Human Organ Systems Research Articles

Human Body and Organ Systems

Human Body and Organ Systems

Blood parameter analysis after short term exposure to weightlessness in parabolic flight.

Parabolic flights offer a unique platform for human experiments in short-term weightlessness. It is generally known that human organ systems react to changes of gravity. Yet, little is known about alterations of blood parameters under these conditions with special emphasis on blood rheology. We investigated the alterations of distinct blood parameters after exposure to weightlessness. 14 healthy volunteers underwent short-term phases of weightlessness induced by parabolic flight. At different time points (baseline, t2:1 hour after landing, and t3:24 hours after baseline), venous blood was drawn and analyzed. Analysis of red blood count revealed significant decreases of hemoglobin and hematocrit post flight. While total white blood counts were unaltered, differential subset analysis revealed significant decreases of eosinophil granulocytes and monocytes. Cortisole levels were unchanged and lacked physiologic circadian decrease. Parameters of renal function were found significantly improved (GFR (ml/min/1,73m2): Baseline: 105 [89;109], t2:117 [98;125], t3:110 [102;119]; p = 0.0013. In the sense of mild myocytolysis, levels of myoglobin were significantly elevated post-flight with fast recovery to baseline levels. In the current analysis, significant alterations of blood parameters after exposure to weightlessness could be detected. These results contribute to the understanding of physiologic adaptations of the human body to weightlessness.

Short-term effect of the demonstration of human dissection and excursion on students´ ideas about the human organ systems: a Slovak experience.

Excursions in natural sciences education are justified in the current school system and within the scope of subject focus. The research aimed to observe the immediate impact of demonstration of the human dissection and excursion on the formation of ideas of students about the human body systems. The experiment involved the first Slovak demonstration of a real human autopsy for students of the Biology Teaching Department (PdF TU in Trnava). Concepts of the structure of the human body were analyzed before and after experimental impact by a projective technique. The evaluation included the representation, description, and abundance of organs in the view of various systems. The subject of the research were also the questions focused on the use of illustrative procedures and tools in the educational process. Significant statistical differences were found in the group affected by human autopsy in understanding of the digestive, urinary, and locomotor systems. Conversely, the skin, endocrine glands, and lymphatic system were the least represented by the experimental groups. Considering the presented results, using different organizational forms and aids (real and virtual) is essential for bringing a positive educational effect on the studied problem (Tab. 1, Fig. 5, Ref. 20).

Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice.

Inborn errors of metabolism (IEMs) are rare genetic or inherited disorders resulting from an enzyme defect in biochemical and metabolic pathways affecting proteins, fats, carbohydrates metabolism or impaired organelle function presenting as complicated medical conditions involving several human organ systems. They involve great complexity of the underlying pathophysiology, biochemical workup, and molecular analysis, and have complicated therapeutic options for management. Age of presentation can vary from infancy to adolescence with the more severe forms appearing in early childhood accompanied by significant morbidity and mortality. The understanding of these complex disorders requires special in-depth training, American Board of Medical Genetics and Genomics (ABMGG) certification and experience. Most primary care physicians (PCPs) are reluctant to deal with IEM due to unfamiliarity and rarity of such conditions compounded by prompt progression to crisis situations along with paucity of time involved in dealing with such complex disorders. While there are biochemical geneticists aka metabolic specialists' expertise available, mostly in larger academic medical centers, with expertise to deal with these rare complex issues, their initial clinical presentation in most newborns, children, adolescents or adults including asymptomatic positive newborn screen (NBS), occur in the out-patient PCP settings. Therefore, it is important that PCPs' comfort to recognize early signs and symptoms is important to initiate appropriate diagnostic and therapeutic interventions, and be able to make appropriate referrals. The following article reviews common IEM clinical presentations for a robust diagnostic differential and discuss evaluation and management approaches of patients with known or suspected IEM.

