Perfusion Rate Research Articles

Study of hot stress dynamic IR thermography for detecting surface cancerous tissue

The early diagnosis of cancer at any location of the human body can help in enhancing the survival rate and in reducing the cost of the treatment. Among the several techniques, the conventional infra-red (IR) thermography suffers from several limitations, including higher patient discomfort and longer time for tumour detection based on the temperature difference between tumour and adjacent healthy tissues. Hence, in this work, a novel non-invasive hot stress dynamic IR thermography system is proposed to detect surface tumour without severe discomfort to the patient. The system is designed to detect the surface tumour under 3 min within a temperature range of 42 and 37 °C. A two-dimensional numerical model based on the bio-heat transfer of tissue consists of cancerous and healthy cells is developed and validated to analysis the thermal contrast arises due to the presence of cancerous and healthy cells while cooling naturally. A light source is introduced with appropriate intensity to achieve a suitable temperature contrast. Moreover, the effects of natural convective heat loss from the tissue to the ambient and the scanning speed of IR Thermography on the tissue are investigated. A temperature difference of about 1.5 °C is found after cooling of tissues for 140 s, which can be detected using a thermographic camera. Finally, a sensitivity study is conducted to access the importance of the individual parameter over the final temperature field. The results predict the blood perfusion rate as the most significant parameter that significantly influences the temperature distribution in the considered domain.

Age-Related Alterations in Brain Perfusion, Venous Oxygenation, and Oxygen Metabolic Rate of Mice: A 17-Month Longitudinal MRI Study.

Background: Characterization of physiological parameters of the aging brain, such as perfusion and brain metabolism, is important for understanding brain function and diseases. Aging studies on human brain have mostly been based on the cross-sectional design, while the few longitudinal studies used relatively short follow-up time compared to the lifespan.Objectives: To determine the longitudinal time courses of cerebral physiological parameters across the adult lifespan in mice.Methods: The present work examined longitudinal changes in cerebral blood flow (CBF), cerebral venous oxygenation (Yv), and cerebral metabolic rate of oxygen (CMRO2) using MRI in healthy C57BL/6 mice from 3 to 20 months of age. Each mouse received 16 imaging sessions at an ~1-month interval.Results: Significant increases with age were observed in CBF (p = 0.017) and CMRO2 (p < 0.001). Meanwhile, Yv revealed a significant decrease (p = 0.002) with a non-linear pattern (p = 0.013). The rate of change was 0.87, 2.26, and −0.24% per month for CBF, CMRO2, and Yv, respectively. On the other hand, systemic parameters such as heart rate did not show a significant age dependence (p = 0.47). No white-matter-hyperintensities (WMH) were observed on the T2-weighted image at any age of the mice.Conclusion: With age, the mouse brain revealed an increase in oxygen consumption. This observation is consistent with previous findings in humans using a cross-sectional design and suggests a degradation of the brain's energy production or utilization machinery. Cerebral perfusion remains relatively intact in aged mice, at least until 20 months of age, consistent with the absence of WMH in mice.

The Use of Core Warming as a Treatment for Coronavirus Disease 2019 (COVID-19): an Initial Mathematical Model

Background: Increasing data suggest that elevated body temperature may be helpful in resolving a variety of diseases, including sepsis, acute respiratory distress syndrome (ARDS), and viral illnesses. SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), may be more temperature sensitive than other coronaviruses, particularly with respect to the binding affinity of its viral entry via the ACE2 receptor. A mechanical provision of elevated temperature focused in a body region of high viral activity in patients undergoing mechanical ventilation may offer a therapeutic option that avoids arrhythmias seen with some pharmaceutical treatments. We investigated the potential to actively provide core warming to the lungs of patients with a commercially available heat transfer device via mathematical modeling, and examine the influence of blood perfusion on temperature using this approach. Methods: Using the software Comsol Multiphysics, we modeled and simulated heat transfer in the body from an intraesophageal warming device, taking into account the airflow from patient ventilation. The simulation was focused on heat transfer and warming of the lungs and performed on a simplified geometry of an adult human body and airway from the pharynx to the lungs. Results: The simulations were run over a range of values for blood perfusion rate, which was a parameter expected to have high influence in overall heat transfer, since the heat capacity and density remain almost constant. The simulation results show a temperature distribution which agrees with the expected clinical experience, with the skin surface at a lower temperature than the rest of the body due to convective cooling in a typical hospital environment. The highest temperature in this case is the device warming water temperature, and that heat diffuses by conduction to the nearby tissues, including the air flowing in the airways. At the range of blood perfusion investigated, maximum lung temperature ranged from 37.6°C to 38.6°C. Conclusions: The provision of core warming via commercially available technology currently utilized in the intensive care unit, emergency department, and operating room can increase regional temperature of lung tissue and airway passages. This warming may offer an innovative approach to treating infectious diseases from viral illnesses such as COVID-19, while avoiding the arrhythmogenic complications of currently used pharmaceutical treatments.

