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One possible cause for the neuronal loss in sporadic amyotrophic lateral sclerosis (S-ALS) is an increase of free radicals, which may produce oxidative damage to susceptible biomolecules, which, in turn, can damage the mitochondrial DNA (mtDNA). Following laser microdissection of single motor neurons from paraffin-embedded autopsy tissue, we analyzed the presence of a common mtDNA deletion, the 5 kb common deletion (CD). Spinal cord neurons showed slightly higher CD detection rate in patients than controls (94% vs 75%). No significant differences were found between patients and controls for neurons derived from other motor or non-motor regions. A PCR assay of serial DNA dilutions (10-fold) showed no CD level differences between motor neurons in S-ALS and controls. These data suggest that neuronal death in S-ALS is not associated with significant accumulation of mtDNA deletions.

Recently, CASPR2 antibody–associated encephalitis was presented as a subentity of encephalitis with antibodies against the voltage-gated potassium channel (VGKC) complex. Besides limbic encephalitis, CASPR2 antibodies are also found in Isaac syndrome and Morvan syndrome.1,2 The specific underlying pathogenic mechanisms in limbic encephalitis are unknown. Our data suggest an antibody- and complement-mediated pathology in CASPR2 antibody–associated encephalitis.

In this paper, we propose a methodology to study the scale effectand zoning effect of the modifiable areal unit problem (MAUP). Insteadof aggregating basic spatial units by the neighborhood criterion, we suggestplacing a square lattice over the centroids representing the enumerationunits in the study area. Areal units are aggregated if their centroidsare in the same square. By changing the size of the square in the lattice,we can study the scale effect. By randomly placing the lattice, we canstudy the zoning effect. This methodology links the MAUP effects to specificscale reflected by the size of grids. We use this method to study theMAUP effects on the segregation index D . Amongthe thirty selected cities in the USA, values of D respond to the MAUP in a diverse pattern. We assess the scale effect on D by examining the changes of averaged valuesof D over the range of scale levels. We also borrowconcepts from fractal analysis to assess the scale effect on D and to measure how sensitive the D values of these cities are to different zonal patterns.

The mdx mouse, an animal model of the Duchenne muscular dystrophy, was used for the investigation of changes in mitochondrial function associated with dystrophin deficiency. Enzymatic analysis of skeletal muscle showed an approximately 50% decrease in the activity of all respiratory chain-linked enzymes in musculus quadriceps of adult mdx mice as compared with controls, while in cardiac muscle no difference was observed. The activities of cytosolic and mitochondrial matrix enzymes were not significantly different from the control values in both cardiac and skeletal muscles. In saponin-permeabilized skeletal muscle fibers of mdx mice the maximal rates of mitochondrial respiration were about two times lower than those of controls. These changes were also demonstrated on the level of isolated mitochondria. Mdx muscle mitochondria had only 60% of maximal respiration activities of control mice skeletal muscle mitochondria and contained only about 60% of hemoproteins of mitochondrial inner membrane. Similar findings were observed in a skeletal muscle biopsy of a Duchenne muscular dystrophy patient. These data strongly suggest that a specific decrease in the amount of all mitochondrial inner membrane enzymes, most probably as result of Ca2+ overload of muscle fibers, is the reason for the bioenergetic deficits in dystrophin-deficient skeletal muscle.

