Identifying chemokines as therapeutic targets in renal disease: Lessons from antagonist studies and knockout mice

Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease. Copyright (C) 2004 S. Karger AG, Basel

Identification of sortase A (SrtA) substrates in Streptococcus uberis: evidence for an additional hexapeptide (LPXXXD) sorting motif

Sortase (a transamidase) has been shown to be responsible for the covalent attachment of proteins to the bacterial cell wall. Anchoring is effected on secreted proteins containing a specific cell wall motif toward their C-terminus; that for sortase A (SrtA) in Gram-positive bacteria often incorporates the sequence LPXTG. Such surface proteins are often characterized as virulence determinants and play important roles during the establishment and persistence of infection. Intramammary infection with Streptococcus uberis is a common cause of bovine mastitis, which impacts on animal health and welfare and the economics of milk production. Comparison of stringently produced cell wall fractions from S. uberis and an isogenic mutant strain lacking SrtA permitted identification of 9 proteins likely to be covalently anchored at the cell surface. Analysis of these sequences implied the presence of two anchoring motifs for S. uberis, the classical LPXTG motif and an additional LPXXXD motif

Protein Expression in the Nucleus Accumbens of Rats Exposed to Developmental Vitamin D Deficiency

Introduction: Developmental vitamin D (DVD) deficiency is a candidate risk factor for schizophrenia. Animal models have confirmed that DVD deficiency is associated with a range of altered genomic, proteomic, structural and behavioural outcomes in the rat. Because the nucleus accumbens has been implicated in neuropsychiatric disorders, in the current study we examined protein expression in this region in adult rats exposed to DVD deficienc

Muscle weakness and lack of reflex gain adaptation predominate during post-stroke posture control of the wrist

Instead of hyper-reflexia as sole paradigm, post-stroke movement disorders are currently considered the result of a complex interplay between neuronal and muscular properties, modified by level of activity. We used a closed loop system identification technique to quantify individual contributors to wrist joint stiffness during an active posture task. Continuous random torque perturbations applied to the wrist joint by a haptic manipulator had to be resisted maximally. Reflex provoking conditions were applied i.e. additional viscous loads and reduced perturbation signal bandwidth. Linear system identification and neuromuscular modeling were used to separate joint stiffness into the intrinsic resistance of the muscles including co-contraction and the reflex mediated contribution. Compared to an age and sex matched control group, patients showed an overall 50% drop in intrinsic elasticity while their reflexive contribution did not respond to provoking conditions. Patients showed an increased mechanical stability compared to control subjects. Post stroke, we found active posture tasking to be dominated by: 1) muscle weakness and 2) lack of reflex adaptation. This adds to existing doubts on reflex blocking therapy as the sole paradigm to improve active task performance and draws attention to muscle strength and power recovery and the role of the inability to modulate reflexes in post stroke movement disorders.Mechanical, Maritime and Materials Engineerin

Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons

We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related WldS protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders

Nutritional upgrading for omnivorous carpenter ants by the endosymbiont Blochmannia