Heating Protocol Design Affected by Nanoparticle Redistribution and Thermal Damage Model in Magnetic Nanoparticle Hyperthermia for Cancer Treatment

Abstract Recent micro-CT scans have demonstrated a much larger magnetic nanoparticle distribution volume in tumors after localized heating than those without heating, suggesting possible heating-induced nanoparticle migration. In this study, a theoretical simulation was performed on tumors injected with magnetic nanoparticles to evaluate the extent to which the nanoparticle redistribution affects the temperature elevation and thermal dosage required to cause permanent thermal damage to PC3 tumors. 0.1 cc of a commercially available ferrofluid containing magnetic nanoparticles was injected directly to the center of PC3 tumors. The control group consisted of four PC3 tumors resected after the intratumoral injection, while the experimental group consisted of another four PC3 tumors injected with ferrofluid and resected after 25 min of local heating. The micro-CT scan generated tumor model was attached to a mouse body model. The blood perfusion rates in the mouse body and PC3 tumor were first extracted based on the experimental data of average mouse surface temperatures using an infrared camera. A previously determined relationship between nanoparticle concentration and nanoparticle-induced volumetric heat generation rate was implemented into the theoretical simulation. Simulation results showed that the average steady-state temperature elevation in the tumors of the control group is higher than that in the experimental group where the nanoparticles are more spreading from the tumor center to the tumor periphery (control group: 70.6±4.7 °C versus experimental group: 69.2±2.6 °C). Further, we assessed heating time needed to cause permanent thermal damage to the entire tumor, based on the nanoparticle distribution in each tumor. The more spreading of nanoparticles to tumor periphery in the experimental group resulted in a much longer heating time than that in the control group. The modified thermal damage model by Dr. John Pearce led to almost the same temperature elevation distribution; however, the required heating time was at least 24% shorter than that using the traditional Arrhenius integral, despite the initial time delay. The results from this study suggest that in future simulation, the heating time needed when considering dynamic nanoparticle migration during heating is probably between 19 and 29 min based on the Pearce model. In conclusion, the study demonstrates the importance of including dynamic nanoparticle spreading during heating and accurate thermal damage model into theoretical simulation of temperature elevations in tumors to determine thermal dosage needed in magnetic nanoparticle hyperthermia design.

Hyperpolarized [1-13 C] alanine production: A novel imaging biomarker of renal fibrosis.

Renal tubulointerstitial fibrosis is strongly linked to the progressive decline of renal function seen in chronic kidney disease. State-of-the-art noninvasive diagnostic modalities are currently unable to detect the earliest changes associated with the onset of fibrosis. This study was undertaken to evaluate the potential for detecting the earliest alterations in fibrogenesis using a biofluid-based method and metabolic hyperpolarized [1-13 C]pyruvate imaging. We evaluated renal fibrosis in a combined ischemia reperfusion-induced and streptozotocin-induced diabetic nephropathy rodent model by hyperpolarized [1-13 C]pyruvate MRI and correlated the metabolic MRI parameters with biomarkers of fibrosis measured on renal tissue and plasma/urine. The hyperglycemic rats experienced maladaptive injury repair after the ischemic insults, as shown by the elevation in the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Renal function was significantly impaired in the ischemic hyperglycemic kidney, as seen in the reduced perfusion and single-kidney glomerular filtration rate. A deranged energy metabolism was detected in the ischemic hyperglycemic kidney, as seen in the reduced fractional perfusion of lactate. Renal fibrosis biomarkers correlated significantly with the alanine production. Hyperpolarized carbon-13 MRI provides a promising approach to assess renal fibrosis in an animal model of fibrotic chronic kidney disease. In particular, the metabolic supply of amino acids for fibrogenesis (alanine production) correlates well with biomarkers of fibrosis. Thus, [1-13 C]pyruvate-to-[1-13 C]alanine conversion might be a candidate for noninvasive assessment of renal fibrogenesis.

Pixel-wise assessment of cardiovascular magnetic resonance first-pass perfusion using a cardiac phantom mimicking transmural myocardial perfusion gradients.

