Behandlungsassoziierte Spätfolgen nach Strahlentherapie maligner Erkrankungen im Kindes- und Jugendalter

BACKGROUND AND PURPOSE: Radiogenic late effects in children and adolescents have been evaluated retrospectively in most analyses, with small patient numbers. The German Group of Pediatric Radiation Oncology (APRO) has generated a concept for a prospective evaluation of radiation-associated late effects in childhood. The aim of this study was to evaluate the feasibility of a nationwide central database for the documentation of radiation parameters and side effects of all children treated within therapy protocols of the German Society of Pediatric Oncology and Hematology (GPOH). PATIENTS AND METHODS: A study center has been implemented in Muenster, the documentation has started in July 2001 in few centers in a pilot phase. Since February 2004 the documentation is done countrywide. Detailed documentation forms have been designed for treatment parameters and for doses applied at organs at risk. Furthermore, a uniform toxicity documentation, according to the RTOG/EORTC criteria, was chosen. Patients were reported from the study centers of the GPOH to the study center. All information was collected and analyzed in the study center. RESULTS: Till July 31, 2005, 438 documentations of radiation and 579 toxicity documentations of side effects have been collected in the study center. 46 centers for radiotherapy in Germany and one center each in Austria and in Switzerland took part in the documentation. The quality of documentation regarding completeness and plausibility fulfilled the expected criteria in most cases. This feasibility analysis showed that important information about organ dose levels and side effects was documented in a large number of patients (Figures 1 and 2). CONCLUSION: This prospective evaluation of radiotherapy and radiogenic side effects in children and adolescents will allow correlating doses at organs at risk and the incidence of acute and late sequelae in Germany. Further documentations and a longer follow-up are necessary to obtain powerful results.     

Social position affects bone mass in childhood through opposing actions on height and weight.

We studied relationships between social position of the mother in pregnancy and bone mass of the child at age 9.9 years. The tendency for social position to increase bone area and bone mass through a positive influence on height was opposed by a negative effect of social position on weight and fat mass. INTRODUCTION: Evidence that social factors influence skeletal growth raises the possibility that bone mass acquisition in childhood is socially determined. MATERIALS AND METHODS: To clarify the role of social factors in bone mass acquisition in childhood, we studied relationships between these variables in the Avon Longitudinal Study of Parents and Children (ALSPAC). Measures of the mother's social position during pregnancy were linked to DXA results obtained at age 9.9 years in 6,702 children. Linear regression analyses were carried out after adjusting for age and gender. Because social position may affect height and weight of the child, analyses were repeated after adjusting for these additional variables. RESULTS: Measures of social position in pregnancy were unrelated to total body BMC in analyses adjusted for age and gender alone. However, after adjusting for height, which was positively related to social position, a strong negative association was observed between BMC and housing tenure (p < 0.001), maternal education (p < 0.001), paternal education (p < 0.001), and social class (p < 0.001). Similar results were obtained for bone area. After adjusting for weight as well as height, an association between social position and BMC and bone area was no longer observed. Hence, social position seems to exert opposing height- and weight-dependent effects on BMC and bone area in childhood. In further analyses, we found that adjusting for fat mass of the child led to similar results to those obtained with weight. CONCLUSIONS: Social position in childhood seems to be positively related to bone mass acquisition in childhood as a consequence of enhanced gain in height (i.e., longitudinal growth). However, this influence is counteracted by the tendency for increased fat deposition in those from a lower social position to increase bone area, presumably reflecting the stimulation of appositional bone growth.     

Creatine Supplementation Normalizes Mutagenesis of Mitochondrial DNA as Well as Functional Consequences

Mutations of mitochondrial (mt) DNA play a role in neurodegeneration, normal aging, premature aging of the skin (photoaging), and tumors. We and others could demonstrate that mtDNA mutations can be induced in skin cells in vitro and in normal human skin in vivo by repetitive, sublethal ultraviolet (UV)-A-irradiation. These mutations are mediated by singlet oxygen and persist in human skin as long-term biomarkers of UV exposure. Although mtDNA exclusively encodes for the respiratory chain, involvement of the energy metabolism in mtDNA mutagenesis and a protective role of the energy precursor creatine have thus far not been shown. We assessed the amount of a marker mutation of mtDNA, the so-called common deletion, by real-time PCR. Induction of the common deletion was paralleled by a measurable decrease of oxygen consumption, mitochondrial membrane potential, and ATP content, as well as an increase of matrix metalloproteinase-1. Mitochondrial mutagenesis as well as functional consequences could be normalized by increasing intracellular creatine levels. These data indicate that increase of the energy precursor creatine protects from functionally relevant, aging-associated mutations of mitochondrial DNA.     

