Ready for Discharge, but Are They Ready to Go Home? Examining Neighborhood-Level Disadvantage as a Marker of the Social Exposome and the Swallowing Care Process in a Retrospective Cohort of Inpatients With Dementia.

PURPOSE: Socioeconomically disadvantaged areas are more resource poor, impacting adherence to swallowing care recommendations. Neighborhood-level disadvantage metrics, such as the Area Deprivation Index (ADI), allow for examination of social determinants of health (SDOH) in a precise region. We examined ADI in a cohort of persons living with dementia (PLWD) to determine representation of those residing in areas of socioeconomic disadvantage (high ADI), distribution of swallowing care provided, and frequency of SDOH-related counseling or resource linking prior to discharge. METHOD: A retrospective chart abstraction was performed for all inpatients with a diagnosis of dementia (N = 204) seen by the Swallow Service at a large academic hospital in 2014. State ADI Deciles 1 (least) to 10 (most socioeconomic disadvantage) and decile groups (1-3, 4-7, and 8-10) were compared with the surrounding county. Frequency of videofluoroscopic swallowing evaluations (VFSEs) based on ADI deciles was recorded. To determine whether SDOH-related counseling or resource linking occurred for those in high ADI (8-10) neighborhoods, speech-language pathology notes, and discharge summaries were reviewed. Descriptive statistics, independent samples t tests, and one-way analysis of variance were calculated. RESULTS: ADI was significantly higher in this cohort (M = 3.84, SD = 2.58) than in the surrounding county (M = 2.79, SD = 1.88, p = .000). There was no significant difference in utilization of swallowing services across decile groups (p = .88). Although the majority (85%) in high ADI areas was recommended diet modifications or alternative nutrition likely requiring extra resources, there was no documentation indicating that additional SDOH resource linking or counseling was provided. CONCLUSIONS: These findings raise important questions about the role and responsibility of speech-language pathologists in tailoring swallowing services to challenges posed by the lived environment, particularly in socioeconomically disadvantaged areas. This underscores the need for further research to understand and address gaps in postdischarge support for PLWD in high-ADI regions and advocate for more equitable provision of swallowing care.

B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart.

AIMS: Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. METHODS AND RESULTS: First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor(-/-) mouse heart under normoxia (21% O(2)) and hypoxia (1% O(2)) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF(164); n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. CONCLUSION: The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.

Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardial infarct size in rats.

Persistent Nuclear Factor-kappaB (NF-kappaB) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappaB signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappaB inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappaB using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappaB in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/-9.7% in % of risk area; n=17) than in control rats (28.2%+/-6.2%; n=15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappaB in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences.

Angiotensin II induces angiogenesis in the hypoxic adult mouse heart in vitro through an AT2-B2 receptor pathway.

Angiotensin II is a vasoactive peptide that may affect vascularization of the ischemic heart via angiogenesis. In this study we aimed at studying the mechanisms underlying the angiogenic effects of angiotensin II under hypoxia in the mouse heart in vitro. Endothelial sprout formation from pieces of mouse hearts was assessed under normoxia (21% O(2)) and hypoxia (1% O(2)) during a 7-day period of in vitro culture. Only under hypoxia did angiotensin II dose-dependently induce endothelial sprout formation, peaking at 10(-7) mol/L of angiotensin II. Angiotensin II type 1 (AT(1)) receptor blockade by losartan did not affect angiotensin II-induced sprouting in wild-type mice. Conversely, the angiotensin II type 2 (AT(2)) receptor antagonist PD 123319 blocked this response. In hearts from AT(1)(-/-) mice, angiotensin II-elicited sprouting was preserved but blocked again by AT(2) receptor antagonism. In contrast, no angiotensin II-induced sprouting was found in preparations from hearts of AT(2)(-/-) mice. Angiotensin II-mediated angiogenesis was also abolished by a specific inhibitor of the B2 kinin receptor in both wild-type and AT(1)(-/-) mice. Furthermore, angiotensin II failed to induce endothelial sprout formation in hearts from B2(-/-) mice. Finally, NO inhibition completely blunted sprouting in hearts from wild-type mice, whereas NO donors could restore sprouting in AT(2)(-/-) and B2(-/-) hearts. This in vitro study suggests the obligatory role of hypoxia in the angiogenic effect of angiotensin II in the mouse heart via the AT(2) receptor through a mechanism that involves bradykinin, its B2 receptor, and NO as a downstream effector.

The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27Kip1 protein levels.

Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27Kip1 was shown to be required for the activation of key cyclin-dependent kinases, thereby triggering the onset of DNA replication and cell cycle progression. Although the SCFSkp2 ubiquitin ligase has been reported to mediate p27Kip1 degradation, the nature of the human ubiquitin-conjugating enzyme involved in this process has not yet been determined at the cellular level. Here, we show that antisense oligonucleotides targeting the human ubiquitin-conjugating enzyme Cdc34 downregulate its expression, inhibit the degradation of p27Kip1, and prevent cellular proliferation. Elevation of p27Kip1 protein level is found to be the sole requirement for the inhibition of cellular proliferation induced upon downregulation of Cdc34. Indeed, reducing the expression of p27Kip1 with a specific antisense oligonucleotide is sufficient to reverse the anti-proliferative phenotype elicited by the Cdc34 antisense. Furthermore, downregulation of Cdc34 is found to specifically increase the abundance of the SCFSkp2) ubiquitin ligase substrate p27Kip1, but has no concomitant effect on the level of IkBalpha and beta-catenin, which are known substrates of a closely related SCF ligase.

Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.

Gene expression profiling of anatomically diverse carcinomas and their corresponding normal tissues was used to identify genes with cancer-associated expression. We show here that the ubiquitin conjugase, UbcH10, is significantly overexpressed in many different types of cancers and is associated with the degree of tumor differentiation in carcinomas of the breast, lung, ovary and bladder, as well as in glioblastomas. We also show that UbcH10 overexpression in gastro-esophageal, and probably other carcinomas may be a direct consequence of chromosomal amplification at the UbcH10 locus, 20q13.1, a region known to be amplified in diverse tumors. To evaluate whether inhibition of UbcH10 function may be therapeutically relevant in cancer, we used small interfering RNAs (siRNAs) to silence UbcH10 transcription selectively. Diminution of UbcH10 expression significantly inhibited both tumor and normal cell proliferation without inducing cell death. However, when combined with agonists of the DR5/TRAIL receptor, siRNAs directed against the UbcH10 transcript dramatically enhanced killing of cancer cells, but not of proliferating primary human epithelial cells or fibroblasts. Together, these data demonstrate that UbcH10 plays an important role in tumor development and that its inhibition in combination with agonists of the TRAIL receptor may provide an enhanced therapeutic index.