Identification of natural antibodies to interleukin-18 in the sera of normal humans and three nonhuman primate species

Natural antibodies to cytokines can be found in the sera of normal healthy individuals in the absence of specific immunostimulation. However, the function, impact, and purpose of natural antibody development have yet to be fully elucidated. Interleukin (IL)-18 is a cytokine that exerts proinflammatory activities and induces natural killer (NK) cell activity. Recombinant human IL-18 (rHuIL-18) is currently in development as a cancer immunotherapy. In this study, the presence of natural antibodies to IL-18 in the sera of normal humans and three nonhuman primate species was evaluated by electrochemiluminescence immunoassay (ECLIA). Of the human sera tested, 6 of 47 samples were positive for natural antibodies to IL-18. Of the nonhuman primate sera tested, 22 of 80 cynomolgus monkey samples, 4 of 31 rhesus monkey samples, and 2 of 20 chimpanzee samples were positive for natural antibodies to IL-18. Natural anti-IL-18 antibodies were neutralizing in 5 of 22 cynomolgus and 2 of 4 rhesus sera. None of the chimpanzee or human sera were able to neutralize IL-18 induction of interferon (IFN)-gamma in vitro. In vivo activity of rHuIL-18 was compared in IL-18 natural antibody-positive and -negative cynomolgus monkeys. The presence of natural antibodies to IL-18 did not alter rHuIL-18 systemic exposure levels, induction of neopterin, or induction of treatment-induced antibodies following intravenous administration of rHuIL-18. In conclusion, our data indicate that, as has been found with other cytokines, natural anti-IL-18 antibodies are relatively common. Moreover, natural anti-IL-18 antibodies do not appear to influence rHuIL-18 activity in vivo and are not predictive of a heightened immune response, suggesting that natural anti-IL-18 antibodies do not impact IL-18 therapy. Finally, our data suggest that the ability to detect natural anti-cytokine antibodies may be a useful measure of the adequacy of an assay for deployment in clinical trials.     

War and peace ‐ reconsidered

The decades-long contamination of Gruinard Island by anthrax is now a well-known part of the history of biological weapons (BW) development, as well as that of military encroachments in the Scottish Highlands and Islands (and the authorities' rather less persistent efforts at damage limitation). Some accounts have included the related episode, reportedly well-remembered by local people, of anthrax contamination on the mainland close to Gruinard. This occurred in 1942-43, when BW experiments were conducted on the island as part of the war effort by scientists from Porton Down under the auspices of the British government. After much top-level discussion, payments were made to the owners of animals that had died as a result of the contamination. The episode had a bearing on discussions about the future of the island and on subsequent policy with regard to the siting, conduct and secrecy of BW experiments.     

Determination of Enantiomers of Terpenic Hydrocarbons in Essential Oils Obtained from Species of Pinus and Abies

The enantiomeric contents of monoterpenes have been determined in essential oils from the following species: Pinus cembra, Pinus nigra, Pinus pinaster, Pinus montana, Pinus sylvestris, Abies alba and Abies sibirica. A gas chromatographic method with a formamide solution of a-cyclodextrin as a stationary phase was applied for the separation and determination of enantiomers.     

Targeting cancer by binding iron: Dissecting cellular signaling pathways

Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer.     

Coexistence of macroprolactinaemia and hyperprolactinaemia in women with oligo-/amenorrhoea is associated with high risk of pituitary adenomas

Macroprolactin may cause elevation of prolactin (PRL) concentrations measured by standard assays. In our study, we assessed the prevalence of pituitary lesions in women with macroprolactinaemia and either oligomenorrhoea or secondary amenorrhoea. Pituitary MRI scans were performed in 61 women aged 31.0 ± 6.7?years (mean ± SD), with raised PRL concentrations due to macroprolactinaemia, detected by 25% polyethylene glycol (PEG) precipitation method (PRL recovery <40%). After PEG precipitation of macroprolactin, free PRL concentrations were still raised in 36 (59%) women. Microadenomas were detected in 10 patients out of 61 (16.4%), with raised free PRL in 9 of these cases, while macroadenomas were detected in 4 out of 61 (6.6%) women, all of whom also had raised free PRL. In case of coexistence of macroprolactinaemia and raised free PRL after PEG precipitation of macroprolactin, the chance of finding of either a micro- or a macroadenoma was 36% (13 cases out of 36). We conclude that hyperprolactinaemia and macroprolactinaemia may coexist in the same patient. Furthermore, if free PRL is raised after PEG precipitation of macroprolactin, then the chance of finding either a pituitary micro- or macroadenoma in women with oligo-/amenorrhoea is over 30%. Therefore pituitary magnetic resonance imaging is mandatory in all such cases.     

Laparoscopic splenectomy for hereditary spherocytosis—preliminary report

Splenectomy is considered standard surgical therapy in hereditary spherocytosis. The procedure is indicated in patients with severe anemia, recurrent hemolytic, and aplastic crises. The aim of the study was to assess treatment outcomes in patients with hereditary spherocytosis who underwent total or partial laparoscopic splenectomy. Fifteen patients aged 4–17 yr underwent laparoscopic splenectomy from 2009 to 2012. Partial and total splenectomies were performed (five and 10 children, respectively). Hematologic parameters, liver function tests, and splenic volume before and after the surgery were analyzed retrospectively. Total follow‐up was 1–30 months. Hospitalization and operating time were similar in both groups. In partial splenectomy group, branches of splenic arteries gave better blood supply than short gastric vessels. In both groups, hematologic parameters were improved. Postoperative markedly elevated platelet count was maintained up to 6 months, and after that, platelet count gradually decreased to normal values. Bilirubin level was decreased in early postoperative period; however, it increased later to achieve levels lower than in preoperative period. No severe general infections were observed in both groups. Laboratory parameters (hemoglobin and bilirubin concentrations and RBC) after the surgery improved in all patients, and the effect was maintained during 12 months of follow‐up. Platelet count increased significantly after the surgery and was maintained at high levels during the next 6 months. However, it returned to preoperative levels within a year after the surgery. Our study showed that partial splenectomy was not inferior to total splenectomy. However, full assessment requires longer follow‐up and larger group of patients.