PurposeCardiovascular magnetic resonance first-pass perfusion for the pixel-wise detection of coronary artery disease is rapidly becoming the clinical standard, yet no widely available method exists for its assessment and validation. This study introduces a novel phantom capable of generating spatially dependent flow values to enable assessment of new perfusion imaging methods at the pixel level.MethodsA synthetic multicapillary myocardial phantom mimicking transmural myocardial perfusion gradients was designed and manufactured with high-precision 3D printing. The phantom was used in a stationary flow setup providing reference myocardial perfusion rates and was scanned on a 3T system. Repeated first-pass perfusion MRI for physiological perfusion rates between 1 and 4 mL/g/min was performed using a clinical dual-sequence technique. Fermi function-constrained deconvolution was used to estimate pixel-wise perfusion rate maps. Phase contrast (PC)-MRI was used to obtain velocity measurements that were converted to perfusion rates for validation of reference values and cross-method comparison. The accuracy of pixel-wise maps was assessed against simulated reference maps.ResultsPC-MRI indicated excellent reproducibility in perfusion rate (coefficient of variation [CoV] 2.4-3.5%) and correlation with reference values (R2 = 0.985) across the full physiological range. Similar results were found for first-pass perfusion MRI (CoV 3.7-6.2%, R2 = 0.987). Pixel-wise maps indicated a transmural perfusion difference of 28.8-33.7% for PC-MRI and 23.8-37.7% for first-pass perfusion, matching the reference values (30.2-31.4%).ConclusionThe unique transmural perfusion pattern in the phantom allows effective pixel-wise assessment of first-pass perfusion acquisition protocols and quantification algorithms before their introduction into routine clinical use.

Association of Cardiovascular Risk Factors with Cerebral Perfusion in Whites and African Americans.

Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for APOE genotype and race. When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither APOE genotype nor race moderated relationships between risk factors and perfusion. Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.

Macrophage Spheroids with Chronological Phenotype Shifting To Promote Therapeutic Angiogenesis in Critical Limb Ischemia

Therapeutic angiogenesis becomes an essential approach to rescue ischemia and the cell-based therapy facilitates ischemia recovery via stimulation of paracrine signals or replacement of damaged cells. Macrophages participate in multiple processes of tissue repair, and the M1 and M2 phenotypes play distinct roles in the sequential stages of healing initiation, angiogenesis stabilization, and tissue maturation. In this study, macrophage spheroids (MøSs) are proposed to promote therapeutic angiogenesis in critical limb ischemia (CLI) via chronological shifting from M1 to M2 phenotypes. Uniform-sized MøSs are prepared by using electrosprayed microcapsules as the confined growth template, and fiber fragments are inoculated to achieve a local release of chrysin for macrophage phenotype manipulation. The macrophage polarization shifting is confirmed from the decreased CD86 expressions (M1 marker) from 64.7 to 31.7% and the concurrent increase in CD206 expressions (M2 marker) from 39.3 to 72.4%. Meanwhile, the tumor necrosis factor-α secretion from M1 is downregulated by around threefold, whereas the levels of interleukin-10 and transforming growth factor-β1 from M2 increase by around threefold. The incubation with conditioned media from the MøS culture could promote the proliferation and migration of endothelial cells (ECs), showing a high healing rate of EC layers. The local treatment of hind-limb ischemia leads to a full recovery from ischemic to normal limbs with a high blood perfusion rate. Histological analysis shows few muscle degeneration and fibrosis areas and high capillary densities. As far as we know, this is the first attempt to develop uniform-sized MøSs and to undergo dynamic phenotypic shifting from early M1 to later M2 for angiogenesis promotion in the CLI treatment.

Semi-analytical solutions for different non-linear models of dual phase lag equation in living tissues

In this study, the heat transfer in a multilayer heated living tissue is investigated. A non-linear dual phase lag (DPL) heat conduction model is presented assuming temperature-dependent blood perfusion rate, heat conductivity and metabolic heat generation. Semi -analytical solutions for the non-linear model are obtained employing the Galerkin weighted residuals method. The effects of the variable thermophysical properties on the temperature distribution within the tissue are investigated through comparison of the results with the corresponding results for the constant thermophysical properties. The results show that the temperature dependence of the blood perfusion rate has a significant effect on the temperature distribution in the different layers of the tissue. As far as the tumor region is considered, 0.43 °C increase in its temperature is observed in comparison with that obtained assuming the constant blood perfusion rate at t = 1800 s. Moreover, increasing the temperature dependence of the thermal conductivity leads to the reduction in the temperature of the tissue except in the muscle layers. Considering the temperature-dependent metabolic heat generation increases the temperature of all of the layers compared to the corresponding temperatures obtained assuming the constant metabolic heat generation.

Comparison of primary T cells cultured in static conditions versus rocking motion bioreactors

