158 research outputs found
Is serum phosphorus control related to parathyroid hormone control in dialysis patients with secondary hyperparathyroidism?
Background
Elevated serum phosphorus (P) levels have been linked to increased morbidity and mortality in dialysis patients with secondary hyperparathyroidism (SHPT) but may be difficult to control if parathyroid hormone (PTH) is persistently elevated. We conducted a post hoc analysis of data from an earlier interventional study (OPTIMA) to explore the relationship between PTH control and serum P.
Methods
The OPTIMA study randomized dialysis patients with intact PTH (iPTH) 300β799 pg/mL to receive conventional care alone (vitamin D and/or phosphate binders [PB]; n = 184) or a cinacalcet-based regimen (n = 368). For patients randomized to conventional care, investigators were allowed flexibility in using a non-cinacalcet regimen (with no specific criteria for vitamin D analogue dosage) to attain KDOQIβ’ targets for iPTH, P, Ca and Ca x P. For those assigned to the cinacalcet-based regimen, dosages of cinacalcet, vitamin D sterols, and PB were optimized over the first 16 weeks of the study, using a predefined treatment algorithm. The present analysis examined achievement of serum P targets (β€4.5 and β€5.5 mg/dL) in relation to achievement of iPTH β€300 pg/mL during the efficacy assessment phase (EAP; weeks 17β23).
Results
Patients who achieved iPTH β€ 300 pg/mL (or a reduction of β₯30% from baseline) were more likely to achieve serum P targets than those who did not, regardless of treatment group. Of those who did achieve iPTH β€ 300 pg/mL, 43% achieved P β€4.5 mg/dL and 70% achieved P β€5.5 mg/dL, versus 21% and 46% of those who did not achieve iPTH β€ 300 pg/mL. Doses of PB tended to be higher in patients not achieving serum P targets. Patients receiving cinacalcet were more likely to achieve iPTH β€300 pg/mL than those receiving conventional care (73% vs 23% of patients). Logistic regression analysis identified lower baseline P, no PB use at baseline and cinacalcet treatment to be predictors of achieving P β€4.5 mg/dL during EAP in patients above this threshold at baseline.
Conclusions
This post hoc analysis found that control of serum P in dialysis patients was better when serum PTH levels were lowered effectively, regardless of treatment received
Precise Switching of Flagellar Gene Expression in Escherichia Coli by the FlgMβFliA Regulatory Network
A remarkable feature of flagellar synthesis in Escherichia coli is that gene expression is sequential and
coupled to the assembly process. The interaction of two key proteins, the flagellar sigma factor FliA and
its anti-sigma factor FlgM serves as a major checkpoint in the assembly process that temporally separates
middle and late gene expression. While the sequential nature within each gene class has been studied
using large-scale transcriptional data, much less is known about the timing controlled by the checkpoint
mechanism. In this article, we analyze timing, sensitivity and robustness of the FlgMβFliA core regulatory
mechanism based on quantitative molecule data and a detailed stochastic as well as reduced deterministic
reaction kinetics model. We find that the pool of free anti-sigma factor FlgM, accumulated during middle
gene expression, acts as a molecular timer that determines the delay between successful completion of the
hook basal body subunit and the start of expression of flagellar filament proteins. Furthermore, we find
that the number of free FliA molecules needs to be tightly controlled for a precise switch from middle
to late gene expression. A sensitivity analysis based on the reduced reaction kinetics model reveals that
the checkpoint mechanism is very sensitive to changes in levels of competing sigma factors, allowing the
bacterium to rapidly adapt to a changing environment. In addition, we find that the reduced model also
shows a high sensitivity to the effective synthesis rates of FliA and FlgM. However, this high sensitivity
does not generally carry over to the original parameters of transcriptional and translational processes
in the detailed model. As a consequence, care has to be taken whenever interpreting results from the
robustness analysis of reaction kinetic models comprising lumped or effective parameters
Alteration of T cell cytokine production in PLPp-139-151-induced EAE in SJL mice by an immunostimulatory CpG Oligonucleotide
