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Key Points Transcapillary flow, which is important for tissue homeostasis, is influenced by the hydrostatic and colloid osmotic pressures of capillaries and interstitium. The interstitial fluid pressure (IFP) of normal tissues is actively regulated through interactions between stromal cells and the extracellular-matrix molecules. Most solid tumours have increased IFP. The reasons for increased tumour IFP include blood-vessel leakiness, lymph-vessel abnormalities, interstitial fibrosis and a contraction of the interstitial matrix mediated by stromal fibroblasts. Increased tumour IFP causes inefficient uptake of therapeutic agents. Lowering of tumour IFP — for example, by certain cytokine antagonists — can improve drug uptake and thereby improve treatment efficiency. Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

Background/Aims: Intradialytic hypotension is the most common complication of modern day haemodialysis (HD). Convective modalities, including haemodiafiltration (HDF) are reported to result in greater cardiovascular stability compared to standard HD, which has been suggested to be due to improved solute transport between compartments. We therefore investigated the effect of treatment on body water by bioimpedance. Methods: We measured the change in extracellular water (ECW) and intracellular water (ICW) in 263 outpatients attending for HD using cooled dialysate and 134 patients for HDF. Results: Patient cohorts were matched for demographics, dialysate composition, ultrafiltration rate, and session duration. The fall in systolic blood pressure following HD was -11.8 mm Hg (-25.3 to 2.3) and not different from that following HDF -12 mm Hg (-27 to 6). Similarly there were no differences in pretreatment serum sodium and dialysate sodium gradient [HD 1 mmol/l (-1 to 3) vs. HDF 2 mmol/l (1 to 4)], or change in serum sodium posttreatment [HD 0 mmol/l (-2 to 2) vs. HDF 1 mmol/l (-1 to 3)]. There were no differences in ICW or ECW pretreatment, and following treatment the reduction in ICW and ECW did not differ [ICW HD -3.5% (-5.7 to -1.8) vs. -4.1% (-6.0 to -1.7), ECW HD -7.1% (-9.4 to -4.7) vs. HDF -7.1% (-9.7 to -4.9)]. Conclusion: We were unable to demonstrate any advantage for HDF over HD using cooled dialysate in terms of changes in blood pressure during a treatment session, or differences in the relative changes in ICW or ECW volumes.

The authors report that in mouse auditory cortex, the sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when animals transitioned from quiescence to active behaviors, while L4 and thalamic responses were unchanged. This laminar-specific gain control could be attributed to an enhancement of L1-mediated inhibition. Cortical sensory processing is modulated by behavioral and cognitive states. How this modulation is achieved by changing synaptic circuits remains largely unknown. In awake mouse auditory cortex, we found that sensory-evoked spike responses of layer 2/3 (L2/3) excitatory cells were scaled down with preserved sensory tuning when mice transitioned from quiescence to active behaviors, including locomotion, whereas L4 and thalamic responses were unchanged. Whole-cell voltage-clamp recordings revealed that tone-evoked synaptic excitation and inhibition exhibited a robust functional balance. The change to active states caused scaling down of excitation and inhibition at approximately equal levels in L2/3 cells, but resulted in no synaptic changes in L4 cells. This lamina-specific gain control could be attributed to an enhancement of L1-mediated inhibitory tone, with L2/3 parvalbumin inhibitory neurons also being suppressed. Thus, L2/3 circuits can adjust the salience of output in accordance with momentary behavioral demands while maintaining the sensitivity and quality of sensory processing.

There are two main types of fluid in bone tissue, blood and interstitial fluid. The chemical composition of these fluids varies with time and location in bone. Blood arrives through the arterial system containing oxygen and other nutrients and the blood components depart via the venous system containing less oxygen and reduced nutrition. Within the bone, as within other tissues, substances pass from the blood through the arterial walls into the interstitial fluid. The movement of the interstitial fluid carries these substances to the cells within the bone and, at the same time, carries off the waste materials from the cells. Bone tissue would not live without these fluid movements. The development of a model for poroelastic materials with hierarchical pore space architecture for the description of blood flow and interstitial fluid flow in living bone tissue is reviewed. The model is applied to the problem of determining the exchange of pore fluid between the vascular porosity and the lacunar–canalicular porosity in bone tissue due to cyclic mechanical loading and blood pressure. These results are basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells.

Interstitial fluid load support (FLS) is a dominant mechanism of lubrication in cartilage, producing a low friction coefficient while enhancing the tissue’s load bearing capabilities. Due to its viscosity, synovial fluid (SF) may retard loss of FLS by slowing the exudation of interstitial fluid from the cartilage. This study tested this hypothesis by comparing the stress-relaxation (SRL) response of immature bovine articular cartilage immersed either in phosphate buffered saline (PBS) or in healthy mature bovine SF, under unconfined compression (fluid exudation across cut lateral tissue boundary) and indentation testing (fluid exudation across articular surface). To investigate the influence of diffusion of SF molecular constituents into cartilage, the effect of incubation time in SF on SRL was also investigated. The SRL response in unconfined compression was not significantly different in PBS versus SF when compared directly (p = 0.98) and had a slope ofm = 1.00 ± 0.04 (R2 = 0.989 ± 0.007). Samples tested in PBS exhibited characteristic relaxation times, τPBS=42.6 ± 5.3 s andτSF = 40.8 ± 4.7 s, that were not significantly different (p = 0.40). Incubation time of 24 h in SF resulted in no significant difference in the SRL response (p = 0.39, m=1.03 ± 0.12; R2=0.983 ± 0.011, andτPBS = 43.4 ± 10.7 s versusτSF = 41.5 ± 4.8 s, p = 0.59). Indentation testing showed some statistically significant, but functionally insignificant, difference in SRL responses in PBS versus SF with a slope ofm = 0.958 ± 0.060 (R2 = 0.957 ± 0.020, p = 0.029, andτPBS = 16.9 ± 2.6 s versusτSF = 19.4 ± 3.3 s, p = 0.073). Based on these results, we reject the hypothesis that healthy SF can retard the loss of FLS in cartilage due to its viscosity.

