Effects of ultra-purified polymerized bovine hemoglobin on local tissue oxygen tension in striated skin muscle - An efficacy study in the hamster

The development of hemoglobin-based oxygen carriers has been propagated for replacement of the oxygen carrying properties of red blood cells for almost one century. Using a Clark-type multi-wire oxygen surface electrode and the dorsal skin fold chamber model of the awake Syrian golden hamster, local tissue pO(2) was analyzed in the thin striated skin muscle before and after administration of an ultrapurified polymerized bovine hemoglobin solution (U-PBHb(R), Biopure Corp., Boston, Mass., USA) under the following experimental conditions: (a) hypervolemic infusion with U-PBHb at similar to 10% of calculated blood volume, and (b) isovolemic exchange transfusion with U-PBHb by replacing similar to50% of calculated blood volume. Control animals of group a received equivalent treatment with either isotonic saline or dextran 60, control animals of group b received dextran 60. Local tissue pO(2) was found slightly decreased after both hypervolemic infusion and isovolemic exchange transfusion with U-PBHb, while frequency distribution curves of local tissue pO(2) were found more narrow (less values 25 mm Hg), suggesting a more homogeneous tissue pO(2) distribution. The data thus indicate that U-PBHb slightly decreases mean tissue pO(2) after both hypervolemic infusion and isovolemic exchange transfusion which is accompanied by an effective homogenization of local tissue pO(2) distribution as compared to dextran 60. Copyright (C) 2002 S. Karger AG, Basel

Quantitative analysis of cell types during growth and morphogenesis in Hydra

Tissue maceration was used to determine the absolute number and the distribution of cell types in Hydra. It was shown that the total number of cells per animal as well as the distribution of cells vary depending on temperature, feeding conditions, and state of growth. During head and foot regeneration and during budding the first detectable change in the cell distribution is an increase in the number of nerve cells at the site of morphogenesis. These results and the finding that nerve cells are most concentrated in the head region, diminishing in density down the body column, are discussed in relation to tissue polarity

Computational fluid dynamic analysis of bioprinted self-supporting perfused tissue models

Natural tissues are incorporated with vasculature, which is further integrated with a cardiovascular system responsible for driving perfusion of nutrient‐rich oxygenated blood through the vasculature to support cell metabolism within most cell‐dense tissues. Since scaffold‐free biofabricated tissues being developed into clinical implants, research models, and pharmaceutical testing platforms should similarly exhibit perfused tissue‐like structures, we generated a generalizable biofabrication method resulting in self‐supporting perfused (SSuPer) tissue constructs incorporated with perfusible microchannels and integrated with the modular FABRICA perfusion bioreactor. As proof of concept, we perfused an MLO‐A5 osteoblast‐based SSuPer tissue in the FABRICA. Although our resulting SSuPer tissue replicated vascularization and perfusion observed in situ, supported its own weight, and stained positively for mineral using Von Kossa staining, our in vitro results indicated that computational fluid dynamics (CFD) should be used to drive future construct design and flow application before further tissue biofabrication and perfusion. We built a CFD model of the SSuPer tissue integrated in the FABRICA and analyzed flow characteristics (net force, pressure distribution, shear stress, and oxygen distribution) through five SSuPer tissue microchannel patterns in two flow directions and at increasing flow rates. Important flow parameters include flow direction, fully developed flow, and tissue microchannel diameters matched and aligned with bioreactor flow channels. We observed that the SSuPer tissue platform is capable of providing direct perfusion to tissue constructs and proper culture conditions (oxygenation, with controllable shear and flow rates), indicating that our approach can be used to biofabricate tissue representing primary tissues and that we can model the system in silico

Perspectives in Microvascular Fluid Handling: Does the Distribution of Coagulation Factors in Human Myocardium Comply with Plasma Extravasation in Venular Coronary Segments?

Background: Heterogeneity of vascular permeability has been suggested for the coronary system. Whereas arteriolar and capillary segments are tight, plasma proteins pass readily into the interstitial space at venular sites. Fittingly, lymphatic fluid is able to coagulate. However, heart tissue contains high concentrations of tissue factor, presumably enabling bleeding to be stopped immediately in this vital organ. The distribution of pro- and anti-coagulatively active factors in human heart tissue has now been determined in relation to the types of microvessels. Methods and Results: Samples of healthy explanted hearts and dilated cardiomyopathic hearts were immunohistochemically stained. Albumin was found throughout the interstitial space. Tissue factor was packed tightly around arterioles and capillaries, whereas the tissue surrounding venules and small veins was practically free of this starter of coagulation. Thrombomodulin was present at the luminal surface of all vessel segments and especially at venular endothelial cell junctions. Its product, the anticoagulant protein C, appeared only at discrete extravascular sites, mainly next to capillaries. These distribution patterns were basically identical in the healthy and diseased hearts, suggesting a general principle. Conclusions: Venular extravasation of plasma proteins probably would not bring prothrombin into intimate contact with tissue factor, avoiding interstitial coagulation in the absence of injury. Generation of activated protein C via thrombomodulin is favored in the vicinity of venular gaps, should thrombin occur inside coronary vessels. This regionalization of distribution supports the proposed physiological heterogeneity of the vascular barrier and complies with the passage of plasma proteins into the lymphatic system of the heart. Copyright (C) 2010 S. Karger AG, Base

Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues

Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation by tissue optical properties, an effect that causes spectral corruption. Predictions of the spectral variations of light fluence in tissue are challenging since the spatial distribution of optical properties in tissue cannot be resolved in high resolution or with high accuracy by current methods. Spectral corruption has fundamentally limited the quantification accuracy of optical and optoacoustic methods and impeded the long sought-after goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical but still unattainable target for the assessment of oxygenation in physiological processes and disease. We discover a new principle underlying light fluence in tissues, which describes the wavelength dependence of light fluence as an affine function of a few reference base spectra, independently of the specific distribution of tissue optical properties. This finding enables the introduction of a previously undocumented concept termed eigenspectra Multispectral Optoacoustic Tomography (eMSOT) that can effectively account for wavelength dependent light attenuation without explicit knowledge of the tissue optical properties. We validate eMSOT in more than 2000 simulations and with phantom and animal measurements. We find that eMSOT can quantitatively image tissue sO2 reaching in many occasions a better than 10-fold improved accuracy over conventional spectral optoacoustic methods. Then, we show that eMSOT can spatially resolve sO2 in muscle and tumor; revealing so far unattainable tissue physiology patterns. Last, we related eMSOT readings to cancer hypoxia and found congruence between eMSOT tumor sO2 images and tissue perfusion and hypoxia maps obtained by correlative histological analysis

Thyroid hormone receptors and ligand, tissue distribution and sexual behavior

The thyroid hormones (THs) triiodothyronine (T3) and tetraiodothyronine, or thyroxine (T4), not only dramatically impact on development and differentiation, but also on the sexual and reproductive function. There is large body of literature, in fact, on the effects of THs on the reproductive function in both humans (Poppe and Velkeniers, 2004; Wajner et al., 2009) and animals (Hapon et al., 2010; Nelson et al., 2011). For a long time the gonads were thought to be unresponsive to THs, but TH receptors (TR) were discovered in rat (Jannini et al., 1990; Palmero et al., 1988) and then in human testis (Jannini et al., 2000). In women, the association of menstrual disturbance with thyroid disease was described as early as 1840 by von Basedow, but the discovery of TRs in the ovary was carried out at the end of last century (Wakim et al., 1994b). Therefore, the link between thyroid and reproductive function was well established. Since then, research has shown that thyroid dysfunction is associated with an adverse effect on fertility, both in men (Wagner et al., 2009) and women (Dittrich et al., 2011). There is also evidence that THs can affect the sex steroid hormone axis (Bagamasbad and Denver, 2011), consequently sexual hormones and the pituitary gland can mediate the action of THs on the reproductive physiology. While the effects of THs on fertility have been widely studied, little is known about their influence on sexual function. In the last few years, an increasing number of evidences have shown the influence of THs on male sexual function, particularly on ejaculation control as well on desire and erectile function (Carani et al., 2005; Corona et al., 2012b; Di Sante et al., 2016). The female sexual function and the relationship with thyroid function is still less studied. Furthermore, studies conducted on animals have shown the presence of TRs in the male (Carosa et al., 2010) and female genitalia (Rodriguez-Castelan et al., 2017). Moreover, knockout mice for TRs showed alterations in sexual behavior (Dellovade et al., 2000). The purpose of this review is to summarize and discuss the available data on the influence of THs on male and female sexual function to understand the molecular mechanisms of the influence of the thyroid gland on sexual behavior and function

Protein kinase a distribution differentiates human glioblastoma from brain tissue

Brain tumor glioblastoma has no clear molecular signature and there is no effective therapy. In rodents, the intracellular distribution of the cyclic AMP (cAMP)-dependent protein kinase (Protein kinase A, PKA) R2Alpha subunit was previously shown to differentiate tumor cells from healthy brain cells. Now, we aim to validate this observation in human tumors. The distribution of regulatory (R1 and R2) and catalytic subunits of PKA was examined via immunohistochemistry and Western blot in primary cell cultures and biopsies from 11 glioblastoma patients. Data were compared with information obtained from 17 other different tumor samples. The R1 subunit was clearly detectable only in some samples. The catalytic subunit was variably distributed in the different tumors. Similar to rodent tumors, all human glioblastoma specimens showed perinuclear R2 distribution in the Golgi area, while it was undetectable outside the tumor. To test the effect of targeting PKA as a therapeutic strategy, the intracellular cyclic AMP concentration was modulated with different agents in four human glioblastoma cell lines. A significant increase in cell death was detected after increasing cAMP levels or modulating PKA activity. These data raise the possibility of targeting the PKA intracellular pathway for the development of diagnostic and/or therapeutic tools for human glioblastoma

Perivascular adipose tissue as a relevant fat depot for cardiovascular risk in obesity

Obesity is associated with increased risk of premature death, morbidity, and mortality from several cardiovascular diseases (CVDs), including stroke, coronary heart disease (CHD), myocardial infarction, and congestive heart failure. However, this is not a straightforward relationship. Although several studies have substantiated that obesity confers an independent and additive risk of all-cause and cardiovascular death, there is significant variability in these associations, with some lean individuals developing diseases and others remaining healthy despite severe obesity, the so-called metabolically healthy obese. Part of this variability has been attributed to the heterogeneity in both the distribution of body fat and the intrinsic properties of adipose tissue depots, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, hormonal control, thermogenic ability, and vascularization. In obesity, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. The adventitial fat layer, also known as perivascular adipose tissue (PVAT), is of major importance. Similar to the visceral adipose tissue, PVAT has a pathophysiological role in CVDs. PVAT influences vascular homeostasis by releasing numerous vasoactive factors, cytokines, and adipokines, which can readily target the underlying smooth muscle cell layers, regulating the vascular tone, distribution of blood flow, as well as angiogenesis, inflammatory processes, and redox status. In this review, we summarize the current knowledge and discuss the role of PVAT within the scope of adipose tissue as a major contributing factor to obesity-associated cardiovascular risk. Relevant clinical studies documenting the relationship between PVAT dysfunction and CVD with a focus on potential mechanisms by which PVAT contributes to obesity-related CVDs are pointed out