Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation.

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low-dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard-dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high-risk (donor+/recipient-) patients (n = 88), the EVR-based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val-)ganciclovir (n = 63), the CMV-free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR-based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard-dose calcineurin inhibitor-based regimen.

Ciprofloxacin-induced acute renal failure in a patient with cystic fibrosis.

Acute renal failure is a rare adverse reaction of antibiotic therapy with quinolones seldom seen in young patients. We report an 18-year-old young woman with cystic fibrosis who experienced a pronounced decline in renal function after oral treatment with ciprofloxacin for 3 weeks. Withdrawal of the drug led to normalization of renal function after 10 days.

In vivo release by histamine agonists and antagonists of endogenous catecholamines in the cat hypothalamus.

The posterior hypothalamus of anaesthetized cats was superfused through a push-pull cannula with histamine agonists and antagonists and the release of endogenous catecholamines was determined in the superfusate. Hypothalamic superfusion with histamine, 2-methylhistamine (H1-agonist), dimaprit (H2-agonist) or metiamide (H2-antagonist) enhanced the release of the catecholamines dopamine, noradrenaline and adrenaline. The releasing effects of these substances depended on the presence of calcium ions. Superfusion with 2-pyridylethylamine (H1-agonist) was virtually ineffective, while superfusion with 2-thiazolethylamine (H1-agonist) enhanced the rates of release of noradrenaline and adrenaline without influencing the release of dopamine. Superfusion with mepyramine (H1-antagonist) inhibited the release of noradrenaline and adrenaline without affecting the release of dopamine. Hypothalamic superfusion with a concentration of procaine which was equi-anaesthetic to that of mepyramine was ineffective. Ranitidine (H2-antagonist) did not alter the rates of release of the catecholamines. The releasing effect of histamine was inhibited on hypothalamic superfusion with mepyramine and ranitidine. Ranitidine also inhibited the releasing effects of dimaprit and 2-methylhistamine thus indicating that the releasing action of the latter compound was mainly due to stimulation of H2-receptors. These data suggest that blockade of H1-receptors of the posterior hypothalamus reduces the release of noradrenaline and adrenaline, while stimulation of H1-receptors seems to increase the rates of release of these two catecholamines. Stimulation of H2-receptors enhances the release of all three catecholamines. Thus, dopaminergic neurones of the hypothalamus seem to possess H2-receptors, while noradrenergic and adrenergic neurones possess H1- and H2-receptors.

Effects of short-lasting and long-lasting blood pressure changes on the release of endogenous catecholamines in the hypothalamus of the conscious, freely moving rabbit.

In anaesthetized rabbits guide cannulae were stereotaxically inserted into the anterior hypothalamic area and into the posterior hypothalamic nucleus. Additionally, catheters were inserted into the carotid artery and the jugular vein. Some days after the operation push-pull cannulae were inserted through the guide cannulae into the hypothalamic regions of the conscious, freely moving animal. The areas were superfused with artificial CSF and the release of the endogenous catecholamines dopamine, noradrenaline and adrenaline was determined in the superfusates. In the two hypothalamic regions the resting release of the catecholamines rhythmically varied with time at approximately 70 min cycles. A rise in blood pressure induced by the intravenous injection of noradrenaline or tramazoline enhanced the rates of release of the catecholamines in the anterior hypothalamic area. A fall of blood pressure elicited by the intravenous injection of nitroprusside or chlorisondamine decreased the release of the catecholamines in this hypothalamic area. The changes in blood pressure coincided with the changes in the rates of release of the catecholamines in the anterior hypothalamic area. These and previous results concerning changes in the release of endogenous catecholamines in the posterior hypothalamic nucleus also indicate that in the conscious, freely moving rabbit changes in blood pressure lead to counteracting alterations in the release of catecholamines in the two hypothalamic regions.

Validity and reliability of 24h blood pressure monitoring in children and adolescents using a portable, oscillometric device.

