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Biomedical subjects

S L Graham

Publications and source records attributed to S L Graham.

At least 73 records · Page 4Linked to original sources
PubMed1995

Incomplete Reiter's syndrome with focal involvement of the posterior segment.

PURPOSE: To describe an unusual variant of Yersinia-induced, HLA-B27 associated incomplete Reiter's syndrome with focal involvement of the posterior segment. METHODS: Review of case records of a patient presenting with incomplete Reiter's syndrome which included a reactive arthritis with keratoconjunctivitis and anterior uveitis. RESULTS: The uveitis progressed to involve the posterior segment with a vitritis and two transient white retinal spots. After resolving, a retinal pigment epithelial (RPE) defect persisted at the site of one of the lesions. CONCLUSIONS: While involvement of the anterior segment of the globe in Reiter's disease is well recognised, a review of the literature reveals that focal posterior involvement is a rare feature in either Reiter's syndrome or the reactive arthritis group.

Adult↗
PubMed1995

Otolaryngology.

Explore the source record for details and available documents.

Child↗
PubMed1994

Pseudopeptide inhibitors of Ras farnesyl-protein transferase.

Inhibitors of Ras farnesyl-protein transferase are described. These are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Deletion of the carbonyl groups between the first two residues of the tetrapeptides either preserves or improves activity, depending on the peptide sequence. The most potent in vitro enzyme inhibitor described (IC50 = 5 nM) is Cys [psi CH2NH]Ile[psi CH2NH]Phe-Met (3). To obtain compounds able to suppress Ras farnesylation in cell culture, further structural modification to include a homoserine lactone prodrug was required. Compound 18 (Cys[psi CH2NH]Ile[psi CH2NH]Ile-homoserine lactone) reduced the extent of Ras farnesylation by 50% in NIH3T3 fibroblasts in culture at a concentration of 50 microM. Structure-activity studies also led to 12 (Cys[psi CH2NH]Val-Ile-Leu), a potent and selective inhibitor of a related enzyme, the type-I geranylgeranyl protein transferase.

Alkyl and Aryl Transferases↗
PubMed1994

Synthesis and biological activity of ras farnesyl protein transferase inhibitors. Tetrapeptide analogs with amino methyl and carbon linkages.

Replacement of the central amino methylene linkage of C[psi CH2NH]A[psi CH2NH]AX tetrapeptide inhibitors with carbon tethers led to compounds with potency in the nanomolar range. Some of the more potent olefinic compounds inhibit Ras processing in intact v-ras transformed NIH 3T3 cells with IC50 values in the 0.1 to 1 microM range, and inhibit selectively the anchorage-independent growth of H-ras transformed Rat1 cells at 10 microM.

3T3 Cells↗
PubMed1994

Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton.

A potent and specific small molecule inhibitor of farnesyl-protein transferase, L-739,749, caused rapid morphological reversion and growth inhibition of ras-transformed fibroblasts (Rat1/ras cells). Morphological reversion occurred within 18 h of L-739,749 addition. The reverted phenotype was stable for several days in the absence of inhibitor before the transformed phenotype reappeared. Cell enlargement and actin stress fiber formation accompanied treatment of both Rat1/ras and normal Rat1 cells. Significantly, inhibition of Ras processing did not correlate with the initiation or maintenance of the reverted phenotype. While a single treatment with L-739,749 was sufficient to morphologically revert Rat1/ras cells, repetitive inhibitor treatment was required to significantly reduce cell growth rate. Thus, the effects of L-739,749 on transformed cell morphology and cytoskeletal actin organization could be separated from effects on cell growth, depending on whether exposure to a farnesyl-protein transferase inhibitor was transient or repetitive. In contrast, L-739,749 had no effect on the growth, morphology, or actin organization of v-raf-transformed cells. Taken together, the results suggest that the mechanism of morphological reversion is complex and may involve farnesylated proteins that control the organization of cytoskeletal actin.

Actins↗
PubMed1994

Pattern electroretinograms from hemifields in normal subjects and patients with glaucoma.

