Human Circulation Research Articles

Dual pattern recognition receptor ligands CL401, CL413, and CL429 as adjuvants for inactivated chikungunya virus

Chikungunya virus (CHIKV) is responsible for incapacitating joint pains and is a significant health hazard in many countries. Though a definite need for a CHIKV vaccine is felt, long disappearance of CHIKV from circulation in humans has been a concern for vaccine development. Use of two separate pattern recognition receptor ligands has been shown to enhance immune response to the administered antigen. In addition, intradermal delivery of vaccine tends to mimic the natural mode of CHIKV infection. Therefore, in this study, we explored whether intradermal and intramuscular immunization with inactivated CHIKV (I–CHIKV) supplemented with dual pattern-recognition receptor ligands, CL401, CL413, and CL429, is an effective approach to enhancing antibody response to CHIKV. Our in vivo data show that I–CHIKV supplemented with these chimeric PRR ligands induces enhanced neutralizing antibody response after intradermal delivery, but is less efficient after intramuscular immunization. These results suggest that intradermal delivery of I–CHIKV with chimeric adjuvants is a possible way to elicited a better antibody response.

Human blood circulation model based on flow laws of intensity and continuity in relation to earth’s surface gravity

With the help of the physical laws of flow, it is possible to describe the entire human blood circulation. However, this requires precise knowledge of the individual parameters. Within this, the determination of the flow rate included in the law of continuity is essential. Together with the data of the heart and circulation examination procedures, in order to establish the average human blood circulation, an intermediate velocity value must be selected, which is located in the middle between the two extreme velocities of the blood circulation. Another important factor from the point of view of the structure and operation of the model is the value of the earth's surface gravity. By finding the average flow speed value and using ‘g’, a torus-shaped circulation can be created, which can actually reflect the circulation conditions. By further refining the model, the pulmonary and systemic circulations can be separated and a ‘folded figure eight’ model can be formed. This realistically reflects the different sizes, flow and pressure conditions of the two blood circulations, as well as the work of the left and right sides of the heart.

Exploring Immersive Co-Design: Comparing Human Interaction in Real and Virtual Elevated Urban Spaces in London

Virtual reality (VR) technology has the potential to revolutionize public engagement in the design of urban projects, leading to more sustainable and inclusive environments. This research scrutinizes this potential through a study of elevated urban spaces, specifically the Sky Garden and Crossrail Place in London. Comparing real and virtual interactions, the aim is to highlight their differences and similarities while underscoring the importance of design decision-making for sustainable public places. Through walk-along interviews with 33 visitors in each space and a VR experiment with a separate group of 33 participants, the study analyses the effectiveness of VR as a co-design tool. The outcomes demonstrate that VR positively influences user involvement and allows for the production and real-time testing of design alternatives. Significantly, the majority of participants, who had not physically visited the spaces, could identify design concerns and propose potential activities and features through the VR experiment. These findings were consistent with those expressed by actual users of the spaces. By comparing human activities, circulation, and design concerns in both physical and virtual environments, the research underscores the potential and limitations of VR as a co-design tool for creating sustainable public spaces.

Kawasaki Disease and Respiratory Viruses: Ecological Spatiotemporal Analysis.

Kawasaki disease is an uncommon vasculitis affecting young children. Its etiology is not completely understood, although infections have been frequently postulated as the triggers. Respiratory viruses, specifically, have often been implicated as causative agents for Kawasaki disease presentations. We aimed to conduct an ecological spatiotemporal analysis to determine whether Kawasaki disease incidence was related to community respiratory virus circulation in a shared region and population, and to describe viral associations before and during the COVID-19 pandemic. We obtained independent statewide data sets of hospital admissions of Kawasaki disease and respiratory multiplex polymerase chain reaction tests performed at two large hospital networks in Victoria, Australia, from July 2011 to November 2021. We studied spatiotemporal relationships by negative binomial regression analysis of the monthly incidence of Kawasaki disease and the rate of positive respiratory polymerase chain reaction tests in different regions of Victoria. Peak viral seasons (95th percentile incidence) were compared to median viral circulation (50th percentile incidence) to calculate peak season increased rate ratios. While no seasonal trend in Kawasaki disease incidence was identified throughout the study period, we found a 1.52 (99% CI 1.27-1.82) and a 1.43 (99% CI 1.17-1.73) increased rate ratio of Kawasaki disease presentations in association with human metapneumovirus and respiratory syncytial virus circulation, respectively, before the COVID-19 pandemic. No respiratory viral associations with Kawasaki disease were observed during the COVID-19 pandemic. Our large ecological analysis demonstrates novel spatiotemporal relationships between human metapneumovirus and respiratory syncytial virus circulation with Kawasaki disease. The disappearance of these associations in the COVID-19 pandemic may reflect the reduced circulation of non-SARS-CoV-2 viruses during this period, supporting the prepandemic associations identified in this study. The roles of human metapneumovirus and respiratory syncytial virus in Kawasaki disease etiology warrant further investigation.

