Acute postpartum uterine inversion with haemorrhagic shock.
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Acute Disease↗
Biomedical subjects
P Chien
Publications and source records attributed to P Chien.
Conformational diversity in a yeast prion dictates its seeding specificity.
A perplexing feature of prion-based inheritance is that prions composed of the same polypeptide can evoke different phenotypes (such as distribution of brain lesions), even when propagated in genetically identical hosts. The molecular basis of this strain diversity and the relationship between strains and barriers limiting transmission between species remain unclear. We have used the yeast prion phenomenon [PSI+]4 to investigate these issues and examine the role that conformational differences may have in prion strains. We have made a chimaeric fusion between the prion domains of two species (Saccharomyces cerevisae and Candida albicans) of Sup35, the protein responsible for [PSI+]. Here we report that this chimaera forms alternate prion strains in vivo when initiated by transient overexpression of different Sup35 species. Similarly, in vitro the purified chimaera, when seeded with different species of Sup35 fibres, establishes and propagates distinct amyloid conformations. These fibre conformations dictate amyloid seeding specificity: a chimaera seeded by S. cerevisiae fibres efficiently catalyses conversion of S. cerevisiae Sup35 but not of C. albicans Sup35, and vice versa. These and other considerations argue that heritable prion strains result from self-propagating conformational differences within the prion protein itself. Moreover, these conformational differences seem to act in concert with the primary structure to determine a prion's propensity for transmission across a species barrier.
Amino Acid Sequence↗
Antigens of Mycobacterium tuberculosis expressed during preclinical tuberculosis: serological immunodominance of proteins with repetitive amino acid sequences.
Four antigens of Mycobacterium tuberculosis that are expressed in vivo after aerosol infection but prior to the development of clinical tuberculosis (TB) in rabbits were identified by immunoscreening of an expression library of M. tuberculosis genomic DNA with sera obtained 5 weeks postinfection. Three of the proteins identified, PirG (Rv3810), polymorphic GC-repetitive sequence (PE-PGRS; Rv3367), and proline-threonine repetitive protein (PTRP) (Rv0538), have multiple tandem repeats of unique amino acid sequences and have characteristics of surface or secreted proteins. The fourth protein, MtrA (Rv3246c), is a response regulator of a putative two-component signal transduction system, mtrA-mtrB, of M. tuberculosis. All four antigens were recognized by pooled sera from TB patients and not from healthy controls, confirming their in vivo expression during active infection in humans. Three of the antigens (PE-PGRS, PTRP, and MtrA) were also recognized by retrospective preclinical TB sera obtained, prior to the clinical manifestation of TB, from human immunodeficiency virus-TB patients, suggesting that they are potential candidates for devising diagnostic tests for active, preclinical TB.
Amino Acid Sequence↗
Thrombosis and shock induced by activating antiplatelet antibodies in human Fc gamma RIIA transgenic mice: the interplay among antibody, spleen, and Fc receptor.
Transgenic mouse lines were created that express Fc gamma RIIA on platelets and macrophages at human physiologic levels, and they were used to explore the consequences in vivo of activating antiplatelet antibodies. Anti-CD9 antibody activated platelets of Fc gamma RIIA transgenic (tg) mice and, following injection in vivo, caused more rapid severe thrombocytopenia than nonactivating antiplatelet antibody. Anti-CD9 injected into Fc gamma RIIA tg crossed with FcR gamma-chain knockout (gamma-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. The shock depended on platelet Fc receptor density and antibody dose. On histologic examination, the lung vasculature of anti-CD9-treated Fc gamma RIIA tg x gamma-KO mice contained extensive platelet-fibrin thrombi. Thrombosis and shock in Fc gamma RIIA tg mice in the context of the FcR gamma-chain knockout suggested the importance of the interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically (splenectomy) or functionally (monoclonal antibody treatment) also facilitated anti-CD9-mediated shock in Fc gamma RIIA tg mice. The spleen, which clears nonactivating antibody-coated platelets leading to thrombocytopenia, appears to play a protective role in the thrombosis and shock observed with activating antiplatelet antibody. The data indicate that antibodies, which activate platelets in an Fc gamma RIIA-dependent manner, can lead to thrombosis, shock, and death. Furthermore, antibody titer, platelet Fc receptor density, and splenic clearance are likely important determinants of the outcome. (Blood. 2000;96:4254-4260)
Animals↗
Molecular basis of a yeast prion species barrier.
