x 24h; n = 5) and K/creat (6.3/8.4/6.2 mol/mol creat; n = 8) remained statistically unchanged during withdrawal. CONCLUSIONS: We demonstrated that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a short-term basis. However, the efficacy of HCT to attenuate disease progression remains to be elucidated.
Adolescent↗
Hypergonadotropic hypogonadism and renal failure due to WT1 mutation.
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Child, Preschool↗
Novel OCRL1 mutations in patients with the phenotype of Dent disease.
BACKGROUND: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter ClC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). METHODS: We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1. RESULTS: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (I257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. CONCLUSION: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.
Chloride Channels↗
Mycophenolate mofetil introduction stabilizes and subsequent cyclosporine A reduction slightly improves kidney function in pediatric renal transplant patients: a retrospective analysis.
Chronic allograft nephropathy (CAN) is the major cause of late graft loss. Among others, chronic calcineurin inhibitor toxicity (CNI) contributes to the development of CAN. Therefore, reduction in CNI dosage may delay the development of CAN, leading to longer graft survival. It was the aim of the present retrospective analysis to investigate the effect of mycophenolate mofetil (MMF) addition with subsequent cyclosporine A (CSA) reduction on renal function in pediatric kidney allograft recipients. Seventeen patients (aged 8.3-17.6 yr) with monotherapy with CSA and progressive loss of renal function at a median of 3.4 yr after kidney transplantation were enrolled. After at least three months of MMF treatment, CSA dosage was stepwise reduced to trough levels of 100, 80, and 60 ng/mL. In all patients, introduction of MMF prevented a further decrease of glomerular filtration rate (GFR). The mean GFR 12 months before study enrollment was 96.1+/-24.5 and 71.0+/-21.0 mL/min/1.73 m2 at start of MMF. After introduction of MMF and unchanged CSA dosage GFR was stabilized to 71.1+/-23.8 mL/min/1.73 m2. After CSA reduction to trough levels of 60 ng/mL, GFR was slightly ameliorated up to 76.3+/-24.1 mL/min/1.73 m2. Within the follow-up period, one borderline rejection occurred in a patient in whom the CSA trough level was 60 ng/mL since seven months. In pediatric kidney allograft recipients with progressive loss of renal function reduction of CSA after introduction of MMF may stabilize and even slightly ameliorate renal function.
Adolescent↗
Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure.
OBJECTIVE: The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Children suffering from chronic renal failure (CRF) have a decreased activity of 11beta-HSD2 contributing to increased arterial blood pressure. The objective was to investigate whether a normal conversion of F to E is achieved after renal transplantation (TX) in children. METHODS: Fifteen children with CRF, 17 children with steroid-free immunosuppression after TX, and 18 healthy controls (CO) were enrolled. The activity of 11beta-HSD2 in plasma was calculated using the ratio of F/E determined by tandem mass spectrometry, the ratio of tetrahydrocortisol (THF) +5alpha-tetrahydrocortisol (5alphaTHF) in urine determined by gas chromatography/mass spectrometry, and the ratio of (THF +5alphaTHF)/tetrahydrocortisone (THE) in urine determined by tandem mass spectrometry. RESULTS: The F/E ratio (mean +/- S.D./S.E.M.) was significantly higher in CRF and TX (5.6 +/- 1.9/0.6, 7.12 +/- 3.1/0.9) than in CO (1.18 +/- 0.2/0.03, P < 0.0001) groups. The (THF + 5alphaTHF)/THE ratio in CRF (1.19 +/- 1.1/0.5) and TX (1.19 +/- 0.1/0.5) groups was significantly higher than in controls (0.21 +/- 0.05/0.18, P < 0.0001). Positive correlations between plasma and urinary ratios (P = 0.0004. R(2) = 0.73 in CRF, P = 0.0013, R(2) = 0.56 in TX, P < 0.0001, R(2) = 0.66 in CO) were found, whereas significant correlations between F/E or (THF + 5alphaTHF)/THE ratios and blood pressure, the number of antihypertensive drugs taken or creatinine clearance could not be found. CONCLUSIONS: In all children with chronic renal failure plasma and urinary cortisol/cortisone ratios are elevated and do not return to normal levels after renal allograft transplantation. This suggests that renal transplantation does not normalize 11beta-HSD2 activity.
11-beta-Hydroxysteroid Dehydrogenase Type 2↗
Does defective hypoxia signalling cause type 2 diabetes?
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Animals↗
Circulating resistin concentrations in children depend on renal function.