Therapeutic applications of nanoparticles targeting neutrophil and extracellular traps.

Neutrophils, the most abundant leukocytes in human circulation, are key effectors and regulators of both innate and adaptive immunity which migrate from the bloodstream to sites of inflammation or infection in response to different stimuli. A growing body of evidence has revealed that dysregulated neutrophil activity contributes to the development of several diseases. Targeting their function has been proposed as a potential strategy to treat or mitigate the progression of these disorders. Additionally, neutrophil tropism has been proposed as a strategy to drive therapeutic agents towards targeted disease sites. In this article, we review the proposed nanomedicine approaches to target neutrophils and their components, the regulation of their function and the use of their tropism in drug delivery for therapeutic purposes.

KRITIK KENYAMANAN BANGUNAN RUMAH KOS DI LOWOKWARU KOTA MALANG

Malang is a student city, marked by the many universities in Malang, but many boarding houses do not provide comfort to the residents. Comfort which is the focus of research is lighting, ventilation and circulation settings. The method used is descriptive deductive architectural criticism, namely departing from theory to gain substantive knowledge and its parameters. Based on the analysis of comfort, it was found that the area of the lighting opening in room 1 was 2.61m2, and in rooms 2, 3 and 4 it was 1.26m2. This means that the lighting in room 1 meets the standard, while rooms 2, 3 and 4 do not meet the standard. In terms of ventilation, room 1 has a ventilation area of 4.74m2 and rooms 2, 3 and 4 have an ventilation area of 2.04m2. Means that all rooms have met the standard. In terms of human and vehicle circulation, the object has a width of 1m which functions as access for motorbikes from the gate to the parking lot, and the motorbike parking area for the object has a size of 1.5m x 3m for 2 motorbikes, meaning it does not meet the standards.

Association between seroprevalence of measles virus in monkeys and degree of human-monkey contact in Bangladesh

Measles infections can cause significant morbidity and mortality in human and monkey populations. The endemicity of measles in human populations and viral circulation within populations of free-living monkeys may have important repercussions for potential zoonotic transmission events and for the long-term health of monkey populations. Yet, there has not yet been a rigorous investigation of the dynamics of measles transmission where human and monkey populations coexist. In this study, to determine the difference in seroprevalence of the measles virus across different contexts of human-monkey contact, we analyzed serum samples collected from 56 apparently healthy Macaca mulatta monkeys who occupied diverse contexts, with different degrees of human-monkey contact, in Bangladesh. This is the first report of measles virus seroprevalence in monkeys in Bangladesh. We found a clear association between measles virus seropositivity in monkeys and the context in which they interact with humans. Seroprevalence was the lowest in wild areas (0.0%) and increased in shrines (4.8%), urban areas (5.9%), and was highest among monkeys who are used as performance animals (50.0%). This work suggests that a One Health approach informed by local interspecies transmission dynamics is necessary to develop strategies that both improve measles vaccination coverage, achieve long-term surveillance in monkey populations, and prevent measles spillback to monkeys. This approach aims to inform conservation efforts and protect the long-term health of human and monkey populations.

Recasting Current Knowledge of Human Fetal Circulation: The Importance of Computational Models.