Background & Aim The FDA approval of Novartis‘ Kymriah and Gilead‘s Yescarta chimeric antigen receptors (CAR)-T cell products in 2017 was a landmark announcement for the cellular immunotherapy field. But despite the excitement, manufacturing of these cell-based therapeutics still remains challenging and expensive. Whereas commercial cell therapy production requires robust and consistent manufacturing platforms, many processes are still highly variable and consist of manual handling steps. Rocking motion (RM) bioreactors are an attractive tool for the expansion of sensitive cells such as CAR-T cells, allowing for automated process control and reducing costs connected to traditional manual process steps. In this work, we compare T cell expansion in a RM bioreactor to classical, static cultures. Furthermore, we aim to improve culture productivity by optimized perfusion feeding in the RM bioreactor. Methods, Results & Conclusion Using human primary T cells enriched from cryopreserved PBMC from healthy donors as a model, we performed T cell expansion in static bags in a CO2 incubator in comparison to expansion in the BIOSTAT® RM TX using Flexsafe® RM TX bags. Keeping other culture parameters such as cell seeding density, medium and feeding constant, we evaluated cell growth, viability and T cell surface markers. In a second step, bioreactor cultures were further optimized by improved perfusion feeding based on glucose and lactate measurements. Our data show that expansion in a rocking motion bioreactor yields comparable or even higher cell growth than expansion in static cultures. Furthermore, in a simple approach based on measurements of glucose and lactate, bioreactor productivity was increased by using an improved perfusion feeding regime, resulting in cell concentrations of almost 5 × 107 c/ml. Further optimization of the expansion process and bioreactor productivity is envisioned by improving the feeding strategy. Based on spent medium analysis, we expect to reduce the perfusion rate and replenish depleted components with bolus additions of those components. In conclusion, RM bioreactors are promising platforms for cell therapy manufacturing processes. The BIOSTAT® RM TX platform allows for incorporation of online monitoring and process automation, thereby reducing labor and COG for manufacturing of commercial cell therapy products. The FDA approval of Novartis‘ Kymriah and Gilead‘s Yescarta chimeric antigen receptors (CAR)-T cell products in 2017 was a landmark announcement for the cellular immunotherapy field. But despite the excitement, manufacturing of these cell-based therapeutics still remains challenging and expensive. Whereas commercial cell therapy production requires robust and consistent manufacturing platforms, many processes are still highly variable and consist of manual handling steps. Rocking motion (RM) bioreactors are an attractive tool for the expansion of sensitive cells such as CAR-T cells, allowing for automated process control and reducing costs connected to traditional manual process steps. In this work, we compare T cell expansion in a RM bioreactor to classical, static cultures. Furthermore, we aim to improve culture productivity by optimized perfusion feeding in the RM bioreactor. Using human primary T cells enriched from cryopreserved PBMC from healthy donors as a model, we performed T cell expansion in static bags in a CO2 incubator in comparison to expansion in the BIOSTAT® RM TX using Flexsafe® RM TX bags. Keeping other culture parameters such as cell seeding density, medium and feeding constant, we evaluated cell growth, viability and T cell surface markers. In a second step, bioreactor cultures were further optimized by improved perfusion feeding based on glucose and lactate measurements.

Oxygenation Profiles of Human Blood, Cell Culture Medium, and Water for Perfusion of 3D-Bioprinted Tissues using the FABRICA Bioreactor Platform

Persistent and saturated oxygen distribution from perfusion media (i.e., blood, or cell culture media) to cells within cell-dense, metabolically-active biofabricated tissues is required to keep them viable. Improper or poor oxygen supply to cells within the tissue bulk severely limits the tissue culturing potential of many bioreactors. We added an oxygenator module to our modular FABRICA bioreactor in order to provide stable oxygenation to biofabricated tissues during culture. In this proof of concept study of an oxygenated and perfused bioreactor, we characterized the oxygenation of water, cell culture medium, and human blood in the FABRICA as functions of augmenting vacuum (air inlet) pressure, perfusion (volumetric flow) rate, and tubing/oxygenator components. The mean oxygen levels for water and cell culture media were 27.7 ± 2.1% and 27.6 ± 4.1%, respectively. The mean oxygen level for human blood was 197.0 ± 90.0 mmHg, with near-physiologic levels achieved with low-permeability PharMed tubing alone (128.0 ± 14.0 mmHg). Hematologic values pre- and post-oxygenation, respectively were (median ± IQR): Red blood cell: 6.0 ± 0.5 (106/μL) and 6.5 ± 0.4 (106/μL); Hemoglobin: 17.5 ± 1.2 g/dL and 19.2 ± 3.0 g/dL; and Hematocrit: 56.7 ± 2.4% and 61.4 ± 7.5%. The relative stability of the hematologic parameters indicates that blood function and thus blood cell integrity were maintained throughout oxygenation. Already a versatile research tool, the now oxygenated FABRICA provides easy-to-implement, in vivo-like perfusion and stable oxygenation culture conditions in vitro semi-independently of one another, which means the bioreactor has the potential to serve as a platform for investigating the behavior of 3D tissue models (regardless of biofabrication method), performing drug toxicity-testing, and testing pharmaceutical efficacy/safety.

The eosinophil actin cytoskeleton undergoes rapid rearrangement in response to fluid shear stress.

