Predictive factors of basic palliative and hospice care among patients with cancer visiting the emergency department in a Hungarian tertiary care center.

Introduction: Patients with advanced cancer tend to utilize the services of the health care system, particularly emergency departments (EDs), more often, however EDs aren't necessarily the most ideal environments for providing care to these patients. The objective of our study was to analyze the clinical and demographic characteristics of advanced patients with cancer receiving basic palliative care (BPC) or hospice care (HC), and to identify predictive factors of BPC and HC prior to their visit to the ED, in a large tertiary care center in Hungary. Methods: A retrospective, detailed analysis of patients receiving only BPC or HC, out of 1512 patients with cancer visiting the ED in 2018, was carried out. Sociodemographic and clinical data were collected via automated and manual chart review. Patients were followed up to determine length of survival. Descriptive and exploratory statistical analyses were performed. Results: Hospital admission, multiple (≥4x) ED visits, and respiratory cancer were independent risk factors for receiving only BPC (OR: 3.10, CI: 1.90-5.04; OR: 2.97, CI: 1.50-5.84; OR: 1.82, CI: 1.03-3.22, respectively), or HC (OR: 2.15, CI: 1.26-3.67; OR: 4.94, CI: 2.51-9.71; OR: 2.07, CI: 1.10-3.91). Visiting the ED only once was found to be a negative predictive factor for BPC (OR: 0.28, CI: 0.18-0.45) and HC (OR: 0.18, 0.10-0.31) among patients with cancer visiting the ED. Conclusions: Our study is the first from this European region to provide information regarding the characteristics of patients with cancer receiving BPC and HC who visited the ED, as well as to identify possible predictive factors of receiving BPC and HC. Our study may have relevant implications for health care planning strategies in practice.

Diagnosis rates, therapeutic characteristics, lifestyle, and cancer screening habits of patients with diabetes mellitus in a highly deprived region in Hungary: a cross-sectional analysis.

Introduction: Low socioeconomic status affects not only diagnosis rates and therapy of patients with diabetes mellitus but also their health behavior. Our primary goal was to examine diagnosis rates and therapy of individuals with diabetes living in Ormánság, one of the most deprived areas in Hungary and Europe. Our secondary goal was to examine the differences in lifestyle factors and cancer screening participation of patients with diagnosed and undiagnosed diabetes compared to healthy participants. Methods: Our study is a cross-sectional analysis using data from the "Ormánság Health Program". The "Ormánság Health Program" was launched to improve the health of individuals in a deprived region of Hungary. Participants in the program were coded as diagnosed diabetes based on diagnosis by a physician as a part of the program, self-reported diabetes status, and self-reported prescription of antidiabetic medication. Undiagnosed diabetes was defined as elevated blood glucose levels without self-reported diabetes and antidiabetic prescription. Diagnosis and therapeutic characteristics were presented descriptively. To examine lifestyle factors and screening participation, patients with diagnosed and undiagnosed diabetes were compared to healthy participants using linear regression or multinomial logistic regression models adjusted for sex and age. Results: Our study population consisted of 246 individuals, and 17.9% had either diagnosed (n=33) or undiagnosed (n=11) diabetes. Metformin was prescribed in 75.8% (n=25) of diagnosed cases and sodium-glucose cotransporter-2 inhibitors (SGLT-2) in 12.1% (n=4) of diagnosed patients. After adjustment, participants with diagnosed diabetes had more comorbidities (adjusted [aOR]: 3.50, 95% confidence interval [95% CI]: 1.34-9.18, p<0.05), consumed vegetables more often (aOR: 2.49, 95% CI: 1.07-5.78, p<0.05), but desserts less often (aOR: 0.33, 95% CI: 0.15-0.75, p<0.01) than healthy individuals. Patients with undiagnosed diabetes were not different in this regard from healthy participants. No significant differences were observed for cancer screening participation between groups. Conclusions: To increase recognition of diabetes, targeted screening tests should be implemented in deprived regions, even among individuals without any comorbidities. Our study also indicates that diagnosis of diabetes is not only important for the timely initiation of therapy, but it can also motivate individuals in deprived areas to lead a healthier lifestyle.