Computational hemodynamic simulations are becoming increasingly important for cardiovascular research and clinical practice, yet incorporating numerical simulations of human fetal circulation is relatively underutilized and underdeveloped. The fetus possesses unique vascular shunts to appropriately distribute oxygen and nutrients acquired from the placenta, adding complexity and adaptability to blood flow patterns within the fetal vascular network. Perturbations to fetal circulation compromise fetal growth and trigger the abnormal cardiovascular remodeling that underlies congenital heart defects. Computational modeling can be used to elucidate complex blood flow patterns in the fetal circulatory system for normal versus abnormal development. We present an overview of fetal cardiovascular physiology and its evolution from being investigated with invasive experiments and primitive imaging techniques to advanced imaging (4D MRI and ultrasound) and computational modeling. We introduce the theoretical backgrounds of both lumped-parameter networks and three-dimensional computational fluid dynamic simulations of the cardiovascular system. We subsequently summarize existing modeling studies of human fetal circulation along with their limitations and challenges. Finally, we highlight opportunities for improved fetal circulation models.

Specific dilation pattern in placental circulation and the NO/sGC role in preeclampsia placental vessels.

Endothelial functions in controlling blood flow in placental circulation are still unclear. The present study compares vascular dilations between placental circulation and other vessels, as well as between normal and preeclampsia placental vessels. Placental, umbilical, and other vessels (cerebral and mesenteric arteries) were collected from humans, sheep, and rats. Vasodilation was tested by JZ101 and DMT. Q-PCR, Western blot, and Elisa were used for molecular experiments. Endothelium-dependent/derived vasodilators, including acetylcholine, bradykinin, prostacyclin, and histamine, mediated no or minimal dilation in placental circulation, which was different from that in other vessels in sheep and rats. There were lower mRNA expressions of muscarinic receptors, histamine receptors, bradykinin receptor 2, endothelial nitric oxide synthesis (eNOS), and less nitric oxide (NO) in human umbilical vessels when compared with placental vessels. Exogenous NO donors (sodium nitroprusside, SNP) and soluble guanylate cyclase (sGC) activators (Bay41-2272) decreased the baseline of vessel tone in placental circulation in humans, sheep, and rats, but not in other arteries. The sGC inhibitor ODQ suppressed the reduced baseline caused by the SNP. The decreased baseline by SNP or Bay41-2272 was higher in placental vessels than in umbilical vessels, suggesting that the role of NO/sGC is more important in the placenta. NO concentrations in preeclampsia placental vessels were lower than those in control, while no significant change was found in umbilical plasma between the two groups. eNOS expression was similar between normal and preeclampsia placental vessels, but phosphorylated eNOS levels were significantly lower in preeclampsia. Following serotonin, SNP or Bay41-2272-mediated dilations were weaker in preeclampsia placental vessels. The decreased amplitude of SNP- or Bay41-2272 at baseline was smaller in preeclampsia. The decreased amplitudes of ODQ + SNP were comparable between the two groups. Despite higher beta sGC expression, sGC activity in the preeclampsia placenta was lower. This study demonstrated that receptor-mediated endothelium-dependent dilation in placental circulation was significantly weaker than other vessels in various species. The results, showed firstly, that exogenous NO played a role in regulating the baseline tone of placental circulation via sGC. Lower NO production and decreased NO/sGC could be one of the reasons for preeclampsia. The findings contribute to understanding specific features of placental circulation and provide information about preeclampsia in placental vessels.

Mechanical and hemodynamic effects of left bundle branch area versus biventricular pacing in virtual heart failure patients with left bundle branch block

