Showing papers by "Humboldt University of Berlin published in 2002"
TL;DR: It is hypothesized that the healthy mucosa is capable of holding back fecal bacteria and that this function is profoundly disturbed in patients with IBD, suggesting that the changes in the mucosal flora in IBD are not secondary to inflammation, but a result of a specific host response.
1,346 citations
TL;DR: PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF) and an antibody against Flt1 suppressed neovascularization in tumors and isChemic retina, and angiogenic and inflammatory joint destruction in autoimmune arthritis.
Abstract: The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.
1,100 citations
TL;DR: Applying measures of complexity based on vertical structures in recurrence plots and applying them to the logistic map as well as to heart-rate-variability data is able to detect and quantify the laminar phases before a life-threatening cardiac arrhythmia occurs thereby facilitating a prediction of such an event.
Abstract: The knowledge of transitions between regular, laminar or chaotic behaviors is essential to understand the underlying mechanisms behind complex systems. While several linear approaches are often insufficient to describe such processes, there are several nonlinear methods that, however, require rather long time observations. To overcome these difficulties, we propose measures of complexity based on vertical structures in recurrence plots and apply them to the logistic map as well as to heart-rate-variability data. For the logistic map these measures enable us not only to detect transitions between chaotic and periodic states, but also to identify laminar states, i.e., chaos-chaos transitions. The traditional recurrence quantification analysis fails to detect the latter transitions. Applying our measures to the heart-rate-variability data, we are able to detect and quantify the laminar phases before a life-threatening cardiac arrhythmia occurs thereby facilitating a prediction of such an event. Our findings could be of importance for the therapy of malignant cardiac arrhythmias.
890 citations
TL;DR: In mice signs of neuronal aging can be diminished by a sustained active and challenging life, even if this stimulation started only at medium age, because activity exerts not only an acute but also a sustained effect on brain plasticity.
Abstract: Neurons are continually born from endogenous stem cells and added to the dentate gyrus throughout life, but adult hippocampal neurogenesis declines precipitously with age. Short-term exposure to an enriched environment leads to a striking increase in new neurons, along with a substantial improvement in behavioral performance. Could this plastic response be relevant for explaining the beneficial effects of leading "an active life" on brain function and pathology? Adult hippocampal neurogenesis in mice living in an enriched environment from the age of 10 to 20 months was fivefold higher than in controls. Relatively, the increase in neuronal phenotypes was entirely at the expense of newly generated astrocytes. This cellular plasticity occurred in the context of significant improvements of learning parameters, exploratory behavior, and locomotor activity. Enriched living mice also had a reduced lipofuscin load in the dentate gyrus, indicating decreased nonspecific age-dependent degeneration. Therefore, in mice signs of neuronal aging can be diminished by a sustained active and challenging life, even if this stimulation started only at medium age. Activity exerts not only an acute but also a sustained effect on brain plasticity.
866 citations
TL;DR: The possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo is discussed, and it is reported two children who were conceived by intracytoplasmic sperm injection and who developed Angelman syndrome are reported.
Abstract: In germ cells and the early embryo, the mammalian genome undergoes widespread epigenetic reprogramming. Animal studies suggest that this process is vulnerable to external factors. We report two children who were conceived by intracytoplasmic sperm injection (ICSI) and who developed Angelman syndrome. Molecular studies, including DNA methylation and microsatellite and quantitative Southern blot analysis, revealed a sporadic imprinting defect in both patients. We discuss the possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo.
703 citations
TL;DR: It is recommended to use the lowest intraabdominal pressure allowing adequate exposure of the operative field, rather than using a routine pressure, and abdominal wall lifting combined with low-pressure pneumoperitoneum might be an alternative.
