Identification of Early Stage Liver Fibrosis by Modifications in the Interstitial Space Diffusive Microenvironment Using Fluorescent Single-Walled Carbon Nanotubes.

During liver fibrosis, recurrent hepatic injuries lead to the accumulation of collagen and other extracellular matrix components in the interstitial space, ultimately disrupting liver functions. Early stages of liver fibrosis may be reversible, but opportunities for diagnosis at these stages are currently limited. Here, we show that the alterations of the interstitial space associated with fibrosis can be probed by tracking individual fluorescent single-walled carbon nanotubes (SWCNTs) diffusing in that space. In a mouse model of early liver fibrosis, we find that nanotubes generally explore elongated areas, whose lengths decrease as the disease progresses, even in regions where histopathological examination does not reveal fibrosis yet. Furthermore, this decrease in nanotube mobility is a purely geometrical effect as the instantaneous nanotube diffusivity stays unmodified. This work establishes the promise of SWCNTs both for diagnosing liver fibrosis at an early stage and for more in-depth studies of the biophysical effects of the disease.

Modeling and Simulation as a Tool to Assess Voriconazole Exposure in the Central Nervous System.

Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h-1 and Qout = 0.63 h-1. Infection was a covariate in the Michaelis-Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.

Intranasally administered extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells quickly incorporate into neurons and microglia in 5xFAD mice.

Introduction: Extracellular vesicles (EVs) released by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) have robust antiinflammatory and neurogenic properties due to therapeutic miRNAs and proteins in their cargo. Hence, hiPSC-NSC-EVs are potentially an excellent biologic for treating neurodegenerative disorders, including Alzheimer's disease (AD). Methods: This study investigated whether intranasally (IN) administered hiPSC-NSC-EVs would quickly target various neural cell types in the forebrain, midbrain, and hindbrain regions of 3-month-old 5xFAD mice, a model of ß-amyloidosis and familial AD. We administered a single dose of 25 × 109 hiPSC-NSC-EVs labeled with PKH26, and different cohorts of naïve and 5xFAD mice receiving EVs were euthanized at 45 min or 6 h post-administration. Results: At 45 min post-administration, EVs were found in virtually all subregions of the forebrain, midbrain, and hindbrain of naïve and 5xFAD mice, with predominant targeting and internalization into neurons, interneurons, and microglia, including plaque-associated microglia in 5xFAD mice. EVs also came in contact with the plasma membranes of astrocytic processes and the soma of oligodendrocytes in white matter regions. Evaluation of CD63/CD81 expression with the neuronal marker confirmed that PKH26 + particles found within neurons were IN administered hiPSC-NSC-EVs. At 6 h post-administration, EVs persisted in all cell types in both groups, with the distribution mostly matching what was observed at 45 min post-administration. Area fraction (AF) analysis revealed that, in both naïve and 5xFAD mice, higher fractions of EVs incorporate into forebrain regions at both time points. However, at 45 min post-IN administration, AFs of EVs within cell layers in forebrain regions and within microglia in midbrain and hindbrain regions were lower in 5xFAD mice than naïve mice, implying that amyloidosis reduces EV penetrance. Discussion: Collectively, the results provide novel evidence that IN administration of therapeutic hiPSC-NSC-EVs is an efficient avenue for directing such EVs into neurons and glia in all brain regions in the early stage of amyloidosis. As pathological changes in AD are observed in multiple brain areas, the ability to deliver therapeutic EVs into various neural cells in virtually every brain region in the early stage of amyloidosis is attractive for promoting neuroprotective and antiinflammatory effects.

Reproductive immune microenvironment.

About 10 %-12 % of couples in the world suffer from infertility, and immunological factors are being paid more and more attention. Attempts to induce peripheral immune tolerance in pregnant women by injecting husband cells have been widely promoted, but ultimately proved unsuccessful. Over the past two decades, our understanding of how the immune system is involved in gametogenesis and embryonic development, especially in early pregnancy, has undergone a major shift, going from the periphery to the local area of reproductive tissue. However, a holistic overview of immune responses in reproductive organs and tissues is currently lacking. Here, we further highlight the importance of regional immunity research for understanding reproductive health by reviewing the research mileage of the testis, ovary, and uterine immune microenvironment. We propose the concept of "reproductive immune microenvironment (RIM)" by summarizing the common features and basic functions of the tissue microenvironment in which immune cells reside, including the interstitial space of the testis, the ovarian stroma and the endometrium. The establishment of the concept of RIM not only focuses on the comprehensive description of the immune response in reproductive tissues, but also provides a macroscopic perspective for a deeper understanding of the immune etiology of reproductive system-related diseases.

