Showing papers by "Medical University of Graz published in 2007"

Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan

Abstract: Mesenchymal stem cells (MSC) are capable of differentiating into bone, fat, cartilage, tendon and other organ progenitor cells. Despite the abundance of MSC within the organism, little is known about their in vivo properties or about their corresponding in vivo niches. We therefore isolated MSC from spongy (cancellous) bone biopsies of healthy adults. When compared with the surrounding marrow, a fourfold higher number of colony-forming units was found within the tight meshwork of trabecular bone surface. At these sites, oxygen concentrations range from 1% to 7%. In MSC cultured at oxygen as low as 3%, rates for cell death and hypoxia-induced gene transcription remained unchanged, while in vitro proliferative lifespan was significantly increased, with about 10 additional population doublings before reaching terminal growth arrest. However, differentiation capacity into adipogenic progeny was diminished and no osteogenic differentiation was detectable at 3% oxygen. In turn, MSC that had previously been cultured at 3% oxygen could subsequently be stimulated to successfully differentiate at 20% oxygen. These data support our preliminary finding that primary MSC are enriched at the surface of spongy bone. Low oxygen levels in this location provide a milieu that extends cellular lifespan and furthermore is instructive for the stemness of MSC allowing proliferation upon stimulation while suppressing differentiation.

Osteoporosis in patients with diabetes mellitus.

Abstract: Demographic trends with longer life expectancy and a lifestyle characterized by low physical activity and high-energy food intake contribute to an increasing incidence of diabetes mellitus and osteoporosis. Diabetes mellitus is a risk factor for osteoporotic fractures. Patients with recent onset of type 1 diabetes mellitus may have impaired bone formation because of the absence of the anabolic effects of insulin and amylin, whereas in long-standing type 1 diabetes mellitus, vascular complications may account for low bone mass and increased fracture risk. Patients with type 2 diabetes mellitus display an increased fracture risk despite a higher BMD, which is mainly attributable to the increased risk of falling. Strategies to improve BMD and to prevent osteoporotic fractures in patients with type 1 diabetes mellitus may include optimal glycemic control and aggressive prevention and treatment of vascular complications. Patients with type 2 diabetes mellitus may additionally benefit from early visual assessment, regular exercise to improve muscle strength and balance, and specific measures for preventing falls.

Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery.

Abstract: Background— The risk of preoperative anemia in patients undergoing heart surgery has not been described precisely. Specifically, the impact of low hemoglobin per se or combined with other risk factors on postoperative outcome is unknown. Thus, we determined the effects of low preoperative hemoglobin and comorbidities on postoperative adverse outcomes in patients with coronary artery bypass graft in a large comprehensive multicenter study. Methods and Results— The Multicenter Study of Perioperative Ischemia investigated 5065 patients with coronary artery bypass graft at 70 institutions worldwide, collecting ≈7500 data points per patient. In 4804 patients who received no preoperative transfusions, we determined the association between lowest preoperative hemoglobin levels and in-hospital cardiac and noncardiac morbidity and mortality and the impact of concomitant risk factors, assessed by EuroSCORE, on this effect. In patients with EuroSCORE <4 (n=2054), only noncardiac outcomes were increased, whereas pati...

