Tissue repair and angiotensin II generated at sites of healing.
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Angiotensin II↗
Biomedical subjects
Y Sun
Publications and source records attributed to Y Sun.
Reliability and validity of clinical outcome measurements of osteoarthritis of the hip and knee--a review of the literature.
High reliability and validity of clinical rating schemes is crucial for their use as outcome measurements of treatment of hip and knee osteoarthritis. In this paper, we review the empirical evidence on the reliability and validity of commonly used clinical scores. Clinical scores and related reliability and validity studies were identified by systematic literature search. Scores were classified according to the type and joint. Reliability and validity studies were characterized according to design, population, number and qualification of observers, number of measurements, time interval between repeat measurements and results. Reliability and validity studies were reported for only 6 and 15 of the 45 identified clinical scores, respectively. Although comparisons are difficult due to differences in study design, relatively high reliability was reported for most measurements of pain, stiffness, and physical function, while results are less conclusive for clinical signs. Most validity studies focused on the correlation between various scores. Correlation was generally found to be high for overall numerical ratings, but scores often differed with respect to the interpretation of these ratings. Validity has been more comprehensively studied for Lequesne's scores, WOMAC, and ILAS, and these scores have shown satisfactory responsiveness to different treatment effects. Overall, knowledge on reliability and validity of clinical scores of hip and knee osteoarthritis is limited, underlining the need for further properly designed and conducted studies.
Hip↗
Prevalence of trabecular microcallus formation in the vertebral body and the femoral neck.
Trabecular microcallus formation (TMF) has been described previously in the human vertebra and femur, but the difference in TMF prevalence at these two sites has not been studied and the role of TMF remains controversial. In this study, the 4th lumbar vertebra (L4) and right proximal femur were removed from 27 male and 23 female cadavers. A 2 cm cube cut from the center of L4 and a 1 cm-thick slice cut from the femoral neck were cleaned, defatted, and dried. The apparent density of the L4 cubes was determined as dry weight/bulk bone volume. Using a dissecting microscope at low magnification (4-60x), TMF were identified and counted in both the vertebral and femoral samples. A 8 mm diameter core was then cut from the center of the L4 cubes in the vertical direction, and selected histomorphometric parameters of the core were evaluated with an X-ray microcomputed tomography system (micro-CT). There was a significantly greater prevalence of TMF in vertebral cubes (82%) than in the femoral slices (11%) (P < 0.001). TMF prevalence did not differ significantly between males and females, but the mean number of TMF in the vertebra was significantly (P < 0.05) greater in females (15.0/vertebra) than in males (7.7/vertebra). In the vertebra, the majority of the observed TMF were in vertical trabeculae. Subjects over 60 years old had a higher TMF prevalence than those under 60 years old (P < 0.01). TMF numbers increased with decreasing apparent density (P < 0.05), whereas no significant correlations were found between TMF and bone volume (BV/TV), trabecular number (Tb.N), or trabecular thickness (Tb.Th) as assessed by micro-CT. In two fractured vertebra, very few TMFs (2 and 4, respectively) were observed. These results demonstrated that the occurrence of TMF is strongly related to the anatomical site, probably due to differences in the applied loads and the trabecular structure between sites. The results were consistent with the hypothesis that TMF is a mechanism acting to maintain bone strength, but further studies are needed to clarify this important issue.
Adult↗
Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion.