Growing Human Parathyroids in a Microphysiological System: A Novel Approach to Understanding and Developing New Treatments for Hyperparathyroidism

We developed a novel model for studying hyperparathyroidism by growing ex vivo 3-dimensional human parathyroids as part of a microphysiological system (MPS) that mimics human physiology. The purpose of this study was to validate the parathyroid portion of the MPS. We prospectively collected parathyroid tissue from 46 patients with hyperparathyroidism for growth into pseudoglands. We evaluated pseudogland architecture and calcium responsiveness. Following 2 weeks in culture, dispersed cells successfully coalesced into pseudoglands ∼500–700 µm in diameter that mimicked the appearance of normal parathyroid glands. Functionally, they also appeared similar to intact parathyroids in terms of organization and calcium-sensing receptor expression. Immunohistochemical staining for calcium-sensing receptor revealed 240–450/cell units of mean fluorescence intensity within the pseudoglands. Finally, the pseudoglands showed varying levels of calcium responsiveness, indicated by changes in parathyroid hormone (PTH) levels. In summary, we successfully piloted the development of a novel MPS for studying the effects of hyperparathyroidism on human organ systems. We are currently evaluating the effect of PTH on adverse remodeling of tissue engineered cardiac, skeletal, and bone tissue within the MPS.

Organ-on-chip models: Implications in drug discovery and clinical applications.

Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three-dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine-gut-stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ-on-chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ-on-chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine.

The Geometry of Emotions: Using Chakra Acupuncture and 5-Phase Theory to Describe Personality Archetypes for Clinical Use.

Background: The 5-Phase theory of Traditional Chinese Medicine has been an integral part of medical acupuncture for 2000 years. The research of John R. Cross PhD, PhDAc, has resulted in a further evolution of the 5-Phase theory to include the Ayurvedic chakra energy centers. By using chakras, a clinician can appreciate the integration of human organ systems, the neuroendocrine system, and personality attributes (both positive and negative) associated with each chakra. Objective: To create personality archetypes from chakras that have practical clinical value. Design: By assigning chakras to the 5-Phase elements on a pentagon per Dr. Cross, it was possible to connect a series of negative or positive emotions, from one to another, using the familiar Ko cycles and Shen cycles, to form theoretical personality archetypes and then to demonstrate archetype usefulness in a sample clinical case. The patient was being treated with Japanese acupuncture. The main outcome sought was to determine the personality types according to the 5-Phase theory with chakra energy centers included and to demonstrate the application of this system in the clinical case. Results: Fourteen personality archetypes-seven composed of positive emotions and seven composed of negative emotions-were identified. Easy-to-remember names and familiar patterns of emotion that are mapped to the nodes of a pentagon (adapted to chakra acupuncture) were produced. The clinical case showed that the patient's work life conflicts resulted in negative archetype emotional patterns (anger, scarcity, lack of self-esteem) consistent with the presentation of irritable bowel syndrome, insomnia, liver illness, and osteoarthritis. Conclusions: Personality archetypes have clinical value for understanding the emotions associated with illness.

Emerging roles of sphingosylphosphorylcholine in modulating cardiovascular functions and diseases.

Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid in blood plasma that is metabolized from the hydrolysis of the membrane sphingolipid. SPC maintains low levels in the circulation under normal conditions, which makes studying its origin and action difficult. In recent years, however, it has been revealed that SPC may act as a first messenger through G protein-coupled receptors (S1P1-5, GPR12) or membrane lipid rafts, or as a second messenger mediating intracellular Ca2+ release in diverse human organ systems. SPC is a constituent of lipoproteins, and the activation of platelets promotes the release of SPC into blood, both implying a certain effect of SPC in modulating the pathological process of the heart and vessels. A line of evidence indeed confirms that SPC exerts a pronounced influence on the cardiovascular system through modulation of the functions of myocytes, vein endothelial cells, as well as vascular smooth muscle cells. In this review we summarize the current knowledge of the potential roles of SPC in the development of cardiovascular diseases and discuss the possible underlying mechanisms.

