Task-related measures of short-interval intracortical inhibition and GABA levels in healthy young and older adults: A multimodal TMS-MRS study.

Establishing the associations between magnetic resonance spectroscopy (MRS)-assessed gamma-aminobutyric acid (GABA) levels and transcranial magnetic stimulation (TMS)-derived 'task-related' modulations in GABAA receptor-mediated inhibition and how these associations change with advancing age is a topic of interest in the field of human neuroscience. In this study, we identified the relationship between GABA levels and task-related modulations in GABAA receptor-mediated inhibition in the dominant (left) and non-dominant (right) sensorimotor (SM) cortices. GABA levels were measured using edited MRS and task-related GABAA receptor-mediated inhibition was measured using a short-interval intracortical inhibition (SICI) TMS protocol during the preparation and premotor period of a choice reaction time (CRT) task in 25 young (aged 18-33 years) and 25 older (aged 60-74 years) adults. Our results demonstrated that GABA levels in both SM voxels were lower in older adults as compared to younger adults; and higher SM GABA levels in the dominant as compared to the non-dominant SM voxel pointed to a lateralization effect, irrespective of age group. Furthermore, older adults showed decreased GABAA receptor-mediated inhibition in the preparation phase of the CRT task within the dominant primary motor cortex (M1), as compared to young adults. Finally, results from an exploratory correlation analysis pointed towards positive relationships between MRS-assessed GABA levels and TMS-derived task-related SICI measures. However, after correction for multiple comparisons none of the correlations remained significant.

Age-Related Declines in Motor Performance are Associated With Decreased Segregation of Large-Scale Resting State Brain Networks.

Aging is typically associated with substantial declines in motor functioning as well as robust changes in the functional organization of brain networks. Previous research has investigated the link between these 2 age-varying factors but examinations were predominantly limited to the functional organization within motor-related brain networks. Little is known about the relationship between age-related behavioral impairments and changes in functional organization at the whole brain (i.e., multiple network) level. This knowledge gap is surprising given that the decreased segregation of brain networks (i.e., increased internetwork connectivity) can be considered a hallmark of the aging process. Accordingly, we investigated the association between declines in motor performance across the adult lifespan (20-75 years) and age-related modulations of functional connectivity within and between resting state networks. Results indicated that stronger internetwork resting state connectivity observed as a function of age was significantly related to worse motor performance. Moreover, performance had a significantly stronger association with the strength of internetwork as compared with intranetwork connectivity, including connectivity within motor networks. These findings suggest that age-related declines in motor performance may be attributed to a breakdown in the functional organization of large-scale brain networks rather than simply age-related connectivity changes within motor-related networks.

[Gender Aspects in Gastrointestinal Tumours and Their Prognosis in Regard to Multimodal Treatment Concepts]. / Genderaspekte bei Tumoren des Gastrointestinaltrakts und ihre Prognose, insbesondere im Rahmen multimodaler Therapiekonzepte.

Systematic analyses of gender effects in gastrointestinal malignancies are currently lacking, partly because sex and gender have not been used as stratification criteria in major studies on the topic. It is, however, indisputable that gastrointestinal tumours differ in risk factors, incidence and prognosis between the genders. This review summarises the most important findings on differences related to biological sex and sociocultural gender and discusses anatomic specifics with immediate significance for surgical interventions. Epidemiological differences in upper gastrointestinal malignancies are most prominent in regard to histological subtypes, directly affecting diagnostics, therapy, and prognosis. Women have a better prognosis in many of these tumour subtypes. For colorectal carcinoma, sex hormones, specifically oestrogens, appear to play a distinct role in tumourigenesis. Histopathological analysis of the expression of oestrogen receptor beta (ERß) in the tumour tissue has attracted interest since it was shown that women with low ERß expression have a better prognosis than men with comparable ERß status. Data on the higher incidence of right-sided colon carcinoma and non-polypoid neoplasms in women could lead to improved screening programmes. Men and women cite differing reasons for avoidance of screening colonoscopies, thus gender specific approaches could improve colon cancer prevention programmes. Data on differing bioavailability of 5-fluorouracil between the genders are useful to minimise adverse effects of chemotherapy and should be accounted for in dosage. Further systematic analysis of gender effects on gastrointestinal tumours is warranted and would be a substantial step towards personalised oncological surgery.

The control of complex finger movements by directional information flow between mesial frontocentral areas and the primary motor cortex.