BACKGROUND: Resistin is a newly discovered peptide hormone that inhibits adipogenesis. Furthermore, it may be involved in regulative processes taking place in insulin resistance and inflammation. In human beings as well as in rodents, the exact physiological role of resistin is unknown. The objective of this study was to examine whether resistin serum concentrations in childhood are regulated by renal function. METHODS: Fifteen patients with end stage renal disease treated by haemodialysis (HD) (6m, 9f; age (median (25-75% percentile)) 16.1 (14.2-16.9) years; body mass index (BMI) 17.8 (17.6-20.6) kg/m2; glomerular filtration rate (GFR)<10 ml/min/1.73 m2), 11 patients with chronic renal failure (CRF) (4m, 7f; age 11.3 (9.2-16.9) years; BMI 17.9 (15.4-22.1) kg/m2; GFR 21.2 (19.8-39.4) ml/min/1.73 m2) and 23 healthy children (13m, 10f; age 7.8 (4.7-14.5) years; BMI 16.5 (14.9-18.1) kg/m2; GFR 168.5 (154.0-197.2) ml/min/1.73 m2) were included. Resistin concentration in serum was measured by ELISA, leptin by RIA. RESULTS: Resistin concentrations were significantly elevated in HD (6.6 (5.7-8.7) ng/ml) and CRF (4.8 (4.1-6.2) ng/ml) compared to healthy controls [2.7 (2.0-3.6) ng/ml; P<0.0001 by multiple regression analysis]. Furthermore, resistin concentrations showed a tendency to be higher in children below the age of 5.5 years (youngest tertile) and above 12.5 years of age (oldest tertile), compared to children aged between 5.5 and 12.5 years (P=0.053 and P=0.043, respectively). Gender (P=0.686) and BMI (P =0.663) did not have a significant influence on resistin concentrations. Resistin and leptin serum concentrations correlated in HD patients only (r=0.62, P=0.013 by Spearman correlation). Haemodialysis did not eliminate resistin. CONCLUSIONS: With decreasing renal function, resistin concentration in serum increases in our small paediatric cohort. Age possibly influences circulating resistin concentration. The hypothesis that elevated serum resistin in children with chronic renal failure or end stage renal disease may add to malnutrition and reduced BMI needs further investigation and is not supported by our data.
Adolescent↗
Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditions.
Glial cells missing a (GCMa) belongs to a new transcription factor family. Syncytin was shown to be a target gene of GCMa. Here, we demonstrate that the protein kinase A (PKA) pathway acts upstream of GCMa. After transient transfection of BeWo cells with PKA, GCMa transcriptional activity and both GCMa and syncytin transcripts were upregulated. This increase was accompanied by further cellular differentiation. Using normoxic or hypoxic conditions to mimic pathophysiological settings known to diminish trophoblast differentiation, we found that gene repressive effects of oxygen deficiency were compensated by the induction of the PKA pathway. We propose that GCMa-driven syncytin expression is the key mechanism for syncytiotrophoblast formation.
Apoptosis↗
Alterations of leptin and ghrelin serum concentrations in renal disease: simple epiphenomena?
The hypothesis that alterations of serum concentrations of the anorexigenic adipose tissue-derived hormone leptin or the orexigenic peptide ghrelin might help to regain appetite and fight malnutrition in patients with chronic renal failure cannot be confirmed at present. For the future, however, strategies interfering with signal transduction of these peptides in the hypothalamus might be more promising and should be investigated and further developed.
Appetite↗
An exceptional Albanian family with seven children presenting with dysmorphic features and mental retardation: maternal phenylketonuria.
BACKGROUND: Phenylketonuria is an inborn error of amino acid metabolism which can cause severe damage to the patient or, in the case of maternal phenylketonuria, to the foetus. The maternal phenylketonuria syndrome is caused by high blood phenylalanine concentrations during pregnancy and presents with serious foetal anomalies, especially congenital heart disease, microcephaly and mental retardation. CASE PRESENTATION: We report on an affected Albanian woman and her seven children. The mother is affected by phenylketonuria and is a compound heterozygote for two pathogenetic mutations, L48S and P281L. The diagnosis was only made in the context of her children, all of whom have at least one severe organic malformation. The first child, 17 years old, has a double-chambered right ventricle, vertebral malformations and epilepsy. She is also mentally retarded, microcephalic, exhibits facial dysmorphies and small stature. The second child, a girl 15 years of age, has severe mental retardation with microcephaly, small stature and various dysmorphic features. The next sibling, a boy, died of tetralogy of Fallot at the age of three months. He also had multiple vertebral and rib malformations. The subsequent girl, now eleven years old, has mental retardation, microcephaly and epilepsy along with facial dysmorphy, partial deafness and short stature. The eight-year-old child is slightly mentally retarded and microcephalic. A five-year-old boy was a premature, dystrophic baby and exhibits mental retardation, dysmorphic facial features, brachydactyly and clinodactyly of the fifth finger on both hands. Following a miscarriage, our index case, the youngest child at two years of age, is microcephalic and mentally retarded and shows minor facial anomalies. All children exhibit features of phenylalanine embryopathy caused by maternal phenylketonuria because the mother had not been diagnosed earlier and, therefore, never received any diet. CONCLUSION: This is the largest family suffering from maternal phenylketonuria reported in the literature. Maternal phenylketonuria remains a challenge, especially in woman from countries without a neonatal screening program. Therefore, it is mandatory to be alert for the possibility of maternal phenylketonuria syndrome in case of a child with the clinical features described here to prevent foetal damage in subsequent siblings.
