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The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.

Background Hypertension (HTN) is an established risk factor for chronic kidney disease (CKD) and end-stage renal disease (ESRD). Whether sex differences in the effect of HTN on CKD and ESRD incidence exist remains unclear. This systematic review and meta-analysis was conducted to evaluate the relative impact of HTN on CKD and ESRD risk in women compared with men. Methods We systematically searched Embase and PubMed for cohort studies until 24 July 2020. Studies were selected if they reported a sex-specific association between systolic blood pressure (SBP) and CKD or ESRD. Random effects meta-analyses with inverse variance weighting were used to pool sex-specific relative risks (RRs) and the women-to-men ratio of RRs (the RRR) for incident CKD and ESRD. Results Data from six cohorts, including 2,382,712 individuals and 6856 incident CKD events, and 833 ESRD events, were included in the meta-analysis. The RR for incident CKD or ESRD associated with HTN (SBP ≥140 mmHg) versus ideal BP (SBP < 120 mmHg) was 1.56 (95% CI, 1.39–1.75) in women and 2.06 (95% CI, 1.64–2.60) in men. The RR for incident CKD or ESRD was 23% lower in women than in men RRR 0.77 [95% CI, 0.63–0.95] with no significant heterogeneity between studies ( p -value for Q test = 0.507, I 2  = 17.7%). Conclusion HTN confers about a fifth lower excess risk of incident CKD or ESRD in women than men. Sex differences in onset, duration, and severity of some risk factors, such as albuminuria, diabetes, cardiovascular disease, obesity, and socioeconomic status, may explain part of the excess risk in men. Another explanation could be that women might be under-diagnosed and less likely to initiate dialysis. Future studies are needed to demonstrate the mechanisms responsible for the observed sex difference.

Background Fluid overload is frequently found in acute kidney injury patients in critical care units. Recent studies have shown the relationship of fluid overload with adverse outcomes; hence, manage and optimization of fluid balance becomes a central component of the management of critically ill patients. Discussion In critically ill patients, in order to restore cardiac output, systemic blood pressure and renal perfusion an adequate fluid resuscitation is essential. Achieving an appropriate level of volume management requires knowledge of the underlying pathophysiology, evaluation of volume status, and selection of appropriate solution for volume repletion, and maintenance and modulation of the tissue perfusion. Numerous recent studies have established a correlation between fluid overload and mortality in critically ill patients. Fluid overload recognition and assessment requires an accurate documentation of intakes and outputs; yet, there is a wide difference in how it is evaluated, reviewed and utilized. Accurate volume status evaluation is essential for appropriate therapy since errors of volume evaluation can result in either in lack of essential treatment or unnecessary fluid administration, and both scenarios are associated with increased mortality. There are several methods to evaluate fluid status; however, most of the tests currently used are fairly inaccurate. Diuretics, especially loop diuretics, remain a valid therapeutic alternative. Fluid overload refractory to medical therapy requires the application of extracorporeal therapies. Summary In critically ill patients, fluid overload is related to increased mortality and also lead to several complications like pulmonary edema, cardiac failure, delayed wound healing, tissue breakdown, and impaired bowel function. Therefore, the evaluation of volume status is crucial in the early management of critically ill patients. Diuretics are frequently used as an initial therapy; however, due to their limited effectiveness the use of continuous renal replacement techniques are often required for fluid overload treatment. Successful fluid overload treatment depends on precise assessment of individual volume status, understanding the principles of fluid management with ultrafiltration, and clear treatment goals.

Fatiguing inspiratory work has been shown to evoke a sympathetically mediated reflex that has systemic cardiovascular consequences, including increases in heart rate and blood pressure and a decrease in resting limb vascular conductance. Moreover, the response to this reflex appears to be attenuated in females compared with males. It remains to be seen whether this respiratory muscle metaboreflex also exerts an effect on cerebral blood flow. Cerebral blood flow is tightly regulated to maintain homeostasis and critical function. Therefore, it stands to reason that cerebrovascular haemodynamics would not be compromised through this respiratory muscle metaboreflex. We hypothesized that fatiguing inspiratory work would reduce resting limb conductance, but cerebral blood flow would be minimally impaired. Females (34 ± 10 years old, n  = 12) and males (31 ± 8 years old, n  = 12) performed a 5 min, high‐intensity bout of inspiratory pressure threshold loading (IPTL) designed to evoke the respiratory muscle metaboreflex. In response to IPTL, mean arterial pressure increased in both males and females ( p < 0.001), and limb vascular conductance decreased to a greater degree in males than in females ( p = 0.005). The cerebrovascular conductance index was higher in females ( p = 0.007) but not affected by IPTL ( p = 0.417). Our findings suggest that cerebral blood flow is spared from the redistribution of blood flow in response to fatiguing inspiratory work and that this protection is true in both males and females. What is the central question of this study? The respiratory muscle metaboreflex is thought to ‘steal’ cardiac output from the peripheral muscles to facilitate the demand of the respiratory muscles. Fatiguing inspiratory muscle work might also negatively impact cerebral blood flow. What is the main finding and its importance? Our findings show that activation of the respiratory muscle metaboreflex does not compromise cerebrovascular function. Additionally, the cerebrovascular response to the muscle metaboreflex response is similar between males and females.