Complex movements require the interplay of local activation and interareal communication of sensorimotor brain regions. This is reflected in a decrease of task-related spectral power over the sensorimotor cortices and an increase in functional connectivity predominantly in the upper alpha band in the electroencephalogram (EEG). In the present study, directionality of information flow was investigated using EEG recordings to gain better understanding about the network architecture underlying the performance of complex sequential finger movements. This was assessed by means of Granger causality-derived directed transfer function (DTF). As DTF measures the influence one signal exerts on another based on a time lag between them, it allows implications to be drawn on causal relationships. To reveal causal connections between brain regions that are specifically modulated by task complexity, we contrasted the performance of right-handed sequential finger movements of different complexities (simple, scale, complex) that were either pre-learned (memorized) or novel instructed. A complexity-dependent increase in information flow from mesial frontocentral to the left motor cortex and, less pronounced, also to the right motor cortex specifically in the upper alpha range was found. Effective coupling during sequences of high complexity was larger for memorized sequences compared with novel sequences (P = 0.0037). These findings further support the role of mesial frontocentral areas in directing the primary motor cortex in the process of orchestrating complex movements and in particular learned sequences.

Altered modulation of intracortical excitability during movement preparation in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.

Deficient intracortical inhibition (SICI) during movement preparation after chronic stroke.

BACKGROUND: In healthy subjects, preparation to move is accompanied by motor cortical disinhibition. Poor control of intracortical inhibitory function in the primary motor cortex (M1) might contribute to persistent abnormal motor behavior in the paretic hand after chronic stroke. METHODS: Here, we studied GABAergic short intracortical inhibition (SICI) in the ipsilesional M1 in well-recovered chronic stroke patients (n = 14; 63.8 +/- 3.0 years) engaged in preparation to move the impaired hand in a reaction time paradigm. RESULTS: The main finding was an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls (n = 14). Additionally, resting SICI was reduced in the patient group relative to controls. CONCLUSIONS: Our findings document a deficit of dynamic premovement modulation of intracortical inhibition in the ipsilesional primary motor cortex of patients with chronic stroke. This abnormality might contribute to deficits in motor control of the paretic hand, presenting a possible target for correction in the framework of developing novel therapeutic interventions after chronic stroke.

[Authorized German translation of the Motor Assessment Scale (MAS)]. / Autorisierte deutsche Ubersetzung der Motor-Assessment-Scale (MAS).

This article describes the method and result of an authorized German translation of the Motor Assessment Scale (MAS) - a measurement tool to scale motor function after stroke. The MAS is widely known in English speaking countries and is used as an outcome measure in clinical trials. It has been well researched regarding its psychometric characteristics. The translation is based on a methodical process according to the guidelines of the American Academy of Orthopaedic Surgeons. A synopsis was produced from two German initial translations, and an English back translation was performed to check the correctness of the content. The publication of the German version of the MAS aims to improve the outcome measurement in the area of rehabilitation after brain lesion.

Effects of seasonal and latitudinal cold on oxidative stress parameters and activation of hypoxia inducible factor (HIF-1) in zoarcid fish.

Acute, short term cooling of North Sea eelpout Zoarces viviparus is associated with a reduction of tissue redox state and activation of hypoxia inducible factor (HIF-1) in the liver. The present study explores the response of HIF-1 to seasonal cold in Zoarces viviparus, and to latitudinal cold by comparing the eurythermal North Sea fish to stenothermal Antarctic eelpout (Pachycara brachycephalum). Hypoxic signalling (HIF-1 DNA binding activity) was studied in liver of summer and winter North Sea eelpout as well as of Antarctic eelpout at habitat temperature of 0 degrees C and after long-term warming to 5 degrees C. Biochemical parameters like tissue iron content, glutathione redox ratio, and oxidative stress indicators were analyzed to see whether the cellular redox state or reactive oxygen species formation and HIF activation in the fish correlate. HIF-1 DNA binding activity was significantly higher at cold temperature, both in the interspecific comparison, polar vs. temperate species, and when comparing winter and summer North Sea eelpout. Compared at the low acclimation temperatures (0 degrees C for the polar and 6 degrees C for the temperate eelpout) the polar fish showed lower levels of lipid peroxidation although the liver microsomal fraction turned out to be more susceptible to lipid radical formation. The level of radical scavenger, glutathione, was twofold higher in polar than in North Sea eelpout and also oxidised to over 50%. Under both conditions of cold exposure, latitudinal cold in the Antarctic and seasonal cold in the North Sea eelpout, the glutathione redox ratio was more oxidised when compared to the warmer condition. However, oxidative damage parameters (protein carbonyls and thiobarbituric acid reactive substances (TBARS) were elevated only during seasonal cold exposure in Z. viviparus. Obviously, Antarctic eelpout are keeping oxidative defence mechanisms high enough to avoid accumulation of oxidative damage products at low habitat temperature. The paper discusses how HIF could be instrumental in cold adaptation in fish.

