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Biomedical subjects

H R Katz

Publications and source records attributed to H R Katz.

At least 37 records · Page 2Linked to original sources
PubMed1996

Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group.

PURPOSE: The purpose of the study is to compare the clinical efficacy and safety of ciprofloxacin ophthalmic solution 0.3% (Ciloxan) with a standard therapy regimen (fortified tobramycin, 1.3%-cefazolin, 5.0%) for treating bacterial corneal ulcers. METHODS: This randomized, parallel group, double-masked, multicenter study was conducted in 324 patients at 28 centers in the United States, Europe, and India. Patients were randomized into 2 treatment groups: 160 to ciprofloxacin and 164 to fortified tobramycin-cefazolin. Positive microbiologic cultures were obtained in 188 (58%) of 324 patients. Of these, 176 patients met protocol criteria and were evaluated for treatment efficacy: 82 in the ciprofloxacin group and 94 in the standard therapy group. The dosing schedule for both treatment groups was 1 to 2 drops of the first study medication (ciprofloxacin or fortified tobramycin) every 30 minutes for 6 hours, then hourly for the remainder of day 1; 1 to 2 drops every hour on days 2 and 3; 1 to 2 drops every 2 hours on days 4 and 5, followed by 1 to 2 drops every 4 hours on days 6 to 14. The second medication (ciprofloxacin or cefazolin) was instilled 5 to 15 minutes after the first drug, following the same dosing frequency. Physician's judgment of clinical success, cure rate, changes in ocular sings, and symptoms and the rate of treatment failures were the primary efficacy criteria. RESULTS: Topical ciprofloxacin monotherapy is equivalent clinically and statistically to the standard therapy regimen of fortified antibiotics. No statistically significant treatment differences were found between ciprofloxacin (91.5%) and standard therapy (86.2%) in terms of overall clinical efficacy (P = 0.34). Similarly, no differences were noted in resolution of the clinical signs and symptoms (P > 0.08) or the time to cure (P = 0.55). The incidence of treatment failures was less in the ciprofloxacin group (8.5%) compared with the standard therapy group (13.8%). Significantly fewer patients treated with ciprofloxacin reported discomfort than did patients treated with the standard therapy regimen (P = 0.01). CONCLUSION: Ciprofloxacin ophthalmic solution 0.3% monotherapy is equivalent clinically and statistically to standard therapy (fortified tobramycin-cefazolin) for the treatment of bacterial corneal ulcers and produces significantly less discomfort.

Adolescent↗
PubMed1996

Tissue-dependent differences in the asynchronous appearance of mast cells in normal mice and in congenic mast cell-deficient mice after infusion of normal bone marrow cells.

The time courses of the appearance of tissue mast cells in six sites were compared in normal WBB6F1(-)+/+ mice (+/+) and in congenic mast cell-deficient WBB6F1-W/Wv mice (W/Wv) that received an intravenous infusion of bone marrow cells from +/+ mice (BM-->W/Wv). As assessed by morphometric analysis of Carnoy's solution-fixed, methylene blue-stained tissue sections, the density of mast cells in the stomach mucosa, stomach submucosa, and spleen of +/+ mice reached maximal levels by 8 weeks of age, whereas the density of mast cells in the skin, extraparenchymal airway walls, and lung parenchyma did not reach maximal levels until 18 weeks of age. When 8-week-old W/Wv mice were infused with 2 x 10(7) bone marrow cells from /+/ mice, mast cells appeared in the stomach mucosa and submucosa after 2.5 weeks, in the spleen and extraparenchymal airway walls after 5 weeks, and in the lung parenchyma after 10 weeks. Twenty weeks after bone marrow infusion, the mast cell densities in the spleen, stomach mucosa, and stomach submucosa were seven-, 13-, and five-fold greater, respectively, than those in age-matched +/+ mice, but were eight-, two-, and five-fold lower in the skin, extraparenchymal airway walls, and lung parenchyma, respectively. Thus, those tissues that in +/+ mice reached maximal mast cell densities earlier exhibited abnormally high mast cell densities in BM-->W/Wv mice, and those that reached maximal mast cell densities later in +/+ mice had abnormally low mast cell densities in BM-->W/Wv mice. Immunological and inflammatory responses are often compared in W/Wv and BM-->W/Wv mice to assess mast cell dependency. Our results indicate that the capacity to restore a mast cell-dependent response in a particular tissue of the latter mice may relate to the local mast cell density and whether the immunological challenge activates mast cells only in that tissue or systemically with attendant widespread release of proinflammatory mediators.