It is well established that vascular dysfunction is common in people with diabetes mellitus and is associated with increased risk of heart attack, ischaemic stroke and peripheral vascular disease. Although our understanding of the molecular mechanisms responsible is incomplete, persistent hyperglycaemia observed in poorly controlled diabetes has long been thought to be a critical factor. Multiple studies have, therefore, investigated the effects of poor glycaemic control on vascular function in multiple experimental settings, from in vitro and ex vivo models of primary human cells and tissues through to pre-clinical models. This review consolidates our current understanding of how metabolic and cell signalling pathways triggered by poor glycaemic control, impact vascular function in diabetes. We also evaluate how these pathways could be exploited to develop targeted therapeutic approaches to improve cardiovascular outcomes specifically in people with diabetes.

Background Apparent treatment-resistant hypertension (aTRH) is a common condition associated with risk of cardiovascular events. However, the risk of cardiovascular mortality associated with aTRH in the US population is unknown. We aimed to assess the risk of cardiovascular disease (CVD) mortality associated with aTRH in the US population. Methods We analyzed data from 6357 adult hypertensive participants of the National Health and Nutrition Examination Survey (1988–1994 and 1999–2010) linked to the National Death Index. Based on presence of uncontrolled hypertension [blood pressure (BP) ≥140/90 mmHg] and the number of antihypertensives prescribed, we classified participants into the following groups: non-aTRH (BP < 140/90 mmHg and ≤ 3 antihypertensives); controlled aTRH (BP < 140/90 mmHg and ≥ 4 antihypertensives); and uncontrolled aTRH (BP ≥140/90 mmHg and ≥ 3 antihypertensives). Results Of the 6357 participants, 1522 had aTRH, representing a US prevalence of 7.6 million. Of the participants with aTRH, 432 had controlled aTRH and 1090 had uncontrolled aTRH. During follow-up (median 6 years), there were 550 CVD deaths. The cumulative incidence of CVD mortality was significantly higher in the aTRH group compared with non-aTRH group (log-rank p  < 0.001). In fully adjusted models, aTRH was associated with a 47% higher risk of CVD mortality compared with the non-aTRH group [1.47 (1.1–1.96)]. Similar increase in risk of CVD mortality was noted across aTRH subgroups compared with the non-aTRH group: controlled aTRH [1.66 (1.03–2.68)] and uncontrolled aTRH [1.43 (1.05–1.94)]. Among non-aTRH subgroups, those on 3 antihypertensive medications had a 35% increased risk of CVD mortality than those on < 3 medications [1.35 (0.98–1.86)]. Conclusions aTRH is a common condition, affecting approximately 7.6 million Americans. Regardless of BP control, people with aTRH remain at a higher risk of cardiovascular outcomes. The risk of cardiovascular disease mortality remains high among those with controlled BP on 3 medications (non-aTRH) or ≥ 4 medications (controlled aTRH), groups not generally considered at high risk. Future risk reduction interventions should consider focusing on these high-risk groups.

Background/Aims: Pulse wave analysis (PWA) and pulse wave velocity (PWV) provide information about arterial stiffness and elasticity, which is mainly used for cardiovascular risk stratification. In the presented prospective observational pilot study, we examined the hypothesis that radiocephalic fistula (RCF)-related changes of haemodynamics and blood vessel morphology including high as well as low flow can be seen in specific changes of pulse wave (PW) morphology. Methods: Fifty-six patients with RCF underwent local ambilateral peripheral PWA and PWV measurement with the SphygmoCor® device. Given that the output parameters of the SphygmoCor® are not relevant for the study objectives, we defined new suitable parameters for PWA in direct proximity to fistulas and established an appropriate analysing algorithm. Duplex sonography served as reference method. Results: Marked changes of peripheral PW morphology when considering interarm differences of slope and areas between the fistula and non-fistula arms were observed in the Arteria radialis, A. brachialis and arterialized Vena cephalica. The sum of the slope differences was found to correlate with an increased flow, while in patients with fistula failure no changes in PW morphology were seen. Moreover, PWV was significantly reduced in the fistula arm. Conclusion: Beside duplex sonography, ambilateral peripheral PWA and PWV measurements are potential new clinical applications to characterize and monitor RCF function, especially in terms of high and low flow.

