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At least 37 records · Page 2Linked to original sources
PubMed2003

Prediction of in vivo tissue distribution from in vitro data. 2. Influence of albumin diffusion from tissue pieces during an in vitro incubation on estimated tissue-to-unbound plasma partition coefficients (Kpu).

PURPOSE: To determine the extent of albumin diffusion from tissue pieces into medium during in vitro incubations, to develop and assess the utility of mathematical models describing this effect on the estimation of tissue-to-unbound plasma partition coefficients (Kpu) of drug substances and to derive factors to correct for associated errors. METHODS: Twelve separate tissues were obtained from rats sacrificed by cervical dislocation, 48 h after an intravenous dose of 125I-human albumin, and tissue pieces incubated to determine the efflux of albumin into media over 2 to 4 h. A mathematical model was developed to predict and correct for the effect of albumin diffusion on the measured Kpu values of drugs. RESULTS: The model predicted that the effect of albumin diffusion from tissue pieces during in vitro incubation (ranging from 14 to 59% remaining in tissue) on Kpu values was generally minimal, except for compounds that are highly plasma bound and have a low measured Kpu. Under these circumstances, the measured Kpu substantially underestimates the true value. An equation was derived from readily available or measurable parameters to correct for this underestimation. CONCLUSIONS: Albumin diffuses from tissue pieces into protein free media during in vitro incubations until equilibrium is reached, defined by the albumin Kpu. Model predictions indicated that for the majority of compounds albumin diffusion would have a minimal effect on the measured Kpu value and that a correction factor could be calculated to account for any deviation.

Albumins↗
PubMedDate not supplied

Muscular tissue engineering: capillary-incorporated hybrid muscular tissues in vivo tissue culture.

Requirements for a functional hybrid muscular tissue are 1) a high density of multinucleated cells, 2) a high degree of cellular orientation, and 3) the presence of a capillary network in the hybrid tissue. Rod-shaped hybrid muscular tissues composed of C2C12 cells (skeletal muscle myoblast cell line) and type I collagen, which were prepared using the centrifugal cell-packing method reported in our previous article, were implanted into nude mice. The grafts, comprised three hybrid tissues (each dimension, diameter, approximately 0.3 mm, length, approximately 1 mm, respectively), were inserted into the subcutaneous spaces on the backs of nude mice. All nude mice that survived the implantation were sacrificed at 1, 2, and 4 wk after the implantation. The grafts were easily distinguishable from the subcutaneous tissues of host mice with implantation time. The grafts increased in size with time after implantation, and capillary networks were formed in the vicinities and on the surfaces of the grafts. One week after implantation, many capillaries formed in the vicinities of the grafts. In the central portion of the graft, few capillaries and necrotic cells were observed. Mononucleated myoblasts were densely distributed and a low number of multinucleated myotubes were scattered. Two weeks after implantation, the formation of a capillary network was induced, resulting in the surfaces of the grafts being covered by capillaries. Numerous elongated multinucleated myotubes and mononucleated myoblasts were densely distributed and numerous capillaries were observed throughout the grafts. Four weeks after implantation a dense capillary network was formed in the vicinities and on the surfaces of the grafts. In the peripheral portion of the graft, multinucleated myotubes in the vicinities of the rich capillaries were observed. Thus, hybrid muscular tissues in vitro preconstructed was remodeled in vivo, which resulted in facilitating the incorporation of capillary networks into the tissues.

Animals↗
PubMedDate not supplied

Tissue engineering of skeletal muscle. Highly dense, highly oriented hybrid muscular tissues biomimicking native tissues.

A highly dense, highly oriented hybrid muscular tissue was devised using C2C12 cells (skeletal muscle myoblast cell line) and Type I collagen. A cold mixture of C2C12 cells suspended in DMEM (Dulbecco's modified Eagle's medium; Gibco Lab Inc., Grand Island, NY) and Type I collagen solution was poured into capillary tube molds of two different sizes (inner diameters: 0.90 mm and 0.53 mm, respectively) sealed at each end. After centrifugation (1000 RPM, 5 min) and subsequent thermal gelation, a rod shaped gel was formed. The resultant gel shrank to become a highly dense tissue after incubation on an agarose gel coated dish. Small diameter rod shaped tissues were composed of numerous multi-nucleated myotubes and a few necrotic cells. On the other hand, a ring shaped tissue fabricated by centrifugation with a specially devised agarose gel mold was subjected to cyclic stretching at 60 RPM. The resultant highly dense, highly oriented hybrid muscular tissue involved both densely accumulated cells and collagen fiber bundles, which tended to be aligned in the direction of stretching. Sequential procedures of a centrifugal cell packing method and a mechanical stress loading method facilitated fabrication of hybrid muscular tissues similar to native muscular tissues in terms of cell density and orientation.