Abstract: Background: The pneumoperitoneum is the crucial element in laparoscopic surgery. Different clinical problems are associated with this procedure, which has led to various modifications of the technique. The aim of this guideline is to define the scientifically proven standards of the pneumoperitoneum. Methods: Based on systematic literature searches (Medline, Embase, and Cochrane), an expert panel consensually formulated clinical recommendations, which were graded according to the strength of available literature evidence. Recommendations: Preoperatively, all patients should be assessed for the presence of cardiac, pulmonary, hepatic, renal, or vascular comorbidity. Presupposing appropriate perioperative measures and surgical technique, there is no reason to contraindicate pneumoperitoneum in patients with peritonitis or intraabdominal malignancy. During laparoscopy, monitoring of end tidal CO2 concentration is mandatory. The available data on closed- (Veress needle) and open-access techniques do not allow us to principally favor the use of either technique. Using 2 to 5-mm instead of 5 to 10-mm trocars improves cosmetic result and postoperative pain marginally. It is recommended to use the lowest intraabdominal pressure allowing adequate exposure of the operative field, rather than using a routine pressure. In patients with limited cardiac, pulmonary, or renal function, abdominal wall lifting combined with low-pressure pneumoperitoneum might be an alternative. Abdominal wall lifting devices have no clinically relevant advantages compared to low-pressure (5–7 mmHg) pneumoperitoneum. In patients with cardiopulmonary diseases, intra- and postoperative arterial blood gas monitoring is recommended. The clinical benefits of warmed, humidified insufflation gas are minor and contradictory. Intraoperative sequential intermittent pneumatic compression of the lower extremities is recommended for all prolonged laparoscopic procedures. For the prevention of postoperative pain a wide range of treatment options exists. Although all these options seem to reduce pain, the data currently do not justify a general recommendation.
684 citations
TL;DR: It is proposed that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival.
Abstract: Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (competitive receptor antagonists, ion channel blockers, and glycine antagonists)—such as selfotel, aptiganel, eliprodil, licostinel and gavestinel—failed to show efficacy in clinical trials of stroke or traumatic brain injury. This failure has been attributed to the deficient properties of the molecules that entered human trials and to inappropriate design of clinical studies. In this article we hypothesise that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival. We propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival.
672 citations
TL;DR: Investigation of the expression of five novel human IL-10-related molecules and their receptors in blood mononuclear cells found IL-19 and IL-20 were found to be preferentially expressed in monocytes, and monocytes and NK, B, and T cells showed clear expression only of IL- 10R1,IL-10R2, andIL-20R2.
Abstract: This study investigated the expression of five novel human IL-10-related molecules and their receptors in blood mononuclear cells. IL-19 and IL-20 were found to be preferentially expressed in monocytes. IL-22 and IL-26 (AK155) expression was exclusively detected in T cells, especially upon type 1 polarization, and in NK cells. IL-24 (melanoma differentiation-associated gene 7) expression was restricted to monocytes and T cells. Detection of these molecules in lymphocytes was predominantly linked to cellular activation. Regarding T cells, IL-26 was primarily produced by memory cells, and its expression was independent on costimulation. In contrast to the high expression of receptors for IL-10 homologs in different tissues and cell lines, monocytes and NK, B, and T cells showed clear expression only of IL-10R1, IL-10R2, and IL-20R2. In these cells, IL-20R2 might be part of a still-unknown receptor complex. Therefore, immune cells may represent a major source but a minor target of the novel IL-10 family members.
601 citations
TL;DR: It is shown that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145), and the identification of TTN mutations in individuals with C MD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.
Abstract: Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20-30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner-nuclear membrane proteins. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-I-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.
549 citations
TL;DR: This work has developed a mathematical theory that describes the regulation of signaling pathways as a function of a limited number of key parameters and finds that phosphatases have a more pronounced effect than kinases on the rate and duration of signaling, whereas signal amplitude is controlled primarily by kinases.
530 citations
TL;DR: Genetic and biochemical experiments provide strong evidence that phytase activity of B. amyloliquefaciens FZB45 is important for plant growth stimulation under phosphate limitation.