Chemically induced carcinogenesis in rodent models of aging: assessing organismal resilience to genotoxic stressors in geroscience research.

There is significant overlap between the cellular and molecular mechanisms of aging and pathways contributing to carcinogenesis, including the role of genome maintenance pathways. In the field of geroscience analysis of novel genetic mouse models with either a shortened, or an extended, lifespan provides a unique opportunity to evaluate the synergistic roles of longevity assurance pathways in cancer resistance and regulation of lifespan and to develop novel targets for interventions that both delay aging and prevent carcinogenesis. There is a growing need for robust assays to assess the susceptibility of cancer in these models. The present review focuses on a well-characterized method frequently used in cancer research, which can be adapted to study resilience to genotoxic stress and susceptibility to genotoxic stress-induced carcinogenesis in geroscience research namely, chemical carcinogenesis induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA). Recent progress in understanding how longer-living mice may achieve resistance to chemical carcinogenesis and how these pathways are modulated by anti-aging interventions is reviewed. Strain-specific differences in sensitivity to DMBA-induced carcinogenesis are also explored and contrasted with mouse lifespan. The clinical relevance of inhibition of DMBA-induced carcinogenesis for the pathogenesis of mammary adenocarcinomas in older human subjects is discussed. Finally, the potential role of insulin-like growth factor-1 (IGF-1) in the regulation of pathways responsible for cellular resilience to DMBA-induced mutagenesis is discussed.

Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.

Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1f/f  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients.

Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection.

Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension-induced CMHs young (3 months) and aged (24 months) mice were treated with angiotensin II plus L-NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension-induced cerebrovascular oxidative stress and redox-sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension-induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients.

Aging impairs myogenic adaptation to pulsatile pressure in mouse cerebral arteries.

Stability of myogenic tone in middle cerebral arteries (MCA) is essential for adequate control over penetration of pressure waves into the distal portion of the cerebral microcirculation. Because the increased pulse pressure observed in advanced aging is associated with cerebromicrovascular injury, the effect of aging on myogenic response of mouse MCAs was determined. Aging did not affect the myogenic constriction in response to static increases in pressure, whereas it significantly impaired pulsatile pressure-induced myogenic tone. Impaired myogenic adaptation of MCAs to pulsatile pressure may allow high pressure to penetrate the distal portion of the cerebral microcirculation, contributing to microvascular damage.

Aging Exacerbates Pressure-Induced Mitochondrial Oxidative Stress in Mouse Cerebral Arteries.

Epidemiological studies demonstrate that in addition to the increased prevalence of hypertension in old patients, the deleterious cerebrovascular effects of hypertension (including atherosclerosis, stroke, and vascular cognitive impairment) are also exacerbated in elderly individuals. The cellular mechanisms by which aging and hypertension interact to promote cerebrovascular pathologies are not well understood. To test the hypothesis that aging exacerbates high pressure-induced mitochondrial oxidative stress, we exposed isolated segments of the middle cerebral arteries of young (3 months) and aged (24 months) C57BL/6 mice to 60 or 140 mmHg intraluminal pressure and assessed changes in mitochondrial reactive oxygen species production using a mitochondria-targeted redox-sensitive fluorescent indicator dye (MitoSox) by confocal microscopy. Perinuclear MitoSox fluorescence was significantly stronger in high pressure-exposed middle cerebral arteries compared with middle cerebral arteries of the same animals exposed to 60 mmHg, indicating that high pressure increases mitochondrial reactive oxygen species production in the smooth muscle cells of cerebral arteries. Comparison of young and aged middle cerebral arteries showed that aging exacerbates high pressure-induced mitochondrial reactive oxygen species production in cerebral arteries. We propose that increased mechanosensitive mitochondrial oxidative stress may potentially exacerbate cerebrovascular injury and vascular inflammation in aging.

