Cell-mediated immunity in localized cutaneous leishmaniasis patients before and after treatment with immunotherapy or chemotherapy

In previous studies of the treatment of localized cutaneous leishmaniasis (LCL) we demonstrated that the therapeutic efficiency of immunotherapy (BCG plus promastigotes of Leishmania mexicana) is equal to that of chemotherapy (Glucantime), without causing the serious side-effects of the drug treatment. In the present study, various aspects of cell-mediated immunity, including the lymphoproliferative response, and leucocyte subpopulations were evaluated both before treatment and after cure in 39 LCL patients who had received immunotherapy (IT), in 34 submitted to chemotherapy (CT), and in 14 patients cured by the administration of BCG alone. We demonstrated evident signs of T-cell activation in cured patients who had received either CT or IT. For example, an increased expression of IL-2 receptors was observed in such patients, compared to their pretreatment values. Also, a significant percentage of patients showed augmented in-vitro responses to mitogen, and both in-vitro and in-vivo reactivity to leishmanial antigen. No evidence was found for the development of an exaggerated immune response to Leishmania parasites in the IT group, because the final level of immunological reactivity was comparable to the CT group. Neither was there any difference in terms of the final immune response between the patients cured by BCG treatment alone and the other groups. However, the therapeutic efficiency of BCG was lower and the mean cure time was longer. We conclude that IT is very useful in the treatment of LCL patients because of its high efficiency, low propensity to produce side-effects, and the fact that it does not induce a state of hyper-reactivity.     

The Andalusian trial on heroin‐assisted treatment: A 2 year follow‐up

Introduction and Aims. In 2003, a randomised controlled trial comparing injected diacetylmorphine and oral methadone was carried out in Andalusia, Spain. The subsequent follow‐up study evaluated the health and drug use status of participants, 2 years after the completion of the trial. Design and Methods. This follow‐up cohort study was carried out between March and August 2006. Data collected included information on socio‐demographics, drug use, health and health‐related quality of life. We compared data collected before randomisation and at 2 years for the following three groups: those currently on heroin‐assisted treatment (C‐HAT), those who have discontinued HAT (D‐HAT), and those who have never received HAT (N‐HAT). Results. From the total 62 randomised participants in 2003, 54 (87%) were interviewed for this study. Participants were distributed as follow: C‐HAT 44.4% (24), N‐HAT 22.2% (12) and D‐HAT 33.3% (18). Illicit heroin use had a statistically significant decrease in the three groups from baseline to 2 years post trial. Mean days of heroin use were 2.42 (SD = 3.02); 6.56 (SD = 9.48) and 13.92 (SD = 12.59) for the C‐HAT, D‐HAT and N‐HAT groups, respectively. Those currently on HAT were the only group that sustained at 2 years, their marked improvement in health after 9 months of treatment during the trial period. Discussion and Conclusions: Patients who received HAT showed better outcomes compared with those not on HAT. The results of this study strengthen the evidence showing that HAT can improve and stabilise the health of long‐term heroin users with severe comorbidities and high mortality.[Oviedo‐Joekes E, March JC, Romero M, Perea‐Milla E. The Andalusian trial on heroin assisted treatment: A 2 year follow‐up. Drug Alcohol Rev 2009]     

“Carba” peptide bond surrogates Different approaches to Gly-Ψ(CH2-CH2)-d,l-Xaa pseudo-dipeptide units

Racemic “carba” pseudo-dipeptide units such as Gly-Ψ(CH₂-CH₂)-d,l -Xaa were obtained either through the Horner-Emmons condensation of N-tert.-butyloxycarbonyl-βalaninal with the appropriate substituted triethyl phosphonoacetate, or from commercially available 3-carbethoxy-2-piperidone.     