Abstract: Several Bacillus strains belonging to the B. subtilis/amyloliquefaciens group isolated from plant-pathogen-infested soil possess plant-growth-promoting activity [Krebs, B. et al. (1998) J Plant Dis Prot 105, 181-197]. Three out of the four strains investigated were identified as B. amyloliquefaciens and were able to degrade extracellular phytate (myo-inositol hexakisphosphate). The highest extracellular phytase activity was detected in strain FZB45, and diluted culture filtrates of this strain stimulated growth of maize seedlings under phosphate limitation in the presence of phytate. The amino acid sequence deduced from the phytase phyA gene cloned from FZB45 displayed a high degree of similarity to known Bacillus phytases. Weak similarity between FZB45 phytase and B. subtilis alkaline phosphatase IV pointed to a possible common origin of these two enzymes. The recombinant protein expressed by B. subtilis MU331 displayed 3(1)-phytase activity yielding D/L-Ins(1,2,4,5,6)P5 as the first product of phytate hydrolysis. A phytase-negative mutant strain, FZB45/M2, whose phyA gene is disrupted, was generated by replacing the entire wild-type gene on the chromosome of FZB45 with a km::phyA fragment, and culture filtrates obtained from FZB45/M2 did not stimulate plant growth. In addition, the growth of maize seedlings was promoted in the presence of purified phytase and the absence of culture filtrate. These genetic and biochemical experiments provide strong evidence that phytase activity of B. amyloliquefaciens FZB45 is important for plant growth stimulation under phosphate limitation.
TL;DR: The dentate gyrus of the adult hippocampal formation generates neurons throughout life, but it remains unclear why and how these neurons are used.
Abstract: The dentate gyrus of the adult hippocampal formation generates neurons throughout life. To date, it remains unclear why. What are the new neurons used for? How can an existing functional neural network integrate and even actively recruit new neurons? The prevailing theories of cognition are based on
TL;DR: In this article, the authors investigated the tendon-bone healing of the anatomic soft-tissue graft interference fit fixation in a model of anterior cruciate ligament (ACL) reconstruction in sheep.
Abstract: Purpose: Tendon-to-bone healing of soft-tissue grafts has been described to progress by the development of a fibrous interzone that undergoes a maturation process leading to the development of an indirect type of ligament insertion. Previous studies used extra-articular models or fixation far away from the joint line; thus, no data are available investigating tendon-to-bone healing of a soft-tissue graft fixed anatomically. Therefore, we studied the tendon-to-bone healing of the anatomic soft-tissue graft interference fit fixation in a model of anterior cruciate ligament (ACL) reconstruction in sheep. Type of Study: Animal study. Methods: Thirty-five mature sheep underwent ACL reconstruction with an autologous Achilles tendon split graft. Grafts were directly fixed with biodegradable poly-(D,L-lactide) interference screws. Animals were euthanized after 6, 9, 12, 24, and 52 weeks and histologic evaluations were performed. Undecalcified specimens were evaluated under normal and polarized light. Additionally, animals received a polychrome sequential labeling (tetracycline, xylenol orange, and calcein green) to determine bone growth per time under fluorescent light. Results: Intratunnel histologic findings at 6 weeks showed a tendon-bone junction with only a partial fibrous interzone between the graft tissue and the surrounding bone. A mature intratunnel tendon-bone junction with a zone of fibrocartilage was found at 9 to 12 weeks. At the tunnel entrance site a wide regular ligamentous insertion site was seen in all specimens after 24 weeks. This insertion showed regular patterns such as the direct type of insertion of a normal ligament with a dense basophilic transition zone consisting of mineralized cartilage. Conclusions: A fibrous interzone between the graft tissue and the bone tunnel was only partially developed, which is in contrast to all previous studies in which nonanatomic fixation was used. Thus, it is reasonable to assume that the tendon-to-bone healing in the present study may progress partially by direct-contact healing without the development of a fibrous interzone. To our knowledge, this is the first report describing the development of a direct type of ligament insertion after ACL replacement with a soft-tissue graft. This is in contrast to previous studies reporting the development of an indirect type of insertion when using nonanatomic fixation far away from the joint line. Thus, histologic data strongly indicate that anatomic interference fit fixation is beneficial for tendon-to-bone incorporation by leading to the development of a direct type of ligament insertion. Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 18, No 2 (February), 2002: pp 124–135
TL;DR: Vascular lesion development initiated by endothelial cell damage is moderated by bone marrow–derived progenitor cells, and 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibition promotes bone marrow-dependent reendothelialization and diminishes vascular lesionDevelopment.