PURPOSE: Because glaucomatous visual field loss predominantly occurs in one hemifield, a baseline ratio of pattern electroretinogram (PERG) hemifield amplitudes (upper field:lower field) was determined in normal subjects and then examined in patients with glaucoma. METHODS: In 26 normal subjects and eight patients with glaucoma with typical arcuate field loss involving the test area (central 20 degrees), hemifield PERGs were recorded using checkerboard screens of check size 0.5 degrees and frequency 3.75 reversals per second (transient) and 15 reversals per second (steady state). RESULTS: The ratios obtained for normal central upper:lower amplitudes were 0.95 +/- 0.13 (transient) and 0.93 +/- 0.10 (steady state Fourier second harmonic). Wide nasal-field (52 degrees x 42 degrees) PERG ratios recorded on two subjects confirmed that the ratio held across large retinal areas. The ratio did not change with age or check size. The ratio showed less variability between patients than PERG amplitudes. In the patients with glaucoma, the hemifield PERG amplitude correlated with summed visual field thresholds for that area. Patients with glaucoma could be discriminated from normals by an abnormal ratio (> 2 SD) in seven of the eight patients. In two additional patients with more peripheral scotomas, the ratio remained normal. CONCLUSIONS: In normals, the upper:lower hemifield PERG ratio is slightly < 1.0 and remains stable with age. In glaucoma, visual field defects are associated with PERG reductions in the corresponding hemifield. An abnormal PERG hemifield ratio can be found in many patients, although more peripheral and symmetrical losses may still be missed.

Adult↗
PubMed1993

Sulfonylmethanesulfonamide inhibitors of carbonic anhydrase.

A series of sulfonylmethanesulfonamide derivatives is described, which are inhibitors of carbonic anhydrase (CA). The most potent of these is the racemic fluoro sulfone 9, which inhibits carbon dioxide hydration catalyzed by human CA II (CA-II) with an IC50 of 3 nM. Binding competition studies versus dansylamide indicate that the enantiomers of 9 have different affinities for CA-II, with equilibrium dissociation constants of 3.6 and 0.6 nM. QSAR analysis suggests that the key factors involved in achieving high affinity in this series are sulfonamide acidity, hydrophobicity, and minimization of steric demands at the carbon atom adjacent to the sulfonamide group.

Animals↗
PubMed1993

Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor.

To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase (FPTase), have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. The tetrapeptide analog L-731,735 is a potent and selective inhibitor of FPTase in vitro. A prodrug of this compound, L-731,734, inhibited Ras processing in cells transformed with v-ras. L-731,734 decreased the ability of v-ras-transformed cells to form colonies in soft agar but had no effect on the efficiency of colony formation of cells transformed by either the v-raf or v-mos oncogenes. The results demonstrate selective inhibition of ras-dependent cell transformation with a synthetic organic inhibitor of FPTase.

Alkyl and Aryl Transferases↗
PubMed1993

Cryotherapy to close a corneal subepithelial aqueous track after trabeculectomy.

After filtering surgery for primary open-angle glaucoma in a 64-year-old man, a persistent wound leak was encountered from the fornix-based conjunctival flap. Cyanoacrylate adhesive was applied but was unsuccessful in sealing the leak. The limbal margin was sutured with 10/0 nylon. One week later a corneal subepithelial fistulous track developed from the edge of the bleb and extended across the cornea towards the inferonasal limbus. The inferior end of the track leaked aqueous. Further surgery was performed to refashion the conjunctival bleb, ablate the fistula at its origin and re-form the anterior chamber. The track recurred 16 days later. The upper cornea was then treated with cryotherapy, which successfully closed the track with maintenance of a functional bleb (ocular pressure 6 mmHg). A faint asymptomatic subepithelial scar persisted.

Aged↗
PubMed1992

HIV-1 protease inhibitors based on hydroxyethylene dipeptide isosteres: an investigation into the role of the P1' side chain on structure-activity.

A systematic investigation was undertaken to determine the role of the P1' sidechain in a series of hydroxyethylene isostere based inhibitors of HIV-1 protease. Substitution and homologation of the benzyl P1' side chain of the Phe-Phe isostere based pseudo peptides 1 (L-682,679) and 2 (L-685,434) with various heteroalkyl groups leads to a series of extremely potent inhibitors of the enzyme. Several examples of the most potent inhibitors were very effective in an ex vivo cell based viral spread assay using human H9 T-lymphocytes and the IIIb isolate of HIV-1. Compound 19 is 120 times more potent than 1 and 16 times more potent than 2 in inhibiting the spread of infection in this assay.

