Репозиторий Университета

© 2019 European Association for the Study of the Liver Background & Aims: An optimal allocation system for scarce resources should simultaneously ensure maximal utility, but also equity. The most frequent principles for allocation policies in liver transplantation are therefore criteria that rely on pre-transplant survival (sickest first policy), post-transplant survival (utility), or on their combination (benefit). However, large differences exist between centers and countries for ethical and legislative reasons. The aim of this study was to report the current worldwide practice of liver graft allocation and discuss respective advantages and disadvantages. Methods: Countries around the world that perform 95 or more deceased donor liver transplantations per year were analyzed for donation and allocation policies, as well as recipient characteristics. Results: Most countries use the model for end-stage liver disease (MELD) score, or variations of it, for organ allocation, while some countries opt for center-based allocation systems based on their specific requirements, and some countries combine both a MELD and center-based approach. Both the MELD and center-specific allocation systems have inherent limitations. For example, most countries or allocation systems address the limitations of the MELD system by adding extra points to recipient's laboratory scores based on clinical information. It is also clear from this study that cancer, as an indication for liver transplantation, requires special attention. Conclusion: The sickest first policy is the most reasonable basis for the allocation of liver grafts. While MELD is currently the standard for this model, many adjustments were implemented in most countries. A future globally applicable strategy should combine donor and recipient factors, predicting probability of death on the waiting list, post-transplant survival and morbidity, and perhaps costs. Lay summary: An optimal allocation system for scarce resources should simultaneously ensure maximal utility, but also equity. While the model for end-stage liver disease is currently the standard for this model, many adjustments were implemented in most countries. A future globally applicable strategy should combine donor and recipient factors predicting probability of death on the waiting list, post-transplant survival and morbidity, and perhaps costs.

© 2019 The Author(s). Background: Liver resection is a treatment of choice for colorectal and neuroendocrine liver metastases, and laparoscopy is an accepted approach for surgical treatment of these patients. The role of liver resection for patients with non-colorectal non-neuroendocrine liver metastases (NCNNLM), however, is still disputable. Outcomes of laparoscopic liver resection for this group of patients have not been analyzed. Material and methods: In this retrospective study, patients who underwent laparoscopic liver resection for NCNNLM at Oslo University Hospital between April 2000 and January 2018 were analyzed. Perioperative and oncologic data of these patients were examined. Postoperative morbidity was classified using the Accordion classification. Kaplan-Meier method was used for survival analysis. Median follow-up was 26 (IQR, 12-41) months. Results: Fifty-one patients were identified from a prospectively collected database. The histology of primary tumors was classified as adenocarcinoma (n = 16), sarcoma (n = 4), squamous cell carcinoma (n = 4), melanoma (n = 16), gastrointestinal stromal tumor (n = 9), and adrenocortical carcinoma (n = 2). The median operative time was 147 (IQR, 95-225) min, while the median blood loss was 200 (IQR, 50-500) ml. Nine (18%) patients experienced postoperative complications. There was no 90-day mortality in this study. Thirty-five (68%) patients developed disease recurrence or progression. Seven (14%) patients underwent repeat surgical procedure for recurrent liver metastases. One-, three-, and five-year overall survival rates were 85%, 52%, and 38%, respectively. The median overall survival was 37 (95%CI, 25 to 49) months. Conclusion: Laparoscopic liver resection for NCNNLM results in good outcomes and should be considered in patients selected for surgical treatment.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. There is a pressing clinical need for advanced colon-specific local drug delivery systems that can provide major advantages in treating diseases associated with the colon, such as inflammatory bowel disease (IBD) and colon cancer. A precise colon targeted drug delivery platform is expected to reduce drug side effects and increase the therapeutic response at the intended disease site locally. In this study, we report the fabrication of hyaluronan (HA) functionalized polymeric hybrid nanoparticulate system (Cur-HA NPs) by using curcumin as a model fluorescent drug. The Cur-HA NPs were about 200–300 nm in size, −51.3 mV overall surface charge after HA functionalization, with 56.0% drug released after 72 h in simulated gastrointestinal fluids. The Cur-HA NPs did not exhibit any cytotoxicity by AlamarBlue, PicoGreen and Live/Dead assays. Following the Cur-HA NPs use on HT-29 monolayer cell cultures demonstrating, the efficacy of HA functionalization increases cellular interaction, uptake when compared to uncoated nanoparticulate system. These findings indicate that HA functionalized nano-hybrid particles are effective in delivering drugs orally to the lower gastrointestinal tract (GIT) in order to treat local colonic diseases.

