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Biomedical subjects

A Yu

Publications and source records attributed to A Yu.

At least 37 records · Page 2Linked to original sources
PubMed2000

Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors.

The importance of IL-2Rbeta function for immune regulation is highlighted by the severe impairment in lymphoid cell function in IL-2Rbeta-deficient mice. It has been speculated that failed IL-2/IL-2R signaling in peripheral T cells causes the associated autoimmunity, imbalanced peripheral lymphoid homeostasis, and defective T cell function. This study explored the requirement for IL-2Rbeta function in mature T lymphocytes. We show that transgenic thymic expression of the IL-2R beta-chain in IL-2Rbeta-deficient mice prevents lethal autoimmunity, restores normal production of B lymphocytes, and results in a peripheral T cell compartment that is responsive to triggering through the TCR, but not the IL-2R. The dysfunction of the IL-2R is illustrated by the near complete failure of mature T cells to proliferate to IL-2 in vitro and in vivo, to differentiate into CTL, and to up-regulate IL-2Ralpha expression. These data indicate that lymphoid homeostasis is largely maintained despite a nonfunctional IL-2R in mature T lymphocytes and suggest that IL-2Rbeta provides an essential signal during thymic development to regulate self-reactivity.

Animals↗
PubMed2000

Hypoxia, HIF-1, and the pathophysiology of common human diseases.

Hypoxia plays a fundamental role in the pathophysiology of common causes of mortality, including ischemic heart disease, stroke, cancer, chronic lung disease, and congestive heart failure. In these disease states, hypoxia induces changes in gene expression in target organs that either fail to result in adequate adaptation or directly contribute to disease pathogenesis. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator that is expressed in response to cellular hypoxia and mediates multiple cellular and systemic homeostatic responses to hypoxia. Recent studies have provided evidence that important pathophysiological responses to hypoxia in pulmonary hypertension, myocardial ischemia, and cancer are mediated by HIF-1. Pharmacologic and gene therapy strategies designed to modulate HIF-1 activity may represent a novel and effective therapeutic approach to these common disorders.

Animals↗
PubMed2000

Studies on common illnesses and medical care utilization patterns of adolescents in Hong Kong.

PURPOSE: To estimate the prevalences of common illnesses in Hong Kong adolescents, the sociodemographic and selected risk factors associated with these illnesses, and their health care utilization behavior and attitudes. METHODS: A cross-sectional questionnaire survey of 3355 participating secondary school students (response rate = 98%). RESULTS: Self-reported 3-month prevalences were obtained for cough/cold/influenza (55.2%), digestive disorders (34.6%), accidental injuries (29.5%), headache/dizziness (23.6%), chronic anxiety/insomnia (20.1%), skin problems (9.5%), asthma (3.8%), liver disease (1.3%), and menstrual pain (13.8% of female students). Self-perceived poor health, smoking, and alcohol consumption were associated with many of these illnesses. Treatment choice depended on the illness suffered (e.g., most students with respiratory problems consulted medical practitioners, whereas most with chronic anxiety/insomnia did not). Many students lacked trust in their doctors, doctor-shopped, relied heavily on self-medication, did not comply with prescribed treatments, would not seek help about medical problems, felt they had insufficient access to health information, and wanted confidential health care. CONCLUSIONS: This study examined for the first time the common illnesses and health care utilization patterns of Hong Kong adolescents. Students with chronic anxiety/insomnia were much less likely to seek care, indicating a need for better education on mental health. Efforts to prevent smoking and alcohol consumption among adolescents need to be strengthened. The students' attitudes, poor compliance and help-seeking behaviors suggest suboptimal use of the health care system. Our findings are useful for international comparisons by medical practitioners, health care managers, and researchers.

Adolescent↗
PubMed2000

Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes.