Neurite Outgrowth Inhibitor B Receptor: A Versatile Receptor with Multiple Functions and Actions.

Members of the reticulon protein family are predominantly distributed within the endoplasmic reticulum. The neurite outgrowth inhibitor (Nogo) has three subtypes, including Nogo-A (200 kDa), Nogo-B (55 kDa), and Nogo-C (25 kDa). Nogo-A and Nogo-C are potent Nogos that are predominantly expressed in the central nervous system. Nogo-B, the splice variant of reticulon-4, is expressed widely in multiple human organ systems, including the liver, lung, kidney, blood vessels, and inflammatory cells. Moreover, the Nogo-B receptor (NgBR) can interact with Nogo-B and can independently affect nervous system regeneration, the chemotaxis of endothelial cells, proliferation, and apoptosis. In recent years, it has been demonstrated that NgBR plays an important role in human pathophysiological processes, including lipid metabolism, angiogenesis, N-glycosylation, cell apoptosis, chemoresistance in human hepatocellular carcinoma, and epithelial-mesenchymal transition. The pathophysiologic effects of NgBR have garnered increased attention, and the detection and enhancement of NgBR expression may be a novel approach to monitor the development and to improve the prognosis of relevant human clinical diseases.

Rab11 family expression in the human placenta: Localization at the maternal-fetal interface.

Rab proteins are a family of small GTPases involved in a variety of cellular processes. The Rab11 subfamily in particular directs key steps of intracellular functions involving vesicle trafficking of the endosomal recycling pathway. This Rab subfamily works through a series of effector proteins including the Rab11-FIPs (Rab11 Family-Interacting Proteins). While the Rab11 subfamily has been well characterized at the cellular level, its function within human organ systems is still being explored. In an effort to further study these proteins, we conducted a preliminary investigation of a subgroup of endosomal Rab proteins in a range of human cell lines by Western blotting. The results from this analysis indicated that Rab11a, Rab11c(Rab25) and Rab14 were expressed in a wide range of cell lines, including the human placental trophoblastic BeWo cell line. These findings encouraged us to further analyse the localization of these Rabs and their common effector protein, the Rab Coupling Protein (RCP), by immunofluorescence microscopy and to extend this work to normal human placental tissue. The placenta is a highly active exchange interface, facilitating transfer between mother and fetus during pregnancy. As Rab11 proteins are closely involved in transcytosis we hypothesized that the placenta would be an interesting human tissue model system for Rab investigation. By immunofluorescence microscopy, Rab11a, Rab11c(Rab25), Rab14 as well as their common FIP effector RCP showed prominent expression in the placental cell lines. We also identified the expression of these proteins in human placental lysates by Western blot analysis. Further, via fluorescent immunohistochemistry, we noted abundant localization of these proteins within key functional areas of primary human placental tissues, namely the outer syncytial layer of placental villous tissue and the endothelia of fetal blood vessels. Overall these findings highlight the expression of the Rab11 family within the human placenta, with novel localization at the maternal-fetal interface.

Alternative Way for Organ Donation in Societies With Traditional Beliefs and Well Organized System of Emergency Medical Care