Antiviral Agents↗
PubMed1991

Selective reduction of oscillatory potentials and pattern electroretinograms after retinal ganglion cell damage by disease in humans or by kainic acid toxicity in cats.

We recorded pattern electroretinograms, scotopic threshold responses, oscillatory potentials and ganzfeld flash electroretinograms in patients with glaucoma or other optic nerve diseases and in cats with inner retinal damage caused by intravitreal injections of kainic acid. In both studies, the scotopic b-wave and the scotopic threshold responses were normal but the oscillatory potentials and pattern electroretinograms were not. The photopic b-wave was also often reduced in patients with scotopic oscillatory potential reduction, and the reduction was proportionate to the oscillatory potential change. Oscillatory potentials were as frequently reduced as pattern electroretinograms in both patient groups, and in the few cases where only one response was reduced, there was no bias toward either measure. In cats, the effects of intravitreal injection of various doses of kainic acid on the retina were evaluated electrophysiologically, and structural damage was assessed histologically. After 25 nmol of kainic acid, the pattern electroretinograms and oscillatory potentials were reduced but neither the b-waves nor the scotopic threshold responses, were affected. Histologic studies of retinas after this dose showed swollen dendrites that were restricted to the outer part (off-sublamina) of the inner plexiform layer. Serial semithin sections indicated that most, if not all, of the swelling was confined to dendrites of large ganglion cells. Our results indicate that the size and sensitivity of the oscillatory potential response may have a role in the diagnosis and management of early glaucoma and optic nerve disease, and that the photopic electroretinogram may give similar information.

Action Potentials↗
PubMed1991

Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679.

A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.

Antiviral Agents↗
PubMed1991

Topically active carbonic anhydrase inhibitors. 4. [(Hydroxyalkyl)sulfonyl]benzene and [(hydroxyalkyl)sulfonyl]thiophenesulfonamides.

For several decades a tantalizing goal for the treatment of primary open-angle glaucoma has been the development of a topically active carbonic anhydrase inhibitor. Recent results from several research groups indicate that considerable progress has been made toward this objective. In this report, we present the design and synthesis of (hydroxyalkyl)sulfonyl-substituted benzene- and thiophenesulfonamides. These compounds exhibit inhibition of carbonic anhydrase II in the nanomolar range and lower intraocular pressure in the alpha-chymotrypsinized rabbit model of ocular hypertension after topical instillation.

Administration, Topical↗
PubMed1991

Methods of treating plantar ulcers.

The purpose of this article is to describe the indications, precautions, and fabrication techniques for orthotic devices the authors use to facilitate the healing of plantar ulcers. The methods of fabricating and applying three types of orthotic devices developed by the staff at the Gillis W Long Hansen's Disease Center--walking casts, walking splints, and cutout sandals--are described. Patient examples are given for each of the methods. These techniques, in conjunction with patient education and the use of special footwear, provide clinicians with procedures they can use to aid in the healing of plantar ulcers secondary to leprosy, diabetes, or other neuropathic conditions.

Casts, Surgical↗
PubMed1991

High correlation between absolute psychophysical threshold and the scotopic threshold response to the same stimulus.

The scotopic threshold response (STR) is a negative potential to low intensity light recorded from the dark-adapted retina. It reflects inner retinal function. The STR is now recorded routinely as part of our electroretinography protocol. The projected absolute threshold calculated from the amplitude versus intensity function for the STR has been found to correlate well (r = 0.59) with the absolute subjective threshold to the same stimulus. The correlation holds for about 1.5 log units above normal. With further elevation the STR is usually abnormal or absent as b wave threshold is approached. The correlation would have been much greater were it not for this truncated range over which both are recordable. This report includes our findings in 127 patients and examines several disease groups. When the STR had a reduced and abnormal intensity series or was absent, the subjective threshold was elevated in almost all cases (92.2%). The converse relationship also held. When there was a discrepancy, recording problems were usually identified. Since the STR requires difficult, time consuming signal averaging for reliable recording, it may be adequate to record the subjective threshold alone to provide a relatively easily recordable indicator of inner retinal function. Additional STR recording will seldom be warranted.

Dark Adaptation↗