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  • br Materials and methods br Results The


    Materials and methods
    Results The average body weights for each group of mice over the course of the study are shown in Fig. 2A. The average body weights of the mice in the saline control group and PACAP group increased slightly during the study. In contrast, starting at day 17, the body weights of the mice treated only with MXT decreased significantly compared to the control and PACAP groups. During the fourth week of the study, two of the mice in the MXT group died. While PACAP significantly attenuated the MXT-induced reduction in body weight, from day 17 onward, the body weights of the mice treated with both PACAP and MXT were significantly lower than in the control groups. In simvastin synthesis to the changes in body weight, there were no significant differences in heart weight among the four groups (Fig. 2B). Fat pads were not found in the MXT-treated mice sacrificed on day 28. Serial echocardiograms were used to monitor cardiac structure and function in the mice. Over the course of the study, there were no significant changes in LVID;d, LV Vol;d, LVPW;d, or IVS;d in the saline or the PACAP groups (Fig. 3A–D). By day 21 of the study, echocardiography revealed that treatment with MXT alone significantly increased LVID;d and LV Vol;d (Fig. 3A and B) compared to saline-treated mice. By day 28, treatment with MXT also significantly decreased LVPW;d and IVS;d (Fig. 3C and D) compared to the saline group. Treatment with PACAP blocked the MXT-induced increases in LVID;d and LV Vol;d (Fig. 3A and B). Treatment with PACAP did not significantly attenuate the MXT-induced decreases in LVPW;d (Fig. 3C); however, it did attenuate the MXT-induced decrease in IVS;d, because IVS;d did not differ significantly between the saline and the PACAP+MXT groups (Fig. 3D). When compared to saline- and PACAP-treated mice, treatment with MXT alone significantly reduced %EF and %FS (Fig. 4A and B). PACAP significantly attenuated the MXT-induced reductions in %EF and %FS; however, these functional parameters in the PACAP+MXT group were still significantly reduced compared to the saline control group (Fig. 4A and B). Histological examination of the mouse hearts failed to show gross evidence of inflammation (e.g., lymphocytic infiltration or myocyte disruption) or fibrosis (Fig. 5). The hearts of mice treated with MXT alone had what appeared to be multiple, large calcified lesions scattered over the epicardial surface (Figs. 5A and B). These lesions were observed in all five of the hearts examined from the MXT group. Similar lesions were not observed in any of the hearts from the mice treated with saline (n=7), PACAP alone (n=7) or PACAP+MXT (n=7). The 24-h treatment with MXT (0.1–25μM) produced dose-related decreases in the viability of U937 cells, a human leukemia cell line (Fig. 6A). Except at the highest concentration tested (1μM), which produced a small, but significant increase in cell death, the 24-h treatment with PACAP alone did not reduce the viability of the U937 cells (Fig. 6B). PACAP did not protect U937 cells from MXT-induced cell death after a 24-h co-treatment and even significantly enhanced the MXT-induced cell death of the U937 cells at the highest concentration tested (Fig. 6B). MXT-induced cell death in U937 cells was accompanied by significant increases in the levels of cleaved caspase 3 (Fig. 6C). The increase in cleaved caspase 3 was not reduced by co-treatment with PACAP. PACAP treatment by itself did not affect caspase 3 cleavage relative to control cells (Fig. 6C).
    Conflict of interest
    Author contributions
    Acknowledgments This work was supported in part by the National Institutes of Health (5P30 GM106392) and the Akira Arimura Foundation.
    Introduction Despite high vaccination coverage, Bordetella pertussis infection remains endemic and reports of increasing incidence in Australia [1], Canada [2] and Europe [3] have been accumulating for the past twenty years. 2012 was the year with the highest whooping cough incidence in US and comparable outbreaks occurred also in the UK and Netherlands, in proportion of inhabitant numbers [4–6]. Adaptation of the circulating pertussis strains to the vaccines, as well as the waning and/or suboptimal efficacy of vaccine-mediated immunity during adolescence has been proposed to account for resurgence, with infected adolescent and adult populations being the major transmitters of disease in community representing a potential reservoir for disease transmission to young children who are yet to be fully vaccinated [7,8]. Furthermore, with the changing epidemiology, pertussis is increasingly becoming a real burden also in adults that experience long-lasting and very heavy cough periods of duration in weeks to months [9]. This underscores the need to pursue research efforts on this disease in order to provide suitable protection to the most vulnerable populations.