<p>Abstract</p> <p>Background</p> <p>Carpenter ants (genus <it>Camponotus</it>) are considered to be omnivores. Nonetheless, the genome sequence of <it>Blochmannia floridanus</it>, the obligate intracellular endosymbiont of <it>Camponotus floridanus</it>, suggests a function in nutritional upgrading of host resources by the bacterium. Thus, the strongly reduced genome of the endosymbiont retains genes for all subunits of a functional urease, as well as those for biosynthetic pathways for all but one (arginine) of the amino acids essential to the host.</p> <p>Results</p> <p>Nutritional upgrading by <it>Blochmannia </it>was tested in 90-day feeding experiments with brood-raising in worker-groups on chemically defined diets with and without essential amino acids and treated or not with antibiotics. Control groups were fed with cockroaches, honey water and Bhatkar agar. Worker-groups were provided with brood collected from the queenright mother-colonies (45 eggs and 45 first instar larvae each). Brood production did not differ significantly between groups of symbiotic workers on diets with and without essential amino acids. However, aposymbiotic worker groups raised significantly less brood on a diet lacking essential amino acids. Reduced brood production by aposymbiotic workers was compensated when those groups were provided with essential amino acids in their diet. Decrease of endosymbionts due to treatment with antibiotic was monitored by qRT-PCR and FISH after the 90-day experimental period. Urease function was confirmed by feeding experiments using ¹⁵N-labelled urea. GC-MS analysis of ¹⁵N-enrichment of free amino acids in workers revealed significant labelling of the non-essential amino acids alanine, glycine, aspartic acid, and glutamic acid, as well as of the essential amino acids methionine and phenylalanine.</p> <p>Conclusion</p> <p>Our results show that endosymbiotic <it>Blochmannia </it>nutritionally upgrade the diet of <it>C. floridanus </it>hosts to provide essential amino acids, and that it may also play a role in nitrogen recycling via its functional urease. <it>Blochmannia </it>may confer a significant fitness advantage via nutritional upgrading by enhancing competitive ability of <it>Camponotus </it>with other ant species lacking such an endosymbiont. Domestication of the endosymbiont may have facilitated the evolutionary success of the genus <it>Camponotus</it>.</p

Assessing International Trade in Healthcare Services

Growing evidence indicates that international trade in healthcare services is growing. Nevertheless, a major literature gap exists with regard to the nature of international healthcare trade and its extent. Taking a comprehensive approach, this research examines the magnitude, directions, patterns of specialisation, growth and other aspects related to international trade in healthcare services. Within this framework, trade is analysed with regard to cross border trade, consumption of healthcare by foreign nationals, commercial presence of healthcare services providers, as well as the movement of healthcare professionals across borders

Glutathione Precursor N-Acetyl-Cysteine Modulates EEG Synchronization in Schizophrenia Patients: A Double-Blind, Randomized, Placebo-Controlled Trial

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy

Muscle and reflex changes with varying joint angle in hemiparetic stroke

<p>Abstract</p> <p>Background</p> <p>Despite intensive investigation, the origins of the neuromuscular abnormalities associated with spasticity are not well understood. In particular, the mechanical properties induced by stretch reflex activity have been especially difficult to study because of a lack of accurate tools separating reflex torque from torque generated by musculo-tendinous structures. The present study addresses this deficit by characterizing the contribution of neural and muscular components to the abnormally high stiffness of the spastic joint.</p> <p>Methods</p> <p>Using system identification techniques, we characterized the neuromuscular abnormalities associated with spasticity of ankle muscles in chronic hemiparetic stroke survivors. In particular, we systematically tracked changes in muscle mechanical properties and in stretch reflex activity during changes in ankle joint angle. Modulation of mechanical properties was assessed by applying perturbations at different initial angles, over the entire range of motion (ROM). Experiments were performed on both paretic and non-paretic sides of stroke survivors, and in healthy controls.</p> <p>Results</p> <p>Both reflex and intrinsic muscle stiffnesses were significantly greater in the spastic/paretic ankle than on the non-paretic side, and these changes were strongly position dependent. The major reflex contributions were observed over the central portion of the angular range, while the intrinsic contributions were most pronounced with the ankle in the dorsiflexed position.</p> <p>Conclusion</p> <p>In spastic ankle muscles, the abnormalities in intrinsic and reflex components of joint torque varied systematically with changing position over the full angular range of motion, indicating that clinical perceptions of increased tone may have quite different origins depending upon the angle where the tests are initiated.</p> <p>Furthermore, reflex stiffness was considerably larger in the non-paretic limb of stroke patients than in healthy control subjects, suggesting that the non-paretic limb may not be a suitable control for studying neuromuscular properties of the ankle joint.</p> <p>Our findings will help elucidate the origins of the neuromuscular abnormalities associated with stroke-induced spasticity.</p