Different Mechanism of Relaxation Induced by Aporphine Alkaloids in Rat Uterus

Abstract— We have examined the uterine relaxant action of three aporphine molecules (S-glaucine, S-boldine and R-apomorphine) in two experimental conditions, with and without calcium in the bathing solution, and compared these effects with those obtained with the calcium antagonists verapamil and diltiazem. The present study shows that the alkaloids relax the uterine muscle but with different mechanisms of action. In Ca²⁺-containing solution all three alkaloids relaxed the uterus previously contracted by KCl or acetylcholine, but in Ca²⁺-free medium only R-apomorphine was able to relax oxytocin-induced contraction. The calcium antagonists, verapamil and diltiazem, relaxed KCl- or acetylcholine-induced contraction in Ca²⁺-containing solution, whereas they only relaxed oxytocin-induced contraction in Ca²⁺-free medium at much higher doses. These results suggest that glaucine and boldine behave as specific calcium entry blockers without affecting the contractile machinery or intracellular Ca²⁺ levels as apomorphine does. The absolute configuration (S-glaucine and S-boldine vs R-apomorphine) may account for this different action.     

Synthesis and characterization of a new labeled gastrin ligand, 125I-BH-[Leu15]-gastrin-(5-17), on binding to canine fundic mucosal cells and Jurkat cells

In the course of our study concerning gastrin and cholecystokinin (CCK) receptors, we have synthesized and characterized a new labeled gastrin ligand, ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) [(3-[¹²⁵I]iodo-4-hydroxyphenyl)-propionyl-[Leu¹⁵]-gastrin-(5-17)]. Binding of ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) to isolated canine fundic mucosal cells was specific, saturable and of high affinity. ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) and ¹²⁵I-BH-CCK-8 [(3-[¹²⁵I]iodo-4-hydroxyphenyl)-propionyl-CCK-8] interact with isolated canine fundic mucosal cells with small differences in maximal binding capacities and affinities, 3800 ± 900 binding sites/cell (Kd = 0.52 ± 0.23 nM) and 6200 ± 1100 binding sites/cell (K_d= 0.31 ± 0.18 nM), respectively. The relative order of potencies for gastrin and CCK analogs in displacing ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) binding correlated well with those obtained using ¹²⁵I-BH-CCK-8. Selective CCK/gastrin antagonists L-364,718 (MK-329) and L-365,260 also inhibited ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) binding. These results indicate that ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) binds to gastrin receptors in isolated canine fundic mucosal cells. We have also characterized ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) binding to the human Jurkat lymphoblastic cell line (Jurkat cells) known to express the CCK-B/gastrin receptor. Saturation experiments have shown that both ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) and ¹²⁵I-BH-CCK-8 interact with a single class of high-affinity binding sites in the Jurkat cell line. Binding characteristics of ¹²⁵I-BH-[Leu¹⁵]-Gastrin-(5-17) and ¹²⁵I-BH-CCK-8 were estimated to be about 2500 ± 400 binding sites/cell (Kd= 0.19 ± 0.09 nM) and 2400 ± 350 binding sites/cell (Kd= 0.06 ± 0.02 nM), respectively. Furthermore, the apparent affinities of CCK analogs and selective antagonists MK-329 and L-365,260 for the sites labeled by both probes were identical. The biological activity of cold ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) and [Leu¹⁵]-gastrin-(5-17) was demonstrated by their ability to increase intracellular calcium concentration in Jurkat cells. All these experiments showed that ¹²⁵I-BH-[Leu¹⁵]-gastrin-(5-17) provides a convenient ligand for gastrin receptor binding studies. © Munksgaard 1994.     

ETHANOL AND DIET-INDUCED ALTERATIONS IN KUPFFER CELL FUNCTION

The effects of 6 weeks of alcohol feeding on phagocytic, metabolicand secretory functions as well as gene expression of hepaticKupffer cells were evaluated in vitro using cultured Kupffercells isolated from male Sprague-Dawley rats. The rats werefed either Teklad pelleted rat chow or the 1982 Lieber-DeCarliliquid diet containing 6% ethanol (36% calories) or the sameliquid diet with maltose-dextrin isocalorically substitutedfor the alcohol. Weight gain was greatest in the chow-fed animalsand least in those receiving ethanol. The alcohol-containingdiet stimulated Kupffer cell phagocytosis, mitochondrial reductionof Mil, secretion of tumor necrosis factor (TNF) and expressionof TNF mRNA. However, each of these cell functions was alsoenhanced by the control Lieber-DeCarli liquid diet alone andthe stimulating effect of the control diet often exceeded thatinduced by ethanol. The results suggest that early in chronicalcohol consumption, the immune system may be stimulated byethanol, and that during studies of ethanol-induced changesin immune system function, close attention must be given topotentially confounding effects of the diet.