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Biomedical subjects

S L Graham

Publications and source records attributed to S L Graham.

At least 19 recordsLinked to original sources
PubMed2006

Intertest variability of mfVEP amplitude: reducing its effect on the interpretation of sequential tests.

PURPOSE: The multi-focal visual evoked potential (mfVEP) has been recently introduced as an alternative to subjective perimetry in detecting visual field defects. This study examines the source of variability in the mfVEP amplitude, and determines the relationship of this variability to the strength of the signal itself across the visual field. It also investigates possible means to reduce the effects of this variability on between-test interpretation to allow for easier detection of progression. METHODS: 85 normal subjects participated in the study. The mfVEP was recorded using Accumap (ObjectiVision Pty Ltd, Sydney, Australia). Each subject was tested twice with an interval between visits of 3-4 weeks. Comparison between tests was performed using coefficient of variability (CV). Variability was also analysed using scaling and clustering procedures. RESULTS: In the majority of the retinal areas CV fell within 15-20%. Variability increased with eccentricity, but there was no age dependency. There was a significant reduction of variability (by 15.8 +/- 6%, Student's t-test p<0.0001) when a scaling procedure was applied and this was consistent at all eccentricities. A clustering procedure reduced variability on average by a further 18.5 +/- 4.5% (Student's t-test p<0.0001). This result was also consistent at all eccentricities. CONCLUSION: Between test comparisons of raw mfVEP traces is limited by a variability of at least 15%. While this variability required the amplitude of the individual VEP signal to change by 30-40% in order to detect progression, scaling and clustering procedures were able to reduce the required change to 20-25%, thus making an interpretation of consecutive test results more clinically viable.

Cluster Analysis↗
PubMed2006

Comparison of objective diagnostic tests in glaucoma: Heidelberg retinal tomography and multifocal visual evoked potentials.

PURPOSE: To compare sensitivity and specificity of functional and structural changes in glaucoma using two objective tests: the multifocal visual evoked potential (m-VEP) and Heidelberg retinal tomography II (HRT). PATIENTS AND METHODS: 41 glaucoma patients and 25 normal individuals participated in the study. One eye per individual was included in the study. Individuals were evaluated with Humphrey visual field (HVF) perimetry, m-VEP, and HRT. Moorfield regression analysis findings of HRT were compared with presence of scotoma on m-VEP. Linear regression analysis of quantitative variables, such as HVF mean deviation (MD), m-VEP discriminant score (Accumap Severity Index) and, global HRT parameters was also performed. RESULTS: m-VEP sensitivity and specificity were 93% and 96% respectively. HRT sensitivity and specificity were 79% and 92% respectively. The area under the receiver operating characteristic curve (ROC) for m-VEP was 0.96 and for HRT varied from 0.79 to 0.86 depending on the parameters used. Linear correlation between MD and Accumap Severity Index score was -77%, while that between HRT global parameters, Accumap Severity Index and MD were at best around 50%. Topographic comparison of the presence of scotoma on HVF and m-VEP in different areas of the visual field showed good agreement. Comparison of optic nerve head structural abnormality with corresponding areas of field defects on HVF and m-VEP showed poor to moderate agreement. CONCLUSION: The objective test of optic nerve function (m-VEP) and structure (HRT) can detect glaucomatous damage, with limited correlation. The 2 functional tests, HVF and m-VEP correlate better with each other than with HRT. It remains important to look for both functional and structural changes in order to detect all glaucoma cases.

Aged↗
PubMed2005

Spatial distribution of antibodies to Salmonella enterica serovar Typhimurium O antigens in bulk milk from Texas dairy herds.

Environmental factors that enhance either the survivability or dispersion of Salmonella enterica serovar Typhimurium (S. Typhimurium) could result in a spatial pattern of disease risk. The objectives of this study were to: (1) describe herd status based on antibody response to Salmonella Typhimurium as estimated from bulk tank milk samples and (2) to describe the resulting geographical patterns found among Texas dairy herds. Eight hundred and fifty-two bulk milk samples were collected from georeferenced dairy farms and assayed by an indirect enzyme-linked immunosorbent assay (ELISA) using S. Typhimurium lipopolysaccharide (LPS). ELISA signal-to-noise ratios for each bulk tank milk sample were calculated and used for geostatistical analyses. Best-fit parameters for the exponential theoretical variogram included a range of 438.8 km, partial sill of 0.060 and nugget of 0.106. The partial sill is the classical geostatistical term for the variance that can be explained by the herd's location and the nugget is the spatially random component of the variance. We have identified a spatial process in bulk milk tank titers for S. Typhimurium in Texas dairy herds and present a map of the expected smoothed surface. Areas with higher expected titers should be targeted in further studies on controlling Salmonella infection with environmental modifications.

Animals↗
PubMed2005

Objective perimetry using the multifocal visual evoked potential in central visual pathway lesions.