Abstract: Objective— Atherosclerosis and restenosis after vascular injury are both characterized by endothelial dysfunction, apoptosis, inappropriate endothelialization, and neointimal formation. Bone marrow–derived endothelial progenitor cells have been implicated in neovascularization, resulting in adult blood vessel formation. Despite the anticipated stem cell plasticity, the role of bone marrow–derived endothelial progenitor cells has not been clarified in vascular lesion development. Methods and Results— We investigated vascular lesion formation in mice after transplantation of bone marrow transfected by means of retrovirus with enhanced green fluorescent protein. Carotid artery injury was induced, resulting in neointimal formation. Fluorescence microscopy and immunohistological analysis revealed that bone marrow–derived progenitor cells are involved in reendothelialization of the vascular lesions. Treatment with rosuvastatin (20 mg/kg body wt per day), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibit...
TL;DR: In this article, a basic revision of the understanding of teleology in biological sciences is proposed, which is strengthened by a group of philosophers of biology, with Hans Jonas as the central figure, who put back on center stage an organism-centered view of the living.
Abstract: This paper proposes a basic revision of the understanding of teleology in biological sciences. Since Kant, it has become customary to view purposiveness in organisms as a bias added by the observer; the recent notion of teleonomy expresses well this “as-if” character of natural purposes. In recent developments in science, however, notions such as self-organization (or complex systems) and the autopoiesis viewpoint, have displaced emergence and circular self-production as central features of life. Contrary to an often superficial reading, Kant gives a multi-faceted account of the living, and anticipates this modern reading of the organism, even introducing the term “self-organization” for the first time. Our re-reading of Kant in this light is strengthened by a group of philosophers of biology, with Hans Jonas as the central figure, who put back on center stage an organism-centered view of the living, an autonomous center of concern capable of providing an interior perspective. Thus, what is present in nuce in Kant, finds a convergent development from this current of philosophy of biology and the scientific ideas around autopoeisis, two independent but parallel developments culminating in the 1970s. Instead of viewing meaning or value as artifacts or illusions, both agree on a new understanding of a form of immanent teleology as truly biological features, inevitably intertwined with the self-establishment of an identity which is the living process.
TL;DR: It is shown that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells, and hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs.
Abstract: During ageing thymic function declines and is unable to meet the demand for peripheral T helper (Th) cell replenishment. Therefore, population maintenance of naive Th cells must be at least partly peripherally based. Such peripheral postthymic expansion of recent thymic emigrants (RTEs) during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) from a subset of naive T cells. We have identified two subsets of naive Th cells in human adult peripheral blood characterized by a striking unequal content of TRECs, indicating different peripheral proliferative histories. TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 compared with peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected. Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells. As CD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs. We describe here the identification of peripherally expanded naive Th cells in human adult blood characterized by the loss of CD31 expression and a highly reduced TREC content.
TL;DR: In this article, a generalization of the variance ratio statistic is suggested, which can be used to test the cointegration rank in the spirit of Johansen (J. Econ. Dyn. Econom. 15 (1992) 159) but assumes nonstationarity under the null hypothesis.
TL;DR: This approach preserves the fundamental semiconducting properties of the conjugated wires, and is effective at both increasing the photoluminescence efficiency and blue-shifting the emission of the Conjugated cores, in the solid state, while still allowing charge-transport.
Abstract: Control of intermolecular interactions is crucial to the exploitation of molecular semiconductors for both organic electronics and the viable manipulation and incorporation of single molecules into nano-engineered devices. Here we explore the properties of a class of materials that are engineered at a supramolecular level by threading a conjugated macromolecule, such as poly(para-phenylene), poly(4,4'-diphenylene vinylene) or polyfluorene through alpha- or beta-cyclodextrin rings, so as to reduce intermolecular interactions and solid-state packing effects that red-shift and partially quench the luminescence. Our approach preserves the fundamental semiconducting properties of the conjugated wires, and is effective at both increasing the photoluminescence efficiency and blue-shifting the emission of the conjugated cores, in the solid state, while still allowing charge-transport. We used the polymers to prepare single-layer light-emitting diodes with Ca and Al cathodes, and observed blue and green emission. The reduced tendency for polymer chains to aggregate allows solution-processing of individual polyrotaxane wires onto substrates, as revealed by scanning force microscopy.