Noninvasive 24h BP monitoring using portable devices is a new method for the diagnosis of arterial hypertension and for the control of antihypertensive therapy in adults. Recently, it is also used in juvenile hypertension. We now report on the validity and reliability of an oscillometric BP recorder (SpaceLabs 90207) widely used in children and adolescents. Single BP recordings with this monitor were compared with manual auscultation of Korotkoff sounds and with measurements by an other oscillometric device (Dinamap). SBP measured by the SpaceLabs monitor was 5 mmHg (2-10 mmHg, median and quartiles) higher than manual readings whereas there was no difference in DBP between these methods. With the Dinamap monitor, SBP was identical to manual readings but DBP was underestimated by 8.5 mmHg (1-13 mmHg). The 24h BP monitoring was performed in 101 children < 13 years of age and in 58 adolescents > 12 years of age. Seventy-eight per cent (64-89%) of all readings were complete in the younger probands and 91% (84-95%) in the older ones (P < 0.01). Measurements failed more often during daytime compared with nighttime in both groups. In conclusion, long-term BP monitoring using an oscillometric device is useful and reliable in adolescents and even in smaller children.

Production of chromatid breaks by single dsb: evidence supporting the signal model.

PURPOSE: The signal model proposes that all chromatid breaks arise from a single DNA double strand break (dsb) via a recombinational exchange mechanism. Here the prediction that chromatid breaks arise from a single dsb is tested. METHOD: The genetically engineered Chinese hamster cell line GS19-43 containing a unique yeast I-SceI recognition site was treated with I-SceI endonuclease (Meganuclease) in the presence of the porating agent streptolysin O. Chromatid breaks were scored at 4h, chromosome breaks at 18 and 22h following treatment (cells used for a 4h fixation were prelabelled with BrdU over two cell-cycles). Positive controls were treated with the restriction endonuclease Pst 1. RESULTS: I-SceI endonuclease produced chromatid breaks and at higher enzyme concentrations isochromatid breaks but no chromatid interchanges. About 16% of the chromatid breaks had a 'colour-switch' between the sister-chromatids at the site of breakage, as revealed by FPG staining. At the longer fixation times (18 and 22 h) chromosome breaks were observed, but again no interchanges were seen. Chromatid and chromosome breaks always appeared on the same chromosome. CONCLUSIONS: The production of chromatid breaks from a single dsb fulfils the prediction of the signal model. Moreover, the production of colour-switch breaks at a similar frequency to that for ionizing radiation indicates that chromatid breaks are produced via recombinational exchanges, a significant proportion of which occurs between sister chromatids. The majority is intrachromatid, not involving strand-switches. The absence of interchromosomal exchanges at all fixation times indicates a requirement of two dsb in two different chromosomes for their formation.

Design and implementation of a computerized diet order entry system for a hospital.

A computerized diet entry system was developed to control entry of diet orders by hospital ward clerks from an established list of items. Three reporting systems were then designed for delivery of the computerized order to the Nutrition Services Department. One report contains only essential information and is printed instantly upon entry for confirmation of a "stat" diet order. Another report collates diet orders by time periods and then organizes them by wards and sequentially by room number. That report is then used for diet changes prior to meal service. The third report stores advance diet orders and test diet orders and reports them upon the date they are to be served. Diet orders are also collated and retained in the system, in sequential order for each patient, to allow for an instant report of the patient's diet history upon demand. This computerized diet order system has resolved problems regarding receipt of complete information required for a diet order and receipt of a diet order for all patients. An overview of the information support system used by the Nutrition Services Department, which was created from programs developed for other hospital departments, is also presented.

Atrial natriuretic peptide and cyclic guanosine-monophosphate in children and adolescents on peritoneal dialysis.

Plasma concentrations of atrial natriuretic peptide (ANP) and its second messenger cyclic guanosine-monophosphate (cGMP) were studied in 28 children and adolescents (1 to 19 years) on peritoneal dialysis and compared to 55 healthy children (1 to 20 years). Dialysate concentrations of the hormones were measured also in the patients. Plasma ANP was not significantly different in patients and controls (28.8 pmol/l [15.5-53.6 pmol/l] [median, lower and upper quartile] versus 26.3 pmol/l [19.9-31.8 pmol/l]). In seven children on peritoneal dialysis it exceeded an upper normal limit of 50 pmol/l, but it fell to normal values in four of them after forced fluid withdrawal. Plasma cGMP was elevated in the patients compared to the control children (1.6 nmol/l [1.1-1.7 nmol/l] versus 1.0 nmol/l [0.8-1.2 nmol/l]; p < 0.05). There were only weak correlations between plasma and dialysate concentrations of ANP and cGMP. Plasma concentrations of ANP seem to be elevated in children on peritoneal dialysis in case of fluid overload.

24-hour blood pressure monitoring in children and adolescents after recovery from hemolytic uremic syndrome.