PURPOSE: To determine if photodynamic therapy with verteporfin (Visudyne; Novartis AG, Bulach, Switzerland), termed verteporfin therapy, can safely reduce the risk of vision loss compared with a placebo (with sham treatment) in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration who were identified with a lesion composed of occult with no classic choroidal neovascularization, or with presumed early onset classic choroidal neovascularization with good visual acuity letter score, METHODS: This was a double-masked, placebo controlled (sham treatment), randomized, multicenter clinical trial involving 28 ophthalmology practices in Europe and North America. The study population was patients with age related macular degeneration, with subfoveal choroidal neovascularization lesions measuring no greater than 5400 mum in greatest linear dimension with either 1) occult with no classic choroidal neovascularization, best-corrected visual acuity score of at least 50 (Snellen equivalent approximately 20/100), and evidence of hemorrhage or recent disease progression; or 2) evidence of classic choroidal neovascularization with a best-corrected visual acuity score of at least 70 (better than a Snellen equivalent of approximately 20/40); assigned randomly (2:1) to verteporfin therapy or placebo therapy. Verteporfin (6 mg per square meter of body surface area) or placebo (5% dextrose in water) was administered by means of intravenous infusion of 30 mi over 10 minutes. Fifteen minutes after the start of the infusion, a laser light at 689 nm delivered 50 J/cm(2) by application of an intensity of 600 mW/cm(2) over 83 seconds using a spot size with a diameter 1000 mum larger than the greatest linear dimension of the choroidal neovascularization lesion on the retina. At follow-up examinations every 3 months, retreatment with the same regimen was applied if angiography showed fluorescein leakage. The main outcome measure was at least moderate vision loss, that is, a loss of at least 15 letters (approximately 3 lines), adhering to an intent-to treat analysis with the last observation carried forward to impute for missing data. RESULTS: Two hundred ten (93%) and 193 (86%) of the 225 patients in the verteporfin group compared with 104 (91%) and 99 (87%) of the 114 patients in the placebo group completed the month 12 and 24 examinations, respectively. On average, verteporfin-treated patients received five treatments over the 24 months of follow-up. The primary outcome was similar for the verteporfin-treated and the placebo-treated eyes through the month 12 examination, although a number of secondary visual and angiographic outcomes significantly favored the verteporfin-treated group. Between the month 12 and 24 examinations, the treatment benefit grew so that by the month 24 examination, the vertepor-fin-treated eyes were less likely to have moderate or severe vision loss. Of the 225 verteporfin-treated patients, 121 (54%) compared with 76 (67%) of 114 placebo-treated patients lost at least 15 letters (P =.023). Likewise, 61 of the verteporfin-treated patients (30%) compared with 54 of the placebo-treated patients (47%) lost at least 30 letters (P = .001). Statistically significant results favoring verteporfin therapy at the month 24 examination were consistent between the total population and the subgroup of patients with a baseline lesion composition identified as occult choroidal neovascularization with no classic choroidal neovascularization, This subgroup included 166 of the 225 verteporfin-treated patients (74%) and 92 of the 114 placebo-treated patients (81%). In these patients, 91 of the verteporfin-treated group (55%) compared with 63 of the placebo-treated group (68%) lost at least 15 letters (P =.032), whereas 48 of the verteporfin-treated group (29%) and 43 of the placebo-treated group (47%) lost at least 30 letters (P =.004). Other secondary outcomes, including visual acuity letter score worse than 34 (approximate Snellen equivalent of 20/200 or worse), mean change in visual acuity letter score, development of classic choroidal neovascularization, progression of classic choroidal neovascularization and size of lesion, favored the verteporfin-treated group at both the month 12 and month 24 examination for both the entire study group and the subgroup of cases with occult with no classic choroidal neovascularization at baseline. Subgroup analyses of lesions composed of occult with no classic choroidal neovascularization at baseline suggested that the treatment benefit was greater for patients with either smaller lesions (4 disc areas or less) or lower levels of visual acuity (letter score less than 65, an approximate Snellen equivalent of 20/50(-1) or worse) at baseline. Prospectively planned multivariable analyses confirmed that these two baseline variables affected the magnitude of treatment benefit. Of the 123 verteporfin-treated patients and 64 placebo-heated patients with either visual acuity score Less than 65 or lesion size 4 disc areas or less at baseline, 60 (49%) and 48 (75%) lost at least 15 letters (P < .001), respectively, and 26 (21%) and 31 (48%) lost at least 30 letters (P 2001 by Elsevier Science Inc. All rights reserved.).

Hintergrund: Die zunehmende Prävalenz von Zivilisationskrankheiten führt zur Suche nach verschiedenen begünstigenden / auslösenden Faktoren, bzw. nach geeigneter Präventionen und gesundheitsfördernden Interventionen. So ist z.B. Adipositas ein ernstes und zunehmendes[for full text, please go to the a.m. URL], 45. Kongress für Allgemeinmedizin und Familienmedizin, Forum Medizin 21

Although studies on the immunopathogenesis of anti-neutrophil cytoplasm antibody (ANCA) vasculitis have been directed at understanding the autoantibody, there is growing evidence that points to the importance of ANCA autoantigen genes and their regulation. Transcriptional analysis indicates that ANCA autoantigen genes are active in mature neutrophils of ANCA vasculitis patients compared to healthy controls. The unusual transcriptional state of neutrophils from ANCA vasculitis patients appears to be a consequence of failed or disrupted epigenetic silencing. Defective epigenetic silencing could have global effects, by altering the transcriptional and phenotypic state of neutrophils, or local effects by permitting transcription of autoantigen genes from both strands resulting in anti-sense transcripts. Although the role of anti-sense transcripts is currently unknown, there are two intriguing possibilities. Anti-sense transcripts could function (as described for other genes) in transcriptional silencing of autoantigen genes, which takes place in normal neutrophil progenitors. In the setting of failed epigenetic silencing, the fate of anti-sense transcripts may be pathological and serve as a template for production of complementary autoantigens. The observation that ANCA vasculitis patients have anti-sense transcripts and antibodies to complementary proteins is consistent with a role of anti-sense transcripts in complementary protein production. A better understanding of epigenetic silencing and complementary proteins in ANCA vasculitis may unlock the underlying pathology of this condition.