Animals↗
PubMed1995

The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts, but not exocytosis, in mouse mast cells.

FK506 and cyclosporin A (CsA) are immunosuppressive agents that inhibit IL-2 production by activated T cells, but only CsA inhibits IgE activation-induced cytokine transcripts in mouse IL-3-dependent, bone marrow-derived mast cells (BMMC). We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein (FKBP) 12, a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro. In this report, we establish that FKBP12 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation-induced cytokine transcripts in a Kirsten murine sarcoma virus-immortalized mast cell line that is FKBP12 deficient. Overexpression of FKBP12 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity (IC50 = 2 nM), compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK506 inhibition of IgE activation-induced transcripts for TNF-alpha decreased from 40 nM in vector control cells to 10 nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM in vector control cells to 35 nM in FKBP12 transfectants. In contrast, activation-elicited release of the secretory granule mediator beta-hexosaminidase was only partially inhibited by FK506 at 1000 nM, regardless of the levels of FKBP12 expressed by the cells. Thus, FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-alpha and IL-6 transcripts.

Animals↗
PubMed1995

FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells.

The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.

Animals↗
PubMed1995

Intraoperative corneal pachymetry in eyes having radial keratotomy.

We prospectively studied 45 eyes that had radial keratotomy for correction of myopia to determine whether significant changes in corneal thickness occurred during the surgical procedure and which paracentral corneal region was the thinnest consistently. We used a standard bidirectional technique with a diamond knife. The inferotemporal paracentral region was the thinnest most frequently (38% of eyes) both pre-incision and post-incision. However, each of the other paracentral regions measured the thinnest in a smaller percentage of eyes: temporal (28% pre-incision and post-incision); inferior (19% pre-incision, 21% post-incision); nasal (11% pre-incision, 9% post-incision); superior (4% pre-incision and post-incision). A statistically significant reduction in corneal thickness occurred intraoperatively in all regions.

Anthropometry↗
PubMed1994

Nd:YAG laser photo-induced adhesion of the corneal epithelium.

We retrospectively studied eight patients with recurrent corneal erosions treated with the Nd:YAG laser using 0.4- to 0.5-mJ pulses applied to the region of Bowman's layer through an intact epithelium. All eight patients had resolution of their symptoms after treatment. Mean follow-up time was 21.2 months (range, 12.6 to 36.6 months). A patient who was scheduled for diagnostic enucleation for a posterior choroidal mass consented to undergo this laser treatment with varied energy settings six days before his enucleation. His cornea was studied with specular microscopy, light microscopy, and transmission electron microscopy. Light microscopy of the cornea disclosed rare 100-microns defects in Bowman's layer with subjacent compaction of the anterior stromal lamellae. Electron microscopy showed minute foci of disruption in Bowman's layer with new collagen formation. Fine fibrils connected the basal epithelial cells to the new collagen. Nd:YAG laser photo-induced adhesion of the corneal epithelium may represent an effective treatment alternative for patients with recurrent corneal erosions.

Adult↗
PubMed1994

Cloning of the gp49B gene of the immunoglobulin superfamily and demonstration that one of its two products is an early-expressed mast cell surface protein originally described as gp49.