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO) Background Left bundle branch area pacing (LBBAP) has been introduced as an alternative, more physiological pacing strategy to biventricular pacing (BiVP). LBBAP can result in selective LBB pacing (sLBBP), non-selective LBB pacing (nsLBBP), or LV septal pacing (LVSP). Direct comparison between the different pacing strategies is challenging due to the practical implications of performing multiple pacing procedures within the same patients, as well as the large heterogeneity of underlying disease in patients. Computational models can be used to perform controlled in silico experiments and to compare all possible pacing modalities under the same conditions. Aim To investigate the effects of LBBAP strategies versus BiVP on cardiac mechanics and hemodynamics in a set of well-defined virtual heart failure patients. Methods An electrophysiological model was used to calculate biventricular electrical activation maps during LBBB and the different pacing strategies. The resulting regional activation times were imposed to the well-validated CircAdapt model of the human four-chamber heart and circulation. A set of virtual patients at different stages of heart failure are then defined within the CircAdapt framework, which is achieved by decreasing the contractility of the LV myocardium, such that LVEF≤35%. The CircAdapt model is then used to compute regional ventricular strain patterns and myocardial work as well as global ventricular pump function during LBBB, BiVP and the different LBBAP modalities. Results Selective LBBP is best at restoring mechanical homogeneity in LV contraction as evidenced by simulated wall strains waveforms (Fig 1, Left). NsLBBP increases septal dyssynchrony and introduces small pre-stretch in the LVfw (1.3±0.3%). This effect is more pronounced in LVSP (2.4±1.4%). In BiVP, pre-stretch occurs only in a single LV free wall (LVfw) segment, but all septal segments display a distinct oscillatory pattern. Work load homogeneity (Fig 1, Center) was best restored in sLBBP (4.9±1.1 kPa). NsLBBP lead to reduced homogeneity (4.9±1.8 kPa). LVSP reduced this further (4.8±2.6kPa), while BiVP performed similarly (4.6±2.6kPa) to LVSP. All modalities vastly improved on the baseline LBBB (4.06±5.6 kPa). Hemodynamically (Fig 1, Right), sLBBP showed greatest improvement in LV function (LVESV:-8.1%; LVEF:+6.8%; MLAP:-16.4%; LVdp/dtmax:+12.8%), followed by nsLBBP (LVESV:-7.2%; LVEF:+6.0%; MLAP:-14.5%; LVdp/dtmax:+12.5%), LVSP (LVESV:-5.6%; LVEF:+4.6%; MLAP:-11.7%; LVdp/dtmax:+12.358%) and finally BiVP (LVESV: -4.6%; LVEF:+3.8%; MLAP:-9.3%; LVdp/dtmax:+9.8%) Conclusion We were able to simulate LBBB and subsequent pacing strategies in virtual heart failure patients. This approach allowed direct comparison of mechanical and hemodynamic effects of BiVP and LBBAP modalities without confounding variables. Our results indicate that all LBBAP modalities perform at least similar to bi-ventricular pacing regardless of mechanical viability.

A retirement mobilities approach to transnational ageing

Transnational ageing processes are usually studied by focusing on the various cross-border practices and mobilities of different categories of ageing migrants. This paper introduces a retirement mobilities approach as an analytical framework that draws on both transnational studies and the new mobilities paradigm to widen the theoretical and empirical debates. It argues that both migrant and non-migrant populations, as well as human and non-human cross-border circulations, have to be taken into account when studying transnational ageing. Based on a mixed-methods study combining original data from a quantitative survey conducted in Switzerland with residents 55+ and semi-structured interviews held in Spain and Switzerland with older adults receiving a Swiss pension, we demonstrate the heuristic value of this approach. Indeed, empirical findings indicate that older adults with and without a migration background represent an internationally mobile population with similar mobility aspirations and transnational lifestyles. However, the motivations driving these two groups’ transnational mobility differ significantly. Moreover, transnational circulations of financial resources, and in particular retirement pensions, are interlinked with mobility in old age. To conclude, a retirement mobilities approach sets a new research agenda, inviting scholars to examine transnational ageing beyond the ageing-migration nexus.