Long acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus

Abstract: Background Despite indications from epidemiological trials that higher blood glucose concentrations are associated with a higher risk for developing micro- and macrovascular complications, evidence for a beneficial effect of antihyperglycaemic therapy in patients with type 2 diabetes mellitus is conflicting. Two large studies, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP), did not find a reduction of cardiovascular endpoints through improvement of metabolic control. The theoretical benefits of newer insulin analogues might result in fewer macrovascular and microvascular events. Objectives To assess the effects of long-term treatment with long-acting insulin analogues (insulin glargine and insulin detemir) compared to NPH insulin in patients with type 2 diabetes mellitus. Search methods Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library and communication with experts in the field as well as insulin producing companies. Selection criteria Studies were included if they were randomised controlled trials in adults with diabetes mellitus type 2 and had a trial duration of at least 24 weeks. Data collection and analysis Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analyses was performed. Main results Six studies comparing insulin glargine to NPH (Neutral Protamine Hagedorn) insulin and two studies comparing insulin detemir to NPH insulin were identified. In these trials, 1715 patients were randomised to insulin glargine and 578 patients to insulin detemir. Duration of the included trials ranged from 24 to 52 weeks. Metabolic control, measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint, and adverse effects did not differ in a clinical relevant way between treatment groups. While no statistically significant difference for severe hypoglycaemia rates was shown in any of the trials, the rate of symptomatic, overall and nocturnal hypoglycaemia was statistically significantly lower in patients treated with either insulin glargine or detemir. No evidence for a beneficial effect of long-acting analogues on patient-oriented outcomes like mortality, morbidity, quality of life or costs could be obtained. Authors' conclusions Our analysis suggests, if at all only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2 treated with "basal" insulin regarding symptomatic nocturnal hypoglycaemic events. Until long-term efficacy and safety data are available, we suggest a cautious approach to therapy with insulin glargine or detemir.

Myeloperoxidase: a target for new drug development?

Abstract: Myeloperoxidase (MPO), a member of the haem peroxidase-cyclooxygenase superfamily, is abundantly expressed in neutrophils and to a lesser extent in monocytes and certain type of macrophages. MPO participates in innate immune defence mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity of MPO is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. The fact that circulating levels of MPO have been shown to predict risks for major adverse cardiac events and that levels of MPO-derived chlorinated compounds are specific biomarkers for disease progression, has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, detailed information on the structure of ferric MPO and its complexes with low- and high-spin ligands is available. This, together with a thorough understanding of reaction mechanisms including redox properties of intermediates, enables a rationale attempt in developing specific MPO inhibitors that still maintain MPO activity during host defence and bacterial killing but interfere with pathophysiologically persistent activation of MPO. The various approaches to inhibit enzyme activity of MPO and to ameliorate adverse effects of MPO-derived oxidants will be discussed. Emphasis will be put on mechanism-based inhibitors and high-throughput screening of compounds as well as the discussion of physiologically useful HOCl scavengers.

Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation

Abstract: Human mesenchymal stem cells (MSC) with the capacity to differentiate into osteoblasts provide potential for the development of novel treatment strategies, such as improved healing of large bone defects. However, their low frequency in bone marrow necessitate ex vivo expansion for further clinical application. In this study we asked if MSC are developing in an aberrant or unwanted way during ex vivo long-term cultivation and if artificial cultivation conditions exert any influence on their stem cell maintenance. To address this question we first developed human oligonucleotide microarrays with 30.000 elements and then performed large-scale expression profiling of long-term expanded MSC and MSC during differentiation into osteoblasts. The results showed that MSC did not alter their osteogenic differentiation capacity, surface marker profile, and the expression profiles of MSC during expansion. Microarray analysis of MSC during osteogenic differentiation identified three candidate genes for further examination and functional analysis: ID4, CRYAB, and SORT1. Additionally, we were able to reconstruct the three developmental phases during osteoblast differentiation: proliferation, matrix maturation, and mineralization, and illustrate the activation of the SMAD signaling pathways by TGF-β2 and BMPs. With a variety of assays we could show that MSC represent a cell population which can be expanded for therapeutic applications.

Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport.

Abstract: Mitochondrial Ca(2+) uptake is crucial for the regulation of the rate of oxidative phosphorylation, the modulation of spatio-temporal cytosolic Ca(2+) signals and apoptosis. Although the phenomenon of mitochondrial Ca(2+) sequestration, its characteristics and physiological consequences have been convincingly reported, the actual protein(s) involved in this process are unknown. Here, we show that the uncoupling proteins 2 and 3 (UCP2 and UCP3) are essential for mitochondrial Ca(2+) uptake. Using overexpression, knockdown (small interfering RNA) and mutagenesis experiments, we demonstrate that UCP2 and UCP3 are elementary for mitochondrial Ca(2+) sequestration in response to cell stimulation under physiological conditions - observations supported by isolated liver mitochondria of Ucp2(-/-) mice lacking ruthenium red-sensitive Ca(2+) uptake. Our results reveal a novel molecular function for UCP2 and UCP3, and may provide the molecular mechanism for their reported effects. Moreover, the identification of proteins fundemental for mitochondrial Ca(2+) uptake expands our knowledge of the physiological role for mitochondrial Ca(2+) sequestration.