Substantial improvements in neurological and neurosurgical care in Russia in the last years led to imminent but expected decrease in organ donation rate. This trend inflicted the need to actively search for new ways to expand donor pool and resulted into emergence of two priority areas. First is based on the liberalization of brain death diagnostic criteria. Second one highlights the application of methods of artificial circulation. Brain death criteria liberalization will inevitably cause alterations in conventional relationship between doctor and patient. Adoption of artificial circulation approach induces the necessity to constructively rethink its role in saving person’s life or, in case of failure, saving organs of deceased person for transplant. Resuscitation procedure algorithm, death record protocol for a patient with non-beating heart, but on artificial circulatory support as well as organ procurement procedure from such donor – all these represents complex non-medical, but socio-humanitarian, philosophical and theological issues. From 2009 till now our transplant team performed 35 procedures of extracorporeal membrane oxygenation in potential organ donors with 60 minutes after irreversible cardiac arrest followed by successful transplantation. Study design, perfusion protocols, procurement and transplant procedures were approved by the Scientific Board and the Ethics Committee of the Saint Petersburg State Research Institute for Emergency (Decision 7/0615/09) and authorized for clinical application by the Federal Advisory Service of the Ministry of Health of the Russian Federation (Resolution N2010/299). All donation and perfusion procedures were approved by local Ethics Committees and Institutional Review Board [1]. Our initial experience clearly demonstrates that new technical knowledge concerning artificial circulatory support in isolated human organs and organ systems all put together with integral knowledge about human (philosophical, theological, anthropological and medical) could lead to a breakthrough in the field of organ donation that does not violate the traditional views of society. Reference: 1. Reznik ON, Skvortsov AE, Reznik AO, Ananyev AN, Tutin AP, Kuzmin DO, et al. (2013) Uncontrolled Donors with Controlled Reperfusion after Sixty Minutes of Asystole: A Novel Reliable Resource for Kidney Transplantation. PLoS ONE 8(5): e64209. https://doi.org/10.1371/journal.pone.0064209.

Bone Morphogenetic Protein-Based Therapeutic Approaches.

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-β family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation.

Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity

The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc.) that can utilize primary liver cells from multiple species (e.g., rat and human). Compared to conventional monolayer cell culture, which typically survives for 5–7days or less, primary rat or human hepatocytes in an MPS exhibited higher viability and improved hepatic functions, such as albumin production, expression of hepatocyte marker HNF4α and canaliculi structure, for up to 14days. Additionally, induction of Cytochrome P450 (CYP) 1A and 3A4 in cryopreserved human hepatocytes was observed in the MPS. The acute cytotoxicity of the potent hepatotoxic and hepatocarcinogen, aflatoxin B1, was evaluated in human hepatocytes cultured in an MPS, demonstrating the utility of this model for acute hepatotoxicity assessment. These results indicate that MPS-cultured hepatocytes provide a promising approach for evaluating chemical toxicity in vitro.

Microphysiological Systems (Tissue Chips) and their Utility for Rare Disease Research.

The scientific and technological development of microphysiological systems (MPS) modeling organs-on-chips, or "tissue chips" (TCs), has progressed rapidly over the past decade. Stem cell research and microfluidic concepts have combined to lead to the development of microphysiological platforms representing an ever-expanding list of different human organ systems. In the context of rare diseases, these bioengineered microfluidics platforms hold promise for modeling of disorders and could prove useful in the screening and efficacy testing of existing therapeutics. Additionally, they have the potential for replacing and refining animal use for new drugs and clinical treatments, or could even act as surrogate human systems for testing of new therapeutics in the future, which could be particularly useful in populations of rare disease sufferers. This chapter will discuss the current state of tissue chip research, and challenges facing the field. Additionally, we will discuss how these devices are being used to model basic cellular and molecular phenotypes of rare diseases, holding promise to provide new tools for understanding of disease pathologies and screening and efficacy testing of potential therapeutics for drug discovery.

Sinogram-based coil selection for streak artifact reduction in undersampled radial real-time magnetic resonance imaging.

Streak artifacts are a common problem in radial magnetic resonance imaging (MRI). We therefore developed a method for automatically excluding receiver coil elements which lead to these artifacts. The proposed coil selection relates to real-time MRI data based on highly undersampled radial acquisitions. It exploits differences between high- and low-resolution sinograms reconstructed from datasets acquired during preparatory scans. Apart from phantom validations, the performance was assessed for real-time MRI studies of different human organ systems in vivo. The algorithm greatly reduces streak artifact strength without compromising image quality in other parts of the image. It is robust with respect to different experimental settings and fast to be included in the online reconstruction pipeline for real-time MRI. The proposed method enables a fast reduction of streak artifacts in radial real-time MRI.