TL;DR: The data suggest that activated Notch1 signaling plays an important role in the pathobiology of Hodgkin and anaplastic large cell lymphoma and that it might be a potential new target for treatment.
TL;DR: Recommendations on glucocorticoid treatment are presented that reflect current and best knowledge available and take into account current clinical practice.
Abstract: In rheumatology and other medical specialties there is a discrepancy between the widespread use and the imprecise designation of glucocorticoid treatment regimens. Verbal descriptions of glucocorticoid treatment regimens used in various phases of diseases vary between countries and institutions. Given this background, a workshop under the auspices of the EULAR Standing Committee on International Clinical Studies including Therapeutic Trials was held to discuss this issue and to seek a consensus on nomenclature for glucocorticoid treatment. This report summarises the panel's discussion and recognises that answers derived from consensus conferences are not definitive. Nevertheless, recommendations on glucocorticoid treatment are presented that (1) reflect current and best knowledge available and (2) take into account current clinical practice. A question-answer rationale presentation style has been chosen to convey the messages, to summarise the meeting in a readable format, and to avoid dogmatism.
TL;DR: In this article, the authors apply the methods developed for computation of type IIA disk instantons using mirror symmetry to a large class of D-branes wrapped over Lagrangian cycles of non-compact Calabi-Yau 3-folds.
Abstract: We apply the methods recently developed for computation of type IIA disk instantons using mirror symmetry to a large class of D-branes wrapped over Lagrangian cycles of non-compact Calabi-Yau 3-folds. Along the way we clarify the notion of "flat coordinates" for the boundary theory. We also discover an integer IR ambiguity needed to define the quantum theory of D-branes wrapped over non-compact Lagrangian submanifolds. In the large N dual Chem-Simons theory, this ambiguity is mapped to the UV choice of the framing of the knot. In a type IIB dual description involving (p, q) 5-branes, disk instantons of type IIA get mapped to (p, q) string instantons. The M-theory lift of these results lead to computation of superpotential terms generated by M2 brane instantons wrapped over 3-cycles of certain manifolds of G 2 holonomy.
TL;DR: This review provides a comparative overview of recent developments in the modelling of cellular calcium oscillations and suggests suggestions concerning the physiological significance of oscillatory behaviour in intra- and intercellular signalling.
Abstract: This review provides a comparative overview of recent developments in the modelling of cellular calcium oscillations. A large variety of mathematical models have been developed for this wide-spread phenomenon in intra- and intercellular signalling. From these, a general model is extracted that involves six types of concentration variables: inositol 1,4,5-trisphosphate (IP3), cytoplasmic, endoplasmic reticulum and mitochondrial calcium, the occupied binding sites of calcium buffers, and the fraction of active IP3 receptor calcium release channels. Using this framework, the models of calcium oscillations can be classified into 'minimal' models containing two variables and 'extended' models of three and more variables. Three types of minimal models are identified that are all based on calcium-induced calcium release (CICR), but differ with respect to the mechanisms limiting CICR. Extended models include IP3--calcium cross-coupling, calcium sequestration by mitochondria, the detailed gating kinetics of the IP3 receptor, and the dynamics of G-protein activation. In addition to generating regular oscillations, such models can describe bursting and chaotic calcium dynamics. The earlier hypothesis that information in calcium oscillations is encoded mainly by their frequency is nowadays modified in that some effect is attributed to amplitude encoding or temporal encoding. This point is discussed with reference to the analysis of the local and global bifurcations by which calcium oscillations can arise. Moreover, the question of how calcium binding proteins can sense and transform oscillatory signals is addressed. Recently, potential mechanisms leading to the coordination of oscillations in coupled cells have been investigated by mathematical modelling. For this, the general modelling framework is extended to include cytoplasmic and gap-junctional diffusion of IP3 and calcium, and specific models are compared. Various suggestions concerning the physiological significance of oscillatory behaviour in intra- and intercellular signalling are discussed. The article is concluded with a discussion of obstacles and prospects.