Animals↗
PubMed1980

The development of white adipose tissue. Effect of litter size on the lipoprotein lipase activity of four adipose-tissue depots, serum immunoreactive insulin and tissue cellularity during the first year of life in male and female rats.

(1.) Male and female rats reared in litters of four gained body weight more rapidly than animals reared in litters of 16. The differences were more marked in males than females and became less marked in both sexes with advancing age. (2.) The relative weights of the perigenital, perirenal, subcutaneous and intramuscular white-adipose-tissue sites in the animals from small litters indicated their relative obesity compared with animals from large litters. A sex-related difference in the distribution of adipose tissue between the four sites was seen in animals reared in litters of both four and 16. (3.) Although at 30 days of age all the animals had more numerous and larger fat-cells in their white-adipose-tissue depots than animals reared in large litters, the pattern of change thereafter was both site- and sex-specific. During the post-weaning period (30-300 days), although detailed differences were apparent between sites, a general pattern of increased cell size in males and increased cell numbers in females emerged as being the important determinants responsible for the differences in depot sizes seen when animals from litters of four and 16 were compared. (4.) Lipoprotein lipase activities, expressed as units/g fresh wt. of tissue, in the depots of animals reared in groups of four were unaltered compared with those reared in groups of sixteen during the post-weaning period (47-300 days of age), and enzyme activities expressed per depot merely reflected differences in tissue weights. (5.) Lipoprotein lipase activities per 10(6) cells were higher in males reared in fours compared with those reared in sixteens of equivalent age, but were unaltered for females. (6.) The persistent hyperinsulinaemia of animals reared in litters of four is discussed in relation to the observed differences in enzyme activity and white-adipose-tissue cellularity.

Adipose Tissue↗
PubMed1981

Tissue distribution of ampicillin: assays in muscle tissue and subcutaneous tissue cage fluid from normal and nephrectomized rabbits.

Tissue distribution of ampicillin following a single intravenous injection was studied in normal and functionally nephrectomized rabbits. Serum concentrations of ampicillin were compared with those obtained in subcutaneous tissue cage fluid, muscle (measured by a direct agar diffusion method) and muscle tissue fluid (obtained from implanted cotton threads). Considerable differences were found. Penetration of ampicillin into rabbit muscle was rapid and the elimination half-life was similar to that of serum. Concentrations in tissue cage fluid were low as compared with muscle tissue fluid levels, and penetration and elimination was slower. Results from experiments in functionally nephrectomized rabbits showed that a steady state between serum and muscle seemed to be attained after 15-30 min. These results were used to estimate the degree of protein binding of ampicillin in muscle tissue fluid.

Ampicillin↗
PubMed2007

FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues.

Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3(+) T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3(+) T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4(+) T cells as well as unique to the FoxP3(+) cell lineage. In the thymus, precursors of FoxP3(+) cells undergo the first trafficking receptor switch (CCR8/CCR9-->CXCR4-->CCR7), generating mostly homogeneous CD62L(+)CCR7(+)CXCR4(low)FoxP3(+) T cells. CXCR4 expression is regained in FoxP3(+) thymic emigrants in the periphery. Consistent with this switch, recent FoxP3(+) thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3(+) thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3(+) T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3(+) and FoxP3(-) T cell populations is that FoxP3(+) T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3(-) T cells, generating FoxP3(+) T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.

Animals↗
PubMed2003

Calretinin expression in human normal and neoplastic tissues: a tissue microarray analysis on 5233 tissue samples.

Calretinin is a calcium-binding protein expressed in different normal and neoplastic tissues. Early studies suggested that calretinin is a useful marker to differentiate adenocarcinomas from malignant mesotheliomas of the lung, but subsequent work has shown that calretinin can be expressed in several other tumor types. To systematically investigate the epidemiology of calretinin expression in normal and neoplastic tissues, we used tissue microarrays (TMAs) to analyze the immunohistochemically detectable expression of calretinin in 5233 tissue samples from 128 different tumor categories and 76 different normal tissue types. At least 1 case with weak expression could be found in 74 of 128 (58%) different tumor types and 46 entities (36%) had at least 1 tumor with strong positivity. In normal tissues, a particularly strong expression was found in Leydig cells of the testis, neurons of the brain, theca-lutein and theca interna cells of the ovary, and mesothelium. In tumors, strong calretinin expression was most frequently found in malignant mesotheliomas (6 of 7), Leydig cell tumors of the testis (5 of 5), adenomas of adrenal gland (5 of 9), and adenomatoid tumors (4 of 9). In summary, calretinin is frequently expressed in many different tumor types. Metastases of various different origins must be included in the differential diagnosis of calretinin-positive pleura tumors.