From critters to cancers: bridging comparative and clinical research on oxygen sensing, HIF signaling, and adaptations towards hypoxia.

The objective of this symposium at the First International Congress of Respiratory Biology (ICRB) was to enhance communication between comparative biologists and cancer researchers working on O(2) sensing via the HIF pathway. Representatives from both camps came together on August 13-16, 2006, in Bonn, Germany, to discuss molecular adaptations that occur after cells have been challenged by a reduced (hypoxia) or completely absent (anoxia) supply of oxygen. This brief "critters-to-cancer" survey discusses current projects and new directions aimed at improving understanding of hypoxic signaling and developing therapeutic interventions.

Adenoviral p53 gene transfer inhibits human Tenon's capsule fibroblast proliferation.

BACKGROUND/AIM: Although antiproliferative drugs have been used successfully to prevent scarring after filtration surgery in patients with glaucoma, complications associated with their use (such as hypotony or endophthalmitis) energise the search for an alternative treatment. Single application of beta radiation leads to long term growth arrest and expression of p53 in human Tenon's capsule fibroblasts (hTf). The authors assume that the activation of p53 is one of the cellular triggers. Their aim was to analyse the effect of p53 overexpression on hTf and to determine which pathways are involved. METHODS: A recombinant adenoviral vector (rAd.p53) containing transgenes encoding for human p53 and green fluorescent protein (GFP) was used to induce overexpression of p53 in hTF and a control vector (rAd.GFP). Transgene expression was detected by western blot (p53 and p21WAF-1/Cip1). Cell proliferation and viability were investigated using cell counts, 5'-bromodeoxyuridine incorporation (BrdU assay) and tetrazolium reduction (MTT assay). RESULTS: Infection of hTf with rAd.p53 resulted in significant inhibition of cell proliferation, DNA synthesis, and metabolic activity in vitro. Western blot showed increased levels of p53 and p21WAF-1/Cip1 in rAd.p53 infected cells, but not in rAd.GFP and uninfected cells. Apoptosis was excluded with flow cytometry. CONCLUSIONS: Adenoviral p53 gene transfer leads to significant growth inhibition in hTf. P53 induces p21(WAF-1/Cip1) expression and does not cause apoptosis in hTf in vitro. p53 as an antiproliferative drug has the potential to replace mitomycin C and 5-fluorouracil in glaucoma surgery.

Mycophenolate mofetil inhibits human Tenon fibroblast proliferation by guanosine depletion.

BACKGROUND/AIM: Mycophenolate mofetil could be a useful antiproliferative drug in glaucoma filtering surgery. In this study the authors set out to investigate whether growth inhibition of mycophenolate mofetil on human Tenon fibroblasts is mediated by guanosine depletion. METHODS: Cultured human Tenon fibroblasts were incubated in various concentrations of mycophenolate mofetil with and without supplementation of guanosine. RESULTS: Growth inhibition was concentration dependent. The effect could be completely antagonised by guanosine supplement. CONCLUSION: Human Tenon fibroblasts depend on the de novo synthesis pathway of guanosine. No sufficient salvage pathway from purine degradation appears to exist.

Production of reactive oxygen species by isolated mitochondria of the Antarctic bivalve Laternula elliptica (King and Broderip) under heat stress.

Formation of reactive oxygen species (ROS) in mitochondrial isolates from gill tissues of the Antarctic polar bivalve Laternula elliptica was measured fluorimetrically under in vitro conditions. When compared to the rates measured at habitat temperature (1 degrees C), significantly elevated ROS formation was found under temperature stress of 7 degrees C and higher. ROS formation correlated significantly with oxygen consumption in individual mitochondrial preparations over the entire range of experimental temperatures (1-12 degrees C). ROS generation per mg of mitochondrial protein was significantly higher in state 3 at maximal respiration and coupling to energy conservation, than in state 4+, where ATPase-activity is inhibited by oligomycin and only proton leakage is driving the residual oxygen consumption. The percent conversion of oxygen to the membrane permeant hydrogen peroxide amounted to 3.7% (state 3) and 6.5% (state 4+) at habitat temperature (1 degrees C), and to 7% (state 3) and 7.6% (state 4+) under experimental warming to 7 degrees C. This is high compared to 1-3% oxygen to ROS conversion in mammalian mitochondrial isolates and speaks for a comparatively low control of toxic oxygen formation in mitochondria of the polar bivalve. However, low metabolic rates at cold Antarctic temperatures keep absolute rates of mitochondrial ROS production low and control oxidative stress at habitat temperatures. Mitochondrial coupling started to fall beyond 3 degrees C, closely to pejus temperature (4 degrees C) of the bivalve. Accordingly, the proportion of state 4 respiration increased from below 30% at 1 degrees C to over 50% of total oxygen consumption at 7 degrees C, entailing reduced ADP/O ratios under experimental warming. Progressive mitochondrial uncoupling and formation of hazardous ROS contribute to bias mitochondrial functioning under temperature stress in vitro. Deduced from a pejus temperature, heat stress commences already at 5 degrees C, and is linked to progressive loss of phosphorylation efficiency, increased mitochondrial oxygen demand and elevated oxidative stress above pejus temperatures.