TL;DR: It is demonstrated that the distributed-order time fractional diffusion equation describes the subdiffusion random process that is subordinated to the Wiener process and whose diffusion exponent decreases in time (retarding sub Diffusion).
Abstract: We propose diffusionlike equations with time and space fractional derivatives of the distributed order for the kinetic description of anomalous diffusion and relaxation phenomena, whose diffusion exponent varies with time and which, correspondingly, cannot be viewed as self-affine random processes possessing a unique Hurst exponent. We prove the positivity of the solutions of the proposed equations and establish their relation to the continuous-time random walk theory. We show that the distributed-order time fractional diffusion equation describes the subdiffusion random process that is subordinated to the Wiener process and whose diffusion exponent decreases in time (retarding subdiffusion). This process may lead to superslow diffusion, with the mean square displacement growing logarithmically in time. We also demonstrate that the distributed-order space fractional diffusion equation describes superdiffusion phenomena with the diffusion exponent increasing in time (accelerating superdiffusion).
TL;DR: In this paper, the authors develop an approach to link conceptually the two dimensions of Europeanization by focusing on the ways in which Member State governments both shape European policy outcomes and adapt to them.
Abstract: Europeanization is a two-way process, which involves the evolution of European institutions that impact on political structures and processes of the Member States. This article develops an approach to link conceptually the two dimensions of Europeanization by focusing on the ways in which Member State governments both shape European policy outcomes and adapt to them. Member States have an incentive to ‘upload’ their policies to the European level to minimize the costs in ‘downloading’ them at the domestic level. But they differ in both their policy preferences and their action capacities. Accordingly, Member States have pursued different strategies in responding to Europeanization. The article draws on evidence from the field of EU environmental policy-making to illustrate when Member States are likely to engage in pace-setting, foot-dragging or fence-sitting. It concludes with some considerations on whether pace-setting, foot-dragging and fence-sitting give rise to interest coalitions, which pitch Member States of diverse levels of economic development against each other.
TL;DR: Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped.
Abstract: Objective
To describe the long-term outcome of juvenile idiopathic arthritis (JIA).
Methods
All patients with JIA referred to a pediatric rheumatology center between 1978 and 1988 were identified and invited to undergo an assessment. Patients with JIA from a population-based cohort from East Berlin were included. The outcome assessment considered changes in body function and structure (e.g., mortality, joint abnormalities, disease activity), activities at the individual level (Health Assessment Questionnaire), and participation in society (e.g., mobility, educational and vocational background).
Results
Of 260 eligible patients, 215 (83%) were evaluated. Subtypes of JIA at disease onset included oligoarthritis (40%), polyarthritis (14%), systemic arthritis (14%), psoriatic arthritis (1%), enthesitis-related arthritis (15%), and other arthritis (16%). Followup was conducted after a median of 16.5 years. No deaths occurred in this cohort. At followup, approximately half of the patients had active disease and/or changes in body structures to a variable extent. Approximately one-third of patients rated themselves as being functionally limited. Patients demonstrated good social integration: few mobility problems were reported, and the educational achievements of patients were higher and their rate of unemployment was lower compared with the age-matched population. No significant differences in outcome were found between the population-based and the referral-based cohorts.
Conclusion
Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped. Because JIA often persists into adulthood, long-term followup and care are necessary.
TL;DR: The responsiveness of plasma blasts to these chemokines is restricted to a few days after their emigration from the spleen, indicating a role for these molecules and their cognate receptors in the regulation of plasma blast migration into the bone marrow and/or inflamed tissues.