Biomarkers↗
PubMed1979

Thyroid-stimulating hormone (TSH) binding to extrathyroidal human tissues: TSH binding to extrathyroidal human tissues: TSH and thyroid-stimulating immunoglobulin effects on adenosine 3',5'-monophosphate in testicular and adrenal tissues.

Binding of [125I]bovine TSH to human thyroid, testicular, fat, adrenal, liver, kidney, pancreas, and lung cell membranes has been studied. The first four tissues were found to have comparable high affinity constant values; the rest of the tissues lacked high affinity sites. With the exception of fat tissue, the capacities of the high affinity sites of the first four tissues were similar. Bovine TSH concentrations of 100-20,000 microIU/ml stimulated increased cAMP production in human cryopreserved testicular slices. Forty percent of the specimens of thyroid-stimulating immunoglobulin (TSI) from Graves' disease sera also increased human testicular cAMP production. In addition, bovine TSH caused a significant rise in cAMP in the whole decapsulated rat testis. Twenty-five percent of the TSI specimens tested also induced such responses. The rat adrenal gland responded with increased cAMP production to concentrations of 1,000 microU/ml bovine TSH. The physiological significance of high affinity bovine TSH and TSI binding and subsequent cAMP production in nonthyroidal tissues in not known. However, since these stimulators are present in hypothyroidism and hyperthyroidism, respectively, it is possible that the pathophysiological effects of this binding could be of some importance.

Adrenal Glands↗
PubMed2004

Surrogate tissue analysis: monitoring toxicant exposure and health status of inaccessible tissues through the analysis of accessible tissues and cells.

Genomics and proteomics have made it possible to define molecular physiology in exquisite detail, when tissues are accessible for sampling. However, many tissues are not accessible for human diagnostic evaluations or experimental studies, creating the need for surrogates that afford insight into exposures and effects in such tissues. Surrogate tissue analysis (STA) incorporating contemporary genomic and proteomic technologies may be useful in determining toxicant exposure and effect, or disease state, in target tissues at the pre- or early clinical stage. We present here a discussion of STA based on presentations given at the Society of Toxicology's 2003 annual meeting's "Innovations in Applied Toxicology" symposium. Speakers at the symposium (Box 1) discussed various potential applications of STA, including the use of peripheral blood lymphocytes (PBLs) as a source of genetic biomarkers to monitor radiation exposure; the use of gene expression analysis of PBLs and hair follicles as a means to monitor the impact of toxicants on inaccessible organs; the characterization of disease-associated gene signatures in peripheral blood mononuclear cells (PBMCs) of renal cell carcinoma (RCC) patients; the use of sperm RNA to determine genetic and environmental effects on sperm development in the testis; and the use of serum protein profiles to monitor the development and progression of various cancers. Also discussed are some of the challenges that must be overcome if the utility of STA is to be proven, and thus permit researchers to move this concept from the laboratory to the clinical environment.

Animals↗
PubMed2000

Acellular vascular tissues: natural biomaterials for tissue repair and tissue engineering.

Various research groups around the world are actively investigating cardiovascular prostheses of biological origin. This review article discusses the need for such bioprosthetics and the potential role for natural tissues in cardiovascular applications such as cardiac valves and vascular grafts. Upon implantation, unmodified natural materials are subject to chemical and enzymatic degradation, seriously decreasing the life of the prosthesis. Therefore, methods such as glutaraldehyde and polyepoxide crosslinking treatments and dye-mediated photooxidation have been developed to stabilize the tissue while attempting to maintain its natural mechanical properties. Also, residual cellular components in a bioprosthetic material have been associated with undesired effects, such as calcification and immunological recognition, and thus have been the motivation for various decellularization processes. The effects of these stabilization and decellularization treatments on mechanical, biological and chemical properties of treated tissues have been investigated, specifically with regard to calcification, immunogenicity, and cytotoxicity concerns. Despite significant advances in the area of cardiovascular prostheses, there has yet to be developed a completely biocompatible, long-lasting implant. However, with the recent advent of tissue engineering, the possibility of applying selective cell seeding to naturally derived bioprosthetics moves us closer to a living tissue replacement.

Animals↗
PubMed1995

Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. On behalf of the Subcommittee on Tissue factor Pathway Inhibitor (TFPI) of the Scientific and Standardization Committee of the ISTH.

