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Biomedical subjects

D G Birch

Publications and source records attributed to D G Birch.

At least 55 records · Page 3Linked to original sources
PubMed1996

Abnormalities of the retinal cone system in retinitis pigmentosa.

Patients with retinitis pigmentosa (RP) show delayed inner retinal responses as measured by the cone ERG response to a 30 Hz stimulus. To determine the extent to which this delay results from abnormalities of cone phototransduction, cone ERGs to single flashes were obtained from 21 patients with RP and a model of cone phototransduction was fitted to the leading edge of the a-waves of these ERGs. Nearly all patients showed an abnormally low sensitivity of cone phototransduction consistent with a reduction in the amplification of transduction. This abnormality can account for part of the delayed 30 Hz response. Analysis of post-receptoral potentials indicated that RP also slows the responses of the inner retina. A combination of these two factors, a sensitivity change at the receptor and a delay in the response of the inner retina, produces the delayed response of the cone flicker ERG in patients with RP.

Adaptation, Ocular↗
PubMed1996

Recovery kinetics of human rod phototransduction inferred from the two-branched alpha-wave saturation function.

Electroretinographic data obtained from human subjects show that bright test flashes of increasing intensity induce progressively longer periods of apparent saturation of the rod-mediated electroretinogram (ERG) alpha wave. A prominent feature of the saturation function [the function that relates the saturation period T with the natural logarithm of flash intensity (ln I(f)] is its two-branched character. At relatively low flash intensities (I(f) below approximately 4 x 10(4) scotopic troland second), T increases approximately in proportion to ln I(f) with a slope [delta T/delta (ln I(f)] of approximately 0.3 s. At higher flash intensities, a different linear relation prevails, in which [deltaT/delta(ln I(f) is approximately 2.3 s [Invest. Ophthalmol. Vis. Sci. 36, 1603 (1995)]. Based on a model for photocurrent recovery in isolated single rods [Vis. Neurosci. 8, 9 (1992)], it was suggested that the upper-branch slope of approximately 2.3 s represents tau R*, the lifetime of photoactivated rhodopsin (R*). Here we show that a modified version of this model provides an explanation for the lower branch of the alpha-wave saturation function. In this model, tau E* is the exponential lifetime of an activated species (E*) within the transducin or guanosine 3', 5'-cyclic monophosphate (cGMP) phosphodiesterase stages of rod phototransduction; the generation of E* by a single R* occurs within temporally defined, elemental domains of disk membrane; and Ex, the immediate product of E* deactivation, is converted only slowly (time constant tau Ex) to E, the form susceptible to reactivation by R*. The model predicts that the decay of flash-activated cGMP phosphodiesterase (PDE*) is largely independent of the deactivation kinetics of R* at early postflash times (i.e., at times preceding or comparable with the lifetime tau E*) and that the lower-branch slope (approximately 0.3s) of the a-wave saturation function represent tau E*. The predicted early-stage independence of PDE* decay and R* deactivation furthermore suggests a basis for the relative constancy of the single-photon response observed in studies of isolated rods. Numerical evaluation of the model yields a value of approximately 6.7s for the time constant tau Ex.

Humans↗
PubMed1996

Beta wave of the scotopic (rod) electroretinogram as a measure of the activity of human on-bipolar cells.

The beta wave of the human electroretinogram (ERG) is widely believed to reflect the activation of on-bipolar cells. However, the shape of the beta wave is also influenced by the activity of other cell types. To assess how the activity of on-bipolar cells is reflected in the human ERG, rod ERG's were recorded in the dark and on the steady fields. Derived P2 responses were obtained by computer subtraction of the receptor contribution to the ERG. The light-adapted derived P2 was shown to have properties similar to those predicted from previous studies of on-bipolar activity. This was also true of the dark-adapted derived P2 if a small (less than 10%) contribution from a negative potential was taken into consideration. The derived P2, and under certain conditions the beta wave, can be used to study rod on-bipolar activity.

Dark Adaptation↗
PubMed1995

Phototransduction in human cones measured using the alpha-wave of the ERG.

To study human cone phototransduction, the alpha-wave of the ERG was recorded from color normals, dichromats, and patients with retinitis pigmentosa. A model of the activation phase of phototransduction, previously fitted to responses from single rods and the rod alpha-wave, was modified and fitted to the human cone alpha-wave. The modified model fits the cone alpha-wave well and allows questions about human cone phototransduction to be addressed. In particular, we conclude that: (1) the amplification of the activation phase of human cone transduction is comparable to that of the human rods. (2) Steady lights have relatively little effect on the amplification of cone transduction. (3) The normal alpha-wave elicited by red flashes is dominated by the L cones, consistent with a ratio of L:M cones of > 1. (4) Retinitis pigmentosa caused by mutations of the rhodopsin gene can affect cone phototransduction. Finally, a simpler computational expression is shown to approximate the modified model's responses.