© 2019, European Society of Radiology. Objectives: Invasive treatment of tumors adjacent to large hepatic vessels is a continuous clinical challenge. The primary aim of this study was to examine the feasibility of ablating liver tissue adjacent to large hepatic and portal veins with magnetic resonance imaging–guided high-intensity focused ultrasound (MRgHIFU). The secondary aim was to compare sonication data for ablations performed adjacent to hepatic veins (HV) versus portal veins (PV). Materials and methods: MRgHIFU ablations were performed in six male land swine under general anesthesia. Ablation cells of either 4 or 8 mm diameter were planned in clusters (two/animal) adjacent either to HV (n = 6) or to PV (n = 6), with diameter ≥ 5 mm. Ablations were made using 200 W and 1.2 MHz. Post-procedure evaluation was made on contrast-enhanced MRI (T1w CE-MRI), histopathology, and ablation data from the HIFU system. Results: A total of 153 ablations in 81 cells and 12 clusters were performed. There were visible lesions with non-perfused volumes in all animals on T1w CE-MRI images. Histopathology showed hemorrhage and necrosis in all 12 clusters, with a median shortest distance to vessel wall of 0.4 mm (range 0–2.7 mm). Edema and endothelial swelling were observed without vessel wall rupture. In 8-mm ablations (n = 125), heat sink was detected more often for HV (43%) than for PV (19%; p = 0.04). Conclusions: Ablations yielding coagulative necrosis of liver tissue can be performed adjacent to large hepatic vessels while keeping the vessel walls intact. This indicates that perivascular tumor ablation in the liver is feasible using MRgHIFU. Key Points: • High-intensity focused ultrasound ablation is a non-invasive treatment modality that can be used for treatment of liver tumors. • This study shows that ablations of liver tissue can be performed adjacent to large hepatic vessels in an experimental setting. • Liver tumors close to large vessels can potentially be treated using this modality.

© 2019 American Pharmacists Association® Various drug delivery systems (DDSs) are often used in modern medicine to achieve controlled and targeted drug release. Diffusional release of drugs from DDSs is often the main mechanism, especially at early times. Generally, average dimensions of DDS are used to model the drug release, but our recent work on drug release from fibers demonstrated that taking into account diameter distribution is essential. This work systematically investigated the effect of size distribution on diffusional drug release from DDSs of various geometric forms such as membranes, fibers, and spherical particles. The investigation clearly demonstrated that the size distribution has the largest effect on the drug release profiles from spherical particles compared to other geometric forms. Published experimental data for drug release from polymer microparticles and nanoparticles were fitted, and the diffusion coefficients were determined assuming reported radius distributions. Assuming the average radius when fitting the data leads to up to 5 times underestimation of the diffusion coefficient of drug in the polymer.

Тhe rapid increase in the frequency of сesarian section (CS) observed in recent years (up to 60% in some countries) is alarming and reduces the reproductive potential of the population. The operated uterus remains the main indication for CS (up to 40%). This is the factor which may allow reducing the frequency of the CS by subsequent delivering through the birth canal. A comparative analysis of maternal and neonatal outcomes enabled the authors to develop a two-stage delivery technology for patients with a caesarean scar, including the usage of the programmed delivery method. The presented algorithm confirmed the validity of vaginal delivery in such patients, and reduced the number of complications up to 4 times. Neonatal morbidity in children born through the birth canal in such patients was comparable to physiological birth.

© 2019, Pleiades Publishing, Inc. Abstract: Genetic engineering is considered as background for crop protection against pest damage by adding new genes inside the grains. Rice, like other cereals is included in gene engineering experiments. The questions about possible gene transfer related to food safety appear. It is important to find any additional genes or fragments in animal tissues after consumption of genetically modified (GM) food. Therefore, in this study, the remaining of CryIA(b) gene and P35 were assessed in the liver of rats fed with GM rice. This work presents an experimental study with the intervention of GM rice feeding by Sprague Dawley rats. Overall, 20 male and 20 female SD rats were fed by pellets made by GM rice in 50% of needed carbohydrate for 90 days. Then, sampling was done from rats liver. DNA extraction was done based on the protocol. The quality and quantity of the extracted DNA was done by agarose gel electrophoresis and spectrophotometry, respectively. Detection of GM genes residues, including CryIA(b), P35, and T35 was done by Polymerase Chain Reaction using specific primer pairs. The results were analyzed by agarose gel electrophoresis alongside with 50 bp DNA ladder. The results were compared with the ones in control groups with feeding by standard pellet of non-modified rice. All amplification tests were done in triplicates. Analysis of the amplification of P35, CryIA(b) and T35 showed no residues inside the liver tissue. The results showed no significant difference in the presence of transgenic gene of cryIA(b), T35, and P35 in the liver tissue between the control and experiment groups. Therefore, this study rejects the possibility of gene settle of GM rice gene residues in liver tissue of the animal model studied.

