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Biomedical subjects

A Cheung

Publications and source records attributed to A Cheung.

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

Brca1 required for T cell lineage development but not TCR loci rearrangement.

Brca1 (breast cancerl, early onset) deficiency results in early embryonic lethality. As Brca1 is highly expressed in the T cell lineage, a T cell-specific disruption of Brca1 was generated to assess the role of Brca1 in relation to T lymphocyte development. We found that thymocyte development in Brca1-/- mice was impaired not as a result of V(D)J T cell receptor (TCR) recombination but because thymocytes had increased expression of tumor protein p53. Chromosomal damage accumulation and abnormal cell death were observed in mutant cells. We found that cell death inhibitor Bcl-2 overexpression, or p53-/- backgrounds, completely restored survival and development of Brca1-/- thymocytes; peripheral T cell numbers were not totally restored in Brcal-/- p53-/- mice; and that a mutant background for p21 (cyclin-dependent kinase inhibitor 1A) did not restore Brca1-/- thymocyte development, but partially restored peripheral T cell development. Thus, the outcome of Brca1 deficiency was dependent on cellular context, with the major defects being increased apoptosis in thymocytes, and defective proliferation in peripheral T cells.

Animals↗
PubMed2000

Agr-independent regulation of fibronectin-binding protein(s) by the regulatory locus sar in Staphylococcus aureus.

Fibronectin-binding proteins (FnBPs) are thought to be important for the attachment of Staphylococcus aureus during infection. The regulation of the genes fnbA and fnbB by the global regulatory loci sar and agr was examined using site-specific regulatory mutants of S. aureus strain Newman. The results from binding assays using both aqueous and solid-phase fibronectin as well as ligand blotting with biotinylated fibronectin showed that the expression of FnBPA is enhanced in the agr mutant but inhibited in the sar mutant and the sar-agr double mutant. The same regulatory pattern was observed in Northern blot analysis using fnbA-specific probes. The introduction of sar on a multicopy plasmid increased the already enhanced fnbA transcription of the agr mutant. FnBPB was not detectable by ligand blotting and the fnbB promoter activity in promoter fusion assays was not affected by either sar or agr. The sequence encompassing ORF3 located upstream of sarA was found to be essential for the activation of fnbA transcription. We hypothesize that this sequence may modulate SarA expression and/or activity on the post-transcriptional level. Gel shift assays demonstrated that SarA binds to the fnbA promoter fragments, probably as a dimer. DNase I footprinting assays with SarA revealed a protected area of 102 bp upstream of fnbA.

Adhesins, Bacterial↗
PubMed2000

The ability to generate normal Ca(2+) transients in response to spermatozoa develops during the final stages of oocyte growth and maturation.

Intracellular Ca(2+) oscillations at fertilization are responsible for triggering egg activation. The aim of this study was to examine the effect of the age of the oocyte donor and in-vitro maturation on the generation of Ca(2+) transients at fertilization. The results show that <10% of in-vivo and in-vitro matured oocytes from 19-day old mice develop to the blastocyst stage in vitro. In contrast, 43% of in-vivo and 25% of in-vitro matured oocytes from 24-day old mice developed to the blastocyst stage. In parallel experiments, intracellular Ca(2+) was monitored at fertilization. Oocytes from 19-day old mice generate significantly fewer transients than oocytes from 24-day old mice. In-vitro maturation significantly decreased the ability of oocytes from 19-day old mice but not 24-day old mice to generate Ca(2+) transients in response to spermatozoa. Furthermore, we investigated the effect of oocyte maturation on Ca(2+) signalling. Immature oocytes generated fewer Ca(2+) oscillations and ceased oscillating earlier than mature oocytes. These studies suggest that the ability to generate Ca(2+) transients in response to spermatozoa increases in the final stages of oocyte development and during oocyte maturation. This may contribute to the acquisition of developmental competence in the final stages of oogenesis.

Aging↗
PubMed2000

The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.

UNLABELLED: We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia. IMPLICATIONS: The alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.

Adrenergic alpha-Agonists↗
PubMed1999

Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus.

Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it has recently been reported that PTP-1B may play a role in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (DM). We therefore determined the amount and activity of PTP-1B in abdominal adipose tissue obtained from lean nondiabetic subjects (lean control (LC)), obese nondiabetic subjects (obese control (OC)), and subjects with both type 2 DM (DM2) and obesity (obese diabetic (OD)). PTP-1B protein levels were 3-fold higher in OC than in LC (1444 +/- 195 U vs 500 +/- 146 U (mean +/- SEM), P < .015), while OD exhibited a 5.5-fold increase (2728 +/- 286 U, P < .01). PTP activity was assayed by measuring the dephosphorylating activity toward a phosphorus 32-labeled synthetic dodecapeptide. In contrast to the increased PTP-1B protein levels, PTP-1B activity per unit of PTP-1B protein was markedly reduced, by 71% and 88% in OC and OD, respectively. Non-PTP-1B tyrosine phosphatase activity was comparable in all three groups. Similar results were obtained when PTP-1B activity was measured against intact human IR. A significant correlation was found between body mass index (BMI) and PTP-1B level (r = 0.672, P < .02), whereas BMI and PTP-1B activity per unit of PTP-1B showed a strong inverse correlation (r = -0.801, P < .002). These data suggest that the insulin resistance of obesity and DM2 is characterized by the increased expression of a catalytically impaired PTP-1B in adipose tissue and that impaired PTP-1B activity may be pathogenic for insulin resistance in these conditions.

Adipose Tissue↗
PubMed1999

Peptidergic innervation of the human clitoris.

In the present study, the distributions of neuropeptides in the normal human clitoris and in a clitoris from an adrenogenital syndrome (AGS) was demonstrated by immunohistochemistry (IHC). Immunohistochemical screening detected a complex network of nerve fibers containing vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), neuropeptide tyrosine (neuropeptide Y), C-flanking peptide of neuropeptide Y (CPON), calcitonin gene-related peptide (CGRP) and substance P immunoreactivities. Special attention was given to the VIP-related peptide helospectin, that has been detected in neuronal elements in the clitoris. No visible differences between the localization and distribution of peptidergic nerve fibers of normal and hypertrophic clitoris from AGS have been observed. Co-localization studies showed the co-existence of VIP, PHM and partly helospectin and neuropeptide Y with CPON within nerve fibers in the cavernous tissue and substance P and CGRP co-expression in nerve fibers especially underneath and within the glans clitoris.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Collision of endometrioid carcinoma and stromal sarcoma of the uterus: a report of two cases.

Two uterine collision tumors are reported, one in an 85-year-old woman and the other in a 47-year-old woman. Each tumor was composed of a smaller grade 1 endometrioid adenocarcinoma that was distinct from a larger component of high-grade stromal sarcoma. The separate components in these tumors could be detected on gross, microscopic, and immunohistochemical studies. The clinicopathologic features and indolent behavior of these tumors suggest that they should be distinguished from malignant mullerian mixed tumors.

Aged↗
PubMed1999

Platelet-erythrocyte adhesion in sickle cell disease.

BACKGROUND: The abnormal adherence of sickle red blood cells (sRBC) to other cell types likely contributes to vaso-occlusion. Increased numbers of platelet-erythrocyte aggregates (PEA) and platelet activation have been described in sickle cell disease. The present study was undertaken to determine the contribution, if any, of the extracellular matrix protein thrombospondin to the adhesion of sRBC and platelets. METHODS: Platelet activation and PEA were measured using fluorescent-labeled monoclonal antibodies and flow cytometry. Platelet red-cell adhesion was measured by a gravity sedimentation assay. Erythrocyte-bound thrombospondin (TSP) was determined by enzyme-linked immunoabsorbant assay (ELISA). RESULTS: Our studies demonstrate significant platelet activation and adhesion of sRBC to platelets in sickle cell disease. Thrombospondin was detected on sRBC. There was variable inhibition of sRBC-platelet adhesion by antibodies to CD36 (thrombospondin receptor) and antibodies to thrombospondin. CONCLUSIONS: Thrombospondin on sRBC may mediate, at least in part, sRBC-platelet adhesion in sickle cell disease. The study of heterotypic cell-cell interactions is important in understanding the pathogenesis of vaso-occlusion in sickle cell disease.

Antibodies, Monoclonal↗
PubMed1998

Sympathetic neuromuscular transmission at a varicosity in a syncytium.

The autonomic neuromuscular junction at a varicosity in the vas deferens is defined by the localization of the vesicle-associated protein syntaxin in high concentrations in the axolemma and a high density of P2x1 receptors in a cluster beneath the varicosity. Calcium fluxes have been observed in all individual varicosities of a nerve terminal on the arrival of an impulse even though recordings made from these varicosities of the electrical signs of transmission with loose-patch electrodes over the varicosities show that they have very different probabilities for the secretion of a quantum. The fact that some varicosities seldom release a quantum on the arrival of an impulse is supported by the observation that antibodies against the N-terminus of synaptotagmin, which uniquely label the inside of synaptic vesicles when they undergo exocytosis, fail to do so in some varicosities during nerve stimulation whereas they do in others. It is suggested that the probability for secretion from a varicosity depends on the number of secretosomes that the varicosity possesses, where a secretosome is a complex of syntaxin, synaptotagmin, an N-type calcium channel, and a synaptic vesicle.