The Human Placenta in Gestational Diabetes Mellitus: The insulin and cytokine network

Abstract: The placenta is a complex fetal organ that fulfills pleiotropic roles during fetal growth. It separates the maternal and fetal circulation, with which it is in contact through different surfaces, i.e., the syncytiotrophoblast exposes the placenta to the maternal circulation and the endothelium is in contact with fetal blood. Because of this unique position, the placenta is exposed to the regulatory influence of hormones, cytokines, growth factors, and substrates present in both circulations and, hence, may be affected by changes in any of these. In turn, it can produce molecules that will affect mother and fetus independently. The human placenta expresses virtually all known cytokines including tumor necrosis factor (TNF)-α, resistin, and leptin, which are also produced by the adipose cells. The discovery that some of these adipokines are key players in the regulation of insulin action suggests possible novel interactions between the placenta and adipose tissue in understanding pregnancy-induced insulin resistance. The interplay between the two systems becomes more evident in gestational diabetes mellitus (GDM). In diabetes, the placenta undergoes a variety of structural and functional changes (rev. in 1–3). Their nature and extent depend on a range of variables including the quality of glycemic control achieved during the critical periods in placental development, the modality of treatment, and the time period of severe departures from excellent metabolic control of a nondiabetic environment. Placental development is characterized by three distinct periods. At the beginning of gestation, a series of critical proliferation and differentiation processes predominantly of the trophoblast eventually lead to the formation of villous and extravillous structures. The latter anchor the placenta in the uterus and remodel the uterine spiral arteries into low resistance vessels. Then the newly formed villi differentiate through various steps of maturation. The end of gestation is associated with placental mass expansion, …

Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties.

Abstract: Binding and transport of a number of endogenous and exogenous compounds is an important function of the main plasma protein, albumin. In vivo and in vitro, albumin may be oxidatively modified in different ways with different agents at different sites. These modifications have various consequences on the physiological functions of albumin. Diabetes mellitus, liver diseases and nephropathy are just a few examples of disorders in which oxidative stress is involved and altered albumin functions have been described. This review is focussed on the consequences of oxidative modification on the binding properties of albumin. These range from no effect to decreased or increased binding affinities depending on the ligand under investigation and the type of modification. Indicators for modification include glycosylation, disulphide formation or the content of carbonyl groups. The redox state of albumin can affect the binding properties in several ways, including altered conformation and consequently altered affinities at binding sites and altered binding when the binding reaction itself is redox sensitive. The physiological or pathophysiological concentrations of different oxidatively modified albumin molecules vary over a wide range and are crucial in assessing the clinical relevance of altered ligand binding properties of a particularly modified albumin species in various disease conditions.

Asymmetrical Dimethylarginine Independently Predicts Total and Cardiovascular Mortality in Individuals with Angiographic Coronary Artery Disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Abstract: Background: Asymmetrical dimethylarginine (ADMA) is increased in conditions associated with increased risk of atherosclerosis. We investigated the use of ADMA to predict total and cardiovascular mortality in patients scheduled for coronary angiography. Methods: In 2543 persons with and 695 without coronary artery disease (CAD) identified by angiography we measured ADMA and recorded total and cardiovascular mortality during a median follow-up of 5.45 years. Results: ADMA was correlated positively to age, female sex, diabetes mellitus, former and current smoking, and C-reactive protein and inversely to HDL cholesterol and triglycerides. ADMA was not associated with body mass index, hypertension, LDL cholesterol, or the presence or absence of angiographic CAD. Glomerular filtration rate and homocysteine were the strongest predictors of ADMA. At the 2nd, 3rd and 4th quartile of ADMA, hazard ratios for all-cause mortality adjusted for age, sex, and cardiovascular risk factors were 1.12 [95% confidence interval (CI) 0.83–1.52], 1.35 (95% CI 1.01–1.81), and 1.87 (95% CI 1.43–2.44), respectively, compared with the 1st quartile. Hazard ratios for cardiovascular death were 1.13 (95% CI 0.78–1.63), 1.42 (95% CI 1.00–2.02), and 1.81 (95% CI 1.31–2.51). ADMA in the highest quartile remained predictive of mortality after accounting for medication at baseline. The predictive value of ADMA was similar to that in the entire cohort in persons with CAD, stable or unstable, but was not statistically significant in persons without angiographic CAD. Conclusions: ADMA concentration predicts all-cause and cardiovascular mortality in individuals with CAD independently of established and emerging cardiovascular risk factors.