Abstract: Plasma blasts formed during memory immune responses emigrate from the spleen to migrate into the bone marrow and into chronically inflamed tissues where they differentiate into long-lived plasma cells. In this study, we analyze the chemokine responsiveness of plasma blasts formed after secondary immunization with OVA. Starting from day 4 and within ∼48 h, OVA-specific plasma blasts emigrate from spleen and appear in the bone marrow. Although these migratory cells have lost their responsiveness to many B cell attracting chemokines, e.g., CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant), they migrate toward CXCL12 (stromal cell-derived factor 1α), and toward the inflammatory chemokines CXCL9 (monokine induced by IFN-γ), CXCL10 (IFN-γ-inducible protein 10), and CXCL11 (IFN-inducible T cell α chemoattractant). However, the responsiveness of plasma blasts to these chemokines is restricted to a few days after their emigration from the spleen, indicating a role for these molecules and their cognate receptors, i.e., CXCR3 and CXCR4, in the regulation of plasma blast migration into the bone marrow and/or inflamed tissues.
TL;DR: Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test).
Abstract: Objective. Pimecrolimus cream (SDZ ASM 981), a nonsteroid inhibitor of inflammatory cytokines, is effective in atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares. Methods. Early intervention with pimecrolimus was compared with a conventional AD treatment strategy (ie, emollients and topical corticosteroids). In this 1-year, controlled, double-blind study, 713 AD patients (2–17 years) were randomized 2:1 to a pimecrolimus-based or conventional regimen. Both groups used emollients for dry skin. Early AD signs/symptoms were treated with pimecrolimus cream or, in the conventional treatment group, vehicle to prevent progression to flares. If flares occurred, moderately potent topical corticosteroids were mandated. The primary efficacy endpoint was ranked flares at 6 months. Safety was monitored clinically, and a skin recall-antigen test was performed at study completion. Results. Baseline Characteristics of the Patients. The mean age for both groups was approximately 8 years, and the majority of patients had moderate disease at baseline. Patient Follow-up and Exposure to Study Medication. The mean duration of follow-up (±standard error) was 303.7 (±5.30) days in the pimecrolimus group and 235.2 (±9.40) days in the control group. The discontinuation rate was significantly higher in the control group than in the pimecrolimus group (51.5% vs 31.6% at 12 months), and proportionately more patients with severe or very severe disease discontinued in the control group. The main reason for the higher discontinuation rate in the control group was unsatisfactory therapeutic effect (30.4% vs 12.4%). This resulted in a substantially higher mean number of study medication treatment days in the pimecrolimus group compared with the control group: 211.9 (69.8% of study days) versus 156.0 (66.3% of study days). Of those patients who completed 12 months on study, 14.2% and 7.0% of patients in the pimecrolimus and vehicle groups, respectively, used study medication continuously. Efficacy. Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test). The proportion of patients who completed 6 or 12 months with no flares was approximately twice as high in the pimecrolimus group compared with control (61.0% vs 34.2% at 6 months; 50.8% vs 28.3% at 12 months). Fewer flares were observed in the pimecrolimus group regardless of baseline disease severity, so even severe patients derived benefit from the treatment. The analysis of time to first flare showed that treatment with pimecrolimus was associated with a significantly longer flare-free period (log- rank test). Covariate analysis indicated a statistically significant effect on time to first flare of baseline Eczema Area and Severity Index score, and whether patients had “severe” or “very severe” disease at baseline according to the Investigators’ Global Assessment, although patients in all baseline disease severity subgroups benefited from treatment. Age had no significant effect. Fewer patients in the pimecrolimus group required topical corticosteroid therapy compared with control (35.0% vs 62.9% at 6 months; 42.6% vs 68.4% at 12 months), and patients in the pimecrolimus group spent fewer days on topical corticosteroid therapy (57.4% vs 31.6% [pimecrolimus vs control, respectively] spent 0 days on topical corticosteroid therapy, 17.1% vs 27.5% 1–14 days, and 25.5% vs 41.0% >14 days over the 12 months of the study). This steroid-sparing effect of pimecrolimus was evident despite pimecrolimus-treated patients being on study longer than patients in the control group. The average proportion of study days spent on second-line corticosteroids was 4.08% in the pimecrolimus group and 9.10% in the control group. Analysis of Eczema Area and Severity Index over time showed significantly lower median scores, thus indicating better disease control in the pimecrolimus group compared with the control group. Similar results were obtained from analysis of the Investigators’ Global Assessment (not shown). The treatment groups were