gp49 was originally defined as a 49-kDa surface glycoprotein preferentially expressed on mouse interleukin-3-dependent, bone marrow-derived mast cells, which are immature progenitor cells. A previously cloned cDNA (gp49A) indicated that gp49 was a member of the immunoglobulin (Ig) superfamily, and genomic DNA analysis indicated that two genes might encode a gp49 family. We have now characterized a 5.6-kilobase pair gene, gp49B, that encodes two novel gp49 cDNAs, gp49B1 and gp49B2. The two cDNAs are identical except that gp49B2 is missing exon 6, which encodes a predicted transmembrane domain. In contrast to gp49A, gp49B1 and gp49B2 have 32 additional amino acids at their C termini containing 4 of the 6 consensus amino acids of the antigen receptor homology 1 motif found on several signal-transducing members of the Ig superfamily. When COS-7 cells were transfected with either the gp49B1 or gp49B2 cDNA, only the gp49B1 transfectants bound the B23.1 monoclonal antibody that originally defined gp49. Reverse transcriptase-polymerase chain reaction analysis of the transfectants established that both transcripts were expressed, suggesting that the product of the gp49B2 transcript was not inserted in the plasma membrane. Thus, cloning of the gp49B gene has established the organization of one of the gp49 genes and provided evidence of alternate splicing of transcripts from that gene.

Amino Acid Sequence↗
PubMed1994

Fc gamma R-mediated endocytosis and expression of cell surface Fc gamma RIIb1 and Fc gamma RIIb2 by mouse bone marrow culture-derived progenitor mast cells.

Mouse IL-3-dependent, bone marrow culture-derived mast cells (BMMC) bind IgG immune complexes through Fc receptors for IgG (Fc gamma R) but express minimal Fc gamma RIII on their surfaces. BMMC do not degranulate appreciably when their Fc gamma R are perturbed with the rat anti-mouse Fc gamma RII/III mAb 2.4G2 and F(ab')2 mouse anti-rat IgG (MAR). In contrast, after their Fc gamma R were cross-linked with mAb 2.4G2 and Na125I-labeled MAR at 37 degrees C, BMMC rapidly internalized the complex. To identify the Fc gamma R species expressed on the surface of BMMC and therefore implicated in the endocytic response, two rabbit antipeptide antisera were raised, one against a sequence common to the cytoplasmic regions of Fc gamma RIIb1 and Fc gamma RIIb2 and the other to a unique cytoplasmic region of Fc gamma RIIb1. When Fc gamma R were immunoprecipitated with mAb 2.4G2 from detergent extracts of BMMC, digested with N-glycosidase F, subjected to SDS-PAGE, and immunoblotted with the Fc gamma RIIb1- and Fc gamma RIIb1/b2-specific antibodies, BMMC were found to express Fc gamma RIIb1 and Fc gamma RIIb2. Selective immunoprecipitation of plasma membrane-localized Fc gamma RIIb1 and Fc gamma RIIb2 from [3H]leucine-labeled BMMC showed that their ratio at the cell surface was similar to their initial biosynthetic ratio. Thus, in contrast to mature serosal mast cells that degranulate on binding of IgG complexes, immature mast cells, of which BMMC are a prototype, may have a role in the clearance of complexes without concomitant release of proinflammatory mediators.

Animals↗
PubMed1993

Comparison of topical ciprofloxacin to conventional antibiotic therapy in the treatment of ulcerative keratitis.

We evaluated the efficacy of ciprofloxacin (3 mg/ml) as the sole topical antibiotic used to treat infectious keratitis in 14 patients. We compared the ciprofloxacin-treated group to a retrospective control group of 30 consecutive culture-positive patients treated with conventional therapy in which cefazolin (50 mg/ml) and fortified gentamicin sulfate (9.1 mg/ml) solutions were used. We found no remarkable difference between the control group and the ciprofloxacin-treated group regarding patient age, risk factors, need for hospitalization, and virulence of organism isolated. The average time to healing in culture-positive ciprofloxacin-treated patients was 34 +/- 33 days vs 45 +/- 71 days in the control group and this difference was not statistically significant. The duration of antibiotic therapy in the culture-positive ciprofloxacin-treated group was 27 +/- 15 days vs 33 +/- 50 days in the control group. Four of the 30 control patients required modification of their antibiotic regimen, whereas no ciprofloxacin-treated patient required a change. Ciprofloxacin appears to be an effective single agent in the treatment of ulcerative keratitis.

Adult↗
PubMed1993

Intracellular degradation of Fc gamma RIII in mouse bone marrow culture-derived progenitor mast cells prevents its surface expression and associated function.