Animals↗
PubMed1998

Preemptive epidural analgesia and recovery from radical prostatectomy: a randomized controlled trial.

CONTEXT: Preemptive analgesia can decrease the sensitization of the central nervous system that would ordinarily amplify subsequent nociceptive input, but a clear demonstration of its clinical efficacy is necessary for it to become a routine component of acute pain therapy. OBJECTIVE: To determine the impact of preemptive epidural analgesia on postoperative pain and other clinically important outcome variables after radical retropubic prostatectomy. DESIGN AND SETTING: A block randomized double-blind clinical trial lasting 20 months at a single academic medical center. PATIENTS: A total of 100 generally healthy and neurologically intact patients scheduled for radical retropubic prostatectomy for the treatment of prostate cancer in whom an epidural catheter for treating postoperative pain was to be placed prior to the induction of general anesthesia. INTERVENTIONS: Epidural bupivacaine, epidural fentanyl, or no epidural drug was administered prior to induction of anesthesia and throughout the entire operation, followed by aggressive postoperative epidural analgesia for all patients. MAIN OUTCOME MEASURES: Daily pain scores during hospitalization and pain scores obtained 3.5, 5.5, and 9.5 weeks after hospital discharge. RESULTS: The patients who received epidural fentanyl or bupivacaine prior to surgical incision (preemptive analgesia) experienced 33% less pain while hospitalized (P=.007). Pain scores in those receiving preemptive analgesia were significantly lower at 9.5 weeks (P=.02), but were not significantly different at 3.5 or 5.5 weeks. At 9.5 weeks, 32 (86%) of 37 patients receiving preemptive analgesia were pain-free compared with 9 (47%) of 19 control patients (P=.004). Patients receiving preemptive analgesia were more active 3.5 weeks after surgery (P=.01), but not at 5.5 or 9.5 weeks. CONCLUSIONS: Even in the presence of aggressive postoperative pain management, preemptive epidural analgesia significantly decreases postoperative pain during hospitalization and long after discharge, and is associated with increased activity levels after discharge.

Aged↗
PubMed1998

The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo.

Mutations in the SMAD4/DPC4 tumor suppressor gene, a key signal transducer in most TGFbeta-related pathways, are involved in 50% of pancreatic cancers. Homozygous Smad4 mutant mice die before day 7.5 of embryogenesis. Mutant embryos have reduced size, fail to gastrulate or express a mesodermal marker, and show abnormal visceral endoderm development. Growth retardation of the Smad4-deficient embryos results from reduced cell proliferation rather than increased apoptosis. Aggregation of mutant Smad4 ES cells with wild-type tetraploid morulae rescues the gastrulation defect. These results indicate that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non-cell autonomous. Rescued embryos show severe anterior truncations, indicating a second important role for Smad4 in anterior patterning during embryogenesis.

Alleles↗
PubMed1998

Platelet activation in patients with sickle cell disease.

Vascular occlusion and vasculopathy underlie much of the morbidity in patients with sickle cell anaemia. Platelets may play a role in this vasculopathy. Samples from 43 patients with sickle cell disease (SCD) were examined for evidence of platelet activation using fluorescent-labelled monoclonal antibodies and flow cytometry. There was increased expression of activation-dependent antigens on the platelets from patients with SCD compared to those from both Caucasian and African-American controls. In addition, SCD patients had increased levels of platelet microparticles. Platelets are activated in patients with sickle cell disease. The contribution of platelet activation to sickle cell pathophysiology is under active investigation in our laboratories.

Adolescent↗
PubMed1998

Impact of vision impairment on functioning.

PURPOSE: The aim of the present study was to determine the impact of vision loss on the activities of adults. METHODS: Focus groups were conducted that were either disease specific, such as for people with age-related macular degeneration, diabetic retinopathy, glaucoma or those with congenital vision impairment, or according to previous involvement in rehabilitation services. Discussions were recorded and transcribed. Because many people were retired, leisure activities and personal independence were paramount. RESULTS/CONCLUSIONS: Younger people were concerned with gaining or continuing in employment or with educational opportunities. The age at onset of vision loss and the cause and duration of vision loss influence its impact. There appears to be a greater level of handicap in people with comorbid eye disease and related disease, such as diabetes.

