[Regional coordination of paediatric oncological care in northwestern Lower Saxony, Germany--network funded by health insurance companies]. / Verbund PädOnko Weser-Ems--Regionale ambulante Versorgung pädiatrisch-onkologischer Patienten aus der Weser-Ems-Region im Rahmen einer Integrierten Versorgung.

The cure rates in pediatric oncology have been substantially improved due to standardized treatment strategies and centralization of therapy. Close clinical and hematological monitoring is mandatory for patients between periods of chemotherapy for early detection and treatment of therapy-related complications such as infections. This results in frequent and time-consuming outpatient examinations for the patient and family at the oncological center in order to evaluate clinical condition and hematological findings. In widespread regions such as the Weser-Ems area in northwest Lower Saxony, Germany, the long distances between patients' home and the oncological center lead to higher risks and impairment of quality of life (QoL) for the patients and their families. Accordingly, in 2001 pediatric hospitals and practices, patient care services and patients' support groups in Weser-Ems founded a network (Verbund PädOnko Weser-Ems). The "Verbund PädOnko" aims at coordinated, high-quality regional outpatient patient treatment in order to reduce risks of long-distance transports to reach the oncological center. Since 2005 a newly established mobile care team realized 1 443 home visits covering a total of 150 300 km. Since 2007 the network has been funded by health insurance organisations. Internal and external benchmarking was performed showing that the rate of short term inpatient treatments were reduced. Treatment quality was assured and the QoL of the patients and their families was improved through the work of the network. The "Verbund PädOnko Weser-Ems" network represents a promising prototype model for the regional coordination of outpatient treatment and care of patients with rare diseases in wide spread areas.

Superantigen-induced lysis of melanoma cells.

Superantigens like the Staphylococcus enterotoxin A (SEA) can direct cytotoxic T lymphocytes expressing certain T cell receptor V beta regions to lyse MHC class II-positive target cells. This superantigen-dependent cellular cytotoxicity (SDCC) has been extended to MHC class II-negative tumour cells by targeting T cells via conjugates of a tumour-specific monoclonal antibody (moAb) and a superantigen. In the present study the MHC class II-negative human melanoma cell lines G361 and MaRI were tested for susceptibility to SDCC in vitro. Antibodies recognizing the disialoganglioside GD3 and the CD10 antigen were linked to SEA either by a recombinant protein A-SEA fusion protein or an anti-kappa moAb-SEA chemical conjugate. Specific lysis of melanoma cells was dose- and effector to target (E:T) cell ratio-dependent. Introduction of a point mutation into the SEA gene (producing SEAm9) in order to reduce MHC II affinity of the superantigen, which has already been shown to severely diminish superantigen-dependent binding and lysis of MHC class II-positive cells, did not influence antibody-targeted SDCC. Cytotoxicity was equal with both antibodies (anti-GD3 and anti-CD10) and independent of whether protein A-SEA, protein A-SEAm9 or anti-kappa-SEA were used.

Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: a multicenter trial including 1141 subjects.

Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 +/- 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 +/- 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6 AM) was 13% +/- 6% and 23% +/- 9% lower compared with the daytime means (8 AM to 8 PM), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children.

[Unusual motivation in double suicide of a lesbian couple. Phenomenology, psychodynamics and influence of contemporary values]. / Ungewöhnlich motivierter Doppelsuizid eines lesbischen Liebespaares. Phänomenologie, Psychodynamik und Zeitgeisteinflüsse.

Double suicides are regarded as uncommon phenomena. In particular, homosexuals are very rarely involved. It is reported on the unusual motivation of a dual suicide by hanging among two 20-year-old lesbian women. Due to abnormal psychic development and mutual induced reaction the thought of dying together and being reborn jointly in one person (a contemporary actor) arose. These ideas were influenced by spiritism and metempsychosis. The case is well-documented by diary records and will be discussed under phenomenological and psychodynamic aspects. Typical and atypical criteria of double suicides are featured.

Superantigen-staphylococcal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells.