24-hour blood pressure monitoring is a valuable method for the diagnosis of arterial hypertension as well as for assessment of the diurnal rhythm of the arterial blood pressure (BP). The nocturnal decrease of blood pressure ("dipping") may be attenuated or abolished in children with advanced renal failure and glomerular diseases. Arterial hypertension is a longlasting problem in children who had recovered from hemolytic uremic syndrome (HUS). We therefore performed BP monitoring in 11 children and adolescents (age 1.3 to 18.8 years, 6 males, 5 females) after HUS using a portable oscillometric device (SpaceLabs 90207). Six of the subjects had a normal renal function (group A). The other 5 patients had impaired renal function with a glomerular filtration rate <60 ml/min/1.73 m2 (group B). Nocturnal dipping was calculated as nocturnal mean blood pressure minus diurnal mean blood pressure given in per cent of diurnal mean blood pressure. Two of the patients in group A had diurnal mean BP above the 95th percentile of the German collaboration study, but none of the group was hypertensive during the night, and nocturnal dipping was 13.6% (9.7-15.5%, median and range) for systolic BP and 23.7% (15.5-29.9%) for diastolic BP which is very similar to healthy children. All of the patients had a normal diurnal BP rhythm. From patients of group B, 4 had elevated diurnal mean BP and also 4 were hypertensive during the night. Nocturnal dipping was 1.4% (0.7-4.1%) for systolic and 6.8% (0-10.7%) for diastolic BP which is clearly attenuated compared to group A. We therefore conclude that arterial hypertension is more common in patients after HUS if they have impaired renal function, and diurnal rhythm of arterial blood pressure is attenuated in these patients. However, nocturnal dipping of blood pressure is not disturbed in children after HUS without renal insufficiency, even if they were hypertensive.

Spontaneous baroreflex sensitivity in children and young adults calculated in the time and frequency domain.

Spontaneous baroreflex receptor sensitivity (BRS) was calculated in 22 healthy normotensive children and young adults (age 14 +/- 5 years) using the sequence technique (time domain) and the alpha-coefficient or the gain of the transfer function between coherent oscillations (frequency domain). BRS estimated by the sequence technique (median: 16.7 ms/mm Hg) was significantly higher than BRS calculated from the gain of the transfer function using all frequencies (median: 13.0 ms/mm Hg; p = 0.009). However, there was a high correlation between these methods (r = 0.92). The reproducibility coefficient (RC) was high for all methods, but the coefficient of variability (VC) was best for the sequence technique and the gain of the transfer function, but significantly worse for the estimates of the alpha-coefficient in the low or high frequency band. The differentiation between increasing or decreasing blood pressure (BP) ramps did not give further information showing the same BRS values. The best BRS estimates will be achieved by using three consecutive beats without lag by the sequence technique and by using only frequencies with a proven correlation of BP and pulse interval (PI) and then calculating the gain of the transfer function using coherent oscillations.

Arterial hypertension in children and adolescents after surgical repair of aortic coarctation defined by ambulatory blood pressure monitoring.

BACKGROUND: Despite early operation, persistent and late systolic hypertension are common among children and adolescents after surgical repair of aortic coarctation and can contribute to early cardiovascular morbidity. METHODS: Ambulatory blood pressure monitoring was performed for 78 patients (aged 3.6-22.8 years, 41 male) after successful surgical repair of aortic coarctation (median duration of follow-up 6.5 years, range 0.7-20.1 years). Hypertension was defined as mean systolic blood pressure exceeding the 95th percentile for sex and height. RESULTS: Twenty-three patients (29%) exhibited systolic hypertension during daytime. Hypertensive patients had been older at the time of operation than had normotensive patients (5.4+/-5.0 versus 2.4+/-3.1 years, P<0.01). Prevalence of hypertension was 21% among patients who had undergone surgery during the first year of life and 38% among patients who had been operated upon later. Decline in blood pressure during night was similar for all patients (systolic 11+/-5% and diastolic 19+/-8%). Systolic hypertension during night-time was found in 24% of patients who were normotensive during day. Diastolic hypertension was rare. Follow-up measurements were performed for 41 patients after 2.3+/-1. 3 years, and most normotensive patients remained normotensive during this time. CONCLUSIONS: Ambulatory blood pressure monitoring allows one to estimate nocturnal hypertension in children and adolescents after surgical repair of aortic coarctation which is common also among normotensive patients during daytime.

Bent subcutaneous peritoneal catheter shape for regular dialysis treatment in children.