Pengaruh Model Pembelajaran Kooperatif Tipe Team Games Tournament (TGT) Berbantuan Media Poster Terhadap Hasil Belajar IPA Terpadu Di SMP Negeri 1 Waibakul

This research was conducted to determine the effect of using the Team Games Tournament (TGT) type of cooperative learning model on the science learning outcomes of class VIII students on the human circulation system material at SMP Negeri 1 Waibakul. The research method uses a quasi experiment, this study uses class VII-A as the control class and class VIII-C as the experimental class. The research design uses a nonequivalent control group design. This study used a sample of 72 students using non-probability sampling. Learning outcomes in the cognitive domain are obtained from pretest and posttest scores. Student learning outcomes were analyzed using statistical analysis and inferential statistics in the form of a t test. The results of the analysis obtained that the average value of the experimental class posttest was 85.33 and the control class posttest was 61.97. Based on testing the hypothesis with the t test at α = 0.05, a sig (2-tailed) value of 0.000 is obtained so that it can be concluded that H1 is accepted and H0 is rejected, meaning that there is an effect of using the Team Games Tournament (TGT) cooperative learning model on students' natural science learning outcomes. VIII on human circulatory system material at SMP Negeri 1 Waibakul.

Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes.

Peroxisome proliferator-activated receptor γ (PPARγ) plays a pivotal role in regulating lipid metabolism and hepatic PPARγ transactivation contributes to fatty liver development. Fatty acids (FAs) are well-known endogenous ligands for PPARγ. Palmitate, a 16-C saturated FA (SFA) and the most abundant SFA in human circulation, is a strong inducer of hepatic lipotoxicity, a central pathogenic factor for various fatty liver diseases. In this study, using both alpha mouse liver 12 (AML12) and primary mouse hepatocytes, we investigated the effects of palmitate on hepatic PPARγ transactivation and underlying mechanisms, as well as the role of PPARγ transactivation in palmitate-induced hepatic lipotoxicity, all of which remain ambiguous currently. Our data revealed that palmitate exposure was concomitant with both PPARγ transactivation and upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis. Importantly, we discovered that PPARγ transactivation by palmitate was blunted by NNMT inhibition, suggesting that NNMT upregulation plays a mechanistic role in PPARγ transactivation. Further investigations uncovered that palmitate exposure is associated with intracellular NAD+ decline and NAD+ replenishment with NAD+-enhancing agents, nicotinamide and nicotinamide riboside, obstructed palmitate-induced PPARγ transactivation, implying that cellular NAD+ decline resulted from NNMT upregulation represents a potential mechanism behind palmitate-elicited PPARγ transactivation. At last, our data showed that the PPARγ transactivation marginally ameliorated palmitate-induced intracellular triacylglycerol accumulation and cell death. Collectively, our data provided the first-line evidence supporting that NNMT upregulation plays a mechanistic role in palmitate-elicited PPARγ transactivation, potentially through reducing cellular NAD+ contents.NEW & NOTEWORTHY Hepatic PPARγ transactivation contributes to fatty liver development. Saturated fatty acids (SFAs) induce hepatic lipotoxicity. Here, we investigated whether and how palmitate, the most abundant SFA in the human blood, affects PPARγ transactivation in hepatocytes. We reported for the first time that upregulation of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing the degradation of nicotinamide, the predominant precursor for cellular NAD+ biosynthesis, plays a mechanistic role in regulating palmitate-elicited PPARγ transactivation through reducing intracellular NAD+ contents.

Evaluation of contemporary methods to determine vascular impedance.

The past decade has seen considerable growth in therapeutics and device technologies to treat patients with hypertension and other cardiovascular disease states. Uncoupling ventriculo-arterial interactions in these patients, however, is often complex and not adequately accounted for by arterial pressure or vascular resistance measurement alone. In reality, the global vascular load presented to the left ventricle (LV) includes both steady-state and pulsatile components. Whereas steady-state load is best represented by the vascular resistance, pulsatile load, which incorporates wave reflections and arterial stiffness, may oscillate during various phases of the cardiac cycle and is best determined by the vascular impedance (Z). In recent years, measurement of Z has become more readily accessible through an array of simultaneous applanation tonometry, echocardiography and cardiac magnetic resonance (CMR) techniques. In the following review, we evaluate existing and newer methods to assess Z so as to better understand the pulsatile characteristics of the human circulation in hypertension and other cardiovascular disease states.

Futuristic perspectives: novel MCS devices.