Superantigens such as the staphylococcal enterotoxin A (SEA) are among the most potent T cell activators known. They bind to major histocompatibility complex (MHC) class II molecules and interact with T cells depending on their T cell receptor (TCR) V beta expression. Superantigens also induce a variety of cytokines and trigger a direct cytotoxic effect against MHC-class-II-positive target cells. In order to extend superantigen-dependent cell-mediated cytotoxicity (SDCC) to MHC-class-II-negative neuroblastoma cells, SEA was linked to the anti-ganglioside GD2 human/mouse chimeric monoclonal antibody (mAb) ch14.18. Ganglioside GD2 is expressed on most tumours of neuroectodermal origin but is expressed to a lesser extent on normal tissues. The linkage of ch14.18 to SEA was achieved either with a protein-A-SEA fusion protein or by chemical coupling. Both constructs induced T-cell-mediated cytotoxicity towards GD2-positive neuroblastoma cells in an effector-to-target(E:T)-ratio- and dose-dependent manner in vitro. To reduce the MHC class II affinity of SEA, a point mutation was introduced in the SEA gene (SEAm9) that resulted in 1000-fold less T cell killing of MHC-class-II-expressing cells as compared to native SEA. However, a protein-A-SEAm9 fusion protein mediated cytotoxicity similar to that of protein-A-SEA on ch14.18-coated, MHC-class-II-negative neuroblastoma cells. Taken together, these findings suggest that superantigen-dependent and monoclonal-antibody-targeted lysis may be a potent novel approach for neuroblastoma therapy.

Antibody-targeted superantigens induce lysis of major histocompatibility complex class II-negative T-cell leukemia lines.

CTLs bearing certain T-cell receptor V beta-regions are directed by the bacterial superantigen Staphylococcus enterotoxin A (SEA) to lyse MHC class II-positive cells. In order to extend superantigen-dependent cytotoxicity to MHC class II-negative carcinoma cells, covalent conjugates of superantigen and mAbs against surface markers of these cells have been used. We now describe a novel strategy which allows rapid selection of mAb suitable for superantigen targeting against MHC class II-negative tumor cells. A recombinant fusion protein of protein A and SEA binding to the mAbs CD7 or CD38 was able to mediate T cell-dependent lysis of MHC class II-negative Molt-4 and CCRF-CEM acute lymphatic leukemia cell lines. Lysis was dose dependent and correlated with E:T cell ratio. In contrast, SEA alone did not induce any significant lysis. In order to decrease the MHC class II affinity of the protein A-SEA complex, a point mutation was introduced into SEA (protein A-SEA mu9). The mutated fusion protein had similar potency as protein A-SEA against Molt-4 cells but was 100-fold less active against MHC class II-positive cells. Considering the efficiency and specificity of the mutated SEA protein interacting with mAb in targeting T lymphocytes against MHC class II-negative leukemia cells while only marginally affecting normal MHC class II-positive cells, we suggest the development of SEA-mAb fusion proteins as a potential adjuvant therapy of leukemias.

Steroid resistant nephrotic syndrome associated with spondyloepiphyseal dysplasia, transient ischemic attacks and lymphopenia.

Focal segmental glomerulosclerosis, nephrotic syndrome and chronic renal failure were associated with spondyloepiphyseal dysplasia, growth failure, lymphopenia and transient ischemic attacks leading to severe neurological symptoms in three children. Two boys and one girl developed the full syndrome at the age of 5, 6 and 10 years. Positron emission tomography revealed perfusion defects of both cerebral and cerebellar arteries. A variant of the disease was found in two other children who had a nephrotic syndrome and terminal renal failure with only mild spondyloepiphyseal dysplasia, impaired growth and a normal cerebral function. It is concluded that there may be a close association between focal segmental glomerulosclerosis and spondyloepiphyseal dysplasias.

Exercise capacity and blood pressure response in children and adolescents after renal transplantation.