Epidemiology of tinea capitis in Europe: current state and changing patterns.

Abstract: Tinea capitis (scalp ringworm) is the most common dermatophyte infection of the scalp affecting mainly children and rarely adults. The epidemiology of tinea capitis varies within different geographical areas throughout the world. It may occur sporadically or epidemically and an increase in its incidence has been noted over the last few decades. The aim of the study is to obtain a general overview of the current state and changing pattern of tinea capitis in Europe. According to the literature, there has been a significant increase in the incidence of tinea capitis and a change in the pattern of infectious agents in particular. Microsporum canis, a zoophilic dermatophyte, is still the most common reported causative agent of tinea capitis in Europe. The countries reporting the highest incidence of M. canis infections are mainly in the Mediterranean but also bordering countries like Austria, Hungary, Germany and Poland. Besides the increase in Microsporum-induced tinea capitis, there is a shift towards anthrophilic tinea capitis mainly in urban areas in Europe. The largest overall increase with anthropophilic dermatophytes has been noted with Trichophyton tonsurans mainly in the UK and with Trichophyton soudanense and Microsporum audouinii in France. The occurrence of anthropophilic infections seems to be geographically restricted and is possibly linked to the immigration from African countries. Children (aged 3-7 years with no predilection of gender) remain the most commonly affected, but recently an increase of tinea capitis has been observed in adults and in the elderly. The results of the study clearly demonstrate the importance of diagnosing and proper treatment of mycotic scalp infection in the Europe. If not diagnosed and treated properly, its prevalence might reach epidemic proportions in the near future. Therefore, an increased level of surveillance (screening in schools), and a highly effective interdisciplinary cooperation among general practitioners, mycologists, veterinarians and dermatologists are strongly recommended.

On some aspects of improving mobile applications for the elderly

Abstract: Improving the quality of life of elderly people is an emerging issue within our information society for both research and development This paper addresses some issues on the development of applications for mobile devices, which have been designed to enhance the quality of life of the growing number of elderly people, and how they can be made more acceptable to the target population We summarize some relevant issues in order to devise a research methodology to cover more than just the technological and physical aspects of user interfacing but also psychological and sociological aspects One aspect of achieving this aim is to confront designers and developers with those problems that the elderly face daily and which are not easily understood - especially by younger designers and developers Finally, we present some issues on how to simulate certain physical constraints of elderly by using the AgeSim, which is a simulation suit However, not only physical but also cognitive impairment cause problems amongst elderly and result in fear, anxiety and consequently in rejection The main goal of this paper is to raise awareness amongst developers on which problems are to be taken into considerations during design and development of mobile applications for the elderly

Radial chromatin positioning is shaped by local gene density, not by gene expression