AIMS: To examine the ability of the multifocal pattern visual evoked potential (mVEP) to detect field loss in neurological lesions affecting the visual pathway from the chiasm to the cortex. METHOD: The mVEPs recorded in the clinic were retrospectively reviewed for any cases involving central neurological lesions. Recordings had been performed with the AccuMap V1.3 objective perimeter, which used an array of four bipolar occipital electrodes to provide four differently oriented channels for simultaneous recording. 19 patients with hemianopias were identified. Of these there were 10 homonymous hemianopias with hemifield type loss, two bitemporal hemianopias, and seven homonymous hemianopias with quadrantanopic distribution. A comparison with subjective field results and CT/MRI findings was done to determine the relation between the two methods of visual field mapping and any relation with the anatomical location of the lesion and the mVEP results. RESULTS: In all hemianopic type cases (12) the defect was demonstrated on the mVEP and showed good correspondence in location of the scotoma (nine homonymous and two bitemporal). The topographic distribution was similar but not identical to subjective testing. Of the seven quadrantanopic type hemianopias, only four were found to have corresponding mVEP losses in the same areas. In the three cases where the mVEP was normal, the type of quadrantanopia had features consistent with an extra-striate lesion being very congruous, complete, and respecting the horizontal meridian. CONCLUSIONS: The mVEP can detect field loss from cortical lesions, but not in some cases of homonymous quadrantanopia, where the lesion may have been in the extra-striate cortex. This supports the concept that the mVEP is generated in V1 striate cortex and that it may be able to distinguish striate from extra-striate lesions. It implies caution should be used when interpreting "functional" loss using the mVEP if the visual field pattern is quadrantic.

Adult↗
PubMed2001

Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models.

Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential anticancer agents targeting the ras oncogene and are currently in clinical trials. Whereas FTIs inhibit the farnesylation of Ha-Ras, they do not completely inhibit the prenylation of Ki-Ras, the allele most frequently mutated in human cancers. Whereas farnesylation of Ki-Ras is blocked by FTIs, Ki-Ras remains prenylated in FTI-treated cells because of its modification by the related prenyltransferase, geranylgeranyl:protein transferase type I (GGPTase-I). Hence, cells transformed with Ki-ras tend to be more resistant to FTIs than Ha-ras-transformed cells. To determine whether Ki-ras-transformed cells can be targeted by combining an FTI with a GGPTase-I inhibitor (GGTI), we evaluated potent, selective FTIs, GGTIs, and dual prenylation inhibitors (DPIs) that have both FTI and GGTI activity. We find that in human PSN-1 pancreatic tumor cells, which harbor oncogenic Ki-ras, and in other tumor lines having either wild-type or oncogenic Ki-ras, treatment with an FTI/GGTI combination or with a DPI blocks Ki-Ras prenylation and induces markedly higher levels of apoptosis relative to FTI or GGTI alone. We demonstrate that these compounds can inhibit their enzyme targets in mice by monitoring pancreatic and tumor tissues from treated animals for inhibition of prenylation of Ki-Ras, HDJ2, a substrate specific for FPTase, and Rap1A, a substrate specific for GGPTase-I. Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation. However, a 72-h infusion of a GGTI, at a dose sufficient to inhibit Ki-Ras prenylation in the presence of an FTI, causes death within 2 weeks of the infusion when administered either as monotherapy or in combination with an FTI. DPIs are also lethal after a 72-h infusion at doses that inhibit Ki-Ras prenylation. Because 24 h infusion of a high dose of DPI is tolerated and inhibits Ki-Ras prenylation, we compared the antitumor efficacy from a 24-h FTI infusion to that of a DPI in a nude mouse/PSN-1 tumor cell xenograft model and in Ki-ras transgenic mice with mammary tumors. The FTI and DPI were dosed at a level that provided comparable inhibition of FPTase. The FTI and the DPI displayed comparable efficacy, causing a decrease in growth rate of the PSN-1 xenograft tumors and tumor regression in the transgenic model, but neither treatment regimen induced a statistically significant increase in tumor cell apoptosis. Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy.

Alkyl and Aryl Transferases↗
PubMed2001

Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.

The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.

Alkyl and Aryl Transferases↗
PubMed2001

Diaryl ether inhibitors of farnesyl-protein transferase.

Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.

Alkyl and Aryl Transferases↗
PubMed2001

2-Arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase.

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.

Alkyl and Aryl Transferases↗
PubMed2001

Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors.

We have identified and characterized potent and specific inhibitors of geranylgeranyl-protein transferase type I (GGPTase I), as well as dual inhibitors of GGPTase I and farnesyl-protein transferase. Many of these inhibitors require the presence of phosphate anions for maximum activity against GGPTase I in vitro. Inhibitors with a strong anion dependence were competitive with geranylgeranyl pyrophosphate (GGPP), rather than with the peptide substrate, which had served as the original template for inhibitor design. One of the most effective anions was ATP, which at low millimolar concentrations increased the potency of GGPTase I inhibitors up to several hundred-fold. In the case of clinical candidate l-778,123, this increase in potency was shown to result from two major interactions: competitive binding of inhibitor and GGPP, and competitive binding of ATP and GGPP. At 5 mm, ATP caused an increase in the apparent K(d) for the GGPP-GGPTase I interaction from 20 pm to 4 nm, resulting in correspondingly tighter inhibitor binding. A subset of very potent GGPP-competitive inhibitors displayed slow tight binding to GGPTase I with apparent on and off rates on the order of 10(6) m(-)1 s(-)1 and 10(-)3 s(-)1, respectively. Slow binding and the anion requirement suggest that these inhibitors may act as transition state analogs. After accounting for anion requirement, slow binding, and mechanism of competition, the structure-activity relationship determined in vitro correlated well with the inhibition of processing of GGPTase I substrate Rap1a in vivo.

