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Biomedical subjects

A S Yu

Publications and source records attributed to A S Yu.

33 records · Page 2Linked to original sources
PubMed1998

Phase I study of a humanized anti-CD11/CD18 monoclonal antibody in multiple sclerosis.

OBJECTIVE: To evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of a humanized anti-CD11/CD18 monoclonal antibody (Hu23F2G) in patients with multiple sclerosis. METHODS: In this phase I uncontrolled dose escalation study, patients (n = 24) with primary or secondary progressive multiple sclerosis received single intravenous infusions of Hu23F2G (0.01 to 4.0 mg/kg). Study parameters included safety, pharmacology, immunogenicity, and brain magnetic resonance imaging (MRI). RESULTS: Hu23F2G had few adverse effects, but 2 cases of urinary tract infection and 2 cases of gingivitis did occur. Transient leukocytes developed in some subjects receiving > or = 1.0 mg/kg. The pharmacokinetic response was nonlinear, with the area under the curve increasing out of proportion to the increase in dose. The mean terminal half-life increased with dose and was 21.9 (SD, 12.8) hours at the 4.0 mg/kg dose. High saturation (> 80%) of CD11/CD18 on circulating leukocytes was achieved with doses > or = 0.2 mg/kg. The duration of high leukocyte saturation was dose-dependent, persisting for more than a week at the 4.0 mg/kg dose. A marked decrease in leukocyte migration in response to cutaneous inflammation was observed. Antibodies against Hu23F2G were not detected. The neurologic examinations were stable except for 1 subject who had worsening weakness associated with an infection. No significant changes were noted on brain MRI scans. CONCLUSIONS: Hu23F2G was tolerated at doses that achieved high degrees of leukocyte CD11/CD118 saturation with in vivo inhibition of leukocyte migration. Because this phase I study was not designed to determine the clinical efficacy of Hu23F2G, further studies are needed.

Adult↗
PubMed1998

Intrarenal and subcellular localization of rat CLC5.

Dent's disease, an inherited disorder characterized by hypercalciuria, nephrolithiasis, nephrocalcinosis, rickets, low-molecular-weight proteinuria, Fanconi's syndrome, and renal failure, is caused by mutations in the renal chloride channel, CLC5. The normal role of CLC5 is unknown. We have investigated the intrarenal and subcellular localization of CLC5 in rat kidney by in situ hybridization and immunohistochemistry. By in situ hybridization, CLC5 mRNA was detected predominantly in cortical medullary ray and outer medullary tubule epithelial cells. Polyclonal antiserum was generated against a CLC5 fusion protein, affinity purified, and immunoadsorbed against CLC3 and CLC4 to yield a CLC5 isoform-specific antiserum. By immunohistochemistry, CLC5 protein was localized to the intracellular domain of tubular epithelial cells in the S3 segment of the proximal tubule and the medullary thick ascending limb. By subcellular membrane fractionation and flow cytometry, CLC5 expression was found in outer medullary endosomes. These findings are consistent with a model in which CLC5 encodes an endosomal chloride channel that facilitates acidification and trafficking of renal epithelial endosomes.

Animals↗
PubMed1997

Paradoxical cerebral air embolism from a hemodialysis catheter.

Air embolism is a rare complication of the use of central venous catheters as vascular access for hemodialysis. We report a patient with an intracardiac shunt who had a paradoxical air embolism following manipulation of her hemodialysis catheter that resulted in transient hemiplegia. This case illustrates the potentially devastating consequences of even a small air leak into the circulation if it gains access to the arterial system.

Catheterization, Central Venous↗
PubMed1997

Hepatolithiasis and biliary parasites.

Hepatolithiasis, or the presence of intrahepatic stones, is prevalent in East Asia and is characterized by the finding of stones within the intrahepatic bile ducts proximal to the confluence of the right and left hepatic ducts. Bile stasis and bacterial infection have been incriminated as the major aetiopathogenic factors. Clinical features include recurrent pyogenic cholangitis, multiple liver abscesses, secondary biliary cirrhosis and cholangiocarcinoma. The goals of management include accurate localization of pathologies, control of biliary sepsis and the elimination of stones and stasis. Ultrasonography, computed tomography and direct cholangiography complement each other in defining the stones, strictures and degree of liver damage. Non-operative biliary decompression by endoscopy and interventional radiology is effective in controlling the infection, but surgery remains the mainstay for the treatment of stones and strictures. Intra-operative ultrasound and flexible choledochoscopy, combined with percutaneous transhepatic cholangioscopy and intraductal lithotripsy, facilitate stone removal. Balloon dilatation and biliary stenting serve to open the bile duct strictures. The creation of a hepaticocutaneous jejunostomy after conventional surgery allows atraumatic access to the biliary system for the removal of recurrent stones. The management of biliary parasites begins with conservative measures, including analgesics and anti-helminthic therapy. In refractory cases or patients with acute cholangitis, endoscopic biliary drainage and the extraction of worms may be necessary. Improvement in sanitation plays a crucial role in the epidemiological control of these biliary diseases.