Rooted in earth, rooted in community: Aging in rural houses of northern China.

Northern China has experienced unprecedented urbanization over the past several decades, with younger Chinese moving to cities while leaving the lion's share of the older population in rural areas. This study explores how this structural change creates unique opportunities and challenges for older adults living in rural houses, which informs their everyday practices, the meanings of homes, and their subsequent housing choices. We examined the housing experiences of rural older adults through a field study conducted in Heilongjiang province. The study employed qualitative in-depth interviews with thirty-two older adults who live or have lived in rural housing, along with systematic documentation of their houses through photography and hand drawings captured from the field. We analyzed the interview narratives and images using the Glaserian grounded theory method to allow a high level of flexibility and conceptualization. The study identified five core categories of residential experiences: (1) houses as sites of production; (2) the earth/dwelling relationship; (3) social life in interstitial spaces; (4) the house as a means to preserve agency in old age and; (5) the burdensome house. These features were directly linked to the older adults' senses of home and their subsequent housing choices. The rural houses offered a strong sense of agency and belonging to rural older adults, but the city's expansion, the changing household registration system, and their aging bodies forced rural older adults to engage in constant reevaluation of their houses, informing their residential choices. We discuss the study's theoretical contributions and offer insights into policies and future planning for residential areas in both rural and urban areas by comparing the spatial configurations of rural dwellings with their urban apartment counterparts.

High-Dosage Fosfomycin Results in Adequate Plasma and Target-Site Exposure in Morbidly Obese and Nonobese Nonhyperfiltration Patients.

The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT>MIC (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC0-24h/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m2) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC ≤ 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of <130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement ß-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. (This study has been registered in the EU Clinical Trials Register under EudraCT no. 2012-004383-22.).

Whether interstitial space features were the main factors affecting sediment microbial community structures in Chaohu Lake.

Sediments cover a majority of Earth's surface and are essential for global biogeochemical cycles. The effects of sediment physiochemical features on microbial community structures have attracted attention in recent years. However, the question of whether the interstitial space has significant effects on microbial community structures in submerged sediments remains unclear. In this study, based on identified OTUs (operational taxonomic units), correlation analysis, RDA analysis, and Permanova analysis were applied into investigating the effects of interstitial space volume, interstitial gas space, volumetric water content, sediment particle features (average size and evenness), and sediment depth on microbial community structures in different sedimentation areas of Chaohu Lake (Anhui Province, China). Our results indicated that sediment depth was the closest one to the main environmental gradient. The destruction effects of gas space on sediment structures can physically affect the similarity of the whole microbial community in all layers in river dominated sedimentation area (where methane emits actively). However, including gas space, none of the five interstitial space parameters were significant with accounting for the microbial community structures in a sediment layer. Thus, except for the happening of active physical destruction on sediment structures (for example, methane ebullition), sediment interstitial space parameters were ineffective for affecting microbial community structures in all sedimentation areas.

Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid.

The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics (PK) as well as cytokine data were collected in humanised mice after iv injection of cibisatamab and CEACAM5-TCB which are binding with different binding affinities to the tumour antigen carcinoembryonic antigen (CEA). The PK data were modelled and coupled to a previously published physiologically based PK model. Corresponding cytokine release profiles were compared to in vitro data. The PK model provided a good fit to the data and precise estimation of key PK parameters. High tumour interstitial concentrations were observed for both TCBs, influenced by their respective target binding affinities. In conclusion, we developed a tailored experimental method to measure PK and cytokine release in plasma and at the site of drug action, namely in the tumour. Integrating those data into a mathematical model enabled to investigate the impact of target affinity on tumour accumulation and can have implications for the PKPD assessment of the therapeutic antibodies.

The glymphatic system and its role in cerebral homeostasis.

The brain's high bioenergetic state is paralleled by high metabolic waste production. Authentic lymphatic vasculature is lacking in brain parenchyma. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system detoxification in place of lymphatics, but the exact processes involved in toxic waste clearance from the brain remain incompletely understood. Over the past 8 yr, novel data in animals and humans have begun to shed new light on these processes in the form of the "glymphatic system," a brain-wide perivascular transit passageway dedicated to CSF transport and interstitial fluid exchange that facilitates metabolic waste drainage from the brain. Here we will discuss glymphatic system anatomy and methods to visualize and quantify glymphatic system (GS) transport in the brain and also discuss physiological drivers of its function in normal brain and in neurodegeneration.

