Clinical and pathologic findings of aortic dissection at autopsy: Review of 336 cases over nearly 6 decades.

BACKGROUND: We aimed to characterize the clinical and pathologic findings of aortic dissection (AD) over a nearly 60-year period. METHODS: The Jesse E. Edwards Registry of Cardiovascular Disease database was queried for cardiac specimens from autopsies with AD as a diagnosis and compared 2 cohorts: early (1956-1992) and current (1993-2015). RESULTS: From 1956 to 2015, 338 cases (166 early, 170 current) with AD were included (mean age: 60; 62% male). The AD was 86% type A and 14% type B. Sixty-two percent of cases were under medical care at time of death (61% early, 62% current, P = not significant). Of those under medical care, 63% were not diagnosed prior to death (64% early, 62% current, P = not significant). Risks for dissection did not differ between time intervals and include left ventricular hypertrophy, suggestive of hypertension (84%), prior cardiovascular surgery (38%), bicuspid valve (14%), and connective tissue disease (9%). An intimal tear was identified in the ascending aorta in the majority (68%), followed by descending (14%), root (9.5%), and arch (7%). Aortic rupture occurred in 58%, most frequently in the ascending aorta (41%). CONCLUSIONS: In a large cardiovascular registry, >60% of cases of AD were not detected clinically and first identified at autopsy. Although diagnostic techniques have significantly improved over the time interval, the percentage of AD discovered at autopsy did not differ from the early to the current era. The most prevalent risk factors for dissection including hypertension and prior cardiovascular surgery remain similar in both time periods. AD death is related to rupture of the aorta in the majority of cases.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated under-nutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC, gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg i.p. BID for 3 weeks). Gastric ICC were analyzed by western blotting (WB) and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.

The high overall genetic homology between humans and rhesus macaques, coupled with the phenotypic conservation of lymphocyte populations, highlights the potential use of nonhuman primates (NHPs) for the preclinical evaluation of vaccine candidates. For HIV-1, experimental models are needed to identify vaccine regimens capable of eliciting desired immune responses, such as broadly neutralizing antibodies (bNAbs). One important neutralization target on the HIV-1 envelope glycoproteins (Envs) is the conserved primary CD4 receptor binding site (CD4bs). The isolation and characterization of CD4bs-specific neutralizing monoclonal Abs (mAbs) from HIV-1-infected individuals have provided insights into how broadly reactive Abs target this conserved epitope. In contrast, and for reasons that are not understood, current Env immunogens elicit CD4bs-directed Abs with limited neutralization breadth. To facilitate the use of the NHP model to address this and other questions relevant to human humoral immunity, we defined features of the rhesus macaque immunoglobulin (Ig) loci and compared these to the human Ig loci. We then studied Env-immunized rhesus macaques, identified single B cells expressing CD4bs-specific Abs, and sequenced and expressed a panel of functional mAbs. Comparison of vaccine-elicited mAbs with HIV-1 infection-induced mAbs revealed differences in the degree of somatic hypermutation of the Abs as well as in the fine specificities targeted within the CD4bs. These data support the use of the preclinical NHP model to characterize vaccine-induced B cell responses at high resolution.