© 2018, MDPI AG. All rights reserved. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Promising directions for the discovery of universal carriers for active pharmaceutical ingredients (APIs) are reviewed. Transdermal delivery of the APIs in medicines is attracting increasing attention from designers of drug formulations. A transdermal therapeutic system (TTS) is a dosage form for external use as controlled-release patches or films. TTSs are classified depending on the mode of API incorporation into several basic types such as reservoir, adhesive, matrix, and microreservoir. Methods for developing TTSs based on microemulsions are described in the review.

© 2018 John Wiley  &  Sons A/S. Published by John Wiley  &  Sons Ltd Background: Laparoscopic living donor liver procurement for transplantation has increased in popularity over the past decade. The purpose of this study was to compare the laparoscopic and open approaches in living donor left lateral sectionectomy (LLS) and to assess the safety and feasibility of this laparoscopic approach. Methods: A total of 103 living donor LLSs were performed at our center from May 2016 to December 2017. Of these, 35 were completely laparoscopic procedures, which represented the subject of this study. An additional 68 open living donor LLSs performed during the same period were studied as a comparison group. To overcome selection bias, LLS donors were balanced on a 1:1 ratio (laparoscopic [n = 35]: open [n = 35]) according to covariates with similar values. The PSM was based on the operation date, recipient age, diagnosis, recipient weight, and donor age. Results: There were significant differences between the laparoscopic and open LLS groups (P < 0.001) in terms of blood loss (96.8 ± 16.5 vs 155.8 ± 17.8 mL) as well as the duration of hospital stay (4 ± 0.4 vs 6.9 ± 0.5 days). Conclusion: Laparoscopic LLS is a feasible and efficacious in the setting of a developed program with advanced laparoscopic expertise.

© 2018 Royal Pharmaceutical Society Objectives: Anxiolytic drug zolpidem was incorporated into the microcontainers based on mesoporous calcium carbonate particles modified by diethylaminoethyl-dextran/hyaluronic acid shell. The release of zolpidem in saline solution and in polymer film modelling nasal mucosa was investigated. The anxiolytic effect of zolpidem upon intranasal administration of microcontainers and free medicine was determined by in vivo experiments on mice. Methods: The structures of all compounds during zolpidem synthesis were established using nuclear magnetic resonance spectroscopy. The loading efficacy and release kinetics of zolpidem were analysed by spectrophotometry. Surface morphology of formulation was investigated by scanning electron microscopy. To determine the effect of zolpidem-loaded containers administration by the intranasal route in vivo experiments was carried out applying the open field test. Key findings: Nasal administration of zolpidem in the form of the microcontainers based on mesoporous calcium carbonate particles modified by diethylaminoethyl-dextran/hyaluronic acid shell has a pronounced anxiolytic effect on the behaviour of the animals in the open field test. Conclusions: The polyelectrolyte shell deposited together with zolpidem enhances the loading efficacy of the microcontainers. In vivo experiments on mice demonstrate increase in anxiolytic effect of zolpidem in microcontainers compared with upon intranasal administration of free medicine.

© 2018 EDIZIONI MINERVA MEDICA. BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum coniugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subiects with a baseline serum coniugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subiects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and y-glutamyltransferase (yGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.

©2018 by the authors. Licensee MDPI, Basel, Switzerland. Engineering of a “smart” drug delivery system to specifically target tumour cells has been at the forefront of cancer research, having been engineered for safer, more efficient and effective use of chemotherapy for the treatment of cancer. However, selective targeting and choosing the right cancer surface biomarker are critical for a targeted treatment to work. Currently, the available delivery systems use a two-dimensional monolayer of cancer cells to test the efficacy of the drug delivery system, but designing a “smart” drug delivery system to be specific for a tumour in vivo and to penetrate the inner core remains a major design challenge. These challenges can be overcome by using a study model that integrates the three-dimensional aspect of a tumour in a culture system. Here, we tested the efficacy of a functionalized folic acid-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) to specifically target and penetrate the inner core of three-dimensional avascular human pancreatic and breast tumour spheroids in culture. The copolymer was quantitatively analyzed for its hydrophobic drug encapsulation efficiency using three different chemical drug structures with different molecular weights. Their release profiles and tumour targeting properties at various concentrations and pH environments were also characterized. Using the anticancer drug curcumin and two standard clinical chemotherapeutic hydrophobic drugs, paclitaxel and 5-fluorouracil, we tested the ability of FA-DABA-SMA nanoparticles to encapsulate the differently sized drugs and deliver them to kill monolayer pancreatic cancer cells using the WST-1 cell proliferation assay. The findings of this study revealed that the functionalized folic acid-conjugated amphiphilic alternating copolymer shows unique properties as an active “smart” tumor-targeting drug delivery system with the ability to internalize hydrophobic drugs and release the chemotherapeutics for effective killing of cancer cells. The novelty of the study is the first to demonstrate a functionalized “smart” drug delivery system encapsulated with a hydrophobic drug effectively targeting and penetrating the inner core of pancreatic and breast cancer spheroids and reducing their volumes in a dose-and time-dependent manner.