Abstract: G- and R-bands of metaphase chromosomes are characterized by profound differences in gene density, CG content, replication timing, and chromatin compaction. The preferential localization of gene-dense, transcriptionally active, and early replicating chromatin in the nuclear interior and of gene-poor, later replicating chromatin at the nuclear envelope has been demonstrated to be evolutionary-conserved in various cell types. Yet, the impact of different local chromatin features on the radial nuclear arrangement of chromatin is still not well understood. In particular, it is not known whether radial chromatin positioning is preferentially shaped by local gene density per se or by other related parameters such as replication timing or transcriptional activity. The interdependence of these distinct chromatin features on the linear deoxyribonucleic acid (DNA) sequence precludes a simple dissection of these parameters with respect to their importance for the reorganization of the linear DNA organization into the distinct radial chromatin arrangements observed in the nuclear space. To analyze this problem, we generated probe sets of pooled bacterial artificial chromosome (BAC) clones from HSA 11, 12, 18, and 19 representing R/G-band-assigned chromatin, segments with different gene density and gene loci with different expression levels. Using multicolor 3D flourescent in situ hybridization (FISH) and 3D image analysis, we determined their localization in the nucleus and their positions within or outside the corresponding chromosome territory (CT). For each BAC data on local gene density within 2- and 10-Mb windows, as well as GC (guanine and cytosine) content, replication timing and expression levels were determined. A correlation analysis of these parameters with nuclear positioning revealed regional gene density as the decisive parameter determining the radial positioning of chromatin in the nucleus in contrast to band assignment, replication timing, and transcriptional activity. We demonstrate a polarized distribution of gene-dense vs gene-poor chromatin within CTs with respect to the nuclear border. Whereas we confirm previous reports that a particular gene-dense and transcriptionally highly active region of about 2 Mb on 11p15.5 often loops out from the territory surface, gene-dense and highly expressed sequences were not generally found preferentially at the CT surface as previously suggested.

Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction

Abstract: The present study was performed to compare serum concentrations of maternal and fetal angiogenic growth factors in IUGR (intrauterine growth restriction) and normal pregnancy at the time of delivery. VEGF (vascular endothelial growth factor), PlGF (placental growth factor), sFlt-1 (soluble fms-like tyrosine kinase 1), sKDR (soluble kinase domain receptor) and bFGF (basic fibroblast growth factor) were measured by ELISA in serum from a maternal peripheral vein, the umbilical vein and the umbilical arteries in 15 women with pregnancies complicated by IUGR and 16 controls (women with normal pregnancies). In IUGR, sFlt-1 was increased, and PlGF and sKDR were decreased, in both maternal serum and serum from the umbilical vein. Additionally, bFGF was increased in serum from the umbilical vein of women with pregnancies complicated by IUGR. No significant differences in growth factor concentrations between the groups were found in serum from the umbilical artery. In both groups, levels of VEGF were higher and levels of sFlt-1 were lower in serum from the umbilical vein and umbilical artery compared with maternal serum. PlGF levels were found to be lower in serum from the umbilical vein compared with maternal serum in both groups, whereas PlGF levels in serum from the umbilical artery were significantly lower only in the control group. These findings suggest an imbalance of angiogenic and anti-angiogenic factors in IUGR, with formation of an anti-angiogenic state in maternal and, to a lesser extent, umbilical vein blood. The placenta appears to play a central role in the release of sFlt-1 into maternal and umbilical blood. Umbilical artery blood was unaffected in IUGR, indicating that the fetus does not contribute to changes in angiogenic growth factor concentrations.

Mitochondria and Ca(2+) signaling: old guests, new functions.