Activities of Daily Living↗
PubMed1997

Altered phosphorylation of a 91-kDa protein in particulate fractions of rat kidney after protracted 1,25-dihydroxyvitamin D3 or estrogen treatment.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] treatment in vitamin D-deficient (-D) rats results in a dose-dependent decrease in phosphorylation of a 91-kDa protein (PP-D91) in particulate fractions of the kidney. This recently reported 1,25(OH)2D3 effect was examined in detail herein. In contrast to the pattern expected of a rapid signal transduction event, time course (4 h-7 days) experiments demonstrated that PP-D91 phosphorylation was not decreased until 3-5 days 1,25(OH)2D3 treatment, resulting in a 61 +/- 3% (P < 0.01, n = 3) decrease in PP-D91 phosphorylation by 7 days. These effects paralleled increases in plasma calcium from 9.3 +/- 0.6 to 13.9 +/- 0.7 mg/dl after 0 vs 7 days 1,25(OH)2D3 treatment, respectively. Subcellular fractionation demonstrated that the renal PP-D91 was predominantly localized and 1,25(OH)2D3-regulated in crude mitochondrial and microsomal fractions. Further, PP-D91 was present and 1,25(OH)2D3-regulated in enriched preparations of both proximal and distal renal tubule segments. Tissue distribution studies demonstrated that the PP-D91 was predominantly present and 1,25(OH)2D3 regulated in the kidney, although low levels of a vitamin D-independent phosphorylated band of similar size were observed in the lung and heart. In contrast to 1,25(OH)2D3, estradiol-17B treatment (1 mg/day x 7 day) significantly (P < 0.01) increased PP-D91 phosphorylation in kidney of both -D and +D rats (increased 118.5 +/- 10.6 and 81.9 +/- 6.3%, respectively). Phosphoamino acid analysis after PP-D91 phosphorylation, isolation, and proteolysis indicated that these hormones alter 32P incorporation into phosphoserine residues. In conclusion, the 1,25(OH)2D3 effect to reduce PP-D91 phosphorylation in particulate fractions of the rat kidney is a protracted, tissue-specific effect which parallels elevated plasma calcium levels in this model. Moreover, renal PP-D91 phosphorylation is differentially regulated by 1,25(OH)2D3 vs E2 treatment and occurs on phosphoserine residues. The parallel between decreased PP-D91 phosphorylation and 1,25(OH)2D3-induced hypercalcemia may suggest a role for PP-D91 in the renal response to hypervitaminosis D.

Animals↗
PubMed1997

Insertional inactivation of streptolysin S expression is associated with altered riboflavin metabolism in Streptococcus pyogenes.

Transposon Tn916 mutagenesis was used to create a mutant of Streptococcus pyogenes M type 3, designated ISS417, in which the ability to produce streptolysin S (SLS) and several other exoproteins was impaired. Concomitantly, the mutant became dependent upon riboflavin for growth and was able to grow in Todd Hewitt broth (THB) when supplemented with riboflavin or riboflavinrich yeast extract. The parent strain was apparently able to utilize THB-derived components as a substitute for riboflavin, while the mutant was not. Although the parent strain grew well in synthetic medium, it was unable to produce SLS, except when it was supplemented with a small amount of THB. Thus, a component of THB was able to "trigger" SLS formation in the parent strain. The mutant grew well in this medium, but was unable to produce SLS even when it was supplemented with THB. Southern hybridization analysis revealed that the ISS417 mutant harbours a single transposon insertion in its chromosome. Phage transduction experiments showed that the riboflavin dependency and the inability to make SLS phenotypes are co-transducible. The pleotrophic properties of the ISS417 mutant differ from those reported for insertional inactivation of the mga locus which regulates production of a number of surface proteins in S. pyogenes and the sar locus which regulates production of a number of exoproteins in Staphylococcus aureus. In view of the possibility that there exist a genetic linkage between the riboflavin biosynthetic pathway and expression of the oxygen-stable SLS, we hypothesize that SLS has a role in the growth economy of S. pyogenes.

Bacterial Proteins↗
PubMed1997

Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia.

Vascular occlusion and vasculopathy underlie much of the morbidity in patients with sickle cell anemia. Platelets may play a role in this vasculopathy. Samples from 12 adults patients with sickle cell anemia were examined for evidence of platelet activation and formation of platelet-erythrocyte aggregates (PEA) using fluorescent-labeled monoclonal antibodies and flow cytometry. We noted an increased expression of activation-dependent antigens on the platelets from patients with sickle cell anemia compared with those from both white and black control subjects. In addition, patients with sickle cell anemia had increased levels of platelet microparticles and PEA. Platelets are activated in patients with sickle cell anemia and they adhere to sickle erythrocytes. The significance of this activation and adherence are the subject of further investigation.

Adolescent↗