Infection by adenovirus 12, transfection with the Ad12 E1B 55 kDa gene, or activation of p53 cause metaphase fragility of four loci (RNU1, PSU1, RNU2, and RN5S) each containing tandemly repeated genes for an abundant small RNA (U1, U2, and 5S RNA). We now show that loss of the Cockayne syndrome group B protein (CSB) or overexpression of the p53 carboxy-terminal domain induces fragility of the same loci; moreover, p53 interacts with CSB in vivo and in vitro. We propose that CSB functions as an elongation factor for transcription of structured RNAs, including some mRNAs. Activation of p53 would inhibit CSB, stalling transcription complexes and locally blocking chromatin condensation. Impaired transcription elongation may also explain the diverse clinical features of Cockayne syndrome.

Acetylation↗
PubMed2000

Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay.

Methylthioadenosine phosphorylase (MTAP) deficiency in tumors can be therapeutically exploited for selective therapy. Many tumors lacking MTAP have been found to homozygously delete the chromosome 9p region containing the p16 tumor suppressor gene. Several methods have been used to detect chromosome 9p deletions in primary tumors. However, the accurate diagnosis of chromosome 9p deletions has been hampered by the presence of contaminating normal cells. In search of an accurate and sensitive diagnostic method, we have developed the real-time polymerase chain reaction assay using the TaqMan chemistry for quantitative detection of MTAP and p16 gene deletions. The assay's feasibility was tested with peripheral blood leukocytes (PBL) from 29 patients with adult T cell leukemia (ATL) previously analyzed with Southern blot analysis and validated on 39 PBL or bone marrow samples from childhood T cell acute lymphoblastic leukemia (T-ALL). Homozygous deletions of MTAP and p16 genes were detected respectively in six (20.7%) and eight (27.6%) of 29 ATL samples and in 15 (38.5%) and 23 (59%) of 39 T-ALL samples. The results correlated well with those of Southern blot analysis. It is of significance that the newly developed method can successfully detect homozygous deletions of these genes in samples containing as low as 33% blast cells. This rapid and sensitive method may be useful in searching for candidates for selective therapy targeting MTAP deficiency.

Adult↗
PubMed2000

Specific cell targeting for delivery of toxins into small-cell lung cancer using a streptavidin fusion protein complex.

New modalities of treatment for small-cell lung cancer (SCLC) are needed, because the majority of patients continue to die of disseminated disease despite an initial response to conventional chemotherapy. Abnormal surface expression of the neural-cell adhesion molecule (NCAM) has been noted to be highly associated with SCLC. We examined the ability and efficiency of a streptavidin-Protein A (ST-PA) fusion protein complexed with an anti-NCAM monoclonal antibody (Mab) to transfer biotinylated beta-galactosidase into human SCLC cell lines NCI-H69, NCI-H526, and NCI-H446. When the surface molecule NCAM was targeted with this system, more than 99% of the targeted cells internalized and exhibited beta-galactosidase activity. In addition, we evaluated cytotoxic activity against SCLC lines NCI-H69 and NCI-H526 by efficient delivery of biotinylated glucose oxidase using the same ST-PA/anti-NCAM Mab complex. Cytotoxicity of the transduced cells (SCLC) was 10-fold and 100-fold greater, respectively, than the glucose oxidase control. This system could be widely applied for specific therapy of cancer cells by targeting unique surface molecules (antigens) using the corresponding Mab/ST-PA complex to transfer a variety of effector molecules; e.g., immunotoxic compounds, into target cells with a high degree of efficiency and specificity.

Animals↗
PubMed2000

The choice between Chinese medicine and Western medicine practitioners by Hong Kong adolescents.

A survey of 3,355 Hong Kong adolescent students showed that the prevalence of TCM clinic consultation in a three-month period was 8.6%. Among students who sought doctor consultation in a three-month period, 17.8% consulted a TCM doctor. Students who sought doctor consultation for fall-related injuries were more likely to have consulted TCM doctors only, while those for skin disease were more likely to have consulted both TCM and western doctors. Perceived cost, efficacy, trust of western doctors and socioeconomic factors were not associated with choice of doctor type. Our findings are different from those on Hong Kong adults' use of health care services as reported in other studies.