OBJECTIVE: Myocardial fibrosis, associated with increased expression of angiotensin converting enzyme (ACE) and bradykinin (BK) receptor binding at sites of tissue repair, accompanies chronic elevations in circulating angiotensin II (AngII) and/or aldosterone (ALDO) that simulate chronic cardiac failure. A role for increased ventricular wall stress, associated with arterial hypertension, that can accompany such neurohormonal activation when ventricular function is not compromised, has been held responsible for this structural remodeling. To address this proposition, we monitored morphology of right and left atria and pulmonary artery, where stress is not increased, and compared these structures with hypertensive aorta. METHODS: Experimental groups included: (1) unoperated and untreated controls; (2) intact rats receiving AngII (9 micrograms/h) for 2 weeks and which causes arterial hypertension; (3) uninephrectomized control rats on a high sodium diet for 6 weeks; and (4) uninephrectomized rats receiving ALDO (0.75 micrograms/h) and a high sodium diet for 6 weeks and which results in gradual onset arterial hypertension. Fibrosis was identified by light microscopy in sections stained with collagen specific picrosirius red, while ACE, AngII and BK receptors binding were localized and quantitated by in vitro autoradiography using 125I-351A, 125I[Sar1,Ile8]AngII, and 125I[Tyr8]BK, respectively. AngII receptor subtype was defined by the presence of excess AT1 (losartan) or AT2 (PD123177) receptor antagonists, respectively. RESULTS: With either AngII or ALDO administration, and compared to controls, we found: (1) microscopic scarring that replaced lost myocytes in both left and right atria; (2) an increase in adventitial collagen of both pulmonary artery and aorta (perivascular fibrosis); (3) markedly increased ACE binding at fibrous tissue sites in both atria and great vessels; (4) unchanged atrial and great vessel AT1 receptor binding; and (5) significantly increased BK receptor binding at sites of atrial and perivascular fibrosis. CONCLUSIONS: Thus, the appearance of atrial fibrosis and perivascular fibrosis of aorta and pulmonary artery, together with associated increase in ACE and BK receptor binding, in rats receiving AngII or ALDO suggests these responses are not related to altered ventricular wall stress or arterial hypertension, but rather to these effector hormones of the circulating renin-angiotensin-aldosterone system. Local BK, regulated by ACE found in fibrous tissue and BK receptor binding may play a role in structural remodeling of atria and great vessels in these rat models that stimulate chronic cardiac failure.
Aldosterone↗
Study on antifertility effect of a novel LHRH antagonist in male rats.
The potential of a novel LHRH antagonist, TX54, to inhibit reproductive function in male rats was evaluated. After subcutaneous injection at a dosage of 200 micrograms/rat, once a week for 2 weeks, all the drug-treated male rats maintained mating behavior. But, only one out of seven female rats mated to treated males was pregnant with two fetuses. At the end of medication, sperm count and motility of caudal epididymal spermatozoa of the treated rats were reduced significantly (TX54 vs. control: 11.3 +/- 3.2 x 10(8)/mg epididymal plasma, 66.4 +/- 13.4% vs 18.4 +/- 2.4 x 10(8)/mg epididymal plasma, 83.0 +/- 2.7%). Suppression of serum testosterone by TX54 was not observed 48 h after drug injection and at the end of experiment. Morphological examination revealed that at the IX stage of seminiferous epithelium cycle, spermiation was impaired in TX54-treated rats. Less elongated spermatids were found in the lumen of seminiferous tubules of the treated rats. The size of Leydig cells decreased; psychosis and apoptosis features occurred.
Animals↗
Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart.
Tissue angiotensin II (AngII) is increased in the infarcted rat heart, where it may have autocrine or paracrine properties that influence cellular protein synthesis and growth and therefore tissue repair. It was our hypothesis that treatment with an AT1 receptor antagonist would attenuate fibrous tissue formation after myocardial infarction (MI). To investigate a role for local AngII in the regulation of connective tissue formation during early and late wound healing that follows MI, this study was undertaken. Animals were randomized into two groups in which rats were or were not treated with the AT1 receptor antagonist losartan (10 mg x kg(-1) daily gavage). At 1 and 4 weeks after experimental MI was induced by coronary artery ligation, rat hearts were examined. Infarct size, infarct area, and collagen volume fraction at the site of infarction and in noninfarcted myocardium were determined by picrosirius red staining with videodensitometry. Quantitative in vitro autoradiography was used to detect AngII receptor binding density ((125)I-(Sar1,Ile8)AngII). Compared with an untreated MI control group, in losartan-treated rats we found (1) infarct size was comparable in both groups at weeks 1 and 4, (2) infarct area was comparable between groups at week 1 but was significantly reduced (p < 0.05) at week 4 in losartan-treated rats, (3) a detectable reduction in collagen volume fraction at the site of MI was not found at week 1 but was reduced (p < 0.05) at remote sites at week 4, (4) AngII receptor binding density was reduced (p < 0.05) by 50% at the site of MI at both weeks 1 and 4 in keeping with delivery of losartan to this site of injury. Thus AT1 receptor antagonism appears to influence late phase wound healing at and remote to the site of MI and suggests an association between AngII and the fibrogenic response that appears in the injured rat heart. Although still speculative, an attenuation in fibrosis after MI may account for less ventricular dysfunction and geometric remodeling of right and left ventricles and ventricular arrhythmias that have been observed in such rats treated with angiotensin converting enzyme inhibitor or AT1 receptor antagonist.