Over the last two decades, considerable progress has been reported in the field of cartilage mechanics that impacts our understanding of the role of interstitial fluid pressurization on cartilage lubrication. Theoretical and experimental studies have demonstrated that the interstitial fluid of cartilage pressurizes considerably under loading, potentially supporting most of the applied load under various transient or steady-state conditions. The fraction of the total load supported by fluid pressurization has been called the fluid load support. Experimental studies have demonstrated that the friction coefficient of cartilage correlates negatively with this variable, achieving remarkably low values when the fluid load support is greatest. A theoretical framework that embodies this relationship has been validated against experiments, predicting and explaining various outcomes, and demonstrating that a low friction coefficient can be maintained for prolonged loading durations under normal physiological function. This paper reviews salient aspects of this topic, as well as its implications for improving our understanding of boundary lubrication by molecular species in synovial fluid and the cartilage superficial zone. Effects of cartilage degeneration on its frictional response are also reviewed.

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T reg ) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-κB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.

Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. A microfluidic cell culture system was designed to apply stable pressure gradients and fluid flow and allow direct visualization of transient responses of cells seeded in a 3D collagen type I scaffold. We used this system to examine the effects of interstitial flow on cancer cell morphology and migration and to extend previous studies showing that interstitial flow increases the metastatic potential of MDA-MB-435S melanoma cells [Shields J, et al. (2007) Cancer Cell 11:526–538]. Using a breast carcinoma line (MDA-MB-231) we also observed cell migration along streamlines in the presence of flow; however, we further demonstrated that the strength of the flow as well as the cell density determined directional bias of migration along the streamline. In particular, we found that cells either at high seeding density or with the CCR-7 receptor inhibited migration against, rather than with the flow. We provide further evidence that CCR7-dependent autologous chemotaxis is the mechanism that leads to migration with the flow, but also demonstrate a competing CCR7-independent mechanism that causes migration against the flow. Data from experiments investigating the effects of cell concentration, interstitial flow rate, receptor activity, and focal adhesion kinase phosphorylation support our hypothesis that the competing stimulus is integrin mediated. This mechanism may play an important role in development of metastatic disease.

Cancers exhibit spatially heterogeneous, unique vascular architectures across individual samples, cell-lines and patients. This inherently disorganised collection of leaky blood vessels contribute significantly to suboptimal treatment efficacy. Preclinical tools are urgently required which incorporate the inherent variability and heterogeneity of tumours to optimise and engineer anti-cancer therapies. In this study, we present a novel computational framework which incorporates whole, realistic tumours extracted ex vivo to efficiently simulate vascular blood flow and interstitial fluid transport in silico for validation against in vivo biomedical imaging. Our model couples Poiseuille and Darcy descriptions of vascular and interstitial flow, respectively, and incorporates spatially heterogeneous blood vessel lumen and interstitial permeabilities to generate accurate predictions of tumour fluid dynamics. Our platform enables highly-controlled experiments to be performed which provide insight into how tumour vascular heterogeneity contributes to tumour fluid transport. We detail the application of our framework to an orthotopic murine glioma (GL261) and a human colorectal carcinoma (LS147T), and perform sensitivity analysis to gain an understanding of the key biological mechanisms which determine tumour fluid transport. Finally we mimic vascular normalization by modifying parameters, such as vascular and interstitial permeabilities, and show that incorporating realistic vasculatures is key to modelling the contrasting fluid dynamic response between tumour samples. Contrary to literature, we show that reducing tumour interstitial fluid pressure is not essential to increase interstitial perfusion and that therapies should seek to develop an interstitial fluid pressure gradient. We also hypothesise that stabilising vessel diameters and permeabilities are not key responses following vascular normalization and that therapy may alter interstitial hydraulic conductivity. Consequently, we suggest that normalizing the interstitial microenvironment may provide a more effective means to increase interstitial perfusion within tumours.

Orthodontic forces deform the extracellular matrix and activate cells of the paradental tissues, facilitating tooth movement. Discoveries in mechanobiology have illuminated sequential cellular and molecular events, such as signal generation and transduction, cytoskeletal re-organization, gene expression, differentiation, proliferation, synthesis and secretion of specific products, and apoptosis. Orthodontists work in a unique biological environment, wherein applied forces engender remodeling of both mineralized and non-mineralized paradental tissues, including the associated blood vessels and neural elements. This review aims at identifying events that affect the sequence, timing, and significance of factors that determine the nature of the biological response of each paradental tissue to orthodontic force. The results of this literature review emphasize the fact that mechanoresponses and inflammation are both essential for achieving tooth movement clinically. If both are working in concert, orthodontists might be able to accelerate or decelerate tooth movement by adding adjuvant methods, whether physical, chemical, or surgical.