Regulation of fibroblast growth factor-23 in chronic kidney disease.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates the renal reabsorption of inorganic phosphate (Pi) and is increased in chronic kidney disease (CKD). The aim of the current investigation was to study the regulation of FGF23 in CKD subjects with various degree of renal function. As such, we analysed the relationship between FGF23, Pi, calcium, parathyriod hormone (PTH), 25(OH) vitamin D3(25(OH)D3), 1,25(OH)2 vitamin D3(1,25(OH)2D3) and estimated glomerular filtration rate (eGFR). METHODS: Intact FGF23 and other biochemical variables were analysed in 72 consecutive adult out-patients with various stages of CKD (eGFR ranging from 4-96 ml/min.) Association studies were performed using linear univariate and multivariate analysis. RESULTS: FGF23 was significantly elevated at CKD stage 4 (266 +/- 315 pg/ml, P < 0.001) and 5 (702 +/- 489 pg/ml, P < 0.001) compared with CKD 1-2 (46 +/- 43 pg/ml). In CKD 4-5 an independent association between log FGF23 and Pi (P < 0.001), 25(OH)D3 (P < 0.05) as well as eGFR (P < 0.01) was observed. In contrast, in CKD 1-3 log PTH (P < 0.05) was the only independent predictor of log FGF23 in multivariate analysis. In CKD 1-5, Pi (P < 0.00001) and log PTH (P < 0.01) were explanatory variables for log FGF23 in multivariate analysis. CONCLUSIONS: We conclude that serum FGF23 increases in CKD 4-5, in parallel with the emerging hyperphosphataemia. Serum Pi is the most important predictor of FGF23 when GFR is less than 30 ml/min. In contrast, our data suggest that Pi may not be an important determinant of FGF23 in normophosphataemic CKD subjects. Finally, the association between FGF23 and PTH in CKD may suggest a co-regulation that remains to be further elucidated.     

Offene Reposition und Osteosynthese mit primärer subtalarer Arthrodese bei intraartikulärer Kalkaneusfraktur

OBJECTIVE: To prevent the development of painful posttraumatic degenerative joint disease by a primary one-stage procedure to treat calcaneal fractures involving obvious comminution or severe and extensive cartilage damage to the subtalar facet. INDICATIONS: Sanders type IV calcaneal fractures with severe and extensive cartilage destruction. The definitive indication for arthrodesis can only be established intraoperatively. CONTRAINDICATIONS: Severe closed IIIrd or IV nd degree soft-tissue injury according to Tscherne & Oestern. Open fractures. Vascular impairment. Diabetes mellitus. Generalized or local inactivity osteoporosis > grade I according to Kanis. Age > approximately 50 years. SURGICAL TECHNIQUE: Extended lateral approach. Osteosynthesis of the calcaneal fracture, reconstruction of axes, subtalar facet denuded of cartilage, bone graft from the anterior iliac crest, arthrodesis by screw fixation of the subtalar joint. POSTOPERATIVE MANAGEMENT: After edema has subsided, mobilization without a cast and partial loading up to 15 kg for 12 weeks. Clinical and radiologic review after 6 and 12 weeks. RESULTS: This operation is performed very rarely. Within a retrospective study including patients over a period of 14 years (1990-2004), a total of 434 patients with a calcaneal fracture were treated surgically. Primary subtalar arthrodesis was performed in only six of these patients. Healing within 4 months was achieved in all six patients. The clinical and radiologic follow-ups took place on average after 4.9 years (2.5-7.5 years). Radiologically, almost anatomic reconstruction of the axes could be achieved (Gissane and B?hler angles, talometatarsal and talocalcaneal angles, calcaneal length and width). The functional outcomes were also good to very good with an average AOFAS (American Orthopaedic Foot and Ankle Society) Score of 88 points (63-94 points) and a Hanover Score of 84 points (62-90 points).     

Value of predictive instruments to determine persisting restriction of function in patients with subacute non-specific low back pain. Systematic review

Low back pain (LBP) can restrict function with all the personal, interpersonal, and social consequences, such as a loss of independence and the inability to fulfil diverse roles in social life. Therefore, the prevention of the consequences of LBP would reduce costs, individual burdens and social burdens. Being able to fulfil the requirements of daily living is a cornerstone of quality of life. Early identification of patients who are likely to develop chronic pain with persistent restricted function is important, as effective prevention needs informed allocation of health care and social work. The aim of this study was to report and discuss the predictive value of instruments used to identify patients at risk of chronic LBP. Medline, Embase, CINAHL, Central, PEDro, Psyndex, PsychInfo/PsycLit, and Sociofile were systematically searched up to July 2004. Reference lists of systematic reviews on risk factors, and reference lists of the studies included were also searched. The selected studies evaluated predictive values of tools or predictive models applied 2-12 weeks after an initial medical consultation for a first or a new episode of non-specific LBP with restriction in function. Instruments had to predict function-related outcomes. Because of the heterogeneity of the instruments used we did not pool the data. Sixteen publications on function-related outcomes were included. The predictive instruments in these studies showed only moderate ability to predict or explain function-related outcome (maximal 51% of the variability). There was great variability in the predictors included and not all known risk factors were included in the models. The reviewed tools showed a limited ability to predict function-related outcome in patients with risk of chronic low back pain. Future instruments should be based on models with a comprehensive set of known risk factors. These models should be constructed and validated by international, coordinated research teams.     