© 2017, Springer Science+Business Media, LLC, part of Springer Nature. Since the 1990s, when it was demonstrated by Hammel and others that liver fibrosis is reversible, researchers and physicians actively search for new antifibrotic therapies. In recent years, knowledge of liver fibrosis pathophysiology has greatly advanced and new cellular and molecular mechanisms were described. The cells that determine extracellular matrix components distribution are myofibroblasts, but their origin is diverse. They can be activated hepatic stellate cells (HSCs), portal fibroblasts (PF), or circulating mesenchymal stem cells of the bone marrow. Among large number of substrates to inhibit activation, to inhibit proliferation of myofibroblasts, and to induce their apoptosis we, chose curcumin and gliotoxin. Primarily, in the current work, we optimized the explantation culture method for isolation of hepatic myofibroblasts and received two different cultures—myofibroblasts of HSC and PF origin. Exposition of 50 μM curcumin and 0.1 μM gliotoxin was the most optimal; we observed suppression of hepatic myofibroblast activation and inhibition of their proliferation. These results extend the current knowledge of the cells within the liver fibrogenic populations and prove inhibitory influence of biologically active substances (curcumin and gliotoxin) on portal myofibroblasts.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The liposomal form of silibinin was obtained, and its antihepatotoxic activity in mice was studied using a model of acute toxic hepatitis caused by injection of carbon tetrachloride or paracetamol. It was shown that the use of the drug in therapy or prevention regimens leads to normalization of levels of transaminases and total protein in the blood of experimental animals. The results of the study showed that liposomal silibinin when administered intravenously shows a more pronounced hepatoprotective effect compared to intragastric administration of free silibinin. Thus, the effectiveness of the therapeutic action of silibinin can be significantly increased by using its liposomal form. Liposomal drug, in contrast to native silibinin, can be injected directly into the blood that significantly increases its bioavailability.

© 2018 Elsevier B.V. The mathematical model describing drug flux through microporated skin was previously developed. Based on this model, two mathematical equations can be used to predict the microporatio-enhanced transdermal drug flux: the complex primal equation containing a variety of experimentally-determined variables, and the simplified straightforward equation. In this study, experimental transdermal fluxes of three corticosteroids through split-thickness human skin treated with a microneedle roller were measured, and the values of fluxes compared with those predicted using both the more complex and simplified equations. According to the results of the study, both equations demonstrated high accuracy in the prediction of the fluxes of corticosteroids. The simplified equation was validated and confirmed as robust using regression analysis of literature data. Further, its capability and ease of use was exemplified by predicting the flux of methotrexate through the skin microporated with laser and comparing with published experimental data.

© 2018 American Chemical Society.  Nanoparticle surface engineering can change its chemical identity to enable surface coupling with functional biomolecules. However, common surface coupling methods such as physical adsorption or chemical conjugation often suffer from the low coupling yield, poorly controllable orientation of biomolecules, and steric hindrance during target binding. These issues limit the application scope of nanostructures for theranostics and personalized medicine. To address these shortfalls, we developed a rapid and versatile method of nanoparticle biomodification. The method is based on a SiO 2 -binding peptide that binds to the nanoparticle surface and a protein adaptor system, Barnase∗Barstar protein pair, serving as a "molecular glue" between the peptide and the attached biomolecule. The biomodification procedure shortens to several minutes, preserves the orientation and functions of biomolecules, and enables control over the number and ratio of attached molecules. The capabilities of the proposed biomodification platform were demonstrated by coupling different types of nanoparticles with DARPin9.29 and 4D5scFv - molecules that recognize the human epidermal growth factor receptor 2 (HER2/neu) oncomarker - and by subsequent highly selective immunotargeting of the modified nanoparticles to different HER2/neu-overexpressing cancer cells in one-step or two-step (by pretargeting with HER2/neu-recognizing molecule) modes. The method preserved the biological activity of the DARPin9.29 molecules attached to a nanoparticle, whereas the state-of-the-art carbodiimide 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysulfosuccinimide method of conjugation led to a complete loss of the functional activity of the DARPin9.29 nanoparticle-protein complex. Moreover, the method allowed surface design of nanoparticles that selectively interacted with antigens in complex biological fluids, such as whole blood. The demonstrated capabilities show this method to be a promising alternative to commonly used chemical conjugation techniques in nanobiotechnology, theranostics, and clinical applications.