78 páginas,7 tablas, 11 figuras., The DO3SE (Deposition of O3 for Stomatal Exchange) model is an established tool for estimating ozone (O3 ) deposition, stomatal flux and impacts to a variety of vegetation types across Europe. It has been embedded within the EMEP (European Monitoring 5 and Evaluation Programme) photochemical model to provide a policy tool capable of relating the risk of vegetation damage to O3 precursor emission scenarios for use in policy formulation. A key limitation of regional flux-based risk assessments so far has been the approximation that soil water deficits are not limiting O3 flux due to the unavailability of evaluated methods for modelling soil water deficits and their influence on stomatal conductance (gsto 10 ), and ultimately O3 flux. This paper describes the development and evaluation of a method to estimate soil moisture status and its influence on gsto for a variety of forest tree species. The soil moisture module uses the Penman-Monteith energy balance method to drive water cycling through the soil-plant-atmosphere system and empirical data describing gsto 15 relationships with pre-dawn leaf water status to estimate the biological control of transpiration. We trial four different methods to estimate this biological control of the transpiration stream, which vary from simple methods that relate soil water content or potential directly to gsto to more complex methods that incorporate hydraulic resistance and plant capacitance that control water flow through the plant system. 20 These methods are evaluated against field data describing a variety of soil water variables, gsto and transpiration data for Norway spruce (Picea abies), Scots pine (Pinus sylvestris), birch (Betula pendula), aspen (Populus tremuloides), beech (Fagus sylvatica) and holm oak (Quercus ilex) collected from ten sites across Europe and North America. Modelled estimates of these variables show consistency with observed 25 data when applying the simple empirical methods, with the timing and magnitude of soil drying events being captured well across all sites and reductions in transpiration with the onset of drought being predicted with reasonable accuracy. The more complex methods which incorporate hydraulic resistance and plant capacitance perform less well, with predicted drying cycles consistently underestimating the rate and magnitude of water lost from the soil. A sensitivity analysis showed that model performance was strongly dependent upon the local parameterisation of key model drivers such as the maximum stomatal conduc- 5 tance, soil texture, root depth and leaf area index. The results suggest that the simple modelling methods that relate gsto directly to soil water content and potential provide adequate estimates of soil moisture and influence on gsto such that they are suitable to be used to assess the potential risk posed by O3 to forest trees across Europe., We acknowledge the UK Department of Food and Rural Affairs (Defra) under contract AQ 601 who provided support for this research, as well as funding from the EU Nitro-Europe project (www.nitroeurope.eu) and EMEP under UNECE.R. Alonso would like to 25 thank for the financial support from the Spanish projects Consolider Montes CSD2008-00040, CGL2009-13188-C03-02 and CAM-Agrisost

Hypoxia can cause severe damage to cells by initiating signaling cascades that lead to cell death. A cellular oxygen sensor, other than the respiratory chain, might exist in sensitive components of these signaling cascades. Recently, we found evidence that mitochondrial ion channels are sensitive to low levels of oxygen. We therefore studied the effects of hypoxia on the mitochondrial BK-channel (mtBK), on the mitochondrial permeability transition pore (PTP), and on their possible interaction. Using single-channel patch-clamp techniques we found that hypoxia inhibited the PTP but substantially increased the mtBK activity of mitoplasts from rat liver and astrocytes. Experiments measuring the mitochondrial membrane potential of intact rat brain mitochondria (using the fluorescence dye safranine O) during hypoxia exhibited an increased Ca(2+)-retention capacity implying an impaired opening of the PTP. We also found a reduced Ca(2+)-retention capacity with 100 nM iberiotoxin, a selective inhibitor of BK-channels. We therefore conclude that there is interaction between the mtBK and the PTP in a way that an open mtBK keeps the PTP closed. Thus, the response of mitochondrial ion channels to hypoxia could be interpreted as anti-apoptotic.

MERRF is typically characterized by myoclonus, generalized seizures and ragged-red fibers in muscular biopsy. We report a family (harbouring the A8344G mutation) with a late onset of the disease and an uncommon clinical manifestation, including episodes of reversible respiratory failure, the presence of ophthalmoplegia, and the absence of seizures and myoclonus in most subjects. We conducted histochemical, biochemical and molecular genetic studies. Mutation analysis revealed that the level of mutated mitochondrial DNA (mtDNA) was above 80% in the skeletal muscle of all siblings. Nevertheless, one severely affected individual did neither present cytochrome c oxidase-negative fibers nor ragged-red fibers in the skeletal muscle biopsy. These data extend the phenotypic range associated with the MERRF syndrome. We suggest that the analysis of mtDNA could be of importance in many cases of unclear multisystem disorders in later life.