The regulatory processes involved in eosinophil trafficking into tissues are poorly understood; therefore, it is crucial to elucidate these mechanisms to advance the quality of clinical care for patients with eosinophil-mediated diseases. The complex interactions between eosinophil integrin receptors and their corresponding ligands on the post-capillary venules of the bronchial endothelium result in distinct modifications to the cytoskeletal architecture that occur in coordinated, temporally regulated sequences. The current study utilizes real-time confocal microscopy and time-based immunofluorescence staining to further characterize the effects of physiologically relevant fluid shear stress on this novel phenomenon of perfusion-induced calcium response. We found that the mere perfusion of fluid over adhered human eosinophils induced a release of intracellular calcium observed in conjunction with changes in cell morphology (flattening onto the coverslip surface, an increase in surface area, and a loss of circularity), suggesting a previously unknown mechanosensing aspect of eosinophil migration out of the vasculature. Although changes in morphology and degree of calcium release remained consistent across varying perfusion rates, the latency of the response was highly dependent on the degree of shear stresses. Eosinophils were fixed post-perfusion at specific timepoints for immunofluorescence staining to track proteins of interest over time. The distribution of proteins was diffuse throughout the cell prior to perfusion; however, they quickly localized to the periphery of the cell within 5 min. The actin cytoskeleton became markedly built up at the cell edges rapidly after stimulation, forming punctate dots by 4 min, suggesting a pivotal role in directed cell motility.

A Study on Non-Linear DPL Model for Describing Heat Transfer in Skin Tissue during Hyperthermia Treatment.

The article studies the simulation-based mathematical modeling of bioheat transfer under the Dirichlet boundary condition. We used complex non-linear dual-phase-lag bioheat transfer (DPLBHT) for analyzing the temperature distribution in skin tissues during hyperthermia treatment of infected cells. The perfusion term, metabolic heat source, and external heat source were the three parts of the volumetric heat source that were used in the model. The non-linear DPLBHT model predicted a more accurate temperature within skin tissues. The finite element Runge–Kutta (4,5) (FERK (4,5)) method, which was based on two techniques, finite difference and Runge–Kutta (4,5), was applied for calculating the result in the case of our typical non-linear problem. The paper studies and presents the non-dimensional unit. Thermal damage of normal tissue was observed near zero during hyperthermia treatment. The effects of the non-dimensional time, non-dimensional space coordinate, location parameter, regional parameter, relaxation and thermalization time, metabolic heat source, associated metabolic heat source parameter, perfusion rate, associated perfusion heat source parameter, and external heat source coefficient on the dimensionless temperature profile were studied in detail during the hyperthermia treatment process.

An Indispensable tool for ultrasound based diagnostics and therapies - Microbubbles

Microbubbles (MBs) are micrometre sized gas spheres comprising a biocompatible shell that provide vascular contrast for diagnostic ultrasound (US) imaging. MBs volumetrically oscillate in an ultrasonic field and scatter acoustic energy over a range of frequencies that can be separated from the tissue response. MBs can also provide organ perfusion rates by imaging their “wash-in” to a region of interest which can be correlated to vascular flow. When driven at higher acoustic pressures, localized biological effects can be induced, including increased tissue permeabilization, thermal effects and localised release of drugs that can be encapsulated in the MBs themselves. Both hydrophobic and hydrophilic drugs can be loaded on to MBs e.g. through the use of liposomal carriers or direct attachment of drug molecules to the bubble shell. Since the early 2000s, MB-based technologies have been well researched, though there was significant regulatory push back starting in 2006 based on a controversial clinical trial. From that point, both physicians and researchers have consistently demonstrated the robust safety of MBs as ultrasound contrast agents and their significant clinical utility. Within the last 5 years, more indications have been approved. A recent first-in-man clinical trial of therapeutic US with MBs reversibly opening the blood brain barrier has also been shown to be safe in amyotrophic lateral sclerosis patients. The following article outlines the coupling of US and MBs as a diagnostic and therapeutic platform with a particular focus on their application to the therapy of surgical diseases.

Sex Difference in Regional Skin Blood Flow Perfusion and Sweat Rates during Exercise in Hot and Cool Conditions