A permanent bowing of the subcutaneous part of the Tenckhoff-type catheter (bent neck--Quinton, and swan neck--Accurate Surgical Instruments) enables the catheter to turn from an upward direction of the subcutaneous tunnel to a downward direction by a smooth 160 degrees-180 degrees bend creating a downward skin exit. We have used this catheter shape in combination with a coiled intra-abdominal edge. Two sizes are available for children. We use 2 cuffs and glue them ourselves according to the body size. In this study we compare the durability of the traditional subcutaneously straight catheter in 8 children aged 0.1-12.6 years (Group A) with the bent shaped catheter in 8 children aged 3.7-15.8 years (Group B). Median duration of function was 10.5 (2-34) and 8 (3-36) months, respectively. Frequency of complications was equal in both groups: peritonitis episodes 0.69/year in Group A and 0.53/year in Group B; tunnel infection 0.16 vs 0.11/year; skin exit infection 0.54 vs 0.53/year; noninfectious complications 0.16 vs 0.32/year; mean number of catheters used was 1.0 vs 1.1/treatment year. Treatment had to be terminated in some patients: kidney transplantation 5, kidney recovery 1, severe peritonitis 1. The bent subcutaneous catheter shape did not show any medical or technical disadvantage compared with the straight type, but the downward directed catheter skin exit can be covered invisibly under bikini or bermuda shorts which means aesthetic and social advantage. Whether the downward drainage of secretes and cell detritus influences the rate of tunnel infection positively cannot be answered to date.

Ambulatory blood pressure monitoring in children and adolescents. Current insights into a new technique.

Ambulatory blood pressure monitoring (ABPM) is a new technique recently introduced into paediatrics. Devices with auscultatory blood pressure measurement may be more precise but give more erroneous readings than those with oscillometric measurement. For the interpretation of the results, mean day- and night-time values should be calculated according to patients' diaries and gender- and height-specific percentiles for ABPM measurements should be used to define hypertension. The use of "blood pressure load" as the percentage of single readings above a given upper level is not standardised in children and adolescents. A nocturnal blood pressure decline of less than 10% is defined as "non-dipping", although this is an arbitrary definition whose prognostic value is not evaluated in paediatric patients. Several studies showed that ABPM in children is superior in detecting "white-coat''-hypertension, shows a better reproducibility and is a better prognostic factor for left ventricular mass compared to casual blood pressure measurements. Clinical studies show the value of ABPM in obese children, in children with renal diseases, on dialysis therapy and after renal transplantation as well as in diabetic children or in children after surgical repair of aortic coarctation. Ambulatory blood pressure monitoring in children and adolescents has grown to a valuable method for the daily management of patients with suspected or established hypertension. However, there is still a lot of work before all technical problems are solved and international guidelines can be published which are based on evidence from follow-up studies.

Determination and characterization of arginine-vasopressin in extracted and unextracted urine and its urinary excretion in normal children and adolescents.

Arginine-vasopressin (AVP) was measured by radioimmunoassay in extracted and unextracted urine using two different antisera. The specificity of the assay was confirmed by high-performance liquid chromatography. By the use of a high specific antiserum, AVP can reliably be measured in unextracted urine. Measurements with a less specific antiserum revealed higher concentrations, probably due to nonspecific binding. The extraction of AVP by the use of octadecasilyl-silica columns is unable to separate the intact hormone from substances interfering with the assay. The urinary AVP excretion in 34 normal children and adolescents ranged between 3.5 and 120 ng/m2/24 h with a mean of 39.1 +/- 29.9 ng/m2/24 h.

Elevated plasma concentrations of neuropeptide Y in children and adults with chronic and terminal renal failure.

Neuropeptide Y (NPY) is a peptide hormone that is expressed, stored, and released in sympathetic neurones together with noradrenaline. Elevated plasma concentrations of NPY have been reported in patients with neural crest tumors (neuroblastoma, pheochromocytoma) and following exercise. We studied plasma concentrations of NPY in children and adults with chronic and terminal renal failure and compared them with those in healthy controls. Neuropeptide Y was significantly higher in children and adolescents receiving peritoneal dialysis (5.3 +/- 2.8 pmol/L; n = 11 [mean +/- SD]) or hemodialysis (5.4 +/- 2.1 pmol/L; n = 14) than in healthy children (2.3 +/- 0.9 pmol/L; n = 19) or pediatric patients with impaired renal function who are not receiving dialysis (2.7 +/- 0.6 pmol/L; n = 8; mean glomerular filtration rate, 41 mL/min x 1.73 m2). There was a small but insignificant negative correlation between glomerular filtration rate and NPY concentrations in children with impaired renal function (r = 0.49; P = 0.25). In healthy adults, NPY concentration was similar to that in healthy children (1.8 +/- 1.0 pmol/L; n = 13), and it was significantly elevated in adults receiving hemodialysis (5.9 +/- 1.7 pmol/L; n = 16). No significant changes in NPY concentrations were found before and after hemodialysis in pediatric or adult patients. We conclude that plasma concentrations of NPY are elevated in patients with chronic renal failure who are receiving either peritoneal or hemodialysis, but not in patients with moderately impaired renal function. Whether elevated NPY concentration indicates increased sympathetic activity or is caused by reduced NPY clearance remains to be shown.