Animals↗
PubMed1995

Molecular characterization of renal calcium channel beta-subunit transcripts.

An apical, hormone-regulated, calcium entry channel in the distal convoluted tubule and/or connecting tubule (DCT/CNT) is thought to play an important role in controlling renal calcium excretion. We previously identified a gene transcript encoding the pore-forming alpha 1-subunit of a calcium channel (alpha 1A, or CaCh4) which may be a candidate for such a molecule. The properties of voltage-dependent calcium channels are known to be modulated by their beta-subunits. To identify the accessory beta-subunit of DCT/CNT calcium channels, degenerate primers based on published beta-subunit sequences were used to amplify rat kidney cDNA by the polymerase chain reaction (PCR), and the products were subcloned and sequenced. Alternatively spliced transcripts of three beta-subunit genes (beta 2, beta 3, and beta 4) were identified. Northern blot analysis indicated that beta 4-subunit is preferentially expressed in kidney cortex. Transcripts of all three beta-subunit genes were detected by PCR in microdissected nephron segments, but only beta 4-subunit was found in DCT/CNT. As the beta 4- and alpha 1A-subunits colocalize to the DCT/CNT, we hypothesize that they may be constituent subunits of a renal calcium channel regulated by a hormone(s).

Alternative Splicing↗
PubMed1994

Tissue-specific expression of Na(+)-Ca2+ exchanger isoforms.

The sodium-calcium exchanger (NCE) plays a critical role in diverse processes in many different tissues including heart, nerve, and kidney. Surprisingly, the NCE is encoded by a single gene. We have isolated and sequenced a rat renal NCE clone, denoted F1, that was identical to previous rat NCEs, except for two unique sequences: one in the 5'-untranslated region and the other at a site of alternative splicing in the coding sequence. To explore these regions further, we examined NCE transcripts in several tissues using "rapid amplification of cDNA 5'-ends" and polymerase chain reaction amplification. Three species were identified each with a different 5'-end exon spliced to a common NCE core at nucleotide -34 in the 5'-untranslated region. Based on Northern analysis, each of these species had a unique tissue distribution. Whereas the F1 5'-end variant was abundantly expressed only in kidney, a second variant was expressed mostly in heart, and the third variant was expressed ubiquitously elsewhere. Investigation of the region of alternative splicing in the coding sequence also revealed tissue-specific expression of five major species. These findings indicate that the NCE expression is controlled and regulated under the influence of different promoters in a tissue-specific fashion. Therefore, we propose that the structural complexity of the single NCE gene allows it to respond independently to the unique demands of different environments.

Alternative Splicing↗
PubMed1994

Calcium channels.

A key step in renal calcium reabsorption is dihydropyridine-sensitive calcium entry across the apical membrane of the distal tubule. Electrophysiologic studies have confirmed the existence of calcium channels that may mediate this pathway. Molecular studies of voltage-dependent calcium channels have revealed a surprising degree of heterogeneity. The pore-forming alpha 1 subunit is encoded by multiple genes, each directing the synthesis of several alternatively spliced transcripts whose products may in turn be posttranslationally cleaved to yield multiple differently-sized peptides. Further heterogeneity is afforded by the presence of accessory subunits, such as the beta subunit, which is also encoded by a multigene family. Site-directed mutagenesis studies of the alpha 1 subunit have begun to explore the molecular structure of the calcium pore. Molecular cloning of rat renal calcium channel transcripts has identified alpha 1 and beta subunit genes that are expressed in the distal tubule. Future studies will address the structure-function relationship of various physiologic properties associated with the channels expressed by these genes.