BackgroundFemales are reported to have lower thermosenstivity for evaporative heat loss and skin blood flow (SKbF) response to an increase in mean body temperature during exercise compared to men. However, sweat rate (SR) and SkBF are typically examined only on the forearm. It is unclear if SR and SkBF differ between sex in various body regions during exercise hyperthermia when matched for exercise heat production.PurposeThis project tested the hypothesis that regional skin blood flow perfusion and sweat rates would differ between men and women exercising at matched exercise heat production.MethodsTwenty‐two healthy active (7 day activity: 8620±3008 steps/day; VO2max: 49±10 mL/kg/min) adults (11M/11F, 22.4±4.9y, 169±7.6cm, 68.3±13kg) exercised at similar metabolic heat production (M: 7.1±1.5 W/kg, F: 6.9±1.4 W/kg; P=0.32) for 60 min (cycle ergometer) in cool (24.0±0.0□C; 14.4±3.6%Rh) and hot (42.3±0.2□C; 27.9±5.5%Rh) conditions in random order separated by at least 7 days. The change for intestinal temperature (ΔTin) and heart rate (ΔHR) utilized a factorial two‐way repeated measure analysis of variance (RMANOVA) for interaction (In) and main effect (ME) for Sex and Condition. Local skin temperature (Tsk), SKbF, and SR were measured at the chest, stomach, forearm, and shoulder regions at rest and continuously during exercise and analyzed within each condition with a factorial two‐way RMANOVA for In and ME for Time and Sex.ResultsMales and females had a similar increase in hot compared to cool for ΔTin (Cool: Δ0.5±0.1□C, Hot: Δ1.5±0.6□C; ME: condition; P&lt;0.0001) and ΔHR (Cool: 58±15 b/min, Hot: 71±15 b/min; ME: Condition; P&lt;0.01). Tsk was hotter at each site in the hot compared to cool condition but not different between sex (ME: Condition, P≤.0001). SkbFchest increased during exercise in both sexes (ME: Time, P&lt;0.0001). SkbFstomach increased during exercise in both conditions, however in the hot increased greater in females compared to males (In: Time × Sex, P&lt;0.002). SkBFforearm increase during exercise in both sexes; however, was attenuated in females in the hot (In: Time × Sex, P&lt;0.002). SkBFshoulder increased during exercise and was greater in females compared to males in the hot (ME: Sex, P&lt;0.04) and more so in the cool (In: Time × Sex, P&lt;0.03). SRchest increased similar between sex in hot but was greater in cool for females (In: Time × Sex, P&lt;0.003). SRstomach increased less for females in the hot (ME: Sex, P&lt;0.04) but similar to males in cool (ME: Time, P&lt;0.0001). SRforearm increased less in females in the hot (In: Time × Sex, P&lt;0.0017). SRshoulder increased similar between sex in hot and cool conditions (ME: Time, P&lt;0.0001).ConclusionThese data indicate that sex differences exist for SkBF and SR in different body regions during exercise in hot and cool conditions. Females have elevated SkBF in the stomach and shoulder and similar in chest and forearm compared to males. SR in females are attenuated in stomach and forearm, but similar in the chest and shoulder regions compared to males.

Effects of Individual or Combined Inhibition of Interleukin‐1 and Interleukin‐18 on the Resuscitation of Donation after Circulatory Death Murine Heart

BackgroundThere is a limited amount of donor hearts to be used for transplantation, which is mainly dependent on Donation after Brain Death (DBD) donors. This pool could be expanded with adoption of Donation after Circulatory Death (DCD) donor hearts. The transplantation of a heart that undergoes the DCD process would expose the organ to ischemia and reperfusion injury (IRI). IRI activates the NLRP3 inflammasome, which promotes the production of interleukin‐1 (IL‐1) and IL‐18.HypothesisCombined pharmacologic inhibition of IL‐1 and IL‐18 confers superior protection compared to individual blockade with IL‐1 or IL‐18 in the DCD heart.MethodsThe DCD mouse model was developed reflecting the clinical DCD protocol. The DCD was induced in C57 mice anesthetized, intubated, ventilated and paralyzed (vecuronium bromide 100 μg/kg) and by removing the ventilatory support to induce anoxia and circulatory failure. Total ischemic time was set at 40 min. Reanimation was achieved on a Langendorff system at 37°C using Krebs Henseleit (KH) buffer alone or supplemented with IL‐1 receptor antagonist (IL‐1Ra, 1 μg/ml), IL‐18 binding protein (IL‐18BP, 1 μg/ml) or their combination (n=8–10/group). Heart rate (HR), perfusion rate, developed pressure (DP) and +/−dP/dt were obtained at 15 min intervals. The rate pressure product (RPP) was calculated. After 90 min, the hearts were collected to measure DNA fragmentation (TUNEL assay). Cardiac troponin‐I (cTnI) levels were measured in the perfusate.ResultsHR and perfusion flow rates were comparable in all groups (table ). IL‐1Ra improved myocardial contractility, although it reached statistical significance only for DP and –dP/dt when compared to the DCD control (table ). IL‐18BP significantly improved all the parameters of myocardial contractility, compared to the control (all p&lt;0.05). Markers of cell injury were significantly better after resuscitation with IL‐18BP, while IL‐1Ra did not reduce the release of cTnI or the DNA fragmentation (Table ). The combination of IL‐1Ra and IL‐18BP did not further improve the contractility nor further reduce damage of the DCD heart compared to the monotherapy treatment.ConclusionPharmacologic blockade of IL‐1 or IL‐18 protects the DCD mouse heart, with better protection with IL‐18BP compared to IL‐1Ra. Combined treatment with IL‐1Ra and IL‐18BP did not give additional benefits compared to the individual inhibitors.Support or Funding InformationThis work was supported by a Merit Review Award and and American Heart Association grant to Dr. Mohammed Quader. DCD DCD KH buffer KH buffer + inhibitors N=10 IL‐1Ra N=8 IL‐18BP N=9 IL‐1Ra+IL‐18BP r&gt;N=5 Functional Data Heart Rate (beats/min) 396±14 401±15 440±10 408±20 Perfusion rate (ml/min) 1.8±0.1 2.2±0.3 2.4±0.1 1.9±0.2 Developed pressure (mmHg) 78.7±5.8 94.1±9.3 108.3±6.5 # 103.0±8.6 # Rate Pressure Product (mmHgxbeats/min) 29233±3293 34198±3634 43082±3191 # 31715±467 (+)dP/dt (mmHg/ms) 3256±266 3272±695 4744±204 # 5312±120 # (−)dP/dt (mmHg/ms) −2278±18 −2992±28 # −3632±29 # −3405±24 # Makers of myocyte damage cTnI (ng/ml) 7.79±0.98 7.68±0.85 4.21±0.67 # 2.63±0.71 # TUNEL+ nuclei (%) 2.09±0.53 2.02±0.76 0.99±0.23 1.01±0.23 Values are expressed as mean ± Standard Error of Mean. #P&lt;0.05 vs DCD K‐H buffer.