Neglected interstitial space in malaria recurrence and treatment.

The interstitial space, a widespread fluid-filled compartment throughout the body, is related to many pathophysiological alterations and diseases, attracting increasing attention. The vital role of interstitial space in malaria infection and treatment has been neglected current research efforts. We confirmed the reinfection capacity of parasites sequestrated in interstitial space, which replenish the mechanism of recurrence. Malaria parasite-infected mice were treated with artemisinin-loaded liposomes through the interstitial space and exhibited a better therapeutic response. Notably, compared with oral administration, interstitial administration showed an unexpectedly high activation and recruitment of immune cells, and resulted in better clearance of sequestered parasites from organs, and enhanced pathological recovery. The interstitial route of administration prolongs the blood circulation time of artemisinin and increases its plasma concentration, and may compensate for the inefficiency of oral administration and the nanotoxicity of intravenous administration, providing a potential strategy for infectious disease therapy.

Vascular ATP-sensitive K+ channels support maximal aerobic capacity and critical speed via convective and diffusive O2 transport.

KEY POINTS: Oral sulphonylureas, widely prescribed for diabetes, inhibit pancreatic ATP-sensitive K+ (KATP ) channels to increase insulin release. However, KATP channels are also located within vascular (endothelium and smooth muscle) and muscle (cardiac and skeletal) tissue. We evaluated left ventricular function at rest, maximal aerobic capacity ( V̇ O2 max) and submaximal exercise tolerance (i.e. speed-duration relationship) during treadmill running in rats, before and after systemic KATP channel inhibition via glibenclamide. Glibenclamide impaired critical speed proportionally more than V̇ O2 max but did not alter resting cardiac output. Vascular KATP channel function (topical glibenclamide superfused onto hindlimb skeletal muscle) resolved a decreased blood flow and interstitial PO2 during twitch contractions reflecting impaired O2 delivery-to-utilization matching. Our findings demonstrate that systemic KATP channel inhibition reduces V̇ O2 max and critical speed during treadmill running in rats due, in part, to impaired convective and diffusive O2 delivery, and thus V̇ O2 , especially within fast-twitch oxidative skeletal muscle. ABSTRACT: Vascular ATP-sensitive K+ (KATP ) channels support skeletal muscle blood flow and microvascular oxygen delivery-to-utilization matching during exercise. However, oral sulphonylurea treatment for diabetes inhibits pancreatic KATP channels to enhance insulin release. Herein we tested the hypotheses that: i) systemic KATP channel inhibition via glibenclamide (GLI; 10 mg kg-1 i.p.) would decrease cardiac output at rest (echocardiography), maximal aerobic capacity ( V̇ O2 max) and the speed-duration relationship (i.e. lower critical speed (CS)) during treadmill running; and ii) local KATP channel inhibition (5 mg kg-1 GLI superfusion) would decrease blood flow (15 µm microspheres), interstitial space oxygen pressures (PO2 is; phosphorescence quenching) and convective and diffusive O2 transport ( Q̇ O2 and DO2 , respectively; Fick Principle and Law of Diffusion) in contracting fast-twitch oxidative mixed gastrocnemius muscle (MG: 9% type I+IIa fibres). At rest, GLI slowed left ventricular relaxation (2.11 ± 0.59 vs. 1.70 ± 0.23 cm s-1 ) and decreased heart rate (321 ± 23 vs. 304 ± 22 bpm, both P < 0.05) while cardiac output remained unaltered (219 ± 64 vs. 197 ± 39 ml min-1 , P > 0.05). During exercise, GLI reduced V̇ O2 max (71.5 ± 3.1 vs. 67.9 ± 4.8 ml kg-1 min-1 ) and CS (35.9 ± 2.4 vs. 31.9 ± 3.1 m min-1 , both P < 0.05). Local KATP channel inhibition decreased MG blood flow (52 ± 25 vs. 34 ± 13 ml min-1 100 g tissue-1 ) and PO2 isnadir (5.9 ± 0.9 vs. 4.7 ± 1.1 mmHg) during twitch contractions. Furthermore, MG V̇ O2 was reduced via impaired Q̇ O2 and DO2 (P < 0.05 for each). Collectively, these data support that vascular KATP channels help sustain submaximal exercise tolerance in healthy rats. For patients taking sulfonylureas, KATP channel inhibition may exacerbate exercise intolerance.