Humic colloid-borne migration of uranium in sand columns.

Column experiments were carried out to investigate the influence of humic colloids on subsurface uranium migration. The columns were packed with well-characterized aeolian quartz sand and equilibrated with groundwater rich in humic colloids (dissolved organic carbon (DOC): 30 mg dm(-3)). U migration was studied under an Ar/1% CO2 gas atmosphere as a function of the migration time, which was controlled by the flow velocity or the column length. In addition, the contact time of U with groundwater prior to introduction into a column was varied. U(VI) was found to be the dominant oxidation state in the spiked groundwater. The breakthrough curves indicate that U was transported as a humic colloid-borne species with a velocity up to 5% faster than the mean groundwater flow. The fraction of humic colloid-borne species increases with increasing prior contact time and also with decreasing migration time. The migration behavior was attributed to a kinetically controlled association/dissociation of U onto and from humic colloids and also a subsequent sorption of U onto the sediment surface. The column experiments provide an insight into humic colloid-mediated U migration in subsurface aquifers.

Temperature-dependence of mitochondrial function and production of reactive oxygen species in the intertidal mud clam Mya arenaria.

Mitochondrial respiration, energetic coupling to phosphorylation and the production of reactive oxygen species (ROS) were studied in mitochondria isolated from the eurythermal bivalve Mya arenaria (Myoidea) from a low-shore intertidal population of the German Wadden Sea. Measurements were conducted both within the range of the habitat temperatures (5-15 degrees C) and when subjected to heat exposure at 20 degrees C and 25 degrees C. Experimental warming resulted in an increase in the rate of state 3 and state 4 respiration in isolated mitochondria. The highest respiratory coupling ratios (RCR) were found at 15 degrees C; at higher temperatures mitochondrial coupling decreased, and release of ROS doubled between 15 and 25 degrees C. ROS production was 2-3% of total oxygen consumption in state 3 (0.3-0.5 nmol ROS mg(-1) protein min(-1)) at the habitat temperature, reaching a maximum of 4.3 % of state 3 respiration and 7 % of oligomycin-induced state 4+ respiration under heat stress. Thus, state 4 respiration, previously interpreted exclusively as a measure of proton leakage, included a significant contribution from ROS formation in this animal, especially under conditions of heat stress. Oxygen radical formation was directly dependent on temperature-controlled respiration rates in states 3 and 4 and inversely related to mitochondrial coupling (RCR+) in state 4. Mitochondrial ROS formation is therefore involved in cellular heat stress in this eurythermal marine ectotherm.

Carbon-13 NMR spectroscopic studies on chemically modified and unmodified synthetic and natural humic acids.

Carbon-13 cross-polarization magic-angle spinning nuclear magnetic resonance spectroscopy ((13)C-CP/MAS-NMR) was applied to study the chemical modification process of humic acids (HA) with diazomethane and the subsequent alkaline hydrolysis of the methylated HA. This modification process results in HA with selectively blocked phenolic OH groups, which can be used for metal ion binding studies with humic substances. Different chemically modified and unmodified natural and synthetic HA with carbon-13 of natural abundance were investigated. In addition, carbon-13 labeled modified synthetic HA, that were synthesized with [(13)C]diazomethane as methylation reagent, were studied to confirm the assumed modification process and to determine the type of functional groups that have the highest affinity for methylation with diazomethane. The results of the NMR studies with carbon-13 labeled modified HA show that predominantly carboxyl and phenolic OH groups are methylated with diazomethane resulting in methyl ester and methyl ether groups, respectively. Due to the alkaline treatment of the methylated HA, the methyl esters of carboxyl groups are hydrolyzed, whereas methyl ethers of phenolic OH groups remain unchanged, which results in modified HA with blocked phenolic OH groups. From the spectra of the modified and unmodified HA with carbon-13 of natural abundance it can be concluded that the applied preparative modification procedure causes only the desired structural changes in HA.

