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Biomedical subjects

S Brodie

Publications and source records attributed to S Brodie.

15 recordsLinked to original sources
PubMed2001

A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Adolescent↗
PubMed2001

Electroretinographic abnormalities in a rat glaucoma model with chronic elevated intraocular pressure.

The purpose of this study was to determine the ability of electroretinographic (ERG) measurements to document progression of the retinopathy in a rat glaucoma model. Thirty four rats with a chronic intraocular pressure (IOP) elevation induced in one eye by cautery of three episcleral/extra-orbital veins were studied in four separate groups. ERGs were recorded sequentially in Group A rats (n = 12) at baseline, and after approximately 20, 40 and 60 days of high IOP, and in three additional groups of rats (n = 6 or 10 per group) after approximately 58, 30 and 175 days of high IOP, respectively. Scotopic ERG parameters recorded simultaneously from both eyes in Group A rats were: a- and b-wave amplitudes, implicit times, oscillatory potential amplitudes (OPs) determined at three different light-flash intensities, and the light-adapted (photopic) ERG b-wave amplitude. In the other groups of rats, only scotopic ERG a-wave, b-wave and OP amplitudes were measured.In Group A rats that were followed sequentially, all the ERG parameters recorded with attenuated stimuli showed significant time-dependent changes in glaucomatous eyes relative to their contralateral normal eyes, with OPs showing the earliest significant difference after only 3 weeks of high IOP. When different groups of unilateral glaucomatous rats were compared beyond 8 weeks of elevated IOP only the OPs showed a continued decrease with time and good discrimination between glaucoma and normal eyes. Over a 25 week period of high IOP the scotopic OPs measured with attenuated light stimuli declined at the rate of approximately 1.5% per week and provided the best ERG measure to monitor progression of retinal pathophysiology in the vein-occlusion rat glaucoma model.

Adaptation, Ocular↗
PubMed2001

Retinal morphology and ERG response in the DBA/2NNia mouse model of angle-closure glaucoma.

PURPOSE: To document the time course of retinal dysfunction by scotopic electroretinography (ERG) and by quantitative morphology in eyes of the DBA/2NNia substrain of mouse (DBA) with inherited angle-closure glaucoma. METHODS: DBA and control C57BL/6J (C57) mice were studied by ERG recordings from 5 to 15 months of age, and by morphology from 1 to 14 months of age. Scotopic ERGs were simultaneously recorded from both eyes of dark-adapted anesthetized mice. Changes in the central neuronal retina were evaluated by quantitative morphometry performed on serial semithin sections of Epon-embedded eyes. RESULTS: When compared with normal C57 mice, DBA mice showed significant reductions of the a-wave and b-wave amplitudes by 7 to 8 months, and the decline continued as the animals aged. The b-wave implicit time in DBA mice showed a gradual prolongation beginning at 8 months of age, when compared with C57 mice. Logistic regression analyses revealed significant correlations in a- and b-wave amplitude reductions between ipsilateral and contralateral eyes of DBA mice at ages when ERG parameters were greatly altered. Morphologically, thinning of the whole retina was already evident in DBA mice at 4 months of age, but loss of ganglion cells and thinning of the outer plexiform layer were first seen in 7- to 8-month-old animals. These changes progressed to the end of the 13-month period studied. CONCLUSIONS: Progressive thinning of the outer retinal layers in DBA mice was found to correlate with decreases in ERG a- and b-wave amplitudes, both occurring from the age of 7 to 8 months onward. Similarities with the findings in human late-stage glaucomatous retinopathy indicate the relevance of this animal model in further glaucoma research.

Animals↗
PubMed1994

Studies of the ocular pulse in primates.