[Concept of membrane anatomy in laparoscopic sleeve gastrectomy procedure].

Membrane anatomy refers to the fascia and/or serosa enveloping the organs and their blood vessels and hanging on the posterior wall of the body cavity, which emphasizes the entirety and integrity of the membrane during operation. The concept can also be applied to most surgical operations. This article mainly expounds the application of the concept of membrane anatomy in the process of laparoscopic sleeve gastrectomy, which is embodied in the key steps of separating the greater omentum, mobilizing the fundus, mobilizing the posterior wall of the stomach, cutting the greater curvature of the stomach, reinforcing the staple line of the stomach, and suturing the greater omentum with staple line, in order to make the laparoscopic sleeve gastrectomy more accurate and precise with less bleeding, fewer complications and faster postoperative recovery.

Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy.

OBJECTIVES: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. METHODS: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. RESULTS: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. DISCUSSION: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Stimulation Modeling on Three-Dimensional Anisotropic Diffusion of MRI Tracer in the Brain Interstitial Space.

Purpose: To build a mathematical model based magnetic resonance (MR) method to simulate drug anisotropic distribution in vivo in the interstitial space (ISS) of the brain. Materials and Methods: An injection of signal intensity-related gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), which is an exogenous drug, was administered, and its diffusion was traced in the ISS of the brain using MRI. Dynamic MRI scans were performed to monitor and record the changes in signal intensity in each pixel of the region of interest. The transport parameters were calculated using the modified equation to simulate three-dimensional anisotropic diffusion, which was resolved using a Laplace transform and a linear regressive model. Results: After Gd-DTPA was introduced into the caudate nucleus, its distribution was demonstrated in real time. As the Gd-DTPA gradually cleared, the associated hyperintensity attenuated over time. The average diffusion coefficient (D) and the clearance rate constant (k) were (1.305 ± 0.364) × 10-4 mm2/s and (1.40 ± 0.206) × 10-5 s-1, respectively. Discussion: The combination of trace-based MRI and modified diffusion mathematical models can visualize and measure the three-dimensional anisotropic distribution of drugs in the ISS of the brain.

Experimental study of muscle permeability under various loading conditions.

The permeability of a few muscle tissues under various loading conditions is characterized. To this end, we develop an experimental apparatus for permeability measurements which is based on the falling head method. We also design a dedicated sample holder which directs the flow through the tissue and simultaneously enables to pre-compress it. Although outside of the scope of this work, we recall that the permeability of the muscle has a crucial role in the pathophysiology of various diseases such as the compartment syndrome. Following the measurements of porcine, beef, chicken and lamb samples, we find that the permeability decreases with the pre-compression of the tissue. Similar decrease is observed following dehydration of the tissue. Remarkably, we find that within a physiological pressure range the permeabilities of the various samples are quite similar. This suggests that the muscle permeability is governed by a common micro-mechanical mechanism in which the blood propagates through the interstitial spaces. Under physiological loading conditions, the muscle permeability is in the range between 80 and 230 [Formula: see text].

Hypoalbuminemia: Pathogenesis and Clinical Significance.

Hypoalbuminemia is associated with inflammation. Despite being addressed repeatedly in the literature, there is still confusion regarding its pathogenesis and clinical significance. Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin. The half-life of albumin has been shown to shorten, decreasing total albumin mass. These 2 factors lead to hypoalbuminemia despite increased fractional synthesis rates in plasma. Hypoalbuminemia, therefore, results from and reflects the inflammatory state, which interferes with adequate responses to events like surgery or chemotherapy, and is associated with poor quality of life and reduced longevity. Increasing or decreasing serum albumin levels are adequate indicators, respectively, of improvement or deterioration of the clinical state. In the interstitium, albumin acts as the main extracellular scavenger, antioxidative agent, and as supplier of amino acids for cell and matrix synthesis. Albumin infusion has not been shown to diminish fluid requirements, infection rates, and mortality in the intensive care unit, which may imply that there is no body deficit or that the quality of albumin "from the shelf" is unsuitable to play scavenging and antioxidative roles. Management of hypoalbuminaemia should be based on correcting the causes of ongoing inflammation rather than infusion of albumin. After the age of 30 years, muscle mass and function slowly decrease, but this loss is accelerated by comorbidity and associated with decreasing serum albumin levels. Nutrition support cannot fully prevent, but slows down, this chain of events, especially when combined with physical exercise.