Adolescent↗
PubMed2000

Chloride channel expression in cultured human fetal RPE cells: response to oxidative stress.

PURPOSE: The human fetal cell line RPE 28 SV4 has been useful for studies of oxidative stress and apoptosis in retinal pigmented epithelium. This cell model is now assessed in functional investigations of chloride channel activity. The study aims to determine the presence of specific chloride channels, including CFTR and ClC channels, to identify the properties of membrane chloride currents and to assess their modulation by hydrogen peroxide, cAMP, and other agents. METHODS: Channel expression was determined using RT-PCR and cDNA cloning and biochemical and immunocytochemical methods. Membrane currents were analyzed using whole-cell, patch-clamp techniques. RESULTS: RT-PCR results confirmed the presence of ClC-5 mRNA, and a full-length clone encoding ClC-3 was isolated from a cDNA library for RPE 28 SV4 cells. Specific staining for CFTR and several ClC channels was detected by immunocytochemistry. Whole-cell chloride currents (under conditions of symmetrical chloride concentrations) averaged 16.9 +/- 3.4 pA/pF (at +100 mV; n = 8), showed outward rectification, and had an anion permeability sequence of Cl(-) > I(-) > cyclamate. Currents were stimulated by cAMP cocktail (250 microM cAMP, 100 microM IBMX, and 25 microM forskolin) and were inhibited by 1 mM DIDS. The oxidative agent hydrogen peroxide (100 microM) decreased the current by 34% +/- 10% (n = 4). CONCLUSIONS. These findings suggest that RPE 28 SV4 cells possess regulated chloride channels including CFTR and members of the ClC chloride channel family. The inhibition of chloride currents by H(2)O(2) suggests that this cell line may be advantageous for studies of chloride channel modulation by oxidative stress.

1-Methyl-3-isobutylxanthine↗
PubMed2000

[Place of value of pelvic lymphadenectomy for treatment of endometrial neoplasms].

OBJECTIVE: To explore the therapeutic value of pelvic lymphadenectomy for endometrial carcinoma. METHODS: One hundred and four cases undergoing pelvic lymphadenectomy were analyzed. Comparisons were carried out between various clinicopathologic factors and incidence of positive node, between 5 years survival rate with pelvic lymphadenectomy and that without pelvic lymphadenectomy. RESULTS: Four point four per cent case with positive node was found in clinical stage I cases. Positive node rate increased with deep myoinvasion and G3, accounting for 37.3% and 37.8% respectively. For clinical stage I and stage II cases, the 5 year survival rate of positive node and negative node was 38.9% and 74.2% respectively, with significant difference (P < 0.005). No significant difference was found between cases with pelvic lymphadenectomy and those without pelvic lymphadenectomy (P > 0.05) in pathologic stage I and stage II cases. CONCLUSIONS: Positive pelvic node is an important prognostic factor in endometrial carcinoma. Pelvic lymphadenectomy can not improve prognosis in early stage patients with endometrial carcinoma. It is not necessary to perform pelvic lymphadenectomy for stage I case, because of low incidence of positive node.

Adult↗
PubMed1999

Cardiac specific overexpression of transglutaminase II (G(h)) results in a unique hypertrophy phenotype independent of phospholipase C activation.