Although mouse interleukin-3-dependent, bone marrow culture-derived progenitor mast cells (BMMC) and a Kirsten sarcoma virus (KiSV)-immortalized mouse mast cell line (MC4w) both express on their surfaces receptors for the Fc portion of IgG (Fc gamma R), only MC4w degranulate upon Fc gamma R perturbation. As shown by surface iodination and SDS-polyacrylamide gel electrophoresis analysis of deglycosylated proteins immunoprecipitated with the Fc gamma R-specific monoclonal antibody 2.4G2, a 26-kDa protein, identified as Fc gamma RIII by immunoblotting with antibody to Fc gamma RIII, was predominantly expressed on the surface of MC4w but minimally on BMMC. However, both BMMC and MC4w expressed mRNA for Fc gamma RIII as determined by RNA blot analysis, and both translated Fc gamma RIII as assessed by intrinsic radiolabeling and SDS-polyacrylamide gel electrophoresis analysis of deglycosylated monoclonal antibody 2.4G2 immunoprecipitates. Pulse-chase analysis showed that intrinsically radiolabeled Fc gamma RIII was stable in MC4w cells but was degraded rapidly in BMMC and that newly synthesized Fc gamma RIII remained sensitive to digestion by endoglycosidase H in BMMC but rapidly became resistant in MC4w. These data suggest that the deficiency in surface Fc gamma RIII expression on BMMC is due to the degradation of Fc gamma RIII in the endoplasmic reticulum. Immunoprecipitation of surface Fc gamma R and Fc receptors for IgE (Fc epsilon RI) from digitonin-extracted cells followed by immunoblotting with antibody to Fc epsilon RI gamma-chain showed that gamma-chain is associated with surface Fc epsilon RI and Fc gamma R in MC4w, but only with Fc epsilon RI in BMMC, which lack surface Fc gamma RIII. Inasmuch as BMMC are progenitors of serosal mast cells, which, like MC4w, express surface Fc gamma RIII and undergo Fc gamma R-mediated activation, the data suggest that maturation of BMMC enables Fc gamma RIII to bypass degradation in the endoplasmic reticulum, resulting in the acquisition of functional Fc gamma RIII/gamma-chain complexes on the cell surface.

Amino Acid Sequence↗
PubMed1993

Mast cell activation enhances airway responsiveness to methacholine in the mouse.

Mast cell-deficient mutant mice and their normal littermates were used to determine whether activation of mast cells by anti-IgE enhances airway responsiveness to bronchoactive agonists in vivo. Pulmonary conductance was used as an index of airway response as the mice were challenged with increasing intravenous doses of methacholine (Mch) or 5-hydroxytryptamine (5-HT). Mast cell activation with anti-IgE enhanced pulmonary responsiveness to Mch in both types of normal mice (P < 0.0001 by analysis of variance) but not in either genotype of mast cell-deficient mouse. Additionally, anti-IgE pretreatment of genetically mast cell-deficient W/Wv mice whose mast cell deficiency had been repaired by infusion of freshly obtained bone marrow cells or bone marrow-derived cultured mast cells from congenic normal mice led to significant (P < 0.0001) enhancement of Mch responsiveness. 5-HT responsiveness was not significantly influenced by anti-IgE pretreatment in any of the mice studied. The data support the hypothesis that IgE-mediated activation of mast cells enhances pulmonary responsiveness to cholinergic stimulation.

Analysis of Variance↗
PubMed1992

Ciprofloxacin-resistant bacterial keratitis.

Ciprofloxacin, a new broad-spectrum antibiotic effective against a variety of gram-positive and gram-negative bacteria, has recently become available in topical ophthalmic solution (3 mg/ml) for the treatment of bacterial keratitis. It has rapidly become the drug of choice in treating bacterial keratitis. We treated three patients with bacterial corneal ulcers that were resistant to ciprofloxacin, yet were effectively treated with other topical antimicrobial agents. The initial culture results are important in the therapy of corneal ulcers.