Physical working capacity and cardiovascular response to graded exercise on a bicycle ergometer were investigated in 70 children and adolescents (33F, 37M) after renal transplantation. Results of static and dynamic lung function tests were within the normal range in all patients. Systolic blood pressure, heart rate, pulmonary ventilation and oxygen uptake increased with workload and returned to pre-exercise levels after 5 m of rest. During exercise, blood pressure values were within the normal range in almost all patients. The increase in heart rate and respiratory frequency was blunted in patients receiving beta blocking agents. Maximum workloads (Wmax) were 2.00 +/- 0.48 W/kg in females and 2.38 +/- 0.54 W/kg in males, which are 78 +/- 18% and 84 +/- 18% of the normal values predicted for age. Maximum oxygen consumption (VO2max) was 23.2 +/- 5.8 ml/min/kg in females and 28.3 +/- 5.8 ml/min/kg in males. Half of the patients had height below the third percentile. For this reason exercise capacity in relation to height is probably a more relevant parameter than age. Using actual height, Wmax was 102 +/- 20% and 102 +/- 29%, and VO2max 74 +/- 14% and 80 +/- 18% of predicted values, respectively. We conclude that the adaption of the cardiovascular and respiratory system to graded exercise was influenced by beta blocking agents. Wmax and VO2max were significantly reduced for age in pediatric patients after renal transplantation. Wmax was normal, but VO2max was still reduced if corrected for height.

Cerebral ultrasonography before and after cardiac surgery in infants.

Cerebral ultrasonography was performed in 66 infants before and after open heart surgery in order to study the incidence of cerebral complications. The underlying cardiac malformations were ventricular septal defect (n = 28), transposition of the great arteries (n = 11), tetralogy of Fallot (n = 8), complete atrioventricular septal defect (n = 5), total anomalous pulmonary venous drainage (n = 3), truncus arteriosus communis (n = 2), and complex cardiac malformations (n = 9). In 60 of the 66 infants ultrasonography of the brain preoperatively was normal, 3 had minor structural abnormalities, and 3 had ventriculomegaly of various degrees. Postoperatively, 46 infants had a normal brain ultrasound scan; 6 had slight structural abnormalities; and 5 had slight symmetric or asymmetric widening of the ventricles. Five infants showed severe ventriculomegaly with cerebral atrophy, and in 4 patients there was intracerebral hemorrhage, associated in 2 cases with severe ventriculomegaly. On repeat examinations it was found that up to 4 weeks after the operation an initially normal cerebral ultrasound scan could convert to a pathologic one. Most of those children who showed significant deterioration on the cerebral ultrasound scan suffered from complex cardiac malformations or had severe problems during the postoperative period.

Continuous arteriovenous haemofiltration in critically ill children.

We report 24 children with acute renal failure treated with continuous arteriovenous haemofiltration (CAVH) between 1987 and 1991. The median age was 2.9 years (range 3 days to 9 years). The main causes of the acute renal failure were: open heart surgery (n = 11) and liver failure of different origins before and after liver transplantation (n = 10). The indication for CAVH was oliguria or fluid overload in all children. The femoral vessels were used as vascular access in most instances. Different filters were used, depending on the size of the patient and an average ultrafiltration of 130 +/- 89 ml/h was achieved, which resulted in a fluid clearance of 4.0 +/- 2.6 ml/min per 1.73 m2. In 18 patients uraemia was adequately controlled. Nine children survived after recovery of their renal function; 15 (62.5%) died as a consequence of multiorgan failure. We conclude that CAVH is an effective method to support critically ill children with acute renal failure.

Twenty-four hour blood pressure monitoring in healthy children.

Blood pressure and heart rate were measured every 20 min during the day and every 30 min during the night in 105 children (51 girls and 54 boys, aged 6-10 years) with a portable automated blood pressure monitor using an oscillometric principle of measurement. The monitor was well accepted by most of the children and the rate of invalid measurements was only 13%. Mean systolic and diastolic blood pressure was 114 +/- 7/72 +/- 5 by day and 99 +/- 7/56 +/- 6 by night. The corresponding heart rates were 93 +/- 8 and 72 +/- 9 beats/min. No significant differences were found between boys and girls. At night, systolic blood pressure dropped by 13% +/- 4%, the diastolic value by 22% +/- 7% and heart rate fell by 22% +/- 6%. Mean systolic and diastolic blood pressure measurements correlated positively with the subject's height, whereas no correlation was found with age.

[Hypothyroid iodine deficiency struma in 2 siblings as a sequela of alternative nutrition]. / Hypothyreote Jodmangelstruma bei 2 Geschwistern als Folge einer alternativen Ernährung.

