Contrary to our results transient increases in cardiac speci

Contrary to our results, transient increases in cardiac-specific troponin have been observed in 12–50% of patients following trastuzumab treatment, most frequently after the first cycle, and troponin-I was found to be the strongest independent predictor of cardiotoxicity in multivariate analyses (Cardinale et al., 2010; Ky et al., 2014; Morris et al., 2011). However, it should be noted that in these studies trastuzumab administration was part of a treatment regime which included cytostatics. An important weakness of the analysis is the comparison to a relatively small placebo group, which consisted of six subjects for body weight and laboratory data. This could potentially skew the placebo population, obscuring trastuzumab\'s effects. Because of the placebo condition as control group, it could also be argued that the observed volume increase is a non-specific effect caused by the administration of a monoclonal antibody. However, experience with intravenous administration of (therapeutic) doses of both experimental and registered monoclonal antibodies in healthy volunteers has revealed neither elevations in body weights nor haemodilution, either in the short or long-term (data on file). Interestingly though, increases in total protein and albumin were observed during the first week after administration in both the placebo and monoclonal antibody arms of those trials, which is similar to the profiles in the placebo treated subjects as presented in Fig. 3.
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Introduction Telomeres are the structures which cap each end of a chromatid, at the extreme end of chromosomal deoxyribonucleic mecamylamine (DNA). Telomeres are composed of a variable number of tandem repeats of the sequence TTAGGG that extend over several thousand base pairs (Blackburn, 2001). The protected state of telomeres is necessary to safeguard the integrity of genomic material. Telomere length is considered a biomarker of human aging, namely an indicator of oxidative stress and cellular senescence (von Zglinicki and Martin-Ruiz, 2005). Additionally, telomere shortening in leukocytes is correlated with atherosclerosis and cardiovascular aging (De Meyer et al., 2011; Butt et al., 2010; Khan et al., 2012). Telomeric DNA is shielded by telomere binding-specific proteins, such as the ‘shelterin complex’, which bind to and protect the terminal loop (t-loop) of telomeres (Bailey et al., 2001; de Lange, 2005). Telomeres are composed of double-stranded repeated DNA with terminal 3′ single-stranded G-rich overhangs called telomere G-tails. The telomere G-tail folds back to form a t-loop, which prevents the end of the telomere from being recognized as a damaged, broken end. Telomere G-tails are thus key structures that protect telomere DNA from DNA damage. Indeed, the telomere G-tail is thought to be a more important factor in chromosome maintenance than total telomere length (Tsai et al., 2007; Anno et al., 2007). However, the association of telomere G-tail length with various cardiovascular risk factors in humans has not been clarified. To our knowledge, only one report has shown an association between the telomere G-tail and cardiovascular events in hemodialysis patients (Hirashio et al., 2014). Endothelial dysfunction plays a critical role in the development of atherosclerosis. Impairment of endothelial function is an important first step in the pathogenesis of atherosclerosis, and is associated with an insufficient endothelial repair mechanism for vascular injury (Deanfield et al., 2007). Ultrasound assessment of brachial artery flow-mediated dilation (FMD), a useful noninvasive method, has been used as an index of endothelium-dependent vasodilation. Several studies have reported that FMD is impaired in patients with coronary disease and cardiovascular risk factors. In addition, impaired FMD is associated with the severity of age-related white matter changes (ARWMCs) (Hoth et al., 2007). However, the association of telomere G-tail length with endothelial dysfunction and ARWMCs remains unclear.