Adult↗
PubMed1995

Metabolism of omega-3 fatty acids in patients with autosomal dominant retinitis pigmentosa.

Abnormalities in lipid metabolism have been reported in numerous patients with retinitis pigmentosa. As an initial step in evaluating these anomalies, two trials of fatty acid intervention were conducted with autosomal dominant retinitis pigmentosa (adRP) patients and controls. The first trial addressed absorption and incorporation of omega 3 long-chain fatty acids from a fish-oil concentrate into red blood cell (RBC) lipids. The utilization of omega 3 long-chain fatty acids by adRP patients was found to be equivalent to that of controls. The second trial addressed the conversion of precursor, eicosapentaenoic acid (EPA, 20:5 omega 3), to end-product, docosahexaenoic acid (DHA, 22:6 omega 3), following oral supplementation of EPA ethyl ester. Although the levels of EPA and the intermediate, docosapentaenoic acid (22:5 omega 3), were both elevated by EPA supplementation in RBCs of adRP patients with rhodopsin gene mutations and controls, DHA production was elevated only in controls. Based on these results, we suggest the presence of a metabolic defect in the final stages of DHA biosynthesis.

Adult↗
PubMed1995

Rod transduction parameters from the a wave of local receptor populations.

The analysis of electroretinogram a waves from locally stimulated populations of rods is complicated by the presence of scattered light within the eye. Scattered-light and cone contributions can be assessed after brief flashes of light designed to saturate only rods in the locally stimulated area. Subtracting the scattered-light and the cone responses from the local electroretinogram gives a pure rod a wave that can be fitted with models of photoreceptor activity. We demonstrate the feasibility of this technique by recording local rod a waves from a group of five normal subjects and by fitting the a waves with the rod model to derive transduction parameters. The local rod a waves are compared with expected responses derived from simulations in which the response of the entire retina to heterogeneous illumination is mimicked.

Adult↗
PubMed1995

Abnormal activation and inactivation mechanisms of rod transduction in patients with autosomal dominant retinitis pigmentosa and the pro-23-his mutation.

PURPOSE: The leading edge of the rod a-wave in normal human subjects can be fit with a computational model of the activation phase of transduction to provide parameters analogous to those obtained from individual photoreceptors. The authors extend this work to the kinetics of recovery after saturating flashes. METHODS: Electroretinograms were recorded from three patients with autosomal dominant retinitis pigmentosa and the pro-23-his rhodopsin mutation, two patients with rod monochromatism, and five normal subjects. Rod-only a-waves were obtained for a series of flashes ranging from 4.4 to 10.1 ln (1.9 to 4.4 log) scot td-sec. One set of parameters describing the activation process was derived from fits to the a-wave model. A double-flash paradigm was used to study inactivation mechanisms. The first flash was achromatic and varied in intensity (I(f)) from 6.1 to 13.9 ln (2.6 to 6.0 log) scot td-sec. The second flash was a short-wavelength probe held constant at 9.3 ln (4.0 log) scot td-sec. Cone components were elicited with a photopically matched long-wavelength stimulus and were computer subtracted. Recovery at each I(f) was followed by measuring the amplitude to the probe flash at various interstimulus intervals (ISI). The critical time (Tc) before the initiation of rod recovery was determined from the function relating relative rod amplitude to ISI. RESULTS: Recovery from activation was similar in normal subjects and in patients with rod monochromatism. Over a large range of I(f) above rod saturation, Tc increased in proportion to ln I(f). The mean slope of the function relating Tc to I(f) was 2.3 s/ln I(f) when I(f) varied between 11 and 13.9 ln scot td-sec. Patients with retinitis pigmentosa and the pro-23-his rhodopsin mutation had a decrease in the gain of activation. They also had significantly slower than normal recovery after high test flash intensities, such that the slope of the function relating Tc to ln I(f) was 12.1 seconds. CONCLUSION: Available data from other species imply that complete, transient activation of transducin (T saturation) occurs within or below the investigated range of flash intensities. Based on the slope of the delay function (delta Tc/ delta ln I(f)) above 11 ln scot td-sec, the authors hypothesize that the lifetime of activated rhodopsin (R) in normal human rods is approximately 2.3 seconds. In patients with the pro-23-his mutation, the gain of the activation mechanism is reduced and the reaction determining the delta Tc/ delta ln I(f) slope is markedly slowed. The activated species that exhibits this prolonged lifetime could be the mutant rhodopsin itself.

Adolescent↗
PubMed1995

Docosahexaenoic acid in red blood cells of patients with X-linked retinitis pigmentosa.

