BackgroundThe mechanisms underlying the possible contribution of chronic inflammation to the development of hypertension remain unclear. We examined the longitudinal association of inflammation with the progression of vascular and/or renal abnormalities in the development of hypertension.Methods and ResultsIn 3274 middle‐aged Japanese men without hypertension at the study baseline, brachial‐ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum CRP (C reactive protein) levels were measured annually during a 9‐year period. During this study period, 474 participants (14.5%) developed hypertension. Analysis of the repeated‐measures data revealed that sustained elevation of serum CRP levels was associated with a longitudinal increase of the brachial‐ankle pulse wave velocity. A linear mixed model analysis revealed that higher log‐transformed serum CRP values (log CRP) at each measurement were associated with a higher annual increase of the brachial‐ankle pulse wave velocity (estimate=32.553±11.635 cm/s per log CRP, P=0.018), and that higher values of the brachial‐ankle pulse wave velocity at each measurement were associated with a higher annual elevation of blood pressure (estimate=0.025±0.002 mm Hg per log CRP, P<0.001).ConclusionsIn middle‐aged Japanese men without hypertension at study baseline, long‐term active inflammation appears to be associated with a longitudinal increase of arterial stiffness. In turn, this longitudinal increase of arterial stiffness appears to be associated with longitudinal elevation of blood pressure to the hypertensive range. Thus, systemic inflammation may play a role in the pathogenesis of hypertension by the progression of arterial stiffness.

A ccording to recently reported meta-analyses, hyperuricemia is an independent risk factor for the development of hypertension, 1,2 although the underlying mechanisms have not yet been fully clarified. Hyperuricemia has also been reported to be associated with the early stages of development of some risk factors for hypertension, such as arterial stiffness, 3 renal function decline, 4 and inflammation. 5 Thus, we attempted to verify the possibility of involvement of these risk factors in the risk of development of hypertension associated with hyperuricemia. 6 Although an observational study would be needed for such an objective, conventional observational studies, in which the relevant assessments are conducted at 2 observational points, have the limitation that they exclude the effects of timevarying confounding variables.7 However, analysis of repeated measures data by mixed model linear (MML) regression analysis and general estimated equation (GEE) analysis may be useful to minimize the effects of time-varying confounders. In the present prospective observational study conducted in Japanese men without hypertension at the study baseline, we analyzed repeated measures data by MML regression analysis and GEE analysis to clarify the longitudinal associations of hyperuricemia with the above-mentioned risk factors for the development of hypertension, and then to examine the longitudinal associations of these risk factors with the development of hypertension. MethodsThe data, analytical methods, and study materials will not be made available to other researchers for the purpose of reproducing the results or replicating the procedure. Design and SubjectsThe present study was conducted in the same cohort as that used in a previously reported prospective observational study. 8,9 The cohort consisted of employees working at the headquarters of a single large Japanese construction company located in downtown Tokyo. According to the Occupational Health and Safety Law in Japan, it is mandatory for all company employees to undergo annual health checkups. Informed consent for participation in this study was obtained from all of the study participants before their enrollment in this study. The study was Correspondence to Hirofumi Tomiyama, Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Tokyo 160-0023, Japan. Email tomiyama@tokyo-med.ac.jp See Editorial Commentary, pp 582-584Abstract-This study analyzed repeated measurement data to clarify the longitudinal associations between hyperuricemia and the risk factors for the development of hypertension (ie, increased arterial stiffness, renal dysfunction, and inflammation), and then examined whether these risk factors show longitudinal associations with the development of hypertension. In 3274 Japanese men without hypertension, the brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum uric acid and CRP (C-reactive protein) levels were measured annually over an 8-year period. Of these, 474 subjects developed hy...

Background DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable pharmacokinetics with the current DNA-demethylating agents, azacitidine (AZA) and decitabine (DAC), because of their rapid deamination by cytidine deaminase in vivo and spontaneous hydrolytic cleavage. Here, we aimed to develop metabolically stable prodrugs of AZA and DAC as novel DNA-demethylating agents. Results Thirty-five 5′-O-trialkylsilylated AZAs/DACs were synthesized with potential resistance to deamination. Out of these, 11 compounds exhibited demethylating activity similar to that of DAC and guadecitabine, and a suitable aqueous solubility. Pharmacokinetic analysis in mice showed that OR-2003 displayed the highest serum concentration and the area under the curve in an intraperitoneal experiment, whereas OR-2100 exhibited high stability to cytidine deaminase. Treatment of cells with OR-2003 and OR-2100 depleted DNA methyltransferase 1 completely and induced both gene-specific and genome-wide demethylation. The treatment suppressed the growth of multiple types of cancer cells and induced re-expression of tumor suppressor genes. The anti-tumor effect and DNA demethylation effect of OR-2003 and OR-2100 were comparable to that of DAC with fewer adverse effects in vivo. Conclusions We developed two novel prodrugs of DAC that exhibited greater stability, comparable DNA demethylation activity, and less toxicity. These compounds are expected to overcome the difficulty in achieving stable pharmacokinetics in patients, leading to maximum DNA demethylation activity with minimum adverse effects. Electronic supplementary material The online version of this article (10.1186/s13148-019-0709-y) contains supplementary material, which is available to authorized users.

Combinations of histone modifications have significant biological roles, such as maintenance of pluripotency and cancer development, but cannot be analyzed at the single cell level. Here, we visualized a combination of histone modifications by applying the in situ proximity ligation assay, which detects two proteins in close vicinity (∼30 nm). The specificity of the method [designated as imaging of a combination of histone modifications (iChmo)] was confirmed by positive signals from H3K4me3/acetylated H3K9, H3K4me3/RNA polymerase II and H3K9me3/H4K20me3, and negative signals from H3K4me3/H3K9me3. Bivalent modification was clearly visualized by iChmo in wild-type embryonic stem cells (ESCs) known to have it, whereas rarely in Suz12 knockout ESCs and mouse embryonic fibroblasts known to have little of it. iChmo was applied to analysis of epigenetic and phenotypic changes of heterogeneous cell population, namely, ESCs at an early stage of differentiation, and this revealed that the bivalent modification disappeared in a highly concerted manner, whereas phenotypic differentiation proceeded with large variations among cells. Also, using this method, we were able to visualize a combination of repressive histone marks in tissue samples. The application of iChmo to samples with heterogeneous cell population and tissue samples is expected to clarify unknown biological and pathological significance of various combinations of epigenetic modifications.

In patients with cardiovascular diseases or cardiovascular risk factors, the new simple markers and the commonly used markers are not interchangeable for assessing vascular damage and/or cardiovascular risk. Further study is proposed to examine whether AVI is higher in subjects with cardiovascular disease than in those without a history of cardiovascular disease. Similar to the case for the commonly used markers, age and the blood pressure significantly influenced both the new markers; therefore, age and the blood pressure need to be taken into account while interpreting the changes in these new simple markers.