The yeast [PSI+] factor is inherited by a prion mechanism involving self-propagating Sup35p aggregates. We find that Sup35p prion function is conserved among distantly related yeasts. As with mammalian prions, a species barrier inhibits prion induction between Sup35p from different yeast species. This barrier is faithfully reproduced in vitro where, remarkably, ongoing polymerization of one Sup35p species does not affect conversion of another. Chimeric analysis identifies a short domain sufficient to allow foreign Sup35p to cross this barrier. These observations argue that the species barrier results from specificity in the growing aggregate, mediated by a well-defined epitope on the amyloid surface and, together with our identification of a novel yeast prion domain, show that multiple prion-based heritable states can propagate independently within one cell.
Amyloidosis↗
Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation.
This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte chemoattractant protein (MCP)-1 and interferon-gamma-inducible protein-10 (IP-10) are largely restricted to astrocytes or other glial cells in these diverse pathological states. The remainder of the review focuses on studies that address the molecular mechanisms which underlie transcriptional regulation of three astrocyte-derived chemokines: MCP-1, IP-10 and beta-R1/interferon-gamma-inducible T-cell chemoattractant (I-TAC). Based on these studies, we propose that the complex promoters of these genes are marvelously organized for flexible and efficient response to challenge. In the case of MCP-1, several different stimuli can elicit gene transcription, acting through a conserved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1. For IP-10 and beta-R1/I-TAC, it appears that efficient gene transcription occurs only in highly inflammatory circumstances that produce aggregates of simultaneous stimuli. These characteristics, in turn, mirror the expression patterns of the endogenous genes: MCP-1 is expressed under a variety of circumstances, while IP-10 appears primarily during immune-mediated processes that feature exposure of resident neuroglia to high levels of inflammatory cytokines.
Autoimmune Diseases of the Nervous System↗
Phagosomal maturation, acidification, and inhibition of bacterial growth in nonphagocytic cells transfected with FcgammaRIIA receptors.
Phagocytosis and killing of microbial pathogens by professional phagocytes is an essential component of the innate immune response. Recently, heterologous transfection of individual receptors into nonmyeloid cells has been used successfully to elucidate the early steps that signal phagosome formation. It is unclear, however, whether the vacuoles formed by such transfected cells are bona fide phagosomes, capable of fusion with endomembranes, of luminal acidification, and of controlling the growth of microorganisms. The aim of the current study was to determine whether COS-1 and Chinese hamster ovary cells, rendered phagocytic by expression of human FcgammaRIIA receptors, express the cellular machinery required to support phagosomal maturation. Immunolocalization studies demonstrated that early endosomes, as well as late endosomes and/or lysosomes, fuse sequentially with phagosomes in the transfectants. Microfluorescence ratio imaging of particles labeled with pH-sensitive dyes revealed that maturation of the phagosome was accompanied by luminal acidification. The drop in pH, which attained levels comparable to those reported in professional phagocytes, was prevented by inhibitors of vacuolar-type H(+)-ATPases. Optimal phagosomal acidification required elevation of cytosolic [Ca(2+)], suggesting that it results from fusion of endomembranes bearing proton pumps. Moreover, the transfected cells effectively internalized live bacteria. Opsonization was essential for bacterial internalization, implying that it occurred by FcgammaRIIA-mediated phagocytosis, as opposed to invasion. Uptake into phagolysosomes was associated with inhibition of bacterial growth, due at least in part to the low intraphagosomal pH. These studies indicate that the biochemical events that follow receptor-mediated particle internalization in cells transfected with FcgammaRIIA receptors closely resemble the process of phagosomal maturation in neutrophils and macrophages. FcgammaRIIA-transfected cells can, therefore, be used as a model for the study of additional aspects of phagocyte biology.
Animals↗
The role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model.
In humans, the Fc receptor for IgG, FcgammaRIIA, is expressed on macrophages and platelets and may play an important role in the pathophysiology of immune-mediated thrombocytopenia. Mice lack the genetic equivalent of human FcgammaRIIA. To better understand the role of FcgammaRIIA in vivo, FcgammaRIIA transgenic mice were generated and characterized. One transgenic mouse line expressed FcgammaRIIA on platelets and macrophages at levels equivalent to human cells, and cross-linking FcgammaRIIA on these platelets induced platelet aggregation. Immune-mediated thrombocytopenia in this transgenic line was studied using i.v. and i.p. administration of anti-mouse platelet Ab. In comparison with matched wild-type littermates that are negative for the FcgammaRIIA transgene, Ab-mediated thrombocytopenia was significantly more severe in the FcgammaRIIA transgenic mice. In contrast, FcR gamma-chain knockout mice that lack functional expression of the Fc receptors FcgammaRI and FcgammaRIII on splenic macrophages did not demonstrate Ab-mediated thrombocytopenia. We generated FcgammaRIIA transgenic x FcR gamma-chain knockout mice to examine the role of FcgammaRIIA in immune clearance in the absence of functional FcgammaRI and FcgammaRIII. In FcgammaRIIA transgenic x FcR gamma-chain knockout mice, severe immune thrombocytopenia mediated by FcgammaRIIA was observed. These results demonstrate that FcgammaRIIA does not require the FcR gamma-chain for expression or function in vivo. Furthermore, taken together, the data suggest that the human Fc receptor FcgammaRIIA plays a significant role in the immune clearance of platelets in vivo.
