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Biomedical subjects

A Wong

Publications and source records attributed to A Wong.

At least 19 recordsLinked to original sources
PubMed1996

Post-prostatectomy incontinence: urodynamic findings and treatment outcomes.

PURPOSE: We examined urodynamic findings and treatment outcomes in a large population of men with post-prostatectomy incontinence. MATERIALS AND METHODS: A total of 215 men was referred for evaluation and treatment of significant post-prostatectomy incontinence. Urodynamic evaluation consisted of provocation multichannel medium fill cystometry with vigorous attempts to demonstrate incontinence. Treatment was directed by the results of the urodynamic study. A pad scoring system was used to gauge the severity of incontinence before and after treatment. RESULTS: Based on the results of urodynamic studies 40% of the men had genuine stress incontinence alone and approximately 60% had a major component of bladder dysfunction contributing to incontinence. Treatment results of 135 men demonstrated a significant decrease in pad score (p<0.001) for those treated with anticholinergics, those undergoing artificial sphincter insertion and those treated pharmacologically before sphincter placement. CONCLUSIONS: In our large series most men with prostatectomy incontinence did not have genuine stress incontinence alone. Thus, urodynamic studies are critical, not only to define cause of incontinence but to direct effective therapy.

Aged↗
PubMed1995

Granulocyte-macrophage colony-stimulating factor induces the transcriptional activation of egr-1 through a protein kinase A-independent signaling pathway.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) rapidly and transiently induces the transcriptional activation of the early growth response gene-1 (egr-1) in the human factor-dependent myeloid leukemic cell line, TF-1. We previously demonstrated that the cAMP response element (CRE) is required for GM-CSF-induced egr-1 expression and that phosphorylation of CREB on serine 133 plays a critical role during GM-CSF signal transduction. To determine whether GM-CSF activates signaling pathways through a protein kinase A-dependent or -independent pathway, we measured cAMP levels following GM-CSF or forskolin treatment of TF-1 cells. Forskolin but not GM-CSF stimulation resulted in an increase in cAMP levels. Transient transfection assays with TF-1 cells were also performed with a -116-nucleotide egr-1 promoter construct and the protein kinase inhibitor, PKI. Although PKI inhibited forskolin induction of the -116-nucleotide construct, it did not affect GM-CSF stimulation of this construct. In the present study, we demonstrated that GM-CSF induces egr-1 expression through a protein kinase A-independent pathway.

Cell Line↗
PubMed1995

Low-molecular-weight heparin for the treatment of acute ischemic stroke.

BACKGROUND: Despite doubts about their efficacy and concern about their safety, antithrombotic agents are often used to treat acute ischemic stroke. Recent experience in patients with other thromboembolic disorders suggests that low-molecular-weight heparin, which requires only subcutaneous administration once or twice daily, may be more effective and safer than standard (unfractionated) heparin. METHODS: We conducted a randomized, double-blind, placebo-controlled trial comparing two dosages of low-molecular-weight heparin with placebo in the treatment of ischemic stroke. Patients were randomly assigned within 48 hours of the onset of symptoms to receive high-dose nadroparin (4100 anti-factor Xa IU twice daily), low-dose nadroparin (4100 IU once daily), or placebo subcutaneously for 10 days. The primary measure of outcome was death or dependency regarding activities of daily living six months after randomization. Secondary outcomes were death, hemorrhagic transformation of the infarction, and other complications at 10 days, and death or dependency at 3 months. RESULTS: A total of 2750 patients were screened for the study. Among 312 patients randomized, 306 had outcomes that were analyzed at six months. Forty-five patients (45 percent) in the high-dose group, 53 patients (52 percent) in the low-dose group, and 68 patients (65 percent) in the placebo group died or became dependent. There was a significant dose-dependent effect among the three study groups in favor of low-molecular-weight heparin (P = 0.005 by the chi-square test for trend). No significant differences among the groups in the occurrence of secondary outcomes were observed at 10 days. CONCLUSIONS: For patients with ischemic stroke treated within 48 hours of the onset of symptoms, low-molecular-weight heparin was effective in improving outcomes at six months.

Activities of Daily Living↗
PubMed1995

Procoagulant activity of reversibly acylated human factor Xa.

The plasma clotting factors used to treat hemophiliacs who have developed inhibitory antibodies have a shared history of limited clinical safety and utility. To improve on existing bypass factors, we have developed a reversibly acylated form of human plasma factor Xa capable of providing a time-dependent release of procoagulant activity. Factor Xa was treated with p-amidinophenyl p'-anisate to generate anisoyl Xa. The chemical modification of the protein involves acylation of the active site serine residue of factor Xa. Anisoyl Xa deacylated in a time, pH, and temperature-dependent manner. Active factor Xa generated on deacylation of anisoyl Xa exhibited amidolytic and prothrombinase complex activities in in vitro assays, the level being comparable to those of untreated factor Xa. When Anisoyl Xa was infused into rabbits, active factor Xa was generated on deacylation of the acylated enzyme, which shortened the activated partial thromboplastin time (APTT) in a dose-dependent manner. The duration of effect on rabbit APTT could be directly correlated to the level of human plasma factor Xa. Because anisoyl Xa bypasses the "tenase" complex that is compromised in hemophilia A and B and is unaffected by inhibitory antibodies, it has the potential to be used as an effective bypass therapy.