Under normal conditions, TFPI expression is restricted to megakaryocytes and the endothelium of the microvasculature. It is not synthesized by normal hepatocytes or by the endothelium of larger vessels. In contrast, endothelium and peripheral blood cells do not express tissue factor under normal conditions. Expression of tissue factor under normal physiologic conditions is widespread and is localized in areas which are physically separated from the circulating blood. During an inflammatory response, circulating monocytes have been shown to express tissue factor, whereas in general, expression of tissue factor has not been observed in the endothelium. Adherent monocytes/macrophages express both tissue factor and TFPI under pathologic conditions. Whether or not circulating peripheral blood monocytes under inflammatory conditions express TFPI is not known.

Animals↗
PubMed1993

Secretion of matrix metalloproteinases and their inhibitors (tissue inhibitor of metalloproteinases) by human prostate in explant cultures: reduced tissue inhibitor of metalloproteinase secretion by malignant tissues.

Unregulated secretion of matrix metalloproteinases (MMPs) or their endogenous protein inhibitors (tissue inhibitor of metalloproteinases, TIMPs) has been implicated in tumor invasion and metastasis. Species of MMPs and TIMPs secreted by epithelial cultures of normal, benign, and malignant prostate were identified and their levels were compared. Fragments of fresh tissue were cultured in a serum-free medium that supported the outgrowth of prostatic epithelial cells. Biochemical analysis of the conditioned media by gelatin zymography and enzyme assays showed that both normal and neoplastic tissues secreted latent and active forms of both M(r) 72,000 type IV collagenase (MMP-2) and M(r) 92,000 gelatinase (MMP-9). However, conditioned media from malignant prostate explants contained a higher proportion of the active form of MMP-2. Significant amounts of free TIMPs were secreted by normal juvenile and adult prostates, but they were either markedly reduced or not detectable in conditioned media from neoplastic tissues. These findings suggest that there is an imbalance of secretion between MMPs and TIMPs in prostatic carcinoma.

Adult↗
PubMed2004

Current good tissue practice for human cell, tissue, and cellular and tissue-based product establishments; inspection and enforcement. Final rule.

The Food and Drug Administration (FDA) is requiring human cell, tissue, and cellular and tissue-based product (HCT/P) establishments to follow current good tissue practice (CGTP), which governs the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps; recordkeeping; and the establishment of a quality program. The agency is also issuing new regulations pertaining to labeling, reporting, inspections, and enforcement that will apply to manufacturers of those HCT/Ps regulated solely under the authority of the Public Health Service Act (PHS Act), and not as drugs, devices, and/or biological products. The agency's actions are intended to improve protection of the public health while keeping regulatory burden to a minimum, which in turn would encourage significant innovation.

Biological Products↗
PubMed1985

Tissue-serum correlates of digoxin-amiodarone pharmacokinetic interaction in rats: evidence for selective tissue accumulation and reduced tissue binding.

The pharmacokinetic interaction between digoxin (1) and amiodarone (2) has drawn increasing attention during recent years, but the tissue correlates of such an interaction are not known. This issue was therefore investigated in three groups of Sprague-Dawley rats. When 1 alone was given (250 micrograms/d), the serum concentration of 1 was 0.88 +/- 0.36 ng/mL; when 1 was combined with 2 (66 mg/kg/d), the level of 1 was 2.62 +/- 1.23 ng/mL (p less than 0.05) and was 5.49 +/- 1.07 ng/mL (p less than 0.05) when the dose of 2 was 132 mg/kg/d. These increases correlated with the serum levels of 2 and the deethyl metabolite 3. The myocardial level of 1 was 29.40 +/- 1.34 ng/g without 2; after a low dose of 2, it was 35.80 +/- 7.52 ng/g (nonsignificant) and, after a high dose, it was 42.80 +/- 7.20 (p less than 0.05). In skeletal muscle, the level of 1 was 22.50 +/- 14.7 ng/g without 2, 41.00 +/- 2.45 ng/g (p less than 0.05) after a low dose, and 77.60 +/- 17.45 ng/g (p less than 0.05) after a high dose. The corresponding values for the brain were 32.20 +/- 5.60 ng/g, 48.20 +/- 7.60 ng/g (p less than 0.05), and 60.90 +/- 11.00 ng/g (p less than 0.05). The tissue-serum ratios for 1 in all three tissues were reduced by 2, suggesting a decrease in the tissue binding of the glycoside. There was less uptake of 1 in the myocardium compared with uptake in the skeletal muscle and brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1985

Management of infected fractures of the tibia with associated soft tissue loss: experience with external fixation, bone grafting and soft tissue reconstruction using pedicle muscle flaps or microvascular composite tissue grafts.