Angiotensin II↗
Computer-assisted adjustment of inspired oxygen concentration improves control of oxygen saturation in newborn infants requiring mechanical ventilation.
Open-loop computer control of inspired oxygen concentration was evaluated in 16 newborn infants requiring mechanical ventilation. FIO2 and oxygen saturation were compared for 2-hour periods of computer versus routine manual FIO2 adjustment. During computer-assisted FIO2 adjustment, patients spent more time at the target SaO2 and less time with SaO2 < 90%.
Humans↗
Intraoperative phototherapy: a comparative study of intravenous and topical photofrin II and aminolevulinic acid.
This study compares the systemic and topical application of photofrin II and aminolevulinic acid as an intraoperative adjuvant therapy in the C3H mouse radiation-induced fibrosarcoma model. Dose-development and time-dependent studies were first conducted followed by intraoperative phototherapy studies with photofrin II and aminolevulinic acid. Study results clearly show that intraoperative phototherapy after aminolevulinic acid topical application is significantly more effective than treatment with photofrin II given intravenously or topically (p < 0.05) in this animal tumor model. The concept of topical application of photosensitizers and the rationale for intraoperative adjuvant phototherapy are discussed.
Aminolevulinic Acid↗
Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D.
BACKGROUND: The identification of potent small molecule ligands to receptors and enzymes is one of the major goals of chemical and biological research. Two powerful new tools that can be used in these efforts are combinatorial chemistry and structure-based design. Here we address how to join these methods in a design protocol that produces libraries of compounds that are directed against specific macromolecular targets. The aspartyl class of proteases, which is involved in numerous biological processes, was chosen to demonstrate this effective procedure. RESULTS: Using cathepsin D, a prototypical aspartyl protease, a number of low nanomolar inhibitors were rapidly identified. Although cathepsin D is implicated in a number of therapeutically relevant processes, potent nonpeptide inhibitors have not been reported previously. The libraries, synthesized on solid support, displayed nonpeptide functionality about the (hydroxyethyl)amine isostere. The (hydroxyethyl)amine isostere, which targets the aspartyl protease class, is a stable mimetic of the tetrahedral intermediate of amide hydrolysis. Structure-based design, using the crystal structure of cathepsin D complexed with the peptide-based natural product pepstatin, was used to select the building blocks for the library synthesis. The library yielded a 'hit rate' of 6-7% at 1 microM inhibitor concentrations, with the most potent compound having a Ki value of 73 nM. More potent, nonpeptide inhibitors (Ki = 9-15 nM) of cathepsin D were rapidly identified by synthesizing and screening a small second generation library. CONCLUSIONS: The success of these studies clearly demonstrates the power of coupling the complementary methods of combinatorial chemistry and structure-based design. We anticipate that the general approaches described here will be successful for other members of the aspartyl protease class and for many other enzyme classes.
Amides↗
Myofibroblasts and local angiotensin II in rat cardiac tissue repair.