A Three-Compartment Pharmacokinetic Model to Predict the Interstitial Concentration of Talaporfin Sodium in the Myocardium for Photodynamic Therapy: A Method Combining Measured Fluorescence and Analysis of the Compartmental Origin of the Fluorescence.

To evaluate the effectiveness of photodynamic therapy occurring in the interstitial space of the myocardium, we estimated the interstitial concentration of talaporfin sodium in the canine myocardium by constructing a three-compartment pharmacokinetic model based on measured changes in talaporfin sodium plasma concentration and myocardial fluorescence. Differential rate equations of talaporfin sodium concentration in the plasma, interstitial space, and cell compartment were developed with individual compartment volume, concentration, and rate constants. Using measured volume ratios based on histological examinations, we defined that the myocardial fluorescence consisted of the linear addition of fluorescence generated from these three compartments. The rate constants were obtained by fitting to minimize the sum of the squared errors between the measured talaporfin sodium concentrations and the calculated concentrations divided by the number of data points using the conjugate gradient method in MATLAB. We confirmed that this fitting operation may be appropriate, because a coefficient of determination between the measured talaporfin sodium changes and the calculated concentrations using our equations was 0.99. Consequently, to estimate the interstitial concentration in the canine myocardium, we propose a three-compartment pharmacokinetic model construction methodology using measured changes in talaporfin sodium plasma concentration and changes in myocardial fluorescence.

Beyond Blood: African Trypanosomes on the Move.

While the African trypanosomes are among the best-studied parasites, almost everything we know about them is based on the brucei group, which includes the human-infective sleeping sickness parasites and the causative agent of the cattle plague nagana. The past decades have seen an ever-more detailed molecular dissection of Trypanosoma brucei, which today is an accepted cell biological model system. Therefore, recent work on some fundamental aspects of trypanosome biology surprises, as we realise that our knowledge about parasite motility and tropism in the changing host microenvironments is far from definitive. In this review, we highlight a few examples of neglected parasitological questions, which may open (or reopen) a new chapter of trypanosome research.

In vivo mimicking model for solid tumor towards hydromechanics of tissue deformation and creation of necrosis.

The present work addresses transvascular and interstitial fluid transport inside a solid tumor surrounded by normal tissue (close to an in vivo mimicking setup). In general, biological tissues behave like a soft porous material and show mechanical behavior towards the fluid motion through the interstitial space. In general, forces like viscous drag that are associated with the fluid flow may compress the tissue material. On the macroscopic level, we try to model the motion of fluids and macromolecules through the interstitial space of solid tumor and the normal tissue layer. The transvascular fluid transport is assumed to be governed by modified Starling's law. The poroelastohydrodynamics (interstitial hydrodynamics and the deformation of tissue material) inside the tumor and normal tissue regions is modeled using linearized biphasic mixture theory. Correspondingly, the velocity distribution of fluid is coupled to the displacement field of the solid phase (mainly cellular phase and extracellular matrix) in both the normal and tumor tissue regions. The corresponding velocity field is used within the transport reaction equation for fluids and macromolecules through interstitial space to get the overall solute (e.g., nutrients, drug, and other macromolecules) distribution. This study justifies that the presence of the normal tissue layer plays a significant role in delaying/assisting necrosis inside the tumor tissue. It is observed that the exchange process of fluids and macromolecules across the interface of the tumor and normal tissue affects the effectiveness factor corresponding to the tumor tissue.

Understanding Qi Running in the Meridians as Interstitial Fluid Flowing via Interstitial Space of Low Hydraulic Resistance.

Qi, blood and the meridians are fundamental concepts in Chinese medicine (CM), which are components of the human body and maintain physiological function. Pathological changes of qi, blood and meridians may lead to discomfort and disease. Treatment with acupuncture or herbal medicine aims to regulate qi and blood so as to recover normal function of the meridians. This paper explores the nature of qi as well as compares and correlates them with the structures of the human body. We propose a conceptualization of qi as being similar to the interstitial fluid, and the meridians as being similar to interstitial space of low hydraulic resistance in the body. Hence, qi running in the meridians can be understood as interstitial fluid flowing via interstitial space of low hydraulic resistance.