Animals↗
PubMed1992

Molecular characterization and nephron distribution of a family of transcripts encoding the pore-forming subunit of Ca2+ channels in the kidney.

Active, transepithelial, Ca2+ reabsorption in kidney occurs primarily in the distal convoluted tubule. Recent evidence suggests that entry of Ca2+ at the apical membrane through channels bearing resemblance to those of the voltage-dependent L type may be the rate-determining step in Ca2+ reabsorption. To determine the molecular identity of the pore-forming subunit of voltage-dependent Ca2+ channel(s) in the kidney, a homology-based PCR cloning strategy was employed. Nondegenerate primers, based on conserved regions of the published cDNA sequences of voltage-dependent Ca2+ channel alpha 1 subunits, were used to amplify cDNA from rat kidney, and the products were subcloned and sequenced. A family of molecular species was identified, representing alternatively spliced transcripts of four known genes encoding these channel subunits. Northern blot analysis indicated that the expression of each of the genes exhibits a distinct spatial distribution within the kidney. One gene, CaCh4, is expressed primarily in the cortex, and by microdissected-tubule PCR was found predominantly in the distal convoluted tubule, consistent with a role in transepithelial Ca2+ reabsorption at this site.

Amino Acid Sequence↗
PubMed1992

Identification and localization of renal Na(+)-Ca2+ exchanger by polymerase chain reaction.

The molecular identity of the renal Na(+)-Ca2+ exchanger was determined by a homology-based polymerase chain reaction (PCR) cloning strategy. Rat kidney RNA was amplified by PCR, using oligonucleotide primers based on regions of low degeneracy in the published canine cardiac Na(+)-Ca2+ exchanger cDNA sequence, and the products were subcloned and sequenced. A 452-bp clone (NCX1) was identified, which shares 89% nucleotide and 98% amino acid sequence identity with the canine cardiac exchanger, suggesting that they are products of the same gene. NCX1 was shown, by Northern analysis, to hybridize to an abundant major transcript of 7 kb and a minor one of approximately 14 kb both localized predominantly to kidney cortex. Microdissected tubule PCR analysis revealed that NCX1 was enriched in distal convoluted tubule compared with other cortical nephron segments. Such a location is consistent with a Na(+)-Ca2+ exchanger corresponding to NCX1 playing a major role in active Ca2+ reabsorption at this site.

Animals↗
PubMed1990

Modulation of osmolytes in MDCK cells by solutes, inhibitors, and vasopressin.

MDCK cells accumulate organic osmolytes in response to hyperosmotic NaCl-supplemented medium. We examined time course and inhibitor sensitivity of myo-inositol, sorbitol, and glycerophosphorylcholine (GPC) accumulation in MDCK cells exposed to hyperosmotic NaCl-, D-glucose-, or mannitol-supplemented media. In NaCl medium, cells preferentially accumulated inositol and GPC. In comparison, in glucose medium cells preferentially accumulated sorbitol and GPC. Inositol demonstrated a late (72-96 h) accumulation in glucose medium, although less than in NaCl medium. Mannitol medium did not significantly stimulate accumulation of any of these three osmolytes at 24 h, suggesting that hyperosmolality alone is not sufficient stimulus for their accumulation in this time frame. GPC accumulation was very rapid in glucose medium, and fell to the level induced by NaCl medium at 96 h (approximately 50 nmol/mg protein). Inositol and sorbitol accumulated more gradually, each reaching greater than 400 nmol/mg protein after 96 h. Sorbitol was still accumulating at 96 h, whereas inositol plateaued at 72-96 h. Phlorizin or sorbinil blocked accumulation of inositol or sorbitol, respectively. Sorbitol and GPC accumulation in glucose medium were partially inhibited in absence of serum or in presence of 1 microM vasopressin. Thus NaCl and glucose appear to stimulate specific cellular mechanisms responsible for accumulation of inositol, sorbitol, and GPC in MDCK cells. This accumulation is also modulated by constituents of serum.

Animals↗
PubMed1982

T helper cells in immune mice amplify the primary anti-tumor cytotoxic response.

In this report we examine the influence of splenic helper cells in the primary cytotoxic T lymphocyte (CTL) response against syngeneic murine leukemia virus-(MuLV) induced tumor cells. We identify an Lyt-1+ 800 R radiation-resistant helper T cell that will amplify the in vitro generation of CTL against syngeneic tumor cells from nonimmune spleen cells.

Animals↗