Abnormalities, Multiple↗
Identification of ghrelin in human saliva: production by the salivary glands and potential role in proliferation of oral keratinocytes.
BACKGROUND: We investigated whether ghrelin is present in human saliva, is produced by salivary glands, and physiologic consequences of these findings. METHODS: Expression of ghrelin and specific receptor mRNA was determined by PCR. Proteins were identified by immunoblotting and size-exclusion fast protein liquid chromatography (FPLC) with consecutive RIA. Specific RIAs were used for quantification of salivary total and bioactive ghrelin. Distribution of ghrelin was investigated by immunohistochemistry in cryosections of the salivary glands. The effect of ghrelin on incorporation of 5-bromo-2'-deoxyuridine as a measure of cell proliferation was investigated in primary oral keratinocytes. RESULTS: Ghrelin is produced by the salivary glands. The hormone was identified in saliva and glands by immunoblotting and by FPLC fractionation of saliva. Immunohistochemistry demonstrated ghrelin distribution in the salivary glands. The receptor was also produced by the glands and by oral keratinocytes and was shown to be functional. Comparison of total ghrelin values for healthy individuals (body mass index, 18-27 kg/m2) showed significantly lower concentrations in saliva than in serum (P < 0.01). The correlation between both matrices was r2 = 0.56 (P < 0.001) with a negative correlation to body mass index (r2 = 0.314; P < 0.01). Bioactive acylated ghrelin was also present in saliva. Incubation of keratinocytes with ghrelin led to significantly increased cell proliferation (P < 0.001). This effect could be completely suppressed by co-incubation with NOX-B11 (50 nmol/L), a novel specific inhibitor of acylated ghrelin. CONCLUSIONS: Ghrelin in saliva is produced and released by salivary glands. The effect of ghrelin on oral cell proliferation adds to the pro-proliferative action of other salivary growth factors.
Adolescent↗
Adrenomedullin reduces mesangial cell number and glomerular inflammation in experimental mesangioproliferative glomerulonephritis.
BACKGROUND: Adrenomedullin (ADM) is a vasodilator peptide that is abundantly expressed in the kidney. ADM has antiproliferative effects on glomerular mesangial cells (MC) in vitro. Whether or not treatment with ADM can reduce MC proliferation in vivo [i.e., in mesangioproliferative glomerulonephritis (GN)] is unknown. We tested the hypothesis that ADM substitution reduces MC proliferation in GN. METHODS: GN in rats was induced by injection of an anti-Thy-1.1 antibody. Rats received osmotic minipumps, which continuously delivered rat ADM (500 ng/hour, N = 11), or vehicle (N = 13) from day 3 to day 6 after GN induction. Rats were sacrificed 6 days after induction of GN. On kidney sections, cells staining positive for proliferating cell nuclear antigen, mesangial cells, monocytes, and apoptotic cells were counted. Parameters of inflammation and fibrosis were measured in renal cortex and sieved glomeruli by real-time polymerase chain reaction (PCR). RESULTS: Systolic blood pressure, diuresis, albuminuria, creatinine clearance, microaneurysm formation, and mesangial matrix expansion were not influenced by ADM infusion. However, ADM treatment significantly reduced the number of MC, showed a tendency to reduce total glomerular cell proliferation, and significantly increased apoptosis. ADM-treated GN animals showed significantly less glomerular monocyte infiltration. ADM treatment normalized transforming growth factor (TGF)-beta1 mRNA expression and reduced monocyte chemoattractant protein-1 (MCP-1), osteopontin, plasminogen activator inhibitor-1 (PAI-1), collagen I, and collagen III mRNA expression significantly. CONCLUSION: Exogenous ADM infusion reduces MC number and glomerular monocyte infiltration in the state of mesangial proliferation during acute experimental mesangioproliferative GN. These findings indicate that ADM can influence the course of mesangioproliferative GN.
Adrenomedullin↗