Tissue repair is a fundamental property of vascularized tissue. At sites of injury, phenotypically transformed fibroblast-like cells are responsible for fibrous tissue formation, expressed principally as type I and III fibrillar collagens. These cells are termed myofibroblasts because they contain alpha-smooth muscle actin microfilaments and are contractile. In vivo studies of injured rat cardiac tissues and in vitro cell culture studies have shown that such fibroblast-like cells contain requisite components for angiotensin peptide generation and angiotensin II receptors. Such locally generated angiotensin II acts in an autocrine paracrine manner to regulate collagen turnover and thereby tissue homeostasis in injured tissue.
Angiotensin II↗
Effect of dilution on the kinetics of cross-linking thermal polymerization of dental composite matrix resins.
The effect of dilution of 2,2-bis-(4-(2-hydroxy-3-methacryloxyprop-1oxy) phenyl) propane (bis-GMA) with triethylene glycol demethacrylate (TEGDMA) on the extent of polymerization, Ep, has been studied using differential scanning calorimetry. The isothermal and dynamic measurements indicate that the Ep is affected dramatically by dilution. The residual polymerization was also found to be strongly influenced by dilution. However, the apparent activation energy, Eapp, was found to be independent of dilution.
Journal Article↗
Domain structure and conformation of a cellobiohydrolase from Trichoderma pseudokiningii S-38.
A cellobiohydrolase (CBH) with a molecular mass of 66 kD was purified from Trichoderma pseudokiningii S-38. Papain digestion produced a 59- to 60-kD core domain with 54% of intact activity on crystalline cellulose and with full activity against soluble substrates. Digestion products also included two small peptides with molecular mass of about 3-4 kD, which are heavily glycosylated and difficult to purify; the mixed peptides displayed the capacity to disorganize the cellulose fiber. The sequencing results indicated that the intact enzyme had a blocked N-terminal and there was a 10-amino-acid sequence in the N-terminal of the core protein of Ser-Gly-Thr-Ala-Val-Thr-Cys-Leu-Ala-Asp. Fluorescence and circular dichroism properties indicated that the core protein has an independent conformation and is conformationally similar to intact enzyme, suggesting that the spectroscopic properties of the intact enzyme come from the core protein.
Amino Acid Sequence↗
KCNE1 mutations cause jervell and Lange-Nielsen syndrome.
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Female↗
Rearrangement and reactivation of the myelin basic protein locus in myelin-deficient (mld) mouse brain.
Myelin-deficient (mld) is a complex mutation affecting the myelin basic protein (MBP) locus of the mouse. It consists of duplication and partial inversion of the MBP gene and results in a dysfunctional MBP locus. The mutant phenotype is reversed, both in vivo and in vitro, in approximately 5% of mld oligodendrocytes. One possible mechanism for the somatic reversion is recombination between homologous sequences of the duplicated gene copies to reconstitute a functional MBP locus. There are several possible recombination events that could reconstitute a functional MBP locus by DNA rearrangement. Two of these would result in reinversion and circularization of specific MBP gene sequences, respectively. In this work polymerase chain reaction analysis was used to detect both reinverted and circularized MBP gene sequences in mld mouse tissues, indicating that DNA rearrangement at the MBP locus does occur. Analysis of individually harvested cells showed that in revertant MBP-positive mld oligodendrocytes DNA rearrangement at the MBP locus was correlated with reactivation of the MBP gene. Fluctuation analysis showed that reactivation of the MBP locus is a stochastic event occurring with a frequency of approximately 1.4 x 10(-6) per cell per cell cycle during oligodendrocyte development. The frequency of rearrangement and reactivation of the MBP locus was comparable in double mutant (mld/mld, scid/scid) and single mutant (mld/mld, +scld/+scld) mice, indicating that the scid factor is not required for MBP gene reactivation in mld. The significance of DNA rearrangement in mammalian development is discussed.
Animals↗
The mouse prosaposin locus: promoter organization.