Two siblings aged 4 and 7 years presented with a goitre and growth retardation. Laboratory data revealed hypothyroidism with elevated TSH, low T4 und T3, and a decreased urinary iodine excretion. Both children suffered from neurodermitis and because of that for already two years on a vegetarian diet free of any milk products; their nutrition contained sufficient calories but not enough iodine or vitamin B.

Growth and pubertal development in nephropathic cystinosis.

In a retrospective investigation growth and pubertal development were evaluated in 30 patients with nephropathic cystinosis. Growth was investigated during the stage of chronic renal insufficiency as well as after successful kidney transplantation and growth rates were related to kidney function. Pubertal development was evaluated in 17 patients between 12 and 25 years of age. Prepubertal growth rates were stable in a range between -2 and -3 height velocity SDS as long as glomerular filtration rate was above 20ml/min per 1.73m2. A decrease in glomerular filtration rate below this threshold was followed by further decrease in height velocity. After kidney transplantation a significant catch-up growth was seen if immunosuppression was performed with cyclosporine A and low dose prednisolone. This did not occur if conventional therapy with azathioprine and high-dose prednisolone was used. Onset of puberty was delayed in all patients. Gonadotropin and oestradiol levels in female patients showed normal fluctuations according to ovulatory cycles. In male patients after puberty there was an increase in gonadotropin levels above the normal range for adult men while testosterone levels remained in the low normal range. These results indicate that adult men with nephropathic cystinosis may develop hypergonadotropic hypogonadism.

[Diseases involving the heart and kidney in children and adults]. / Krankheiten mit Beteiligung von Herz und Niere bei Kindern und Erwachsenen.

An association of renal and cardiac manifestations can be observed in a variety of diseases. The pathogenetic factors may include, firstly, a disturbance of organ development due to chromosomal aberration or an underlying syndrome or, secondly, infectious, immunologic and metabolic factors. In addition, primarily isolated diseases of the heart or the kidney may lead to damage of the previously unaffected organ. The present article gives a review on renal diseases associated with heart diseases in children and adults.

Post-renal transplant erythrocytosis in a child.

We report the case of a 7-year-old boy who developed severe erythrocytosis 4 months after successful kidney transplantation, with a well-functioning graft. When the haematocrit rose above 60%, phlebotomy had to be performed once to twice a week in order to keep the haematocrit below 50%. A 3-month course of theophylline therapy did not influence the erythrocytosis significantly. There were 5 further patients with erythrocytosis out of 186 children who had undergone kidney transplantation at our centre.

Renal involvement in patients with congenital cyanotic heart disease.

Patients with congenital cyanotic heart disease may develop a glomerulopathy with proteinuria and impaired renal function. In order to investigate this problem we conducted a study on 27 patients with uncorrected cyanotic heart disease who were between 1 day and 25 years old. As a consequence of hypoxaemia haematocrit was elevated to 57%. Proteinuria was above 150 mg/day/1.73 m2 body surface in 12 patients. Only one of 9 children under 10 years of age had pathological proteinuria presenting as isolated albuminuria. Seven out of 10 patients between 11 and 20 years had an elevated proteinuria with a glomerular pattern. Creatinine clearance was normal in these patients. All four patients above 20 years of age had a considerable glomerular proteinuria with a mean excretion of 5.7 g/24 h/1.73 m2 body surface. These patients suffered additionally from chronic cardiac failure and creatinine clearance was below the normal range. There was a clear relationship between pathological proteinuria and age of the patients and thus duration of hypoxaemia. Patients with pathological proteinuria had a significant higher erythrocyte count (7.3 +/- 1.3 vs 5.6 +/- 1.4 10(12)/l p less than 0.01) and a lower mean corpuscular haemoglobin. In summary, children with persistent congenital cyanotic heart disease have substantial risk of developing a glomerulopathy if the cyanosis remains unchanged for more than ten years.

Dependence on monoamine oxidase inhibitors in high dose.

A 37-year-old woman with a personality disorder and chronic dysthymia developed a dependence on MAOIs. She ingested 440 mg tranylcypromine daily without any side-effects while taking no dietary precautions. The features of MAOI dependence and their resemblance to amphetamine dependence are discussed.