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PI Levels (pi + level)

Distribution by Scientific Domains

Life Sciences	80%

Selected Abstracts

Clinical benefit of interventions driven by therapeutic drug monitoring

HIV MEDICINE, Issue 5 2005
AL Rendón
Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source]

Pathogen trafficking pathways and host phosphoinositide metabolism

MOLECULAR MICROBIOLOGY, Issue 6 2009
Stefan S. Weber
Summary Phosphoinositide (PI) glycerolipids are key regulators of eukaryotic signal transduction, cytoskeleton architecture and membrane dynamics. The host cell PI metabolism is targeted by intracellular bacterial pathogens, which evolved intricate strategies to modulate uptake processes and vesicle trafficking pathways. Upon entering eukaryotic host cells, pathogenic bacteria replicate in distinct vacuoles or in the host cytoplasm. Vacuolar pathogens manipulate PI levels to mimic or modify membranes of subcellular compartments and thereby establish their replicative niche. Legionella pneumophila, Brucella abortus, Mycobacterium tuberculosis and Salmonella enterica translocate effector proteins into the host cell, some of which anchor to the vacuolar membrane via PIs or enzymatically turnover PIs. Cytoplasmic pathogens target PI metabolism at the plasma membrane, thus modulating their uptake and antiapoptotic signalling pathways. Employing this strategy, Shigella flexneri directly injects a PI-modifying effector protein, while Listeria monocytogenes exploits PI metabolism indirectly by binding to transmembrane receptors. Thus, regardless of the intracellular lifestyle of the pathogen, PI metabolism is critically involved in the interactions with host cells. [source]

The glycosylphosphatidylinositol (GPI) biosynthetic pathway of bloodstream-form Trypanosoma brucei is dependent on the de novo synthesis of inositol

MOLECULAR MICROBIOLOGY, Issue 1 2006
Kirstee L. Martin
Summary In bloodstream-form Trypanosoma brucei (the causative agent of African sleeping sickness) the glycosylphosphatidylinositol (GPI) anchor biosynthetic pathway has been validated genetically and chemically as a drug target. The conundrum that GPI anchors could not be in vivo labelled with [3H]-inositol led us to hypothesize that de novo synthesis was responsible for supplying myo -inositol for phosphatidylinositol (PI) destined for GPI synthesis. The rate-limiting step of the de novo synthesis is the isomerization of glucose 6-phosphate to 1- d -myo -inositol-3-phosphate, catalysed by a 1- d -myo -inositol-3-phosphate synthase (INO1). When grown under non-permissive conditions, a conditional double knockout demonstrated that INO1 is an essential gene in bloodstream-form T. brucei. It also showed that the de novo synthesized myo -inositol is utilized to form PI, which is preferentially used in GPI biosynthesis. We also show for the first time that extracellular myo- inositol can in fact be used in GPI formation although to a limited extent. Despite this, extracellular inositol cannot compensate for the deletion of INO1. Supporting these results, there was no change in PI levels in the conditional double knockout cells grown under non-permissive conditions, showing that perturbation of growth is due to a specific lack of de novo synthesized myo -inositol and not a general inositol-less death. These results suggest that there is a distinction between de novo synthesized myo -inositol and that from the extracellular environment. [source]

The regulation and function of phosphate in the human body

BIOFACTORS, Issue 1-4 2004
Eiji Takeda
Abstract Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. Pi is abundant in the diet, and intestinal absorption of Pi is efficient and minimally regulated. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi need. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotransporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by hormones and nonhormonal factors. Recent studies of inherited and acquired hypophosphatemia which exhibit similar biochemical and clinical features, have led to the identification of novel genes, phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and fibroblast growth factor-23 (FGF-23), that play a role in the regulation of Pi homeostasis. The PHEX gene encodes an endopeptidase, predominantly expressed in bone and teeth but not in kidney. FGF-23 may be a substrate of this endopeptidase and inhibit renal Pi reabsorption. In a survey in the United States and in Japan, the amount of phosphorus from food is gradually increasing. It is thought that excess amounts of phosphorus intake for long periods are a strong factor in bone impairment and ageing. The restriction of phosphorus intake seems to be important under low calcium intake to keep QOL on high level. [source]

Ablation of Systemic Phosphate-Regulating Gene Fibroblast Growth Factor 23 (Fgf23) Compromises the Dentoalveolar Complex

THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2010
E.Y. Chu
Abstract Fibroblast growth factor-23 (FGF23) is a hormone that modulates circulating phosphate (Pi) levels by controlling Pi reabsorption from the kidneys. When FGF23 levels are deficient, as in tumoral calcinosis patients, hyperphosphatemia ensues. We show here in a murine model that Fgf23 ablation disrupted morphology and protein expression within the dentoalveolar complex. Ectopic matrix formation in pulp chambers, odontoblast layer disruption, narrowing of periodontal ligament space, and alteration of cementum structure were observed in histological and electron microscopy sections. Because serum Pi levels are dramatically elevated in Fgf23,/,, we assayed for apoptosis and expression of members from the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, both of which are sensitive to elevated Piin vitro. Unlike X-linked hypophosphatemic (Hyp) and wild-type (WT) specimens, numerous apoptotic osteocytes and osteoblasts were detected in Fgf23,/, specimens. Further, in comparison to Hyp and WT samples, decreased bone sialoprotein and elevated dentin matrix protein-1 protein levels were observed in cementum of Fgf23,/, mice. Additional dentin-associated proteins, such as dentin sialoprotein and dentin phosphoprotein, exhibited altered localization in both Fgf23,/, and Hyp samples. Based on these results, we propose that FGF23 and (Pi) homeostasis play a significant role in maintenance of the dentoalveolar complex. Anat Rec 293:1214,1226, 2010. © 2010 Wiley-Liss, Inc. [source]