Experimental autoimmune encephalomyelitis (EAE) is - in certain aspects - regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specific immunity is induced in a defined way, the initial processes leading to CNS autoimmunity in humans are so far unknown. Despite essential restrictions, which exist regarding the interpretation of EAE data towards MS, EAE might be a useful model to study certain basic aspects of CNS autoimmunity. Studies in MS have demonstrated that established autoimmune pathology can be critically influenced by environmental factors, in particular viral and bacterial infections. To investigate this interaction, EAE as an instrument to study CNS autoimmunity under defined conditions appears to be a suitable experimental tool. For this reason, we here investigated the influence of the Toll-like-receptor (TLR) ligand CpG oligonucleotide (CpG) on already established CNS autoimmunity in murine proteolipid protein (PLP)-induced EAE in SJL mice. CpG were found to co-stimulate PLPp-specific IFN-Ξ³ production in the peripheral immune system and in the CNS. However, CpG induced Interleukin (IL)-17 production in the inflamed CNS both alone and in combination with additional PLPp stimulation. These findings might indicate a mechanism by which systemic infections and the microbial stimuli associated with them may influence already existing CNS autoimmune pathology
3D-Π²ΠΈΠ·ΡΠ°Π»ΠΈΠ·Π°ΡΠΈΡ Π² ΡΠ»ΡΡΡΠ°Π·Π²ΡΠΊΠΎΠ²ΠΎΠΉ Π΄Π΅ΡΠ΅ΠΊΡΠΎΡΠΊΠΎΠΏΠΈΠΈ
ΠΠ° ΡΠ΅Π³ΠΎΠ΄Π½ΡΡΠ½ΠΈΠΉ Π΄Π΅Π½Ρ ΡΡΡΠ΅ΡΡΠ²ΡΠ΅Ρ ΠΌΠ½ΠΎΠΆΠ΅ΡΡΠ²ΠΎ ΡΡΠ΅Π΄ΡΡΠ² Π²ΠΈΠ·ΡΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΡΠ»ΡΡΡΠ°Π·Π²ΡΠΊΠΎΠ²ΡΡ
Π΄Π°Π½Π½ΡΡ
, Π½ΠΎ Π²ΡΠ΅ ΠΎΠ½ΠΈ, ΠΊΠ°ΠΊ ΠΏΡΠ°Π²ΠΈΠ»ΠΎ, ΠΈΠ½ΡΠ΅Π³ΡΠΈΡΠΎΠ²Π°Π½Ρ Π² Π΄Π΅ΡΠ΅ΠΊΡΠΎΡΠΊΠΎΠΏΡ. ΠΠΎΠ³Π΄Π° Ρ Π½Π°Ρ Π²ΠΎΠ·Π½ΠΈΠΊΠ°Π΅Ρ ΠΏΠΎΡΡΠ΅Π±Π½ΠΎΡΡΡ ΠΈΠ·Π²Π»Π΅ΡΡ Π΄Π°Π½Π½ΡΠ΅ ΡΠΊΠ°Π½ΠΈΡΠΎΠ²Π°Π½ΠΈΡ, ΠΏΡΠΎΠΈΠ·Π²Π΅ΡΡΠΈ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΡΡ ΠΎΠ±ΡΠ°Π±ΠΎΡΠΊΡ, ΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²ΠΈΡΡ Π² ΡΡΠ΅Ρ
ΠΌΠ΅ΡΠ½ΠΎΠΌ ΠΈΠ·ΠΎΠ±ΡΠ°ΠΆΠ΅Π½ΠΈΠΈ, ΡΠΎ ΠΌΡ ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅ΠΌΡΡ Π»ΠΈΡΠ΅Π½Π½ΡΠΌΠΈ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΡΡΠΈ Π²ΠΈΠ·ΡΠ°Π»ΠΈΠ·Π°ΡΠΈΠΈ. ΠΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½Π½ΠΎΠ΅ ΠΏΡΠΎΠ³ΡΠ°ΠΌΠΌΠ½ΠΎΠ΅ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠ΅Π½ΠΈΠ΅ Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ Π°Π»Π³ΠΎΡΠΈΡΠΌΠ° SAFT ΠΏΠΎΠ·Π²ΠΎΠ»ΡΠ΅Ρ ΠΏΡΠΎΠΈΠ·Π²Π΅ΡΡΠΈ ΠΏΠΎΡΡΠΎΠ±ΡΠ°Π±ΠΎΡΠΊΡ Π΄Π°Π½Π½ΡΡ
ΡΠΊΠ°Π½ΠΈΡΠΎΠ²Π°Π½ΠΈΡ (Π-ΡΠΊΠ°Π½ΠΎΠ²) ΠΈ Π΄Π²ΡΠΌΠ΅ΡΠ½ΡΡ ΠΈ ΡΡΠ΅Ρ
ΠΌΠ΅ΡΠ½ΡΡ Π²ΠΈΠ·ΡΠ°Π»ΠΈΠ·Π°ΡΠΈΡ
Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis
Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base
Erythropoietin Ameliorates Rat Experimental Autoimmune Neuritis by Inducing Transforming Growth Factor-Beta in Macrophages
Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. In addition, in various preclinical models EPO exhibited protective activity against tissue injury. There is an urgent need for potent treatments of autoimmune driven disorders of the peripheral nervous system (PNS), such as the Guillain-BarrΓ© syndrome (GBS), a disabling autoimmune disease associated with relevant morbidity and mortality. To test the therapeutic potential of EPO in experimental autoimmune neuritis (EAN) - an animal model of human GBS β immunological and clinical effects were investigated in a preventive and a therapeutic paradigm. Treatment with EPO reduced clinical disease severity and if given therapeutically also shortened the recovery phase of EAN. Clinical findings were mirrored by decreased inflammation within the peripheral nerve, and myelin was well maintained in treated animals. In contrast, EPO increased the number of macrophages especially in later stages of the experimental disease phase. Furthermore, the anti-inflammatory cytokine transforming growth factor (TGF)-beta was upregulated in the treated cohorts. In vitro experiments revealed less proliferation of T cells in the presence of EPO and TGF-beta was moderately induced, while the secretion of other cytokines was almost not altered by EPO. Our data suggest that EPO revealed its beneficial properties by the induction of beneficial macrophages and the modulation of the immune system towards anti-inflammatory responses in the PNS. Further studies are warranted to elaborate the clinical usefulness of EPO for treating immune-mediated neuropathies in affected patients
CCR5Ξ32 Genotype Leads to a Th2 Type Directed Immune Response in ESRD Patients
BACKGROUND: In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Ξ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Ξ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Ξ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Ξ32 genetic variant after stimulation. METHODOLOGY/PRINCIPAL FINDINGS: We tested this hypothesis by determining the levels of IFN-Ξ³ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Ξ32 genotype. The extracellular levels of IFN-Ξ³ and IL-4 did not differ between CCR5Ξ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Ξ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-Ξ³ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Ξ32 genotype. CONCLUSIONS/SIGNIFICANCE: This first, functional human study shows a more pronounced Th2 type immune response in CCR5Ξ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Ξ32
- β¦