Measurement of blood pressure at home: survey among pediatric nephrologists.

Recently, an international consensus paper was published for standardization of home self-blood pressure (BP) measurement in adults. However, few data exist regarding home BP measurement in children, although it is recommended for all pediatric patients on renal replacement therapy in Germany. Therefore, a survey was performed among German-speaking pediatric nephrologists (members of the Arbeitsgemeinschaft Pädiatrische Nephrologie) in order to study their opinions about home blood pressure measurements. Approximately 75% of German pediatric nephrology centers responded to the survey. More than 70% of the interviewees prescribed a blood pressure device for all children with renal diseases and hypertension or on renal replacement therapy. For children with antihypertensive medication, 2.8 daily measurements were recommended at mean and 2.2 measurements for children without therapy. Auscultation of Korotkoff sounds and oscillometric BP measurements were used in the same percentage for home BP recordings. The upper cut of level for home blood pressure values was rated by the pediatric nephrologists and compared to reference values of casual blood pressure. There was good agreement for upper systolic BP, but as many as 40 to 50% of the interviewees accepted upper diastolic BP values higher than the 97th percentile for casual BP. Home BP measurement was judged to be more important than office BP measurement by 64% of the nephrologists and less important than 24 h ambulatory blood pressure monitoring by 67%. The results of the survey showed wide discrepancies for standards of home BP measurement in children and adolescents, especially for the recommendations for upper diastolic BP. Before home blood pressure measurements can be recommended unrestrictedly in children and adolescents, we stress the need for standardization of blood pressure devices and measurement. Prospective studies in children are needed to demonstrate that these standards facilitate better prediction of cardiovascular outcome using home BP measurements compared to office BP recordings in children.

Plasma concentration and urinary excretion of arginine vasopressin in children with moderately impaired renal function.

Plasma concentration and urinary excretion of arginine vasopressin (AVP) were measured in 20 children and adolescents with normal or moderately impaired renal function. Plasma AVP was higher in children with an inulin clearance less than 60 ml/min X 1.73 m2, whereas plasma osmolality did not differ in all children. Urinary excretion and urinary clearance of AVP (UCAVP) decreased in relation to impairment of renal function, and a strong negative correlation was found between plasma AVP and log UCAVP. Reduced urinary excretion of AVP may contribute to elevated plasma AVP in children with impaired renal function.

[24-hour blood pressure measurement in normal children and adolescents]. / 24-Stunden-Langzeitblutdruckmessung bei normalen Kindern und Jugendlichen.

Blood pressure was continuously monitored over 24 h in 33 healthy children and adolescents (18 girls, 15 boys, age 6-17 years) using a portable monitor. The results were compared with European blood pressure centiles for normal children and adolescents. On average, 67% (57-88%, median and quartiles) of the measurements were completed. The day's mean for systolic blood pressure for girls was 0.04 (-0.67-1.00) standard deviations above the mean of the reference group with corresponding body-height, and for diastolic blood pressure, 1.08 (0.50-1.63) standard deviations. The corresponding values for boys were 0.42 (0.09-0.45) for systolic and 1.11 (1.00-1.39) for diastolic blood pressure. Mean systolic blood pressure for girls decreased during the night by 10% (5-13%) compared to the day time measurements, and the diastolic blood pressure decreased overnight by 23% (12-28%). Systolic blood pressure for boys decreased overnight by 8% (6-11.5%), and diastolic blood pressure decreased by 15% (12-19%).

Sudden death in cystinosis.

We report on an 8-year-old boy with infantile cystinosis. The patient died in hospital for unknown reason after cardiopulmonary arrest although resuscitation was started immediately. As opposed to other cases [1-3], neither laboratory investigations nor autopsy in out patient gave an explanation for the sudden death.