Large Animal Models: The Key to Translational Discovery in Digestive Disease Research.

Gastrointestinal disease is a prevalent cause of morbidity and mortality and the use of animal models have been instrumental in studying mechanisms of digestive pathophysiology. As investigators attempt to translate the wealth of basic science information developed from rodent models, large animal models provide a number of translational advantages. The pig, in particular, is arguably one of the most powerful models of human organ systems, including the gastrointestinal tract. The pig has provided important tools and insight into intestinal ischemia/reperfusion injury, intestinal mucosal repair, as well as new insights into esophageal injury and repair. Porcine model development has taken advantage of the size of the animal, allowing increased surgical and endoscopic access. In addition, cellular tools such as the intestinal porcine epithelial cell (IPEC-J2) line and porcine enteroids are providing the methodology to translate basic science findings using in-depth mechanistic analyses. Further opportunities in porcine digestive disease modeling include developing additional transgenic pig strains. Collectively, porcine models hold great promise for the future of clinically relevant digestive disease research.

A Wearable Electrochemical Platform for Noninvasive Simultaneous Monitoring of Ca(2+) and pH.

Homeostasis of ionized calcium in biofluids is critical for human biological functions and organ systems. Measurement of ionized calcium for clinical applications is not easily accessible due to its strict procedures and dependence on pH. pH balance in body fluids greatly affects metabolic reactions and biological transport systems. Here, we demonstrate a wearable electrochemical device for continuous monitoring of ionized calcium and pH of body fluids using a disposable and flexible array of Ca(2+) and pH sensors that interfaces with a flexible printed circuit board. This platform enables real-time quantitative analysis of these sensing elements in body fluids such as sweat, urine, and tears. Accuracy of Ca(2+) concentration and pH measured by the wearable sensors is validated through inductively coupled plasma-mass spectrometry technique and a commercial pH meter, respectively. Our results show that the wearable sensors have high repeatability and selectivity to the target ions. Real-time on-body assessment of sweat is also performed, and our results indicate that calcium concentration increases with decreasing pH. This platform can be used in noninvasive continuous analysis of ionized calcium and pH in body fluids for disease diagnosis such as primary hyperparathyroidism and kidney stones.

Improving the physiological realism of experimental models.

The Virtual Physiological Human (VPH) project aims to develop integrative, explanatory and predictive computational models (C-Models) as numerical investigational tools to study disease, identify and design effective therapies and provide an in silico platform for drug screening. Ultimately, these models rely on the analysis and integration of experimental data. As such, the success of VPH depends on the availability of physiologically realistic experimental models (E-Models) of human organ function that can be parametrized to test the numerical models. Here, the current state of suitable E-models, ranging from in vitro non-human cell organelles to in vivo human organ systems, is discussed. Specifically, challenges and recent progress in improving the physiological realism of E-models that may benefit the VPH project are highlighted and discussed using examples from the field of research on cardiovascular disease, musculoskeletal disorders, diabetes and Parkinson's disease.

A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives.

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-β family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

Transdisciplinary Approach to Human Aging Research

<p>The aging of elderly people in the transdiciplinary approaches has been described on the results of the analysis of the scientific literature. That thanks to the scientific achievements in different spheres the human life expectancy increases thus aging becomes an active participation process and due to the increase of the number of elderly people in the world a new branch of science – gerontology develops that turns its attention to researching the aging processes and the possibilities of lengthening the life expectancy; it includes three main research approaches – biological that deals with functional and morphological changes in human organ systems, psychological (changes in the sensory perception and mental processes) and sociological – human role and the changes of their interaction in the social structure. Aging is a regressive process, which is also influenced by negative and harmful factors that decrease the adaptation abilities of the organism. Gradually people reach a general status of inability. Thus the biological psychological and social aging is mutually closely connected. The authors has developed the theoretical framework on the studies of the aging theories.</p>