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Biomedical subjects

J Rae

Publications and source records attributed to J Rae.

At least 37 records · Page 2Linked to original sources
PubMed1997

Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.

Administration, Oral↗
PubMed1996

Dye transfer between cells of the lens.

Dye transfer between lens fiber cells and between lens epithelial cells and underlying fiber cells was studied using a wide dynamic range-cooled CCD camera, H2O immersion objectives and image analysis techniques. Each lens was decapsulated by a new technique which leaves the epithelial cells adherent to the lens fiber mass. Lucifer Yellow CH was injected into either single epithelial cells or single fiber cells using the standard whole cell configuration of the patch voltage clamp technique. The results demonstrate extensive dye communication between fiber cells at the lens posterior surface, anterior surface, and equatorial surface. Dye transfer between deep fiber cells was also observed. Dye transfer between approximately 10% of epithelial cells and their underlying fiber cells was apparent when care was taken to yield wide dynamic range images. This was required because the relatively high concentration of dye in the epithelial cell masks the presence of much lower dye concentrations in the underlying fiber cell. A mathematical model which includes dye concentration, time, and spatial spread suggests that those epithelial cells that are coupled to an underlying fiber cell are about as well dye coupled as the epithelial cells themselves. The relatively low dye concentration in a fiber cell is due to its larger volume and diffusion of the dye along the axis of the fiber away from the fiber/epithelial junction.

Animals↗
PubMed1995

Cytochrome b-245 of the neutrophil superoxide-generating system contains two nonidentical hemes. Potentiometric studies of a mutant form of gp91phox.

Analysis of potentiometric titrations of the cytochrome b-245 from a X+ chronic granulomatous disease patient with an Arg54 --> Ser mutation in gp91phox indicates that the mutant form of the cytochrome contains two nonidentical hemes with midpoint potentials of Em7 = -220 and Em7 = -300 mV. In the light of this information, reanalysis of redox titrations of wild-type cytochrome b-245 implies that it probably also contains two separate heme centers with midpoint potentials of Em7 = -225 and Em7 = -265 mV. The effect of the Arg54 --> Ser substitution is to reduce the midpoint potential of one of the heme centers by approximately 35 mV and suggests possible interaction between Arg54 and a heme propionate side chain.

Cytochrome b Group↗
PubMed1995

A variant X-linked chronic granulomatous disease patient (X91+) with partially functional cytochrome b.

Genetic analysis of a patient with the variant cytochrome b-245-positive form of chronic granulomatous disease revealed a missense mutation resulting in a Arg54-->Ser substitution in the gp91phox subunit of cytochrome b-245. As a consequence, although no O2- is made, NADPH oxidase-associated FAD accepts electrons from NADPH in the cell-free activation system and becomes reduced. The reduced flavin exhibits normal levels of iodonitrotetrazolium violet diaphorase activity, and the patient's neutrophils exhibit high levels of intracellular oxidant production and show a low level of NBT staining in the NBT slide test. Thus, this mutation appears to render the heme center of NADPH oxidase present but nonfunctional, while leaving the flavin center fully functional.

Amino Acid Sequence↗
PubMed1995

A new X-linked variant of chronic granulomatous disease characterized by the existence of a normal clone of respiratory burst-competent phagocytic cells.

Chronic granulomatous disease (CGD) is characterized by recurrent infections, and is usually associated with a complete inability of phagocytic cells to generate superoxide anion (O2-). Rarely, variant forms of CGD have been reported in which there is reduced, but detectable, O2- production by phagocytic cells. We describe three adult males in two kindreds with a unique form of X-linked cytochrome b558-deficient (X91-) CGD not previously reported. All three patients had two distinct populations of phagocytic cells, with one subset capable of normal respiratory burst activity and the other larger subset inactive, as in classic CGD (X91 (0)). The respiratory burst activity in neutrophils purified from each patient was approximately 10% of normal as determined by O2- production, O2 consumption, cytochrome b558 spectroscopy, and membrane oxidase activity using a cell-free activation system. In contrast with other patients with X91(-)-variant CGD, the unique feature of these patients is the presence of a small but significant population (5% to 15%) of circulating neutrophils and monocytes with completely normal respiratory burst activity as assessed by nitroblue tetrazolium (NBT) reduction and flow-cytometric measurement of dihydrorhodamine oxidation. NBT reduction of peripheral blood granulocyte-macrophage progenitor cells also showed the presence of a subset of colonies derived from myeloid progenitor cells that had normal respiratory burst capabilities. A mosaic XX chromosome karyotype and an unstable oxidase complex that might occur during myeloid maturation were both excluded as possible explanations. In these families, the molecular defect in the gp91-phox gene, which is currently under investigation, appears to prevent expression of the gene in the majority of neutrophils, but not in a small subset. Our studies suggest that commitment to either a respiratory burst-competent or -incompetent phagocytic cell occurs at the level of the myeloid progenitor cell.

Adult↗
PubMed1994

Scalp-ear-nipple syndrome: additional manifestations.

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal dominant condition that causes aplasia cutis congenita of the scalp, alteration of the shape of the external ear, and hypoplasia of the nipple. Women in a new family, the fifth to be described, had virtually complete aplasia of the breast and a small skin dimple without any pigmentation instead of a normal nipple, although other affected women had normal breast and nipple development. Dental changes included widely spaced or missing secondary teeth; the ears were cupped or folded and stood out from the head, axillary apocrine secretion and axillary hair growth were reduced; and finger nails were brittle. There was no generalized abnormality of sweating. Some patients had partial syndactyly of the 3rd and 4th fingers, and complete cutaneous syndactyly of the 2nd and 3rd toes. and 3rd toes.

