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.     

Current role of chemotherapy in head and neck cancer.

Although cytotoxic chemotherapy is not fully established as an accepted part of the primary management of head and neck cancer, numerous studies over the past 10 years have been undertaken, notably in the USA and Europe. Several classes of antineoplastic chemotherapy have activity and can induce tumour regression in patients with squamous or anaplastic cancers, the most common cell types. While response rates with newer combinations, such as cisplatin and fluorouracil, are reportedly as high as 90%, response duration is generally short-lived. The most promising use of chemotherapy appears to be synchronous or adjuvant therapy with radiotherapy and/or surgery. Combined modality therapy of this type is able to improve the local control rates; 2 prospectively randomised studies from the United Kingdom each with several hundred patients have suggested a possible improvement in overall survival as well. The most active agents are methotrexate, cisplatin, bleomycin and fluorouracil. Further studies are urgently needed to assess the true role of and the indications for chemotherapy, and because of the world-wide importance of these tumours, the identification of even a modest improvement would have profound benefit. The use of chemotherapy outside studies should still be discouraged.