Adenosine Triphosphate↗
PubMed2001

3,8-Diazabicyclo[3.2.1]octan-2-one peptide mimetics: synthesis of a conformationally restricted inhibitor of farnesyltransferase.

A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.

Alkyl and Aryl Transferases↗
PubMed2001

Central corneal thickness, tonometry, and ocular dimensions in glaucoma and ocular hypertension.

PURPOSE: To assess possible correlations between central corneal thickness, tonometry, and ocular dimensions. PATIENTS AND METHODS: One hundred seventeen eyes of 117 patients who were not taking any intraocular pressure-lowering medications were studied prospectively. Forty-one patients had ocular hypertension; 13 patients had primary open-angle glaucoma; and 10 patients had normal-pressure glaucoma. Twenty-three healthy eyes were included. Thirty glaucoma suspects (10 patients monitored for possible normal-pressure glaucoma and 20 patients with intermittent ocular hypertension) were included for correlation analysis. Tonometry was performed with Goldmann applanation and pneumotonometry, and central corneal thickness, anterior chamber depth, lens thickness, and axial length were measured ultrasonically. RESULTS: Central corneal thickness was lowest in eyes with normal-pressure glaucoma (538 +/- 51 microm), highest in eyes with ocular hypertension (570 +/- 32 microm), and intermediate and similar in eyes with primary open-angle glaucoma and healthy eyes (547 +/- 34 microm and 554 +/- 32 microm, respectively). These differences were significant (P = 0.028). Goldmann applanation tonometry and central corneal thickness were weakly correlated (r = 0.12, P = 0.205), with a 0.2-mm Hg change per 10-microm variation in central corneal thickness. Pneumotonometry measurements were more strongly correlated with central corneal thickness (r = 0.21, P < 0.05). Lens thickness was strongly correlated with age (r = 0.57, P < 0.001). Anterior chamber depth was negatively correlated with lens thickness and age (r = -0.29, P < 0.005 and r = -0.25, P < 0.01). Axial length was correlated with anterior chamber depth and age (r = 0.5, P < .001 and r = -0.19, P < 0.05). CONCLUSION: Eyes diagnosed as having ocular hypertension have thicker corneas and eyes labeled as having normal-pressure glaucoma have thinner corneas, when compared with healthy eyes or eyes with primary open-angle glaucoma. The effect of central corneal thickness on Goldmann applanation tonometry accuracy appears to be small and usually not clinically relevant. When corneal thickness is markedly different from normal, the clinician may need to factor this into diagnosis and management.

Aged↗
PubMed2001

Triangular wire.

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Humans↗
PubMed2001

Electroencephalogram-based scaling of multifocal visual evoked potentials: effect on intersubject amplitude variability.

PURPOSE: The interindividual variability of the visual evoked potential (VEP) has been recognized as a problem for interpretation of clinical results. This study examines whether VEP variability can be reduced by scaling responses according to underlying electroencephalogram (EEG) activity. METHODS: A multifocal objective perimeter provided different random check patterns to each of 58 points extending out to 32 degrees nasally. A multichannel VEP was recorded (bipolar occipital cross electrodes, 7 min/eye). One hundred normal subjects (age 58.9 +/- 10.7 years) were tested. The amplitude and inter-eye asymmetry coefficient for each point of the field was calculated. VEP signals were then normalized according to underlying EEG activity recorded using Fourier transform to quantify EEG levels. High alpha-rhythm and electrocardiogram contamination were removed before scaling. RESULTS: High intersubject variability was present in the multifocal VEP, with amplitude in women on average 33% larger than in men. The variability for all left eyes was 42.2% +/- 3.9%, for right eyes 41.7% +/- 4.4% (coefficient of variability [CV]). There was a strong correlation between EEG activity and the amplitude of the VEP (left eye, r = 0.83; P < 0.001; right eye, r = 0.82; P < 0.001). When this was used to normalize VEP results, the CVs dropped to 24.6% +/- 3.1% (P < 0.0001) and 24.0% +/- 3.2% (P < 0.0001), respectively. The gender difference was effectively removed. CONCLUSIONS: Using underlying EEG amplitudes to normalize an individual's VEP substantially reduces intersubject variability, including differences between men and women. This renders the use of a normal database more reliable when applying the multifocal VEP in the clinical detection of visual field changes.

Adult↗