Does Early Inhibition of Interleukin‐1 and Interleukin‐18, Adds to The Cardioprotection as Seen with Delayed Interleukin Inhibition Given at Reperfusion in Donation after Circulatory Death Murine Heart Model?

BackgroundDonation after circulatory death (DCD) donors can expand the heart donor pool for transplantation, which primarily is dependent on donation after brain death (DBD) donors. Inherent to the DCD process is ischemia and reperfusion injury, predominantly mediated by interleukin‐1 (IL‐1) and IL‐18, the downstream mediators of inflammasome.HypothesisPharmacologic blockage of IL‐1 or IL‐18 with recombinant IL‐1 receptor antagonist (IL‐Ra) or IL‐18 binding protein (IL‐18 BP) prior to initiation of DCD process is superior to the myocardial protection with IL‐1 or IL‐18 blockade given at reperfusion alone.MethodsFollowing clinical protocol, DCD mice model was developed with in‐situ warm ischemia time maintained at 40 minutes. Mice (strain C57bl6/j) were randomly assigned to DCD control, DCD IL‐1Ra early and late or DCD IL‐18 BP early and late groups (n = 8–10 each). Pharmacologic inhibition of IL‐1 and IL‐18 was obtained with recombinant IL‐1Ra or IL‐18BP, respectively. Anesthetized mice were ventilated while monitoring heart with EKG and echocardiography. After muscle paralysis with vecuronium, ventilatory support was terminated and cardiac asystole observed. Hearts were procured and reanimated for 90 minutes on a Langendorff system with Krebs Henseleit (KH) buffer at 37°C. Physiologic parameters including heart rate, perfusion rate, developed pressure (DP), +/− dP/dt were obtained at 15‐minute intervals. After reanimation, hearts were collected for molecular and histological analysis. In early inhibition groups IL‐1 receptor antagonist (10 mg/kg) or IL‐18 binding protein (1 mg/kg) were given intraperitoneally, 30 minutes prior to DCD process (termination of ventilation). In the late inhibition groups IL‐1Ra and IL‐BP, 1μg/ml and 1μg/ml respectively were added to KH buffer. Coronary sinus samples were analyzed for cardiac troponin‐I (cTnI) levels.ResultsHeart rate and perfusion flow rates were comparable in all groups. In IL‐1 inhibition group, myocardial contractility was better (improved developed pressure, dP/dt compared to control group, however the differences attained statistical significance for DP and −ve dP/dt only). No additional incremental benefit was noted with early inhibition of IL‐1. In IL‐18 group, there was better physiologic function of heart compared to control (DP, +/−dP/dt and rate pressure product, all P = &lt;0.05). Compared to late IL‐18 inhibitor group the early IL‐18 inhibitor group did not have significant improvements in myocardial function parameters. Markers of cell injury were significantly better with IL‐18 inhibition compared to control and IL‐1 inhibition groups.ConclusionPharmacologic blockade of IL‐1 or IL‐18 is protective to the DCD mice hearts, with better protection with IL‐18 inhibition compared to IL‐1 inhibition. Early treatment with IL‐1Ra or IL‐18BP did not afford any additional benefits compared to what is observed with late inhibition given at reanimation. Our study findings are relevant to the clinical practice as only late interventions are allowed in clinic DCD process.Support or Funding InformationWork supported by Merit Review Award and American Association grant to Dr. Quader DCD Control DCD IL‐1 Inhibition DCD IL‐18 Inhibition N=10 Early IL‐1Ra N = 13 Late IL‐1Ra N = 8 Early IL‐18BP N = 8 Late IL‐18BP N=9 Functional Data Heart Rate b/min mean±SEM 396±14 418±13 401±15 445±20 440±10 Perfusion rate ml/min 1.8±0.1 2.2±0.1 2.2±0.3 2.8±0.2 2.4±0.1 Developed pressure mmHg mean±SEM 78.7±5.8 99.3±6.5 # 94.1±9.3 99.5±8.1 # 108.3±6.5 # Rate Pressure Product 29,233±3,293 37,344±3,005 34,198±3,634 41781±4327 # 43082±3191 # Rate of positive developed pressure dt/dp mmHg/ms mean±SEM 3256±266 3595±481 3272±695 4923±44 # 4744±204 # Rate of negative developed pressure −dt/dp mmHg/ms mean±SEM −2278±18 −2991±19 # −2992±28 # −3256±29 # −3632±29 # Makers of myocyte damage Eluate troponin level ng/ml 7.79±0.98 6.16±1.12 7.68±0.85 4.21±0.67 # 3.82±0.65 # TUNEL assay 2.09±0.53 2.13±0.54 2.02±0.76 0.66±0.18 # 0.99±0.23 DCD = Donation after Circulatory Death, IL‐IRa = IL‐1 receptor antagonist, IL‐18 BP IL‐18 receptor binding protein, SEM = Standard Error of Mean, #P&lt;0.05 vs DCD control

Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice.

Preclinical studies have shown a larger inhibition of tumour growth when exercise begins prior to tumour implant (preventative setting) than when training begins after tumour implant (therapeutic setting). However, post-implantation exercise may alter the tumour microenvironment to make it more vulnerable to treatment by increasing tumour perfusion while reducing hypoxia. This has been shown most convincingly in breast and prostate cancer models to date and it is unclear whether other tumour types respond in a similar way. We aimed to determine whether tumour perfusion and hypoxia are altered with exercise in a melanoma model, and compared this with a breast cancer model. We hypothesised that post-implantation exercise would reduce tumour hypoxia and increase perfusion in these two models. Female, 6-10 week old C57BL/6 mice were inoculated with EO771 breast or B16-F10 melanoma tumour cells before randomisation to either exercise or non-exercising control. Exercising mice received a running wheel with a revolution counter. Mice were euthanised when tumours reached maximum ethical size and the tumours assessed for perfusion, hypoxia, blood vessel density and proliferation. We saw an increase in heart to body weight ratio in exercising compared with non-exercising mice (p = 0.0008), indicating that physiological changes occurred with this form of physical activity. However, exercise did not affect vascularity, perfusion, hypoxia or tumour growth rate in either tumour type. In addition, EO771 tumours had a more aggressive phenotype than B16-F10 tumours, as inferred from a higher rate of proliferation (p<0.0001), a higher level of tumour hypoxia (p = 0.0063) and a higher number of CD31+ vessels (p = 0.0005). Our results show that although a physiological training effect was seen with exercise, it did not affect tumour hypoxia, perfusion or growth rate. We suggest that exercise monotherapy is minimally effective and that future preclinical work should focus on the combination of exercise with standard cancer therapies.

Association of intracranial arteriovenous malformation embolization with more rapid rate of perfusion in the peri-nidal region on color-coded quantitative digital subtraction angiography

BackgroundHemodynamic alterations post-embolization of intracranial arteriovenous malformations (AVMs) may cause delayed edema/hemorrhage in brain parenchyma adjacent to the lesion.ObjectiveTo quantify and compare cerebral perfusion changes in the peri-AVM territory pre-...

Spatio-temporal investigation of doxorubicin in a 3D heterogeneous tumor microenvironment

Doxorubicin (Adriamycin) is a type of chemotherapy drugs using to treat diseases such as breast cancer, bladder cancer, Kaposi’s sarcoma, and lymphoma. Additionally, it can be first prescribed to reduce tumor size. The ratio of killed cells is varied depending on the clinical dosage regimen. Hence, the exact dosage of the drug must be administered to prevent the toxicity that could impair the immune system or leading to heart failure. In the present study, a 3D heterogeneous geometry with a solid tumor and healthy tissue is modeled for the drug delivery investigation. At the first stage, the physical properties of tumor microenvironment are obtained. Then, a five-compartmental model is used to evaluate the free, bound and internalized drug via the convection–diffusion-reaction (CDR) equation. Results are shown that a percent increase of 37.5% and 47.1% for the 75 mg m−2 to 50 mg m−2 in the AUC of bound drug and free drug concentration, respectively. The free and bound drugs have the same trend in time showing an apex at the earliest time of injection and then drops to the lowest amount about 9 hours after treatment. Moreover, the internalized drug has a different trend in time. It increases and reaches a constant amount of drug concentration in the cells. Besides, the fraction of surviving cells is also evaluated for both tumor and healthy tissues showing a 88.62% and 97.76% of surviving cells with 50 mg m−2 of doxorubicin after the treatment, respectively. This model is developed to predict the heterogenous distribution of doxorubicin in three different drug concentrations for patient-specific drug treatment. This model could be used for different drugs to show the rate of perfusion and the ability to kill cancerous cells regarding their different doses and toxicity effects.