PTH/PTHrP activity and the programming of skeletal development in utero.

There is increasing evidence that nutritional deficiency in utero adversely affects bone development and the risk of developing osteoporosis in later life. Although the mechanisms involved are unknown, circumstantial evidence points to an important role of PTH/PTHrP activity. It is recognized that PTH and PTHrP are critically involved in regulating fetal calcium homeostasis, actions that are mediated at least in part by PPR. As well as playing a central role in the maintenance of calcium homeostasis in the fetus, studies in transgenic mice show that PTH, PTHrP, and PPR exert similar effects on skeletal development in utero, acting to increase the size of the trabecular envelope and decrease that of the cortical envelopes. Taken together, these observations raise the possibility that stimulation of PTH/PTHrP activity in the fetus in response to calcium deficiency acts to increase the size of the trabecular envelope but to reduce that of the cortical envelope. Although any increase in trabecular bone at birth is likely to be relatively transient, a decrease in size of the cortical envelope may have a persistent effect on the trajectory of bone growth in subsequent childhood. Consistent with this proposal, preliminary findings from birth cohort studies suggest that maternal calcium intake and cord blood calcium levels are positively related to bone mass of the offspring as assessed later in childhood. Further studies are justified to determine whether alterations in fetal PTH/ PTHrP activity caused by calcium stress lead to a reduction in size of the cortical envelope at birth that persists into childhood and later adult life and to identify modifiable maternal factors that are responsible for these changes.     

The effects of neurofeedback training on the spectral topography of the electroencephalogram.

OBJECTIVE: To investigate the impact of EEG frequency band biofeedback (neurofeedback) training on spectral EEG topography, which is presumed to mediate cognitive-behavioural training effects. In order to assess the effect of commonly applied neurofeedback protocols on spectral EEG composition, two studies involving healthy participants were carried out. METHODS: In Experiment 1, subjects were trained on low beta (12-15 Hz), beta1 (15-18 Hz), and alpha/theta (8-11 Hz/5-8 Hz) protocols, with spectral resting EEG assessed before and after training. The specific associations between learning indices of each individual training protocol and changes in absolute and relative spectral EEG topography was assessed by means of partial correlation analyses. Results of Experiment 1 served to generate hypotheses for Experiment 2, where subjects were randomly allocated to independent groups of low beta, beta1, and alpha/theta training. Spectral resting EEG measures were contrasted prior and subsequent to training within each group. RESULTS: Only few associations between particular protocols and spectral EEG changes were found to be consistent across the two studies, and these did not correspond to expectations based on the operant contingencies trained. Low-beta training was found to be somewhat associated with reduced post-training low-beta activity, while more reliably, alpha/theta training was associated with reduced relative frontal beta band activity. CONCLUSIONS: The results document that neurofeedback training of frequency components does affect spectral EEG topography in healthy subjects, but that these effects do not necessarily correspond to either the frequencies or the scalp locations addressed by the training contingencies. The association between alpha/theta training and replicable reductions in frontal beta activity constitutes novel empirical neurophysiological evidence supporting inter alia the training's purported role in reducing agitation and anxiety. SIGNIFICANCE: These results underline the complexity of the neural dynamics involved EEG self-regulation and emphasize the need for empirical validation of predictable neurophysiological outcomes of training EEG biofeedback protocols.     

Historical reflections on hypertension

Sixty million Americans have hypertension, a major cardiovascular risk factor. Its presence accelerates the atherosclerotic process, producing strokes, heart attacks, heart failure, renal failure, and peripheral vascular disease. This article highlights the historical landmarks in the study of this disease from the first documented measurement of blood pressure in 1733, through the most recent pharmacologic approaches to treatment. In addition, the roles of the kidney and the renin-angiotensin-aldosterone system are examined.     

Intramedullary spinal cord metastases, mainly of nonneurogenic origin

The clinical data and imaging studies of 12 patients with intramedullary metastases were reviewed retrospectively to see if these lesions had a typical radiographic appearance and to determine the sensitivity of the various radiologic examinations. The lesions were identified antemortem by either myelography, CT, MR, and/or intraoperative spinal sonography (IOSS). Final diagnosis was based on biopsy material from either the spinal cord lesion, another metastatic site, and/or the primary tumor. Ten patients had primary tumors located outside the central nervous system, while only two patients had primary brain tumors. Metrizamide myelography and CT demonstrated a definite intramedullary mass in nine of 11 patients. In five patients the mass was relatively small, well-defined, single, and resembled a primary spinal cord neoplasm. In the other four patients, longer and sometimes several segments of the cord were involved. These appeared irregular and nodular and were often associated with intradural lesions at separate sites. MR detected not only enlargement and abnormal signal in the cord but also clinically unsuspected brain lesions. IOSS localized lesions for biopsy and monitored tumor resection. These various imaging procedures showed that cord metastases were often more extensive than anticipated clinically. Spread of tumor into the spinal and intracranial subarachnoid space was common. Imaging of the entire spinal canal and brain, preferably with MR, is therefore recommended to aid in diagnosis, prognosis, and treatment.