Abstract: Mitochondria are ancient endosymbiotic guests that joined the cells in the evolution of complex life. While the unique ability of mitochondria to produce adenosine triphosphate (ATP) and their contribution to cellular nutrition metabolism received condign attention, our understanding of the organelle’s contribution to Ca2+ homeostasis was restricted to serve as passive Ca2+ sinks that accumulate Ca2+ along the organelle’s negative membrane potential. This paradigm has changed radically. Nowadays, mitochondria are known to respond to environmental Ca2+ and to contribute actively to the regulation of spatial and temporal patterns of intracellular Ca2+ signaling. Accordingly, mitochondria contribute to many signal transduction pathways and are actively involved in the maintenance of capacitative Ca2+ entry, the accomplishment of Ca2+ refilling of the endoplasmic reticulum and Ca2+-dependent protein folding. Mitochondrial Ca2+ homeostasis is complex and regulated by numerous, so far, genetically unidentified Ca2+ channels, pumps and exchangers that concertedly accomplish the organelle’s Ca2+ demand. Notably, mitochondrial Ca2+ homeostasis and functions are crucially influenced by the organelle’s structural organization and motility that, in turn, is controlled by matrix/cytosolic Ca2+. This review intends to provide a condensed overview on the molecular mechanisms of mitochondrial Ca2+ homeostasis (uptake, buffering and storage, extrusion), its modulation by other ions, kinases and small molecules, and its contribution to cellular processes as fundamental basis for the organelle’s contribution to signaling pathways. Hence, emphasis is given to the structure-to-function and mobility-to-function relationship of the mitochondria and, thereby, bridging our most recent knowledge on mitochondria with the best-established mitochondrial function: metabolism and ATP production.

Progression of Leukoaraiosis and Cognition

Abstract: Background and Purpose— Leukoaraiosis is used interchangeably with the term white matter lesions on MRI and seen to some degree in more than half of the routine scans in older persons. Clinicians often struggle to explain the implications of these findings to their patients. Recent data on the progression rate of ischemic white matter damage and its cognitive consequences may help in patient counseling and have implications on treatment trials in vascular cognitive impairment. Summary of Review—Leukoaraiosis progresses over time. Its extent at baseline is an important predictor for the subsequent rate of lesion progression. Subjects with punctate abnormalities on MRI have a low tendency for progression, individuals with early confluent and confluent changes tend to progress rapidly. Differences in measurement methods and cohort composition make it difficult to compare progression rates reported by different studies. Nevertheless, in community-dwelling cohorts, white matter lesions volume increased by as m...

Pediatric KIT–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors

Abstract: Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor A (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT–wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT–wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT– wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT–wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT–wild-type GIST. [Cancer Res 2007;67(19):9084–8]

Inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance.

Abstract: Obesity is a growing health care problem that is increasing the incidence and morbidity of cardiovascular diseases Emerging evidence suggests that obesity is associated with a systemic inflammatory response that is characterized by endothelial cell dysfunction, oxidative stress, and the activation of circulating immune cells Adipocytes produce and release a variety of cytokines (IL-1, TNF-alpha) and cytokine-like substances (leptin, resistin) that appear to mediate the inflammatory response that accompanies obesity The abrogating influence of weight loss on the inflammatory response supports this contention The insulin resistance that often accompanies obesity may also contribute to this inflammatory phenotype Studies in experimental animals and clinical studies suggest that the microvascular dysfunction associated with pathological states, such as sepsis, is greatly exacerbated by obesity Although the microvasculature appears to be a major target for the deleterious inflammatory consequences of obesity, relatively little attention has been devoted to characterizing the effects of obesity on inflammatory responses in different regional vascular beds and to defining the mechanisms that underlie the resultant microvascular dysfunction

Biobanks: transnational, European and global networks

Abstract: Biobanks contain biological samples and associated information that are essential raw materials for advancement of biotechnology, human health, and research and development in life sciences Population-based and disease-oriented biobanks are major biobank formats to establish the disease relevance of human genes and provide opportunities to elucidate their interaction with environment and lifestyle The developments in personalized medicine require molecular definition of new disease subentities and biomarkers for identification of relevant patient subgroups for drug development These emerging demands can only be met if biobanks cooperate at the transnational or even global scale Establishment of common standards and strategies to cope with the heterogeneous legal and ethical landscape in different countries are seen as major challenges for biobank networks The Central Research Infrastructure for Molecular Pathology (CRIP), the concept for a pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), and the Organization for Economic Co-operation and Development (OECD) global Biological Resources Centres network are examples for transnational, European and global biobank networks that are described in this article

Melanoma screening with cellular phones.