Treatment with the cytochrome P450 ω-hydroxylase inhibitor HET0016 attenuates cerebrovascular inflammation, oxidative stress and improves vasomotor function in spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Hypertension increases cerebrovascular oxidative stress and inflammation and impairs vasomotor function. These pathological alterations lead to dysregulation of cerebral blood flow and exacerbate atherogenesis, increasing the morbidity of ischaemic cerebrovascular diseases and promoting vascular cognitive impairment. We aimed to test the hypothesis that increased production of the arachidonic acid metabolite 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) contributes to hypertension-induced cerebrovascular alterations. EXPERIMENTAL APPROACH: We treated male spontaneously hypertensive rats (SHR) with HET0016 (N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine), an inhibitor of 20-HETE synthesis. In middle cerebral arteries (MCAs) of SHRs, we focused on vasomotor responses and end points that are highly relevant for cellular reactive oxygen species (ROS) production, inflammatory cytokine expression and NF-κB activation. KEY RESULTS: SHRs treated with HET0016 remained hypertensive (SHR + HET0016: 149 ± 8 mmHg, Wistar-Kyoto rat: 115 ± 4 mmHg; P < 0.05.), although their systolic blood pressure was decreased compared to untreated SHRs (191 ± 6 mmHg). In MCAs of SHRs, flow-induced constriction was increased, whereas ACh- and ATP-induced dilations were impaired. This functional impairment was reversed by treatment with HET0016. Treatment with HET0016 also significantly decreased oxidative stress in MCAs of SHRs (as shown by dihydroethidium staining and analysis of vascular 5-nitrotyrosine, 4-hydroxynonenal and carbonyl content) and inhibited cerebrovascular inflammation (shown by the reduced mRNA expression of TNFα, IL-1ß and IL-6). Treatment of SHRs with HET0016 also attenuated vascular NF-κB activation. In vitro treatment with 20-HETE significantly increased vascular production of ROS and promoted NF-κB activation in cultured cerebromicrovascular endothelial cells. CONCLUSIONS AND IMPLICATIONS: Taken together, treatment with HET0016 confers anti-oxidative and anti-inflammatory effects in the cerebral arteries of SHRs by disrupting 20-HETE-mediated autocrine/paracrine signalling pathways in the vascular wall. It is likely that HET0016-induced decreases in blood pressure also potentiate the cerebrovascular protective effects of the drug.

Isolated human and rat cerebral arteries constrict to increases in flow: role of 20-HETE and TP receptors.

Elevation of intraluminal pressure increases vasomotor tone, which thought to have a substantial role in regulation of cerebral blood flow (CBF). Interestingly, responses of cerebral vessels to increases in flow varied and have not been studied in human cerebral arteries. We hypothesized that increases in flow elicit constrictions of isolated human and rat cerebral arteries and aimed to elucidate the underlying mechanisms. Human cerebral arteries and rat middle cerebral arteries constricted to increases in flow (P<0.05). Simultaneous increase in intraluminal flow+pressure further reduced the diameter compared with pressure-induced changes (P<0.05), leading to constant estimated CBF. Flow-induced constrictions were abolished by HET0016 (inhibitor of synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) or inhibition of COXs or blocking TP (thromboxane A(2)/prostaglandin H(2), receptors and attenuated by scavenging reactive oxygen species (ROS). Flow-enhanced ROS formation was significantly reduced by HET0016. In conclusion, in human and rat cerebral arteries (1) increases in flow elicit constrictions, (2) signaling mechanism of flow-induced constriction of cerebral arteries involves enhanced production of ROS, COX activity, and mediated by 20-HETE via TP receptors, and (3) we propose that simultaneous operation of pressure- and flow-induced constrictions is necessary to provide an effective autoregulation of CBF.