Abnormalities, Multiple↗
PubMed1993

Effect of volume changes on a potassium current in rabbit corneal epithelial cells.

Patch-clamp recordings from rabbit corneal epithelial cells have identified a large-conductance (167 pS in symmetrical 150 mM KCl) K channel that is the major contributor to the whole cell current (J. L. Rae and G. Farrugia. J. Membr. Biol. 129: 81-87, 1992). We report here on the regulation of this channel by changes in cellular osmolality and/or volume. Exchanging the bath solution with a hyposmotic (225 or 150 mosM) solution resulted in cellular swelling and selective activation of the K current (126 +/- 86 and 273 +/- 184% increase, respectively). Hyperosmotic solution changes (380 mosM) resulted in cell shrinkage and deactivation of the K current (44.2 +/- 21% decrease). Similar increases in the cell volume and whole cell current were observed on increasing (in perforated patch experiments) the chloride ion concentration (50 mM) in the pipette intracellular solution (127 +/- 63% increase). These changes were accompanied by marked shifts in the resting membrane voltage. We conclude that the K channels in these cells can respond to alteration in cellular osmolality or volume, resulting in changes in the whole cell current and resting voltage.

Animals↗
PubMed1992

Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity.

Recombinant interferon-gamma (rIFN-gamma) therapy has become an effective form of prophylaxis for patients with chronic granulomatous disease (CGD). Preliminary studies with CGD suggested that rIFN-gamma treatment enhanced phagocyte oxidase activity and increased superoxide (O2-) production. We evaluated several aspects of neutrophil NADPH oxidase activity in 19 CGD patients (representing all four known types of CGD) receiving prolonged rIFN-gamma therapy (6 to 27 months). In contrast to earlier studies, we failed to detect any improvement in neutrophil NADPH oxidase activity in 18 of the 19 CGD patients as determined by (1) intact cell O2- production (continuous assay), (2) nitroblue tetrazolium (NBT) staining, (3) cytochrome b558 spectroscopy, and (4) activity levels of cytosol and membrane oxidase components using a cell-free activation system. One patient with a variant form of X-linked CGD had a transient increase in neutrophil O2- production following 3 months of rIFN-gamma therapy. However, this was not sustained, and was not associated with any change in cytochrome b levels. In some patients, rIFN-gamma therapy was associated with the appearance of a small subset of circulating monocytes (1% to 20%) that were NBT-positive. Although the functional significance of this monocyte subpopulation needs to be determined, these results suggest that one possible mechanism by which rIFN-gamma may benefit CGD patients is by partially correcting the respiratory burst defect in a subset of monocytes. We conclude that the clinical benefit of prolonged rIFN-gamma therapy in the vast majority of CGD patients is not due to enhanced neutrophil NADPH oxidase activity. The mechanism of action of rIFN-gamma in most CGD patients remains unknown.

Child↗
PubMed1992

Potassium currents from isolated frog lens epithelial cells.

Using the perforated patch version of whole-cell recording, we have measured currents from isolated frog lens epithelial cells. Three types of currents were seen. A time-independent outwardly rectifying potassium current was identified that sets the resting voltage. This potassium current differs significantly from any of the potassium currents recorded with the whole-cell technique in mammalian lens epithelial cells. In addition to the potassium current, the two other currents present were both outwardly rectifying: one was time-independent while the other showed distinct activation.

Animals↗
PubMed1991

Low access resistance perforated patch recordings using amphotericin B.

We present experimental procedures describing the creation of perforated patches by use of amphotericin B. In 13 different cellular preparations, access resistances below 10 M omega were achieved and with blunt electrode tips, access resistances of 3-4 M omega were possible. In addition to using the techniques to measure whole cell currents, we have used them to measure single channel currents in a new "outside-out patch" preparation and we have utilized them to measure the resting voltage of epithelial monolayers. We conclude that these new approaches can provide a substantial increase in versatility and quality for many kinds of electrophysiological measurements.

Amphotericin B↗
PubMed1989

Börjeson-Forssman-Lehmann syndrome: clinical manifestations and gene localization to Xq26-27.

We have studied 7 males in one family with mild/moderate intellectual handicap, long thick ears, deep-set eyes, small testes, and post pubertal gynecomastia. The affected males and some of the heterozygous females also had tapering fingers and short, widely spaced flexed toes. The pedigree demonstrates X-linked recessive inheritance. The clinical manifestations are similar to those described in the Börjeson-Forssman-Lehmann (BFL) syndrome but differ in the degree of mental handicap and the absence of "dwarfism" and microcepaly. This milder manifestation may represent either phenotypic or genotypic variation. DNA marker studies demonstrated linkage to the DXS86, DXS51, and F9 cluster at Xq26-q27. The maximum lod score was 2.1 with DXS51, at theta = 0.0. Definite recombinants were observed between DXS10 (at Xq26 but proximal to DXS86), DXS105 (at Xq27 but distal to F9), and BFL. Thus, the regional localization for BFL is Xq26-q27 between DXS10 and DXS105.

Abnormalities, Multiple↗
PubMed1980

God and the doctor.

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Philosophy, Medical↗