well balanced with respect to the number of patients using antihistamines during the study (57.2% vs 62.9%, pimecrolimus vs control, respectively). Safety. There were no appreciable differences between treatment groups in the overall incidence of adverse events. The most frequent adverse events were common childhood infections and ailments, including nasopharyngitis, headache, and cough. The incidence of suspected drug-related adverse events was not significantly different in the pimecrolimus group (24.7% vs 18.7%—pimecrolimus vs control), and the incidence of serious adverse events was low (8.3% vs 5.2%—pimecrolimus vs control). Life-table analysis of incidence of adverse events revealed no significant differences between the treatment groups, except for cough. Local tolerability was good in both treatment groups. The most common application site reaction reported was sensation of burning (10.5% vs 9.3%—pimecrolimus vs control). There were no major differences between treatment groups in the duration or severity of application site reactions, most of which were mild-to-moderate and transient, occurring within the first week of treatment. Skin infections were reported in both groups. There were no between-group differences in the life-table analysis of time to first occurrence of bacterial skin infections nor in the adjusted incidence of bacterial skin infections. Although there were no significant differences between treatment groups in the incidence of individual viral skin infections, the incidence of grouped viral skin infections (12.4% vs 6.3%—pimecrolimus vs control) showed a slightly higher incidence in the pimecrolimus group. Laboratory values and vital signs showed no significant between-group differences. There were no significant differences between treatment groups in response to recall antigens in those patients who remained on study for 12 months. Conclusions. Treatment of early AD signs/symptoms with pimecrolimus was effective in preventing progression to flares in more than half the patients, reducing or eliminating the need for topical corticosteroids. The benefits were consistently seen at 6 months across important disease severity subgroups and with respect to the various predefined efficacy endpoints. Furthermore, these benefits were sustained for 12 months, providing evidence that long-term treatment with pimecrolimus leads to better control of AD. Treatment with pimecrolimus was well tolerated and was not associated with clinically relevant adverse events compared with the conventional treatment group. The results reported here offer the prospect of effective long-term management of AD with reduced need for topical corticosteroids.
TL;DR: The association of symptoms in the patients with NKX1-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
Abstract: The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
TL;DR: In this article, a detailed discussion of the scattering of fast atoms and ions from solid surfaces under a grazing angle of incidence is presented Theoretical and experimental results are used to demonstrate that collisions employing this scattering geometry provide interesting new phenomena and insights into atom-surface interactions.
TL;DR: The results support the conclusion that dorsolateral prefrontal and superior parietal cortices are involved in the coordination of concurrent and interfering task processing.
Abstract: We report a study that investigated the neuroanatomical correlates of executive functions in dual-task performance with functional magnetic resonance imaging. Participants performed an auditory and a visual three-choice reaction task either separately as single tasks or concurrently as dual tasks. In the dual-task condition, two stimuli were presented in rapid succession to ensure interference between the component tasks (psychological refractory period). The behavioral data showed considerable performance decrements in the dual-task compared to the single-task condition. Dual-task-related activation was detected with two different neuroimaging methods. First, we determined dual-task-related activation according to the method of cognitive subtraction. For that purpose, activation in the dual-task was compared directly with activation in the single-task conditions. This analysis revealed that cortical areas along the inferior frontal sulcus (IFS), the middle frontal gyrus (MFG), and the intraparietal sulcus (IPS) are involved in dual-task performance. The results of the subtraction method were validated with the method of parametric manipulation. For this purpose, a second dual-task condition was introduced, where the difficulty of the dual-task coordination was increased compared with the first dual-task condition. As expected, behavioral dual-task performance decreased with increased dual-task difficulty. Furthermore, the increased dual-task difficulty led to an increase of activation in those cortical regions that proved to be dual-task related with the subtraction method, that is, the IFS, the MFG, and the IPS. These results support the conclusion that dorsolateral prefrontal and superior parietal cortices are involved in the coordination of concurrent and interfering task processing.