Animals↗
A longitudinal study of C3, C3d and factor Ba in burn patients in Hong Kong Chinese.
A longitudinal study of serum C3, C3d and fragment Ba was carried out in 53 burn patients of Chinese origin whose total burn surface area ranged from I to 45%. Complement C3 was found to be activated on or before day 7 post-burn. The sharp increase in C3d suggested an acute inflammatory response. In addition factor Ba was increased in these patients, suggesting that the alternative pathway was also activated following thermal injuries. The fluctuations of C3, C3d and Factor Ba observed about 1 year after injury suggested chronic inflammation associated with long term of outcome of healing in the burn sites.
Adult↗
Frequency of 22q11 deletions in patients with conotruncal defects.
OBJECTIVES: This study was designed to determine the frequency of 22q11 deletions in a large, prospectively ascertained sample of patients with conotruncal defects and to evaluate the deletion frequency when additional cardiac findings are also considered. BACKGROUND: Chromosome 22q11 deletions are present in the majority of patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes in which conotruncal defects are a cardinal feature. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. METHODS: Two hundred fifty-one patients with conotruncal defects were prospectively enrolled into the study and screened for the presence of a 22q11 deletion. RESULTS: Deletions were found in 50.0% with interrupted aortic arch (IAA), 34.5% of patients with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Two of 6 patients with a posterior malalignment type ventricular septal defect (PMVSD) and only 1 of 20 patients with double outlet right ventricle were found to have a 22q11 deletion. None of the 45 patients with transposition of the great arteries had a deletion. The frequency of 22q11 deletions was higher in patients with anomalies of the pulmonary arteries, aortic arch or its major branches as compared to patients with a normal left aortic arch regardless of intracardiac anatomy. CONCLUSIONS: A substantial proportion of patients with IAA, TA, TOF and PMVSD have a deletion of chromosome 22q11. Deletions are more common in patients with aortic arch or vessel anomalies. These results begin to define guidelines for deletion screening of patients with conotruncal defects.
Aorta, Thoracic↗
Abrogation of the Fc gamma receptor IIA-mediated phagocytic signal by stem-loop Syk antisense oligonucleotides.
The role of Syk kinase in Fc gamma receptor (Fc gamma R) IIA-mediated phagocytosis was examined with two forms of antisense oligodeoxynucleotides (ODNs) designed to hybridize to human Syk mRNA. Monocytes were incubated with linear and stem-loop antisense ODNs targeted to Syk mRNA. When complexed with cationic liposomes, stem-loop Syk antisense ODN with phosphorothioate modification exhibited stability in fetal bovine and human serum. The stem-loop Syk antisense ODN at a concentration of 0.2 microM inhibited Fc gamma RIIA-mediated phagocytosis by 90% and completely eliminated Syk mRNA and protein in monocytes, whereas scrambled-control ODNs had no effect. The Syk antisense ODNs did not change beta-actin mRNA levels and Fc gamma RII cell-surface expression. In addition, stem-loop Syk antisense ODN inhibited Fc gamma RI and Fc gamma RIIIA-mediated phagocytosis. These data indicate the efficacy of stem-loop Syk antisense ODN for targeting and degrading Syk mRNA and protein and the importance of Syk kinase in Fc gamma receptor-mediated phagocytosis. Immunoblotting assay demonstrated that Fc gamma RII tyrosine phosphorylation after Fc gamma RII cross-linking did not change in the absence of Syk protein. These results indicate that Syk kinase is required for Fc gamma RIIA-mediated phagocytic signaling and that Fc gamma RII cross-linking leads to tyrosine phosphorylation of Fc gamma RII independent of Syk kinase.
Animals↗
Finasteride inhibits 5 alpha-reductase activity in human dermal fibroblasts: prediction of its therapeutic application in androgen-related skin diseases.