Tissue type transglutaminase (TGII, also known as G(h)) has been considered a multifunctional protein, with both transglutaminase and GTPase activity. The role of the latter function, which is proposed as a coupling mechanism between alpha(1)-adrenergic receptors and phospholipase C (PLC), is not well defined. TGII was overexpressed in transgenic mice in a cardiac specific manner to delineated relevant signaling pathways and their consequences in the heart. Cardiac transglutaminase activity in the highest expressing line was approximately 37-fold greater than in nontransgenic lines. However, in vivo signaling to PLC, as assessed by inositol phosphate turnover in [(3)H]myoinositol organ bath atrial preparations, was not increased in the TGII mice at base line or in response to alpha(1)-adrenergic receptor stimulation; nor was protein kinase Calpha (PKCalpha) or PKCepsilon activity enhanced in the TGII transgenic mice. This is in contrast to mice moderately (approximately 5-fold) overexpressing G(alphaq), where inositol phosphate turnover and PKC activity were found to be clearly enhanced. TGII overexpression resulted in a remodeling of the heart with mild hypertrophy, elevated expression of beta-myosin heavy chain and alpha-skeletal actin genes, and diffuse interstitial fibrosis. Resting ventricular function was depressed, but responsiveness to beta-agonist was not impaired. This set of pathophysiologic findings is distinct from that evoked by overexpression of G(alphaq). We conclude that TGII acts in the heart primarily as a transglutaminase, and modulation of this function results in unique pathologic sequelae. Evidence for TGII acting as a G-protein-like transducer of receptor signaling to PLC in the heart is not supported by these studies.

Animals↗
PubMed1999

Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1.

Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS domain transcription factor that mediates changes in gene expression in response to changes in O2 concentration. Genes that are transcriptionally activated by HIF-1 in hypoxic cells encode proteins that increase O2 delivery or allow metabolic adaptation to limited O2 availability. HIF-1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF-1 and VEGF. Expression of HIF-1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O2-regulated HIF-1 alpha subunit. Mouse embryos lacking HIF-1 alpha expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF-1 functions as a master regulator of O2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.

Animals↗
PubMed1999

Effects of high pressure and temperature on the wild-type and F29W mutant forms of the N-domain of avian troponin C.

The N-domain of troponin C (residues 1-90) regulates muscle contraction through conformational changes induced by Ca2+ binding. A mutant form of the isolated domain of avian troponin C (F29W) has been used in previous studies to observe conformational changes that occur upon Ca2+ binding, and pressure and temperature changes. Here we set out to determine whether the point mutation itself has any effects on the protein structure and its stability to pressure and temperature in the absence of Ca2+. Molecular dynamics simulations of the wild-type and mutant protein structures suggested that both structures are identical except in the main chain and the loop I region near the mutation site. Also, the simulations proposed that an additional cavity had been created in the core of the mutant protein. To determine whether such a cavity would affect the behavior of the protein when subjected to high pressures and temperatures, we performed 1H-NMR experiments at 300, 400, and 500 MHz on the wild-type and F29W mutant forms of the chicken N-domain troponin C in the absence of Ca2+. We found that the mutant protein at 5 kbar pressures had a destabilized beta-sheet between the Ca2+-binding loops, an altered environment near Phe-26, and reduced local motions of Phe-26 and Phe-75 in the core of the protein, probably due to a higher compressibility of the mutant. Under the same pressure conditions, the wild-type domain exhibited little change. Furthermore, the hydrophobic core of the mutant protein denatured at temperatures above 47 degrees C, while the wild-type was resistant to denaturation up to 56 degrees C. This suggests that the partially exposed surface mutation (F29W) significantly destabilizes the N-domain of troponin C by altering the packing and dynamics of the hydrophobic core.

Animals↗
PubMed1999

Coexpression of the adenovirus 12 E1B 55 kDa oncoprotein and cellular tumor suppressor p53 is sufficient to induce metaphase fragility of the human RNU2 locus.