▪ Abstract  We review major experimental and theoretical studies on microcirculation and hemorheology, focusing on mechanics of blood flow and the vascular wall. We discuss flow of the blood formed elements [red blood cells (RBCs), white blood cells or leukocytes (WBCs) and platelets] in individual arterioles, capillaries, and venules, and in microvascular networks. We also review mechanical and rheological properties of the formed elements and their interactions with the vascular wall. We discuss short-term and long-term regulation of the microvasculature; the modes of regulation include metabolic, myogenic, and shear-stress-dependent mechanisms as well as vascular adaptation such as angiogenesis and vascular remodeling.

Background Acute Kidney injury (AKI) is common and increases mortality in the intensive care unit (ICU). We carried out this study to explore whether fluid overload is an independent risk factor for AKI. Methods Single-center prospective, observational study. Consecutively admitted, ICU patients were followed for development of AKI. Intravenous fluid volumes, daily fluid balances were measured, hourly urine volumes, daily creatinine levels were recorded. Results Three hundred thirty nine patients were included; AKI developed in 141 (41.6%) patients; RISK in 27 (8%) patients; INJURY in 25 (7%); FAILURE in 89 (26%) by the RIFLE criteria. Fluid balance was significantly higher in patients with AKI; 1755 ± 2189 v/s 924 ± 1846 ml, p  < 0.001 on ICU day 1. On multivariate regression analysis, a net fluid balance in first 24 h of ICU admission, OR 1.02 (95% CI 1.01,1.03 p  = 0.003), percentage of fluid accumulation adjusted for body weight OR1.009 (95% CI 1.001,1.017, p  = 0.02), fluid balance in first 24 h of ICU admission with serum creatinine adjusted for fluid balance, OR 1.024 (95% CI 1.012,1,035, p  = 0.005), Age, OR 1.02 95% CI 1.01,1.03, p  < 0.001, CHF, OR 3.1 (95% CI 1.16,8.32, p  = 0.023), vasopressor requirement on ICU day one, OR 1.9 (95% CI 1.13,3.19, p  = 0.014) and Colistin OR 2.3 (95% CI 1.3, 4.02, p  < 0.001) were significant predictors of AKI. There was no significant association between fluid type; Chloride-liberal, Chloride-restrictive, and AKI. Conclusions Fluid overload is an independent risk factor for AKI.

Background Spironolactone can improve endothelial dysfunction in the setting of heart failure and diabetes models. However, its beneficial effect in the cardiovascular system is not clear in the setting of non-diabetic renal failure. We conducted this study to investigate whether spironolactone can ameliorate endothelial dysfunction in a 5/6 nephrectomy model, and to determine the underlying mechanism. Methods Twenty-four Sprague-Dawley rats were divided into four groups. A renal failure model was created using the 5/6 nephrectomy method. The four groups included: Sham-operation group (Group1), chronic kidney disease (CKD; Group2), CKD + ALT-711 (advanced glycation end products [AGEs] breaker; Group 3), and CKD + spironolactone group (Group4). Acetylcholine (Ach)-mediated vasodilatation responses were compared between the four groups. To investigate the underlying mechanism, we cultured human aortic endothelial cells (HAECs) for in-vitro assays. Differences between two groups were determined with the paired student’s t test. Differences between three or more groups were determined through one-way analysis of variance (ANOVA) with post-hoc analysis with LSD method. Results Compared with Group 1, Group 2 has a significantly impaired Ach-mediated vasodilatation response. Group 3 and 4 exhibited improved vasoreactivity responses. To determine the underlying mechanism, we performed an in-vitro study using cultured HAECs. We noted significant sirtuin-3 (SIRT3) protein downregulation, reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 (p-eNOS), and increased intracellular oxidative stress in cultured HAECs treated with AGEs (200 μg/mL). These effects were counter-regulated when cultured HAECs were pretreated with spironolactone (10 μM). Furthermore, the increased p-eNOS production by spironolactone was abrogated when the HAECs were pretreated with tenolvin (1 μM), a SIRT3 inhibitor. Conclusions Spironolactone could ameliorate endothelial dysfunction in a 5/6 nephrectomy renal failure model through AGEs/Receptor for AGEs (RAGEs) axis inhibition, SIRT3 upregulation, and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) and its associated intracellular oxidative stress attenuation.