BACKGROUND: The potential role of finasteride in treating androgen related skin disorders was investigated. METHODS: Pooled human dermal fibroblasts were used to assess the effect of finasteride on the 5 alpha-reductase activity in skin tissue. Vmax and Km were estimated in the presence of 0, 10, and 200 nM finasteride. RESULTS: Vmax values remain constant near 1.20 pmol/mg protein/h in the presence of increasing concentrations of finasteride; however, apparent Km increases from 0.27 nM at 0 nM finasteride to 0.31 nM and 0.44 nM at 10 nM and 200 nM finasteride, respectively. This suggests that finasteride competes with testosterone and has a high affinity for same binding site of the 5 alpha-reductase enzyme. Apparent Ki was estimated at 282 nM, indicating that a high concentration of finasteride is required to significantly suppress the enzyme activity. CONCLUSIONS: This study confirms that finasteride inhibits the conversion of testosterone to dihydrotestosterone in human reticular dermal fibroblasts. Finasteride may have therapeutic potential in treating skin disorders influenced by the action of dihydrotestosterone.
Androgen Antagonists↗
A quantifiable approach in the comparison of isokinetic assessment data--new correlation equations for the Johnson antishear device and standard shin pad in the isokinetic assessment of the knee.
The rehabilitation of the knee with a deficient anterior cruciate ligament (ACL) always presents a great challenge. Isokinetic assessment allows muscle performance to be quantified. The antishear device, introduced by Johnson, has the distinct advantage of minimizing the anterior translation force during isokinetic exercise. In a previous report, there was a significant difference between the Johnson double pad antishear device and the standard single pad device in knee extension. The main purpose of this study was to define a correlation equation such that data generated in the use of the two different devices can be compared for assessment. Ten subjects were tested with the Cybex isokinetic dynamometer with a randomly selected sequence of test speeds. Correlation coefficient (r), regression analysis and paired t tests (P) were performed to estimate the correlation and difference between the two devices. It is concluded that a significant difference in the data generated between the two devices indicated that a single device should be selected to carry out a series of comparisons on a particular subject. However, if the two devices are used in a series of testings, a set of correlation equations has been defined to facilitate such comparison. The findings in this study will widen the application of comparison of isokinetic data in the quantitative approach of rehabilitation of the knee with a deficient anterior cruciate ligament.
Adult↗
Substitutions and deletions in the cytoplasmic domain of the phagocytic receptor Fc gamma RIIA: effect on receptor tyrosine phosphorylation and phagocytosis.
Fc gamma RIIA in the absence of other Fc receptors or receptor subunits induces the ingestion of IgG-coated cells. The cytoplasmic domain of Fc gamma RIIA contains two Y-x-x-L sequences similar to those in other Ig gene family receptors plus an additional tyrosine residue not in a Y-x-x-L motif. Upon cross-linking, Fc gamma RIIA is phosphorylated on tyrosine and the cytoplasmic tyrosines, Y275 (Y1), Y282 (Y2), and Y298 (Y3), may be important for its phagocytic activity. Because COS-1 cells can serve as a model for examining molecular structures involved in phagocytosis, substitutions and deletions were introduced into the cytoplasmic domain of Fc gamma RIIA and examined in COS-1 cell transfectants for their effects on phagocytosis and tyrosine phosphorylation. Disruption of a single cytoplasmic Y-x-x-L motif by substitution of tyrosine Y2 or Y3 by phenylalanine or by removing the threonine and leucine residues within the motif inhibited phagocytosis 50% to 65%. Tyrosine phosphorylation of Fc gamma RIIA also was inhibited, although to a greater extent by the substitution of Y3 than of Y2. Replacement of the N-terminal first cytoplasmic domain tyrosine, Y1, which is not within a typical Y-x-x-L, by itself did not inhibit phagocytosis, but replacement of Y1 in mutants lacking Y2 or Y3 virtually eliminated phagocytic activity and receptor tyrosine phosphorylation. Thus, at least two cytoplasmic tyrosines, including at least one typical single Y-x-x-L motif, are required for phagocytosis by Fc gamma RIIA. The data suggest that there is a close but not a simple relationship between phosphorylation of the Fc gamma RIIA cytoplasmic tyrosines and Fc gamma RIIA-mediated phagocytosis. Y3 appears to be particularly important because its removal by truncation or replacement with phenylalanine inhibits both tyrosine phosphorylation and phagocytosis in parallel. Alterations in the 12 residue proline-containing sequence between the two Y-x-x-L motifs also reduced phagocytic activity and tyrosine phosphorylation. Thus, the specific structure of the Fc gamma RIIA cytoplasmic domain accounts for its ability to stimulate phagocytosis in the absence of other subunits.
Amino Acid Sequence↗
The high affinity Fc gamma receptor (CD64) induces phagocytosis in the absence of its cytoplasmic domain: the gamma subunit of Fc gamma RIIIA imparts phagocytic function to Fc gamma RI.
