Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-κB binding activity and TNF-α secretion of T cells

The aim of this study was to analyze the differential effects of three anti-CD4 monoclonal antibodies (mAbs) (with distinct epitope specifities) in the treatment of rat adjuvant arthritis (AA) and on T-cell function and signal transduction. Rat AA was preventively treated by intraperitoneal injection of the anti-CD4 mAbs W3/25, OX35, and RIB5/2 (on days -1, 0, 3, and 6, i.e. 1 day before AA induction, on the day of induction [day 0], and thereafter). The effects on T-cell reactivity in vivo (delayed-type hypersensitivity), ex vivo (ConA-induced proliferation), and in vitro (mixed lymphocyte culture) were assessed. The in vitro effects of anti-CD4 preincubation on T-cell receptor (TCR)/CD3-induced cytokine production and signal transduction were also analyzed. While preventive treatment with OX35 and W3/25 significantly ameliorated AA from the onset, treatment with RIB5/2 even accelerated the onset of AA by approximately 2 days (day 10), and ameliorated the arthritis only in the late phase (day 27). Differential clinical effects at the onset of AA were paralleled by a differential influence of the mAbs on T-cell functions, i.e. in comparison with OX35 and W3/25, the 'accelerating' mAb RIB5/2 failed to increase the delayed-type hypersentivity (DTH) to Mycobacterium tuberculosis, increased the in vitro tumor necrosis factor (TNF)-α secretion, and more strongly induced NF-κB binding activity after anti-CD4 preincubation and subsequent TCR/CD3-stimulation. Depending on their epitope specificity, different anti-CD4 mAbs differentially influence individual proinflammatory functions of T cells. This fine regulation may explain the differential efficacy in the treatment of AA and may contribute to the understanding of such treatments in other immunopathologies

Novel Synthetic Opioids (NSO) Use in Opioid Dependents Entering Detoxification Treatment

© 2022 Specka, Kuhlmann, Bonnet, Sawazki, Schaaf, Kühnhold, Steinert, Grigoleit, Eich, Zeiske, Niedersteberg, Steiner, Schifano and Scherbaum. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Introduction: Over the last decade, the use of New/Novel Synthetic Opioids (NSO) has emerged as an increasing problem, and especially so in the USA. However, only little is known about the prevalence and history of NSO use in European heroin dependents. Method: A cross-sectional multicenter study, carried out with the means of both standardized interviews and urine toxicology enhanced screening, in a sample of opioid addicted patients referred for an in-patient detoxification treatment. Results: Sample size included here n = 256 patients; prior to admission, 63.7% were prescribed with an opioid maintenance treatment. Lifetime use of heroin and opioid analgesics was reported by 99.2 and 30.4%, respectively. Lifetime NSO/fentanyl use was reported by 8.7% (n = 22); a regular use was reported by 1.6% (n = 4), and ingestion over the 30 days prior to admission by 0.8% (n = 2). Most typically, patients had started with a regular consumption of heroin, followed by maintenance opioids; opioid analgesics; and by NSO. Self-reported data were corroborated by the toxicology screenings carried out; no evidence was here identified for the presence of heroin being contaminated by fentanyl/derivatives. Discussion: NSO and also opioid analgesics did not play a relevant role in the development and the course of opioid/opioid use disorders in German patients referred for an inpatient detoxification treatment.Peer reviewe

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

Objectives Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. Conclusions These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these association

Determination of nutrient salts by automatic methods both in seawater and brackish water: the phosphate blank

9 páginas, 2 tablas, 2 figurasThe main inconvenience in determining nutrients in seawater by automatic methods is simply solved: the preparation of a suitable blank which corrects the effect of the refractive index change on the recorded signal. Two procedures are proposed, one physical (a simple equation to estimate the effect) and the other chemical (removal of the dissolved phosphorus with ferric hydroxide).Support for this work came from CICYT (MAR88-0245 project) and Conselleria de Pesca de la Xunta de GaliciaPeer reviewe

Study of doubly strange systems using stored antiprotons

Bound nuclear systems with two units of strangeness are still poorly known despite their importance for many strong interaction phenomena. Stored antiprotons beams in the GeV range represent an unparalleled factory for various hyperon-antihyperon pairs. Their outstanding large production probability in antiproton collisions will open the floodgates for a series of new studies of systems which contain two or even more units of strangeness at the P‾ANDA experiment at FAIR. For the first time, high resolution γ-spectroscopy of doubly strange ΛΛ-hypernuclei will be performed, thus complementing measurements of ground state decays of ΛΛ-hypernuclei at J-PARC or possible decays of particle unstable hypernuclei in heavy ion reactions. High resolution spectroscopy of multistrange Ξ−-atoms will be feasible and even the production of Ω−-atoms will be within reach. The latter might open the door to the |S|=3 world in strangeness nuclear physics, by the study of the hadronic Ω−-nucleus interaction. For the first time it will be possible to study the behavior of Ξ‾+ in nuclear systems under well controlled conditions