Aged↗
PubMed1992

Secretory granule mediator release and generation of oxidative metabolites of arachidonic acid via Fc-IgG receptor bridging in mouse mast cells.

The releases of beta-hexosaminidase, LTC4, LTB4, and PGD2 after the bridging of Fc gamma R3 were assessed in mouse IL-3-dependent bone marrow-derived progenitor mast cells (BMMC), BMMC maintained in coculture with 3T3 fibroblasts separated by a filter to achieve maturation of the granules toward those of a serosal mast cell (SMC), and SMC that are the prototype of a mouse connective tissue mast cell. Bridging of Fc gamma R on BMMC with the 2.4G2 rat anti-Fc gamma RII/III mAb and anti-rat IgG elicited only 4% net release of beta-hexosaminidase and 4, 2, and 1 ng/10(6) cells of immunoreactive LTC4, LTB4, and PGD2, respectively. Bridging of Fc-IgE receptors (Fc epsilon R) on BMMC yielded 35% net release of beta-hexosaminidase and 9, 4, and 3 ng/10(6) cells of immunoreactive LTC4, LTB4, and PGD2, respectively. BMMC maintained in coculture responded to the bridging of Fc gamma R with statistically significant increases in the net percent release of beta-hexosaminidase to 16% and in the generation of immunoreactive LTC4 to 11 ng/10(6) cells, but without a significant change in the production of either LTB4 or PGD2. Bridging of Fc epsilon R on cocultured mast cells yielded a net percent release of beta-hexosaminidase and lipid mediator amounts and profile similar to those for BMMC. Bridging of Fc gamma R on purified mouse SMC resulted in a maximal net percent release of beta-hexosaminidase of 10% and the generation of 4, 1, and 17 ng/10(6) cells of immunoreactive LTC4, LTB4, and PGD2, respectively; the net percent release of beta-hexosaminidase and PGD2 generation were significantly greater than those obtained from BMMC. The Fc epsilon R-mediated net percent release of beta-hexosaminidase from purified SMC was 34%, with PGD2 being the predominant metabolite of arachidonic acid. That the predominant lipid mediator generated with activation by either Fc gamma R or Fc epsilon R is LTC4 for cocultured mast cells and PGD2 for SMC suggests that the mast cell phenotype rather than the receptor class being bridged determines the lipid mediator profile. The responsiveness to Fc gamma R bridging elicited by coculture of BMMC with fibroblasts in vitro and present in SMC derived in vivo relative to BMMC may relate to the previously measured increases in receptor number per cell, but may also involve the acquisition of an enhanced signal transduction capability, possibly through the increased expression of Fc gamma RIII.

Antigens, Differentiation↗
PubMed1991

Molecular cloning of gp49, a cell-surface antigen that is preferentially expressed by mouse mast cell progenitors and is a new member of the immunoglobulin superfamily.

gp49 is a Mr 49,000 glycoprotein expressed on the surface of mouse bone marrow-derived mast cells, which are progenitors for the major in vivo mast cell subclasses, typified by intestinal mucosal mast cells and serosal mast cells. The amino-terminal amino acid sequence of gp49 was determined after isolation of the solubilized membrane protein by affinity chromatography with the B23.1 anti-gp49 monoclonal antibody. Redundant oligonucleotides were used to isolate a full-length 1.3-kilobase cDNA from a mouse mast cell library. The predicted amino acid sequence contains a signal peptide of 23 residues, an extracellular domain of 215 residues with three potential sites of N-linked glycosylation, a transmembrane domain of 23 residues, and a cytoplasmic tail of 42 residues. Hybridization of the gp49 cDNA was limited to mRNA extracted from those cell types that also bound the B23.1 monoclonal antibody as assessed by cytofluorographic analyses. The predicted extracellular domain of gp49 contains two regions of 48 and 51 amino acids, each flanked by cysteine residues. Both regions meet criteria for being C2-type domains of the immunoglobulin superfamily based upon the alignment of consensus amino acids and their predicted secondary structure organization. Thus, gp49, a membrane glycoprotein preferentially expressed by the progenitor mast cell population, is a new member of the immunoglobulin superfamily.

Amino Acid Sequence↗