Treatment of heart failure needs a firm understanding of anatomy and physiology of the circulatory system and the heart. Ancient India takes credit for the "modern concepts" of human circulation. This short review encompasses futuristic perspectives on mechanical circulatory devices (MCS). The heart is a complex structure which has evolved over millennia both in its structure and mechanical functionality. Evolving from a simple tube with peristaltic action such as in annelids, it evolved rapidly to form a more complexity as animals evolved from oceanic to terrestrial adaptation. The major advance is the innovation of placing the actuation mechanism within the blood flow path, such as in continuous flow technology (axial or centrifugal) when contrasted to the positive displacement pumps. We present novel concepts but also touch upon what we would consider as fundamental problems or paradigms that need to be addressed to move this field ahead. Finally, we propose what would be termed a "futuristic" MCS device.

Uncovering neglected subtypes and zoonotic transmission of Hepatitis E virus (HEV) in Brazil

Hepatitis E virus (HEV) circulation in humans and swine has been extensively studied in South America over the last two decades. Nevertheless, only 2.1% of reported HEV strains are available as complete genome sequences. Therefore, many clinical, epidemiological, and evolutionary aspects of circulating HEV in the continent still need to be clarified. Here, we conducted a retrospective evolutionary analysis of one human case and six swine HEV strains previously reported in northeastern, southern, and southeastern Brazil. We obtained two complete and four nearly complete genomic sequences. Evolutionary analysis comparing the whole genomic and capsid gene sequences revealed high genetic variability. This included the circulation of at least one unrecognized unique South American subtype. Our results corroborate that sequencing the whole capsid gene could be used as an alternative for HEV subtype assignment in the absence of complete genomic sequences. Moreover, our results substantiate the evidence for zoonotic transmission by comparing a larger genomic fragment recovered from the sample of the autochthonous human hepatitis E case. Further studies should continuously investigate HEV genetic diversity and zoonotic transmission of HEV in South America.

High antioxidant load impairs cutaneous microvascular function in healthy women

PURPOSE: Human cutaneous circulation is used as an in vivo bioassay to examine mechanisms of systemic vascular dysfunction in cohorts of patients with accelerated cardiovascular disease risk. Local drug infusions, including atorvastatin (statin; LOX inhibitor) and systemic interventions to investigate anti-inflammatory mechanisms (e.g., oral salsalate) have been used to elucidate mechanisms underlying microvascular dysfunction. However, in healthy cohorts, high antioxidant load can attenuate total vasodilation and nitric oxide (NO)-dependent vasodilation. Thus, we aimed to examine endothelial function during high antioxidant load from these localized and systemic treatments in healthy control groups. We hypothesized that combined localized and systemic treatments will attenuate endothelial function in healthy women. METHODS: In a randomized placebo control design, oral salsalate (1500mg/twice daily/5 days) was used to assess the impact of systemic inflammation on cutaneous vascular function. Four intradermal microdialysis fibers were placed into the intradermal space of the ventral forearm of six healthy women (32±7 years). Laser-Doppler flowmeter probes, used to measure cutaneous blood flow, were placed in local heating units set to 33°C. Increasing concentrations of acetylcholine (ACh; endothelium-dependent vasodilator) from 10 -10 to 10 -1 M were co-perfused with one of the following: Lactated Ringer’s (control), 0.02 mM statin, 15 mM N G -nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase inhibitor), and statin + L-NAME (COMBO) sequentially for 5 min each. Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43°C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux and mean arterial pressure and normalized as a percentage of the site-specific maximum (%CVC max ). Data at each intervention were compared with control using a two-way (dose x site) analysis of variance. Responses at each dosage were compared using paired t-tests and corrected for multiple comparisons. RESULTS: Following oral salsalate, there was no difference in the %CVC max response to ACh with local L-NAME (p=0.896) or COMBO interventions (p=0.617) as compared to the placebo. However, following oral salsalate, there was a significant reduction in %CVC max in the statin treated site at higher ACh concentrations (10 -5 M, 10 -4 M, 10 -3 M; all p<0.01). CONCLUSION: Endothelial function was attenuated when subjects were introduced to a combination of oral salsalate and statin localized treatments. Five-day oral salsalate intake and local statin may result in high antioxidant load in healthy women creating a shift in redox balance, thus leading to impaired endothelial function. Supported by NIH Grant R01 HL161000 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Studies of the retinal microcirculation using human donor eyes and high-resolution clinical imaging: Insights gained to guide future research in diabetic retinopathy.