Abstract: Background. Mobile teledermatology has recently been shown to be suitable for teledermatology despite limitations in image definition in preliminary studies. The unique aspect of mobile teledermatology is that this system represents a filtering or triage system, allowing a sensitive approach for the management of patients with emergent skin diseases. Methodology/ Principal Findings. In this study we investigated the feasibility of teleconsultation using a new generation of cellular phones in pigmented skin lesions. 18 patients were selected consecutively in the Pigmented Skin Lesions Clinic of the Department of Dermatology, Medical University of Graz, Graz (Austria). Clinical and dermoscopic images were acquired using a Sony Ericsson with a built-in two-megapixel camera. Two teleconsultants reviewed the images on a specific web application (http://www. dermahandy.net/default.asp) where images had been uploaded in JPEG format. Compared to the face-to-face diagnoses, the two teleconsultants obtained a score of correct telediagnoses of 89% and of 91.5% reporting the clinical and dermoscopic images, respectively. Conclusions/Significance. The present work is the first study performing mobile teledermoscopy using cellular phones. Mobile teledermatology has the potential to become an easy applicable tool for everyone and a new approach for enhanced self-monitoring for skin cancer screening in the spirit of the eHealth program of the European Commission Information for Society and Media.

Facilitated endogenous repair: making tissue engineering simple, practical, and economical.

Abstract: Facilitated endogenous repair is a novel approach to tissue engineering that avoids the ex vivo culture of autologous cells and the need for manufactured scaffolds, while minimizing the number and invasiveness of associated clinical procedures. The strategy relies on harnessing the intrinsic regenerative potential of endogenous tissues using molecular stimuli, such as gene transfer, to initiate reparative processes in situ. In the simplest example, direct percutaneous injection of an osteogenic vector is used to stimulate bone healing. If necessary, additional progenitor cells and space-filling scaffolds can be provided by autologous bone marrow, muscle, fat, and perhaps other tissues. These can be harvested, processed, and reimplanted by simple, expedited, intraoperative procedures. Examples of repair of experimental osseous and osteochondral lesions in laboratory animals are described. If successful, these strategies will provide methods for tissue regeneration that are not only effective but also inexpensive, safe, and clinically expeditious. Although orthopaedic examples are given here, the technology should be more generally applicable.

Prognostic ability of simplified nuclear grading of renal cell carcinoma.

Abstract: BACKGROUND. The Fuhrman grading system is an established predictor of survival in patients with renal cell carcinoma (RCC). The predictive accuracy of various Fuhrman grading schemes was tested with the intent of improving the prediction of RCC-specific survival (RCC-SS). METHODS. The analyses targeted 5453 patients from 14 institutions. Univariable, multivariable, and predictive accuracy analyses addressed RCC-SS. The statistical significance of the gain in predictive accuracy was quantified with the Mantel-Haenszel test. RESULTS. The median follow-up time was 4.5 years. In both univariable and multivariable analyses, Fuhrman grade achieved independent predictor status regardless of the coding scheme. When Fuhrman grade was not considered in multivariable analyses, the predictive accuracy was 83.8%. Addition of Fuhrman grade to the multivariable model resulted in predictive accuracy gains of 0.8% for all 3 grading schemes tested. CONCLUSION. Fuhrman grade must to be considered when RCC-SS is assessed. However, modified or conventional Fuhrman grading schemes perform equally well as the conventional grading system. Cancer 2007 © 2007 American Cancer Society.

A review of the genetics of essential hypertension.

Abstract: Purpose of review Essential hypertension affects more than 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. Several strategies have been used to identify hypertension susceptibility genes. This review highlights recent efforts in genetic dissection of essential hypertension. Recent findings Recently, further chromosomal regions harboring blood pressure loci have emerged in genome-wide linkage studies. Findings from a new systematic two-dimensional genome scan are presented, as well as sex-specific loci linked to hypertension in inbred rodent models. Many case-control association studies have been carried out, but results so far have been equivocal. This review discusses some interesting studies combining linkage and association strategies using gene-gene interactions, and studies the use of haplotypes instead of SNPs. Two novel hypertension susceptibility genes are presented, and a short summary on new insights into genes of the renin-angiotensin and adrenergic systems is given. Summary To date, linkage and association studies have not been convincing. Genome-wide association studies may prove to be an effective approach to the problems posed by complex traits. Combined with candidate gene approaches, it is hoped this strategy will yield convincing evidence for genes associated with essential hypertension.