Emerging radio access technologies such as wireless personal and metropolitan area networks and digital broadcasting arc a new era for wireless communications. These standards aim at complementing existing cellular/Wi-Fi networks in order to offer a wide range of available access modes to mobile terminals. Multiradio wireless systems, referred to as composite radio access networks, bear diverse capabilities, with the optimal radio being invoked to perform a specific set of functions. Composite reconfigurable radio networks support the collaboration of a wide range of heterogeneous radio access technologies under a single or multiple administrative boundaries, adding further intelligence to the way devices attach to and switch between networks spatially and temporally. The EU End-to-End Reconfigurability (E 2R) research project envisages composite reconfigurable radio networks coupled with legacy as well as evolved core network architectures, yielding simpler and more flexible configurations for reduced latencies, autonomie operation, and adaptive functionality. This article presents a cohesive model for controlling and managing such networks, elaborates on the constituent, functional entities, and maps this model to two-tier network support, architecture. Finally, key security issues for software download over reconfigurable radios and systems are identified and solutions for software certification and authorization as well as for the authentication of roaming terminals are proposed. © 2006 IEEE.

The FGFR4 codon 388 polymorphism (Arg(388), Arg/Gly(388) or Gly(388)) was determined in glioblastoma multiforme (GBM), anaplastic astrocytomas (AA), diffuse astrocytomas (DA), and control muscles. Arg(388) was rare in AA, GBM, muscles, and was absent in DA. The Arg/Gly(388) and the Gly(388) frequency was equal among GBM and controls. FGFR4 expression was not related to codon 388 in GBM, and no survival differences between Arg/Gly(388) and Gly(388) tumors were found. U87 cells (Arg/Gly(388)) did not show higher invasion than U138 cells (Gly(388)). This suggests that the FGFR4 codon 388 status does not play a major role in malignant gliomas.

Combining observed vertical height and gravity changes at the same location is not an ordinary task because of possible mass redistribution effects caused by e.g. ground water, atmosphere and the ocean. At Medicina uninterrupted gravity records are available since the beginning of 1998. To determine the instrumental effects of the Superconducting Gravimeter (SG) repeated absolute gravity observations are performed at least once a year, but often more frequently, two or three times a year. Over the 1998-2003 observation period, the long-term gravity signal is a composition of seasonal effects with a superimposed, mostly linear, trend. For an appropriate modeling and interpretation of the gravity data record, additional observations from different techniques, namely CGPS (continuous GPS), InSAR and several meteoclimatic data series are being collected. Geodetic space techniques provide the means to monitor continuously in a unique global reference system three dimensional station coordinates on the Earth's surface thus allowing the computation of high-accuracy horizontal as well as vertical velocities. Whereas CGPS observations provide pointwise information, i.e. the local behavior of a station, the InSAR technique can contribute more to acquire information on the regional deformation effects. To enlarge the local view to a regional area is important because the gravimeter is affected by both local and regional signals. All the available information is used to model the environmental effects and verify the deformation and mass attraction components by the observed height and gravity variations.

We tested whether rat and human MPO have similar antigenic determinants using 36 human MPO-ANCA positive sera, one mouse anti-rat MPO and four mouse anti-human MPO monoclonal reagents. Purified rat and human MPO were used in ELISA, with or without crossinhibition by preincubation with human MPO or irrelevant antigen in the liquid phase. Only one human MPO ANCA positive serum exhibited significant binding in rat MPO ELISA. This binding was poorly inhibited by preincubation with human MPO in the liquid phase, but was conserved after adsorption of non specific anti-rat activity in a chromatography column. Three mouse anti-human MPO IgG monoclonal antibodies did not recognize rat MPO. Only one mouse anti-human MPO IgA monoclonal antibody bound to rat MPO. This binding was poorly inhibited by preincubation with human MPO (35% at 2 µg/ml). Conversely, the mouse anti-rat MPO monoclonal did not bind human MPO. We have concluded that: (1) Most human MPO-ANCA recognize antigenic determinants on human MPO which are absent on rat MPO. Therefore, human auto-antibodies bind to epitopes which recently appeared after species evolution; (2) Inversely, the mouse anti-rat MPO monoclonal do not bind human MPO. Therefore, rat MPO epitopes have been altered during species evolution; (3) Mice injected with human MPO preferentially develop antibodies against xeno-epitopes which are not present in rodents. Therefore, human MPO may not be the best antigen to raise ANCA in animal models and (4) A comparison of the amino acid sequences of rat and human MPO may help elucidate the major antigenic epitopes.