Adenovirus 12 (Ad12), but not adenovirus 2 or 5, induces metaphase chromosome fragility at four specific loci in humans: RNU1, RNU2, PSU1, and RN5S. As each of these sites corresponds to a tandemly repeated multigene family encoding a small, abundant structural RNA, we proposed that Ad12 hinders metaphase chromatin condensation, interfering either directly or indirectly with transcriptional regulation or chromatin packing of these small RNA genes. We and others subsequently found that Ad12-induced fragility of the RNU2 locus requires U2 promoter elements, viral early functions, and p53. We now show that RNU2 fragility can be induced by transfection with an expression vector encoding Ad12 E1B 55 kDa alone but not by an E1 vector encoding all E1 products (3 E1A proteins, as well as the E1B 19 kDa and 55 kDa proteins). Although Ad12 E1B 55 kDa efficiently induced fragility in transfected cells, Ad2 E1B 55 kDa did not. By swapping domains between the Ad12 and Ad2 E1B, we found that the aminoterminus of Ad12 E1B is required for induction of fragility and that the ability of the hybrid E1B proteins to induce fragility appears to correlate with nuclear localization. Furthermore, in Saos-2 cells lacking p53 function, RNU2 fragility could be induced by cotransfection with vectors encoding Ad12 E1B 55 kDa and either wild-type p53 or the R273H mutant with impaired DNA binding activity. We conclude that a functional (and probably physical) interaction between Ad12 E1B 55 kDa and p53 within the nucleus is sufficient to induce metaphase fragility of the RNU2 locus.

Adenovirus E1B Proteins↗
PubMed1999

Prevalence and correlates of physical abuse in Hong Kong Chinese adolescents: a population-based approach.

OBJECTIVE: The objectives were to estimate the prevalence and correlates of physical abuse-related outcomes in the family setting in Hong Kong's adolescent population. METHOD: A cross-sectional study design was used. A randomly selected sample of 3,355 secondary school students in Kwai Tsing District of Hong Kong was surveyed. The response rate was 98%. RESULTS: The prevalence rates of corporal punishment, being beaten by parents for no apparent reason, being beaten to injury by family members in the past 3 months and any one of the above three were 4.9% (95% CI, 4.2% to 5.6%), 2.0% (95% CI, 1.5% to 2.5%), 1.1% (95% CI, .98% to 1.2%) and 6.6% (95% CI, 5.7% to 7.5%), respectively. Students who had experienced the above physical abuse-related outcomes were at a significant disadvantage for a wide range of morbidity indicators, including self-perceived bad health, anxiety and stress, somatic illnesses (such as asthma and epigastric pain), injuries and accidents, and hospitalization. They were more likely to have poor familial relations and coping skills, and to take up habits which potentially put their health at risk, such as smoking, alcohol consumption, and fighting with others. CONCLUSIONS: Our prevalence estimates of physical abuse in the family setting for a student population in Hong Kong is an improvement over previous local estimates of physical abuse occurrence, which were mainly based on case notifications and clinical samples. The results also show that the abused adolescents are growing up in an environment filled with physical, psychological, and familial adversities.

Adaptation, Psychological↗
PubMed1999

Conceptualization, reporting and underreporting of child abuse in Hong Kong.

OBJECTIVE: To understand the conceptualization of child abuse and attitudes on reporting behaviors of Hong Kong adults. METHODS: Cross-sectional telephone survey of 1,001 randomly selected subjects. MAIN RESULTS: There is a discrepancy between perceived prevalence and the ability to name different child abuse types without prompting: 79.9% named physical abuse, while 41.2% felt it was common: 21.0% named child neglect, while 76.9% felt it was common; 13.4% named psychological abuse, while 47.4% felt it was common; 6.8% named sexual abuse, while 23.5% felt it was common. Most respondents classified severe physical abuse situations as abusive (e.g., "severely injuring a child"). Other scenarios such as "mildly injuring a child" and neglect and psychological abuse scenarios (e.g., "leaving a young child alone at home" and "shouting at a child often") were often not classified as abusive. As regards case-reporting behavior, only about 40% would report abuse cases to authorities. Those who would not report abuse were less likely to classify abuse situations as abusive and more likely to think that seeking help is difficult, troublesome and unhelpful. CONCLUSIONS: The official reported prevalence figures for child abuse in Hong Kong should be interpreted with care, because underreporting is likely to be serious. Hong Kong people's conceptualization and awareness of what comprises child abuse is found to differ from official definitions. They are reluctant to report abuse cases, due to their perceived low efficacy of case reporting. Both the difference in conceptualization and the reluctance to report might partly be attributable to Chinese culture.

Adolescent↗
PubMed1999

Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study.

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25,000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50,000/microl or patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.

Adolescent↗