Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure. Part 1: Oral route

Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM‐202 and 203) and two precipitated (NM‐200 and ‐201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)‐modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose‐dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. Environ. Mol. Mutagen. 56:218–227, 2015. © 2014 Wiley Periodicals, Inc.     

Prevention of recurrent amiodarone-induced hyperthyroidism by iodine-131

Amioradone-induced hyperthyroidism is a common complication of amiodarone therapy. Although definitive interruption of amiodarone is recommended because of the risks of aggravation of the arrhythmias, some patients may require the reintroduction of amiodarone several months after normalisation of thyroid function. The authors undertook a retrospective study of the effects of preventive treatment of recurrences of amiodarone-induced hyperthyroidism with I131. The indication of amiodarone therapy was recurrent, symptomatic, paroxysmal atrial fibrillation in 13 cases and ventricular tachycardia in 5 cases (M = 14, average age 64 +/- 13 years). The underlying cardiac disease was dilated cardiomyopathy (N = 5), ischaemic heart disease (N = 3), hypertensive heart disease (N = 2), arrhythmogenic right ventricular dysplasia (N = 2) or valvular heart disease (N = 2). Two patients had idiopathic atrial fibrillation. An average dose of 576 +/- 184 MBq of I131 was administered 34 +/- 37 months after an episode of amiodarone-induced hyperthyroidism. Amiodarone was reintroduced in 16 of the 18 patients after a treatment-free period of 98 +/- 262 days. Transient post-radioiodine hyperthyroidism was observed in 3 cases (17%). Sixteen patients (89%) developed hypothyroidism requiring replacement therapy with L-thyroxine. There were no recurrences of amiodarone-induced hyperthyroidism. After 24 +/- 17 months follow-up, the arrhythmias were controlled in 13 of the 16 patients (81%) who underwent the whole treatment sequence. The authors conclude that preventive treatment with I131 is an effective alternative to prevent recurrence of amiodarone-induced hyperthyroidism in patients requiring reintroduction of amiodarone to control their arrhythmias.     

Efficacy of two versions of emotion-focused therapy for resolving child abuse trauma

Abstract

This study evaluated and compared emotion-focused therapy for trauma (EFTT) with imaginal confrontation (IC) of perpetrators (n=20) and EFTT with empathic exploration (EE) of trauma material (n=25). Clients were women and men with histories of different types of childhood maltreatment (emotional, physical, and sexual abuse; emotional neglect). Clients were randomly assigned to treatment condition. Outcome measures assessed symptom distress, self and interpersonal problems, and abuse resolution. Results indicated statistically and clinically significant improvements on eight measures at posttest, maintenance of gains at follow-up, and no statistically significant differences between conditions. There were higher rates of clinically significant change in IC and a lower attrition rate for EE (7% vs. 20%). More severe personality pathology negatively influenced some dimensions of outcome, particularly in EE.     

Apraxia of tool use: More evidence for the technical reasoning hypothesis

Various distinct cognitive processes such as semantic memory, executive planning or technical reasoning have been shown to support tool use. The aim of this study is to investigate the relationship between these processes. To do so, a large apraxia battery was submitted to 16 patients with left brain-damage (LBD) and aphasia and 19 healthy controls. The battery included: classical apraxia tests (Pantomime of Tool Use and Single Tool Use), familiar and novel tool use tests (Tool-Object Pairs and Sequential Mechanical Problem-Solving), semantic memory tests (Recognition of tool utilization gestures and Functional and Categorical Associations) as well as the Tower Of London. The Sequential Mechanical Problem-Solving task is a new task which permits the evaluation of pre-planning in unusual tool use situations. In this task as well as in the Tool-Object Pairs task, participants solved a tool use problem in a Choice and a No-Choice condition to examine the effect of tool selection. Globally, left brain damaged patients were impaired as compared to controls. We found high correlations in left brain damaged patients between performances on classical apraxia tests, familiar and novel tool use tests and Functional and Categorical Associations but no significant association between these performances and Tower Of London or Recognition of tool utilization gestures. Furthermore, the two conditions (Choice and No-Choice) of Tool-Object Pairs and Sequential Mechanical Problem-Solving were associated. In sum, all tasks involving tool use are strongly associated in LBD patients. Moreover, the ability to solve sequential mechanical problems does not depend on executive planning. Also, tool use appears to be associated with knowledge about object function but not with knowledge about tool manipulation. Taken together, these findings indicate that technical reasoning and, to a lesser extent, semantic memory may both play an important role in tool use.     