Isolation and characterization of an Achromobacter xylosoxidans strain B3 and other bacteria capable to degrade the synthetic chelating agent iminodisuccinate.

Three bacterial strains were isolated, which used the synthetic chelating agent iminodisuccinate (IDS) as sole carbon source for growth in mineral salts media (MSM). Taxonomic analysis and 16S rDNA sequence analysis identified one of these isolates (B3), which was isolated from sewage sludge, as a strain of Achromobacter xylosoxidans subsp. xylosoxidans. It exhibited a doubling time of approximately 3 h in liquid MSM supplemented with IDS and grew even in the presence of 1.0% (w/v) IDS. Since photometric and high performance liquid chromatography analysis showed that IDS, which came onto the market only recently as an alternative for ethylenediaminetetraacetate, was completely degraded by axenic cultures of bacteria; it will probably be readily degraded in the environment.

Three-dimensional imaging of nerve tissue by x-ray phase-contrast microtomography.

We show that promising information about the three-dimensional (3D) structure of a peripheral nerve can be obtained by x-ray phase-contrast microtomography (p-microCT; Beckmann, F., U. Bonse, F. Busch, and O. Günnewig, 1997. J. Comp. Assist. Tomogr. 21:539-553). P-microCT measures electronic charge density, which for most substances is proportional to mass density in fairly good approximation. The true point-by-point variation of density is thus determined in 3D at presently 1 mg/cm3 standard error (SE). The intracranial part of the rat trigeminal nerve analyzed for the presence of early schwannoma "microtumors" displayed a detailed density structure on p-microCT density maps. The average density of brain and nerve tissue was measured to range from 0.990 to 0.994 g/cm3 and from 1.020 to 1.035 g/cm3, respectively. The brain-nerve interface was well delineated. Within the nerve tissue, a pattern of nerve fibers could be seen that followed the nerve axis and contrasted against the bulk by 7 to 10 mg/cm3 density modulation. Based on the fact that regions of tumor growth have an increased number density of cell nuclei, and hence of the higher z element phosphorus, it may become possible to detect very early neural "microtumors" through increases of average density on the order of 10 to 15 mg/cm3 by using this method.

Tocopherol synthesis from homogentisate in Capsicum anuum L. (yellow pepper) chromoplast membranes: evidence for tocopherol cyclase.

The present study shows for the first time appreciable tocopherol cyclase activities in plastidial membrane preparations of Capsicum annuum L. (yellow pepper) fruits. When chromoplast membranes from yellow peppers were incubated with [3H]homogentisate and phytyl pyrophosphate under strictly reducing conditions, all biosynthesis precursors were labelled. The main labelling was found in gamma-tocopherol. These observations contradict the hypothesis that assigns a rate-limiting function to tocopherol cyclase in plastidial alpha-tocopherol biosynthesis. The stoichiometry of alpha-tocopherol, 2,3-dimethylphytylquinol and gamma-tocopherol formation and the inhibition of alpha-tocopherol synthesis by increasing gamma-tocopherol concentrations suggests the regulation of this pathway by its precursors.

Epidemiologic evaluation of encephalitic listeriosis in goats.

OBJECTIVE: To evaluate host and environmental factors associated with the development of encephalitic listeriosis in goats. DESIGN: Retrospective analysis of diagnostic laboratory records and survey of veterinarians and goat producers. SAMPLE POPULATION: 355 goat herds accessible through laboratory records; 38 veterinarians who treated goats and 76 goat producers. PROCEDURE: Data regarding breed and use for goats affected with encephalitic listeriosis were obtained from surveys and case follow-up information. Listeria monocytogenes isolates from the brains of 7 affected goats were serotyped and subjected to DNA restriction analysis. RESULTS: Odds ratio for the development of encephalitis listeriosis in Angora (mohair-producing) goats was 22.9 by use of diagnostic laboratory records. Survey also revealed a high prevalence in herds of Angora and other breeds that subsisted on woody browse, although Angora goats feeding predominantly on hay or pasture were not affected. Listeria monocytogenes isolates from 4 Angora goats in 3 herds differed in DNA restriction patterns, although the pattern was identical in 3 other goats from another herd. CLINICAL IMPLICATIONS: Encephalitic listeriosis can be observed in all goat breeds, but a lifestyle of heavy browse consumption seems important to the development of disease in some herds.