Ocular pulse amplitude (OPA) and intraocular pressure (IOP) were measured in groups of human subjects with primary open-angle glaucoma (POAG), ocular hypertension (OHT), low-tension glaucoma (LTG), retinal degenerations (RD), in OHT volunteers treated with single doses of 2% epinephrine, 4% pilocarpine, 0.5% timolol or 1% p-amino-clonidine, and in normal subjects before and after exercise. Compared to normal controls, OHT subjects showed significantly higher IOP and OPA, while OPA was significantly lower in ocular normotensive LTG and RD subjects groups. All drug treatments lowered IOP in OHT subjects, but did not change OPA significantly. Exercise in normal volunteers increased calculated ocular perfusion pressure by 22.5%, lowered IOP by 32%, but showed no significant change in OPA. When IOP was elevated > or = 5 mmHg in lasered monkey eyes peak pulse volume (PPV) was increased significantly in the unlasered eyes. Epinephrine 2% or 1% p-aminoclonidine lowered IOP moderately with no change in PPV, while treatment with 4% pilocarpine or 0.5% timolol reduced IOP and increased PPV significantly. The findings suggest that LTG may be associated with an ocular vascular abnormality. OPA in OHT or normal human subjects did not change when IOP was decreased by antiglaucoma drug treatments or exercise, respectively. These results indicate that OPA may be physiologically autoregulated in human subjects with IOPs in the 11-21 mmHg range. However, laser-induced glaucomatous monkey eyes with higher IOP (30-35 mmHg) did not autoregulate, but showed a low peak pulse volume, which increased when IOP was reduced 5 mmHg or more by means of antiglaucoma drug treatment.

Adult↗
PubMed1992

Aneurysmal bone cyst in a Holstein bull.

A 3-year-old Holstein bull was examined because of a mass involving the cranial portion of the right hemimandible and the oral cavity. The mass had been observed 2 weeks earlier. The bull had lost weight throughout the 45 days before admission, and was anorectic at the time of admission. An aneurysmal bone cyst of the mandible was diagnosed.

Animals↗
PubMed1985

Intraocular injection of lidocaine.

Lidocaine was inadvertently injected intraocularly in three patients. In the one patient who had not received prior mydriatics, the drug caused immediate dilation and paralysis of the pupil and diminished visual acuity to counting fingers. Retinal function began to improve after four hours and both retinal and pupillary function recovered completely by 16 hours. A second patient also recovered completely. The third patient developed a permanent field defect. The effects of intraocular lidocaine were then studied in an animal model. Lidocaine temporarily paralyzed the pupil in mydriasis and temporarily extinguished the b-wave of the electroretinogram. Light and electron microscopy study of the retina revealed no damage beyond that at the perforation site.

Animals↗
PubMed1985

A carrier state of X-linked juvenile retinoschisis.

The carrier state of X-linked juvenile retinoschisis has not been known to be associated with any fundus abnormalities. We report a case where there are funduscopic changes and mild visual acuity changes in one eye of a carrier.

Adult↗
PubMed1982

Expanding gas bubbles for the repair of tears in the posterior pole.

Expanding, long-lived intraocular perfluorocarbon gas bubbles can make possible the repair of retinal detachments with holes or tears in the posterior pole. Vitrectomy is not necessary for injecting the gas. The patient should be prone in order to bring the gas bubble to the top of the visual axis. Four perfluorocarbon gases have the appropriate coefficient of expansion to provide adequate intraocular gas volumes by displacing the fluid vitreous. Volumes of 1 to 2 cc are sufficient. Intraocular space for these amounts can be obtained either by draining subretinal fluid or by injecting 0.6 cc of C2F6 (which expands 3.3x) without draining. If the patient cannot tolerate being prone, most of the fluid vitreous can be displaced with an intraocular injection of 0.9 cc of C4F10 (which expands 5x).

Fluorocarbons↗
PubMedDate not supplied

Modified ERG-jet contact lens electrodes for use in infants and toddlers.

A simple modification of the standard ERG-jet contact lens recording electrode for use in infants and small children was developed. A small Plexiglas cylinder is fixed to the front surface of the electrode, which prevents lid closure and facilitates handling. Sedation or general anesthesia is rarely needed. Waveforms obtained with the modified electrode appear comparable to those obtained with standard electroretinogram electrodes.

Adult↗