Acylation↗
PubMed1995

Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung tumors.

The murine Unp proto-oncogene encodes a nuclear ubiquitin protease whose overexpression leads to oncogenic transformation of NIH3T3 cells. We have cloned cDNAs originating from the human homolog of this gene, designated herein as Unph (Unp, human), and have used these cDNAs to map the gene to 3p21.3, a region frequently rearranged in human tumor cells. Unph mRNA levels are consistently elevated in small cell tumors and adenocarcinomas of the lung, suggesting a possible causative role for the gene in the neoplastic process.

3T3 Cells↗
PubMed1995

Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus.

In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P < 0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

Adult↗
PubMed1995

Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing.

We have identified three allelic, maternal-effect mutations that affect developmental and behavioral timing in Caenorhabditis elegans. They result in a mean lengthening of embryonic and postembryonic development, the cell cycle period and life span, as well as the periods of the defecation, swimming and pumping cycles. These mutants also display a number of additional phenotypes related to timing. For example, the variability in the length of embryonic development is several times larger in the mutants than in the wild type, resulting in the occasional production of mutant embryos developing more rapidly than the most rapidly developing wild-type embryos. In addition, the duration of embryonic development of the mutants, but not of the wild type, depends on the temperature at which their parents were raised. Finally, individual variations in the severity of distinct mutant phenotypes are correlated in a counterintuitive way. For example, the animals with the shortest embryonic development have the longest defecation cycle and those with the longest embryonic development have the shortest defecation cycle. Most of the features affected by these mutations are believed to be controlled by biological clocks, and we therefore call the gene defined by these mutations clk-1, for "abnormal function of biological clocks."

Alleles↗
PubMed1995

Identification of hepatitis C virus genotypes among hospitalized patients in British Columbia, Canada.

The distribution pattern of hepatitis C virus (HCV) genotypes among patients from British Columbia has been investigated by reverse transcription polymerase chain reaction (PCR) amplification of the 5' noncoding region (NCR) and direct DNA sequencing of the PCR product. The sequence data obtained from the British Columbia isolates were compared with HCV sequences for the NCR obtained from GenBank for the construction of a phylogenetic tree using the GDE program, version 2.2. The data show that in British Columbia there are 7 subtypes distributed among major genotypes 1, 2, and 3. The study also shows a new subtype of genotype 1 that represents 29% of the analyzed cases.

Base Sequence↗
PubMed1995

A subgroup of human VH3 germline genes that encode a high-avidity synovial rheumatoid factor.

We have previously derived and identified a highly avid monoclonal IgM rheumatoid factor (mRF), C6, from unstimulated rheumatoid synovial cells (RSC). At the time, the closet VH germline gene, VH26, demonstrated only 88% homology with C6. To identify the germline counterpart of C6, genomic DNA from the same rheumatoid arthritis (RA) patient from whom C6 was derived was used in the polymerase chain reaction (PCR). Four of the six closely related germline genes that we sequenced had exonic regions that were identical with the VH region of C6 cDNA. These six germline sequences differed in their intronic regions, suggesting that they were distinct, but closely related genomic sequences. To further evaluate the extent of these related genes we identified nine additional germline genes having VH-encoding exons that were 86-97% identical to the C6 cDNA sequence. Furthermore, we examined the polymorphic nature of the C6 VH gene using single strand conformation polymorphism (SSCP), and identified two peaks, confirming the existence of highly homologous genes. The sequence and polymorphism data suggest that: (1) the VH region of the high avidity mRF C6 was derived from an unmutated germline gene; (2) C6 was encoded by a VH gene belonging to a set of homologous genes within the larger VH3 family; and (3) in addition to somatic rearrangements of B-cell genes and antigen-driven somatic mutation, gene duplication and conversion events of germline genes could be important in generating diversity and polyclonality among high-affinity pathogenic autoantibodies.

Amino Acid Sequence↗
PubMed1994

Identification of a novel thrombin receptor sequence required for activation-dependent responses.