The microcirculation plays a key role in delivering oxygen to and removing metabolic wastes from energy-intensive retinal neurons. Microvascular changes are a hallmark feature of diabetic retinopathy (DR), a major cause of irreversible vision loss globally. Early investigators have performed landmark studies characterising the pathologic manifestations of DR. Previous works have collectively informed us of the clinical stages of DR and the retinal manifestations associated with devastating vision loss. Since these reports, major advancements in histologic techniques coupled with three-dimensional image processing has facilitated a deeper understanding of the structural characteristics in the healthy and diseased retinal circulation. Furthermore, breakthroughs in high-resolution retinal imaging have facilitated clinical translation of histologic knowledge to detect and monitor progression of microcirculatory disturbances with greater precision. Isolated perfusion techniques have been applied to human donor eyes to further our understanding of the cytoarchitectural characteristics of the normal human retinal circulation as well as provide novel insights into the pathophysiology of DR. Histology has been used to validate emerging in vivo retinal imaging techniques such as optical coherence tomography angiography. This report provides an overview of our research on the human retinal microcirculation in the context of the current ophthalmic literature. We commence by proposing a standardised histologic lexicon for characterising the human retinal microcirculation and subsequently discuss the pathophysiologic mechanisms underlying key manifestations of DR, with a focus on microaneurysms and retinal ischaemia. The advantages and limitations of current retinal imaging modalities as determined using histologic validation are also presented. We conclude with an overview of the implications of our research and provide a perspective on future directions in DR research.

Preparation of pH-Sensitive Polymeric Nanoparticles for the Targeted Delivery of Doxorubicin with High Drug Capacity

In this study, pH-responsive prodrug nanoparticles PEG-Schiff-doxorubicin (PEG-Schiff-DOX) were designed and synthesised using chemical conjugation method and can self-assembly into spherical micelles in aqueous solution. These nanoparticles show good storage stability which can be stored over one week under normal condition. The acid-liable Schiff linker is stable under neutral pH and cleave under acidic environment, allowing the prodrug micelles to withhold DOX anticancer drug when being delivered in human circulation and disassemble to release drug once enter tumor cell tissue or taken into intracellular endosomal and lysosomal compartments. In addition to the enhanced permeation and retention (EPR) effect possessed by nanoparticle [1], the nanoparticle prodrug PEG-Schiff-DOX possess an advanced drug release behaviour, resulting in higher intracellular drug concentration in cancer cells and prolonged time of action. The superior anticancer effect of these nanoparticles against Hela cells is also investigated with CCK-8 assays, demonstrating the great potential for clinical application of PEG-Schiff-DOX in cancer treatment.

Mock circulatory loop applications for testing cardiovascular assist devices and in vitro studies.

The mock circulatory loop (MCL) is an in vitro experimental system that can provide continuous pulsatile flows and simulate different physiological or pathological parameters of the human circulation system. It is of great significance for testing cardiovascular assist device (CAD), which is a type of clinical instrument used to treat cardiovascular disease and alleviate the dilemma of insufficient donor hearts. The MCL installed with different types of CADs can simulate specific conditions of clinical surgery for evaluating the effectiveness and reliability of those CADs under the repeated performance tests and reliability tests. Also, patient-specific cardiovascular models can be employed in the circulation of MCL for targeted pathological study associated with hemodynamics. Therefore, The MCL system has various combinations of different functional units according to its richful applications, which are comprehensively reviewed in the current work. Four types of CADs including prosthetic heart valve (PHV), ventricular assist device (VAD), total artificial heart (TAH) and intra-aortic balloon pump (IABP) applied in MCL experiments are documented and compared in detail. Moreover, MCLs with more complicated structures for achieving advanced functions are further introduced, such as MCL for the pediatric application, MCL with anatomical phantoms and MCL synchronizing multiple circulation systems. By reviewing the constructions and functions of available MCLs, the features of MCLs for different applications are summarized, and directions of developing the MCLs are suggested.