The aim of this study was to assess the results of treatment given by a team of orthopaedic and plastic surgeons in a series of infected unhealed fractures of the tibia associated with loss of adjacent soft tissues. Twenty-five lower leg fractures, treated during a 10 year period, entered the study and were grouped according to the principles of treatment followed. In the earlier Group A (nine patients), the osteosynthesis implants were retained or changed to more stable internal fixation devices, the soft tissue defects were closed by conventional muscle or musculocutaneous flaps and bone grafting procedures were performed late in the treatment scheme. In the later Group B (16 patients) the implants were removed and the fracture stabilised by external fixation; the defects were covered with pedicle muscle flaps or with microvascular composite tissue grafts and cancellous bone grafting was performed at the same operation. Twenty-three fractures healed. One fracture developed non-union and in one patient infection necessitated below-knee amputation. The time of union after surgical reconstruction was significantly shorter in Group B (24 +/- 3 weeks) than in Group A (47 +/- 11 weeks). The results suggested that: in severe infected fractures of the tibia surgical implants used previously for fracture treatment should be removed and replaced with an external frame using firm axial compression, microvascular composite grafts seem to improve greatly the rate of healing, early bone grafting should be included in the reconstruction and late infections can be largely avoided even after extensive one-stage reconstructive procedures.

Adolescent↗
PubMed2004

Hepatocyte paraffin 1 expression in human normal and neoplastic tissues: tissue microarray analysis on 3,940 tissue samples.

Hepatocyte paraffin 1 (Hep Par 1) is a monoclonal antibody developed from hepatic tissue from a failed liver allograft. Several studies have shown that Hep Par 1 is a useful marker to differentiate hepatocellular carcinoma (HCC) from other types of adenocarcinoma metastatic to the liver. The aim of our study was the systematic investigation of the epidemiology of Hep Par 1 expression in 3,940 tissue samples using the tissue microarray technique. Strong Hep Par 1 expression was found most frequently in 35 (73%) of 48 HCCs. In nonhepatic tumors, strong Hep Par 1 expression was detected in adenocarcinoma of the lung (2/50), gallbladder (3/31), pancreas (2/48), stomach (3/74), small intestine (1/11), adenoma of the colon with high-grade dysplasia (1/49), adrenal gland carcinoma (1/6), paraganglioma (1/9), and malignant melanoma (2/48). Our data suggest that Hep Par 1 is a highly specific marker for HCC, although several nonhepatic tumors occasionally can show some Hep Par 1 positivity.

Adenocarcinoma↗
PubMed1997

The importance of the binding of factor Xa to phospholipids in the inhibitory mechanism of tissue factor pathway inhibitor: the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory action of tissue factor pathway inhibitor.

To investigate the inhibitory mechanism of tissue factor pathway inhibitor (TFPI), an attempt was made to examine the inhibitory activity of TFPI toward the factor VIIa-truncated tissue factor (TF1-219) complex, which lacks its transmembrane and cytoplasmic domains. Factor VIIa-TF1-219 activity was significantly inhibited by TFPI-factor Xa complex in the presence of phospholipids, but was not in the absence of phospholipids. In addition, TFPI did not inhibit factor VIIa-TF1-219 activity in the presence of gamma-carboxyglutamic acid-domainless factor Xa. The ability of TFPI-factor Xa complex to inhibit factor VIIa-TF1-219 activity was totally dependent on the presence of phospholipids and was neutralized by prothrombin fragment 1 in a dose-dependent manner. These results indicate that the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory mechanism of TFPI and confirm that the binding of factor Xa to phospholipids through its gamma-carboxyglutamic acid domain is essential for this reaction.

Anticoagulants↗
PubMed1997

Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells.

Angiotensin converting enzyme inhibitors (ACE-I) have been reported to prevent the recurrence of cardiovascular events. The mechanism of this decrease, however, can not be completely explained by anti-hypertensive and anti-hypertrophic effects of ACE-I. To investigate the mechanism of this decrease, we studied the regulation of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (TPA), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) by angiotensin II (Ang II) in cultured rat aortic endothelial cells. Ang II increased PAI-1 and TF mRNA expression without affecting that of TPA or TFPI. These inductions were accompanied by increases in PAI-1 and TF activities and were inhibited by a type I Ang II receptor antagonist. The results suggest that Ang II decreases the antithrombotic properties of endothelial cells which increases the chance of thrombosis. Thus, inhibition of the renin-angiotensin system may be beneficial to prevent thrombus formation in treatment of ischemic heart disease.

Angiotensin II↗