49 research outputs found
Undetectable mannose binding lectin and corticosteroids increase serious infection risk in Rheumatoid Arthritis
Background: Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections.
Objective: Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease-modifying antirheumatic drug (DMARD) therapy.
Methods: Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy.
Results: High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple Sis were similar, irrespective of the use of a biologic agent. Undetectable MBL (\u3c56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P \u3c .001), respectively.
Conclusions: Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA
Therapeutic targeting of cathepsin C::from pathophysiology to treatment
Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials
ChemInform Abstract: INVESTIGATIONS ON DIAZO COMPOUNDS AND AZIDES, XXVI. ALDOL ADDITION OF PHOSPHORYLDIAZOALKANES-SYNTHESIS AND REACTIVITY OF α-DIAZO-β-HYDROXYPHOSPHINOXIDES AND -PHOSPHONIC ESTERS
ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation
Ca2� homeostasis requires balanced uptake
and extrusion, and dysregulation leads to disease.
TRPV6 channels are homeostasis regulators, are upregulated
in certain cancers, and show an unusual allelespecific
evolution in humans. To understand how Ca2�
uptake can be adapted to changes in metabolic status,
we investigate regulation of Ca2�-influx by ATP and
phosphorylation. We show that ATP binds to TRPV6,
reduces whole-cell current increments, and prevents
channel rundown with an EC50 of 380 �M. By using
both biochemical binding studies and patch-clamp analyses
of wild-type and mutant channels, we have mapped
one relevant site for regulation by ATP to residues
within the ankyrin repeat domain (ARD) and identify an
additional C-terminal binding region. Stimulation of
PKC largely prevented the effects of ATP. This regulation
requires PKC�II and defined phosphorylation sites
within the ARD and the C-terminus. Both regulatory
sites act synergistically to constitute a novel mechanism
by which ATP stabilizes channel activity and acts as a
metabolic switch for Ca2� influx. Decreases in ATP
concentration or activation of PKC�II disable regulation
of the channels by ATP, rendering them more
susceptible to inactivation and rundown and preventing
Ca2� overload.—Al-Ansary, D., Bogeski, I., Disteldorf,
B. M. J., Becherer, U., Niemeyer, B. A. ATP modulates
Ca2� uptake by TRPV6 and is counteracted by isoformspecific
phosphorylation