Efficiently stimulated adult microglia cross‐prime naive CD8+ T cells injected in the brain

Microglia are the major myeloid‐immune cells of the brain parenchyma. In a steady state, microglia monitor their environment for pathogens or damaged cells. In response to neural injury or inflammation, microglia become competent APCs able to prime CD4⁺ and CD8⁺ T lymphocytes. We previously demonstrated that neonatal and adult microglia cross‐present exogenous soluble Ags in vitro. However, whether microglia are able to cross‐present Ag to naive CD8⁺ T cells in vivo, within the brain microenvironment, remains undetermined. Here, we have designed an original protocol in order to exclude the involvement in cross‐presentation activity of peripheral migrating APCs and of CNS‐associated APCs. In C57Bl/6 mice, in which the body but not the head has been properly irradiated, we analyzed the ability of resident microglia to stimulate intracerebrally injected CD8⁺ T cells in vivo. This study demonstrates for the first time that adult microglia cross‐present Ag to naive CD8⁺ T cells in vivo and that full microglia activation is required to overcome the inhibitory constrains of the brain and to render microglia able to cross‐prime naive CD8⁺ T cells injected in the brain. These observations offer new insights in brain‐tumor immunotherapy based on the induction of cytotoxic antitumoral T cells.     

Mucosal IL-10 and TGF-beta play crucial roles in preventing LPS-driven, IFN-gamma-mediated epithelial damage in human colon explants

IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10-inducible, immunosuppressive gene BCL3 and upregulation of IFN-gamma, TNF-alpha, and IL-17. Interestingly, TGF-beta blockade also strongly induced IFN-gamma production. In addition, the high levels of IFN-gamma produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-gamma production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-gamma secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-gamma-mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-beta play crucial roles in maintaining human colonic mucosa homeostasis.     

Significance of an upward shift of the ST segment during an exercise test

The objective of this study is to investigate the significance of the occurrence of an upward shift of the ST segment curing a stress test in patients with no previous history of myocardial infarction. Over 10 years, totalling 9,500 stress tests, we have collected 10 cases. They always concern men including one with angina on exertion, one with spontaneous angina, one with spontaneous angina occurring at the end of an intense stress, and 7 with mixed angina. None of them had a previous history of myocardial infarction or documented spastic angina. The upward shift of the ST segment occurred 9 times during stress and once during recovery. 9 patients had a coronary arteriogram with in 8 cases severe fixed coronary lesions. The patient with the upward shift of ST during the recovery period had a normal coronary arteriogram with a positive methylergometrin test. There is a good correlation between the appearance of an upward shift of ST during stress in the anterior derivations and a significant involvement of the anterior interventricular artery. In our series, there were no complications, especially myocardial infarction, in the immediate period following the stress test. 7 patients underwent an aorto-coronary by-pass. The 10 patients are presently asymptomatic after a 47 months follow-up. The occurrence of an upward shift of ST during stress, in the absence of a previous history of myocardial infarction, represents in more than 80 p. cent of the cases the existence of severe coronary lesions leading to hospitalization and the immediate performance of a coronary arteriogram.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoregulation of the gonadotropin-releasing hormone (GnRH) system during puberty: effects of antagonistic versus agonistic GnRH analogs in a female rat model

To address whether gonadotropin-releasing hormone (GnRH) regulates its own expression and the expression of its receptor in the hypothalamus and ovary, we treated five groups of prepubertal/peripubertal female rats from postnatal days 25-36 with either the GnRH agonist triptorelin (TRIP) or the GnRH antagonist cetrorelix (CET), each 10 or 100 microgram/day, or a placebo. We compared their effects regarding pubertal development, serum gonadotropins and the expression of GnRH and GnRH-receptor in the hypothalamus, pituitary, ovary and uterus. Onset of puberty was determined by vaginal opening, and expression levels of GnRH and GnRH-receptor were determined using either quantitative real-time PCR or competitive RT-PCR. Onset of puberty was retarded by both analogs but CET (100 microgram/day) inhibited while TRIP (10 and 100 microgram/day) stimulated serum gonadotropins (P<0.05). The expression of GnRH in the preoptic area did not show significant differences among the treatment groups but ovarian GnRH mRNA levels were significantly stimulated by CET (100 microgram/day). GnRH mRNA could not be detected in the uterus by either real-time PCR or competetive RT-PCR. The GnRH-receptor expression in the hypothalamus (preoptic area and mediobasal hypothalamus) did not vary among any of the groups, whereas in the pituitary GnRH-receptor mRNA levels were stimulated by TRIP (10 microgram/day) but inhibited by CET (100 microgram/day). In contrast, in the ovary GnRH-receptor mRNA levels were inhibited by both TRIP (100 microgram/day) and CET (100 microgram/day). Interestingly, the GnRH-receptor was even expressed in the uterus where it was strongly stimulated by both CET and TRIP in a dose-related manner. This shows that in addition to their different pituitary effects, the GnRH analogs cetrorelix and triptorelin exert different actions at the hypothalamic, ovarian and uterine level. This study also demonstrates an organ-specific regulation of GnRH and GnRH-receptor gene expression which is likely part of a local autoregulatory system. We conclude that the ovarian and uterine effects of GnRH analogs must be considered in addition to their known pituitary effects when deciding which GnRH analog is most suitable for treating precocious puberty.