© 2018 Osipov, Machneva, Buravlev and Vladimirov. The biological roles of heme and nonheme nitrosyl complexes in physiological and pathophysiological conditions as metabolic key players are considered in this study. Two main physiological functions of protein nitrosyl complexes are discussed-(1) a depot and potential source of free nitric oxide (NO) and (2) a controller of crucial metabolic processes. The first function is realized through the photolysis of nitrosyl complexes (of hemoglobin, cytochrome c, or mitochondrial iron-sulfur proteins). This reaction produces free NO and subsequent events are due to the NO physiological functions. The second function is implemented by the possibility of NO to bind heme and nonheme proteins and produce corresponding nitrosyl complexes. Enzyme nitrosyl complex formation usually results in the inhibition (or enhancement in the case of guanylate cyclase) of its enzymatic activity. Photolysis of protein nitrosyl complexes, in this case, will restore the original enzymatic activity. Thus, cytochrome c acquires peroxidase activity in the presence of anionic phospholipids, and this phenomenon can be assumed as a key step in the programmed cell death. Addition of NO induces the formation of cytochrome c nitrosyl complexes, inhibits its peroxidase activity, and hinders apoptotic reactions. In this case, photolysis of cytochrome c nitrosyl complexes will reactivate cytochrome c peroxidase activity and speed up apoptosis. Control of mitochondrial respiration by NO by formation or photolytic decay of iron-sulfur protein nitrosyl complexes is an effective instrument to modulate mitochondrial metabolism. These questions are under discussion in this study.

©2018 Osipov, Machneva, Buravlev and Vladimirov. The biological roles of heme and nonheme nitrosyl complexes in physiological and pathophysiological conditions as metabolic key players are considered in this study. Two main physiological functions of protein nitrosyl complexes are discussed-(1) a depot and potential source of free nitric oxide (NO) and (2) a controller of crucial metabolic processes. The first function is realized through the photolysis of nitrosyl complexes (of hemoglobin, cytochrome c, or mitochondrial iron-sulfur proteins). This reaction produces free NO and subsequent events are due to the NO physiological functions. The second function is implemented by the possibility of NO to bind heme and nonheme proteins and produce corresponding nitrosyl complexes. Enzyme nitrosyl complex formation usually results in the inhibition (or enhancement in the case of guanylate cyclase) of its enzymatic activity. Photolysis of protein nitrosyl complexes, in this case, will restore the original enzymatic activity. Thus, cytochrome c acquires peroxidase activity in the presence of anionic phospholipids, and this phenomenon can be assumed as a key step in the programmed cell death. Addition of NO induces the formation of cytochrome c nitrosyl complexes, inhibits its peroxidase activity, and hinders apoptotic reactions. In this case, photolysis of cytochrome c nitrosyl complexes will reactivate cytochrome c peroxidase activity and speed up apoptosis. Control of mitochondrial respiration by NO by formation or photolytic decay of iron-sulfur protein nitrosyl complexes is an effective instrument to modulate mitochondrial metabolism. These questions are under discussion in this study.

© 2017 Elsevier B.V. Microneedles is the technique of drug delivery enhancement, which was primarily designed for facilitating percutaneous drug delivery. Started from the development of simple solid microneedles, providing microporation of stratum corneum and therefore enhancement of topical drug delivery, for two decades the technique has progressed in various modifications such as hollow, coated, dissolving and hydrogel forming microneedles. In their turn, the modifications have resulted in new mechanisms of drug delivery enhancement and followed by the expansion of applicability range in terms of targeted tissues and organs. Thus, in addition to percutaneous drug delivery, microneedles have been considered as an efficient technique facilitating ocular, oral mucosal, gastrointestinal, ungual and vaginal drug administration. It is anticipated that the technique of microneedle-assisted drug delivery will soon become relevant for majority of organs and tissues.