The high affinity Fc gamma receptor, Fc gamma RI, is unique among the three classes of macrophage Fc gamma receptors not only in its affinity for IgG, but also in the structure of its cytoplasmic domain. Fc gamma RIIA and the gamma subunit of Fc gamma RIIIA have tyrosine-containing motifs within their cytoplasmic domains that are phosphorylated when crosslinked and that are required for phagocytosis by COS-1 cell transfectants. In contrast to these other Fc gamma receptors, Fc gamma RI does not contain cytoplasmic tyrosines and does not induce phagocytosis in COS-1 transfectants. We transfected wild-type (WT) and mutant (MT) Fc gamma RI lacking the cytoplasmic domain into COS-1 cells and murine macrophages and assessed phagocytosis using IgG-coated red blood cells (RBCs) and RBCs conjugated with Fab anti-human Fc gamma RI monoclonal antibody (mAb). Fc gamma RI, in contrast to Fc gamma RIIA, did not induce phagocytosis in COS cells. However, both WT and MT Fc gamma RI induced phagocytosis in murine macrophages, and phagocytosis was inhibited by the tyrosine kinase inhibitor tyrphostin 23. Human monocytes also phagocytosed Fc gamma RI-targeted RBCs, and activation of Fc gamma RI on monocytes with Fab anti-Fc gamma RI induced phosphorylation of Fc gamma RII on tyrosine residues. However, Fc gamma RI activation of Fc gamma RI-Fc gamma RIIA COS-1 cotransfectants did not induce tyrosine phosphorylation of Fc gamma RIIA, and coexpression of Fc gamma RI and Fc gamma RIIA in COS cells did not confer Fc gamma RI phagocytic capability. In contrast, coexpression in COS-1 cells of Fc gamma RI with the gamma subunit of Fc gamma RIIIA conferred phagocytic function to both Fc gamma RI and the MT Fc gamma RI lacking the cytoplasmic domain. Thus, Fc gamma RI does not require its cytoplasmic domain to mediate a phagocytic signal and interacts with the gamma subunit of Fc gamma RIIIA to induce phagocytosis.
Animals↗
The Johnson antishear device and standard shin pad in the isokinetic assessment of the knee.
Isokinetic training and assessment of the knee joint has been the mainstay of rehabilitation, especially in patients with anterior cruciate ligament deficiency. Besides the original shin pad used, the antishear device was introduced by Johnson in 1982. This device has been shown biomechanically to prevent excessive anterior translation of force on the tibia during training. However, there is a need to compare the antishear device and the standard shin pad in the isokinetic assessment. Hence, the major objective of this study is to define, if any, the difference in patient assessment between the new double pad device and the old single shin pad. Ten subjects with no previous history of injury on either knee were tested with the Cybex Isokinetic Dynamometer. There were four men and six women and the mean age was 25.2 years. They were randomized into different test sequences with different shin pads at different speeds. Correlation and paired t tests (P) were performed to find out the correlation and difference between the two devices. There was significant difference in performance assessment between the two devices in knee extension (P < 0.05) but no significant difference in knee flexion (P > 0.05). There was also a high correlation (r > 0.75) between the two devices. It is concluded that because of the significant difference of data generated between the two devices, it is important to select one single device with each patient during a series of testings.
Adult↗
Hong Kong Sports Institute: sports medicine and science from theory to practice.
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Athletic Injuries↗
Sports causing most injuries in Hong Kong.
A prospective survey was carried out on 2293 patients attending the Sports Injury Clinic in the Prince of Wales Hospital between May 1984 and December 1990. A Sports Injury Report Form was completed for each patient. Subjects in this study represent a group of nonprofessional and non-élite athletes in a metropolitan area. Soccer, basketball, volleyball, long-distance running and cycling in descending order were the five most common sports causing injury. Different sports produced different injury patterns. In four of the five sports, the knee (27.27-50.47%) and the ankle (16.78-24.67%) were the commonest sites of injury. In cycling, the face (19.46%) was the commonest site of injury. There was a higher injury rate to the lower than the upper limb in soccer, basketball, volleyball and long-distance running, with a ratio of upper- to lower-limb injury ranging from 1:1.13 to 1:46.10. In cycling, upper limb injury was more frequent (upper- to lower-limb injury ratio was 1:0.53). Sprain was the commonest injury overall (44.60%). It was also the commonest injury condition in volleyball (55.15%), basketball (55.34%), soccer (51.41%) and long-distance running (39.33%). In cycling, abrasion (24.83%) was commonest.
Adolescent↗