Guidelines for using proton MR spectroscopy in multicenter clinical MS studies.

Abstract: Proton MR spectroscopy (MRS) allows noninvasive characterization of chemical-pathologic changes in the brain In patients with multiple sclerosis (MS), proton MRS reveals chemical pathology in focal inflammatory lesions as well as in regions of the brain that are not associated with structural abnormalities on conventional MRI In MS studies, it has been particularly useful as a method for the assessment of neurodegeneration based on decreases in the levels of the neuro-axonal marker compound, N-acetylaspartate Also, MRS has provided evidence of chemical pathology and repair involving non-neuronal brain cells based on changes in metabolites, including choline, myo-inositol, glutamate, and GABA Despite its greater pathologic specificity for axonal integrity compared to conventional MRI, MRS has been used only infrequently in clinical trials This prompted us to review current MRS clinical applications in MS, discuss the potential and limitations of the technique, and suggest recommendations for the application of MRS to clinical trials

Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients

Abstract: Background Urinary catecholamine metabolites are well-known to be elevated in patients with neuroblastoma. Some investigators have described different patterns in favorable and unfavorable cases. However, extended studies have not been published. Procedure We investigated urinary catecholamine patterns and their correlation to stage, biological features, and outcome in 114 consecutively clinically diagnosed neuroblastoma patients. Results Sensitivity of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) was 80.7, 71.9, and 61.3%, respectively. In 91.2% of patients at least one parameter was above normal. High VMA levels were associated with favorable biological features, high DA levels were predominantly found in biologically unfavorable disease. Whereas patients with normal HVA levels had a significant better outcome, the other parameters showed no significant association with prognosis. For disseminated neuroblastoma of infancy, DA/VMA ratio proved to be helpful for the discrimination of stage 4 versus stage 4s. Conclusion Urinary catecholamines appear to be useful to give a first but important hint about the biological behavior and thus the prognosis of the underlying disease. Particularly DA/VMA ratio may serve as a tool for “biological grading”—especially in disseminated disease of infancy. In addition, it may be speculated that HVA negativity and low DA/VMA ratio may be helpful for the decision of a “wait and see” strategy in selected neuroblastoma patients with localized disease. Pediatr Blood Cancer 2007;48:504–509. © 2006 Wiley-Liss, Inc.

Kisspeptins and the placenta: regulation of trophoblast invasion

Abstract: The invasion of extravillous trophoblasts into the uterine wall is of crucial importance for placental and fetal development, and its dysregulation has been implicated in a wide spectrum of abnormal pregnancies. Mechanistically, trophoblast invasion strongly resembles the invasion of tumour cells, but differs from it by tight regulation in time and space. This regulation is accomplished by different factors including cytokines and hormones, which are produced by both fetal as well as maternal tissues i.e., placenta and uterus, respectively. Recently, products of the KiSS-1 gene (kisspeptins) have been identified to not only inhibit metastasis in various tumours, but also to repress trophoblast invasion via binding to the G protein-coupled receptor KiSS-1R. In the placenta, expression levels of kisspeptins and their receptor are highest in the first trimester in humans and at day 12.5 in rats, respectively. This coincides with the time when invasiveness peaks and invasion regulation is of central importance. Human kisspeptins are predominantly produced by the syncytiotrophoblast, whereas KiSS-1R is additionally expressed on the invading extravillous trophoblasts indicating a paracrine regulation of extravillous trophoblast invasion by the syncytiotrophoblast. In the structurally different rat placenta both KiSS-1 and its receptor are predominantly expressed by the invasive trophoblast giant cells, thus establishing an autocrine system in the invasion regulation of this trophoblast subpopulation. Amongst all kisspeptins the highly conserved kisspeptin Kp-10 has strongest invasion inhibiting effects suggesting its major role in regulation of trophoblast invasion.