Thrombin receptor (TR) activation by alpha-thrombin requires proteolytic cleavage, although synthetic peptides modeled after the new N-terminus directly effect receptor activation without cleavage, presumably by interacting with an unidentified region of the receptor. To further define critical residues responsible for receptor activation, we performed epitope mapping of anti-TR1-160, a previously described polyclonal antibody that inhibits peptide ligand-induced receptor activation in various cell types expressing a functional TR. An enzyme-linked immunosorbent assay (ELISA) using overlapping decapeptides derived from the TR extracellular domains identified four immunodominant peaks within the long N-terminal extension centered between amino acids 34-44, 48-67, 65-79, and 87-94. Soluble peptides derived from regions 83-94, but not those from other regions of the receptor, neutralized the ability of anti-TR1-160 to inhibit peptide ligand-induced platelet aggregation, suggesting that antibodies directed against this region of the TR are important in ligand-mediated activation. Thrombin receptor mutants lacking discrete regions of the TR were subsequently evaluated using microinjected Xenopus oocytes. Whereas a TR mutant lacking amino acid residues Thr67-Lys82 (TR delta 67-82) showed normal to exaggerated responses to either alpha-thrombin or synthetic peptide ligands, only TR mutants with limited deletions spanning the residues Gln83-Ser93 exhibited dysfunctional responses to either agonist (200 nmol/L alpha-thrombin or 200 mumol/L TR42-47). These data provide a model for receptor activation that implicates a discrete and previously uncharacterized sequence within the TR N-terminal extension that is necessary for initiation of signal transduction events independent of the initiating agonist.

Amino Acid Sequence↗
PubMed1994

Cloning, sequencing and disruption of a gene from Streptomyces clavuligerus involved in clavulanic acid biosynthesis.

During the purification of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase (ACVS) from Streptomyces clavuligerus, a small protein (CLA) involved in clavulanic acid production co-purified with ACVS. A 24-mer mixed-DNA probe based on the N-terminal amino-acid sequence of CLA was used to isolate the corresponding gene (cla), located near one end of the known cluster of penicillin and cephamycin biosynthetic genes, 5.7 kb downstream from the pcbC gene which encodes isopenicillin-N synthase. The sequence of cla would encode a protein of 313 aa with a high degree of similarity to amidinohydrolase enzymes. The cla gene is located immediately upstream from the previously described clavaminate synthase 2-encoding gene (cs2), and cla homologs were only present in streptomycetes which produced clavam compounds. Replacement of cla with a disrupted copy of the gene blocked the production of clavulanic acid in starch asparagine medium (SA).

Amino Acid Sequence↗
PubMed1994

Preferential utilization of a novel V lambda 3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients.

OBJECTIVE: To further our understanding about the molecular genetics of rheumatoid factor (RF) in rheumatoid arthritis (RA). METHODS: The heavy and light chain variable region (V) genes of 5 new human monoclonal IgM RFs were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide termination method. RESULTS: The results reveal the recurrent usage in two RA patients of a novel V lambda 3 germline gene, designated Humlv3c93. Specifically, in 2 of 3 RFs (C93 and D53) from one patient, the light chains in the V lambda gene-encoded region were identical to each other and to the light chain of an RF (H4) from another patient. Serologically, the light chains of these 3 RFs were classified as members of the V lambda 3b sub-subgroup. Each of the RFs was encoded by a different VH gene. Both C93 and D53 bound specifically with human and rabbit IgG, whereas H4 was monospecific for rabbit IgG. CONCLUSION: Since the lv3c93 gene is not homologous to any reported V lambda sequence from natural autoantibodies, it is possible that lv3c93 may represent a disease-specific RF-related V lambda gene. Moreover, the amino acid sequence CSGGSCY in the third complementarity-determining regions of 2 of the RF heavy chains is encoded by the DLR2 gene segment and has been found previously in 2 other RA-derived RFs, and thus may play a significant role in antigen binding.

Amino Acid Sequence↗
PubMed1994

Outcome after temporary vascular occlusion for the management of renal trauma.

To determine the impact of temporary vascular occlusion on patient outcome after surgery for renal trauma, we reviewed the records of 30 patients managed since 1977 whose injuries represented 17% of a total of 181 injuries in 175 patients. Reconstruction was judged to be adequate in 25 patients, while the remaining 5 underwent immediate nephrectomy. Compared with patients whose renal injuries did not require temporary occlusion, these 30 were more likely to have renovascular trauma, shock at presentation and higher transfusion requirements. Postoperatively, of 20 patients renal imaging (9) and radionuclide scanning (11) demonstrated preservation of significant renal parenchyma or function in 18 (90%). Although complications were more common in patients whose renal injuries required temporary vascular occlusion, only 2 were related to the renal injury or its method of repair (urinary extravasation in 1 patient and azotemia in 1 with bilateral injury). Temporary vascular occlusion can be performed expeditiously and safely, and may have an important role in preserving renal function. Our results support the routine use of early vascular control and the selective use of temporary vascular occlusion in renal injuries requiring exploration.

Adolescent↗