Prosaposin is a multifunctional protein that, when secreted, functions as a neurotrophic agent and, when retained in the lysosomes, is processed to essential glycosphingolipid hydrolase activator proteins. The prosaposin locus is temporarily and spatially regulated at the transcriptional and post-translational levels. The prosaposin gene has been partially characterized, but the 5' region has not. RACE, S1 nuclease protection, and sequence analysis were used to characterize the first intron and first exon as well as the 5'-flanking regions from murine P1 clones. The first intron is approximately 15 kb in length and the complete gene is approximately 25 kb. The transcriptional initiation sites are located 87 and 94 bp 5' to the ATG in exon 1. Using luciferase as a reporter gene and transfection into NS20Y, NIH-3T3, or SF-7 Sertoli cell cultures, deletion constructs from the 5' putative promoter region were shown to contain positive and negative regulatory elements within 2,400 bp 5' to the transcription start site. A negative regulatory element is located between 742 and 310 bp 5' to the transcription start site. These studies provide insight into the regulation of this unique "lysosomal" locus.
3T3 Cells↗
Grafting assay distinguishes promotion sensitive from promotion resistant JB6 cells.
The JB6 mouse epidermal cell system has been used extensively as an in vitro transformation model for the study of tumor promotion. The standard JB6 cell assay for promotion of transformation is carried out in soft agar or other anchorage independent conditions. The present study was directed to the development of an in vivo model to distinguish the promotion resistant (P-) and promotion sensitive (P+) progression phenotypes. Results indicate that the grafting assay distinguishes P- and P+ cells in vivo with P+ but not P- cells forming tumors within 7-9 weeks. Expression of dominant negative mutant jun TAM67 blocks both anchorage independent transformation response and graft bed tumor formation by P+ cells, suggesting that the requirement for AP-1 activation in transformation now applies in vivo. Expression of mutated p53 produced a gain of P+ phenotype in P- cells in vitro, but not in vivo. Histochemical and Northern blot analysis for expression of various keratinocyte markers revealed no evidence for expression, suggesting a loss of keratinocyte markers following establishment in culture. In summary, the skin-grafting assay described in this study appears to be a valid in vivo assay for distinguishing the preneoplastic progression phenotypes represented by JB6 P- and P+ cells.
Animals↗
New electrode system for rapid whole-body and segmental bioimpedance assessment.
Skeletal muscle is a clinically important body composition component which at present is difficult to quantify in vivo. Previous studies suggest that measured appendicular resistance at 50 kHz can be used to predict extremity skeletal muscle mass, although accurate technician placement of multiple gel electrodes is required. In the present study we developed a new bioimpedance analysis (BIA) electrode stand designed for rapid whole-body and segmental resistance and reactance measurements. The new system incorporates stainless steel hand and foot contact electrodes in place of gel electrodes and employs a previously reported lead placement algorithm for deriving extremity resistances without the need for placing conventional proximal limb gel electrodes. This report describes the new electrode system's design and examines the relationships between contact and gel electrode-measured resistance and between appendicular resistance measured with the recently reported lead placement algorithm and conventionally placed segmental electrodes. Results in healthy adults demonstrate high correlations between contact and gel electrodes (e.g., hand-to-hand, N = 12, r = 0.994, P < 0.001) and between segmental resistance measured by the recently reported approach and conventionally-measured segmental resistance (e.g., right arm, N = 13; r = 0.997, P < 0.001). These results strongly support the validity of the new electrode system's resistance measurements and suggests the feasibility of developing a BIA system for rapidly measuring extremity skeletal muscle mass.
Adult↗
The pathogenesis of ED71, a defined deletion mutant of equine herpesvirus-1, in a murine intranasal infection model for equine abortion.
A series of mutants of equine herpesvirus-1 (EHV-1) which contain deletions in non-essential genes was previously characterized in a murine intranasal infection model. One mutant, ED71 which was shown to be attenuated in the model, was further characterized by inoculation into pregnant mice. Despite the attenuation previously reported, intranasal inoculation of pregnant mice resulted in premature parturition and the birth of dead or dying foetuses. Furthermore, mice inoculated before pregnancy with the same mutant, and subsequently challenged 14 days after conception with wild-type virus, were not protected from abortion.
Abortion, Veterinary↗