PURPOSE: Abnormalities in the distribution of long-chain polyunsaturated fatty acids (LCPUFA) have been documented in plasma of patients with X-linked retinitis pigmentosa (XLRP). In this study, fatty acid profiles of red blood cells (RBC) were used as an index for LCPUFA metabolism in patients with XLRP because RBC lipids reflect membrane-associated fatty acids. Correlations between LCPUFA content and electroretinographic (ERG) function were assessed. METHODS: Mean ages for the XLRP group (n = 18) and control group (n = 28) were 22 +/- 18 years and 24 +/- 16 years, respectively. Electroretinographic assessment included the International Society for the Clinical Electrophysiology of Vision standard protocol. Methyl esters of RBC fatty acids were analyzed by capillary column gas chromatography. RESULTS: The content of the omega 3 fatty acid, docosahexaenoic acid (DHA), was 40% lower in the group with XLRP (23.1 +/- 5.9 micrograms/ml RBC [mean +/- 1 SD]) than in normal subjects (38.6 +/- 9.4 micrograms/ml RBC, t = 6.24, P < 0.0001). Total omega 3 LCPUFA content in patients with XLRP was reduced by 30% from normal levels compared to a 10% reduction in omega 6 LCPUFA levels. Elongation reactions for omega 3, omega 6, saturated fatty acids, and monounsaturated fatty acids were markedly lower for patients with XLRP than for normal subjects. Multiple regression analysis revealed that RBC-DHA was a significant determinant for amplitude and implicit time of cone ERG responses. CONCLUSIONS: The overwhelming majority of patients with XLRP have lower levels of DHA in RBCs compared to normally sighted control subjects. An analysis of fatty acid profiles suggests a metabolic defect in fatty acid chain elongation mechanisms. The significant association between DHA content and cone ERG response parameters is consistent with an effect of lipid abnormalities on membrane environment and physiology in retinal photoreceptors.

Adolescent↗
PubMed1995

Rod phototransduction in retinitis pigmentosa. Distinguishing alternative mechanisms of degeneration.

PURPOSE: To test alternative hypotheses concerning the mechanisms of rod degeneration in retinitis pigmentosa (RP). METHODS: Full-field rod electroretinograms and rod visual fields were measured for 15 patients with RP and a normal control group. The rod a-wave was fitted with a computational model based on known transduction biochemistry. The values of td (the initial delay), S (a sensitivity parameter), and RmP3 (the maximum amplitude) were estimated. Rod b-wave amplitudes were fitted with the Michaelis-Menten equation, and the parameters Kbw (the semisaturation intensity--a sensitivity parameter) and Vmax (the maximum amplitude) were estimated. RESULTS: The patients all had significantly reduced values of RmP3, indicating rod receptor damage, and a wide range of S values. Three patients had S values in the normal range. Four had abnormal S values but normal thresholds in some locations in their visual field. The remaining patients had abnormal values of S and entirely abnormal visual fields. Three of those had a history of large elevations in Kbw. For all patients, the changes in Kbw and Vmax followed closely the changes in S and RmP3, respectively. CONCLUSION: Retinitis pigmentosa has a varying initial impact on the activation phase of rod transduction. Available evidence suggests that the activation of transduction is initially normal in most patients with RP. In some patients, RP appears to result in a reduced transduction amplification from birth. In all patients, subsequent degeneration of the rods effects progressive reductions in transduction amplification but no other major functional changes. Outer segment shortening and local dropout of rods appear to have little functional impact.

Adolescent↗
PubMed1994

Safety and efficacy of omega-3 fatty acids in the nutrition of very low birth weight infants: soy oil and marine oil supplementation of formula.

Because formula-fed preterm infants may be at risk of omega 3 essential fatty acid deficiency, we tested experimental formulas supplemented with soy oil to provide alpha-linolenic acid or marine oil to provide preformed omega 3 long-chain polyunsaturated fatty acids at a level comparable to that of human milk. This report addresses the effect of feeding formula supplemented with soy oil or with soy and marine oils on growth, clinical tolerance, coagulation test results, changes in erythrocyte membrane fluidity, and plasma concentrations of vitamins A and E in very low birth weight infants from 30 to 57 weeks of postconceptional age. "Healthy" preterm infants were maternally selected to receive human milk or selected at random to receive commercial ready-to-feed liquid formula, which provided limited omega 3 fatty acid, or experimental formulas supplemented with soy oil or soy and marine oils. Results of this study indicate that formula enriched with soy oil or soy and marine oils containing preformed omega 3 long-chain polyunsaturated fatty acids does not induce abnormalities in growth, clotting function, erythrocyte membrane fluidity, or vitamin A or E levels in healthy very low birth weight preterm infants. Additional studies to evaluate safety in a representative preterm population are required.

Analysis of Variance↗
PubMed1994

Understanding changes in the b-wave of the ERG caused by heterogeneous receptor damage.

PURPOSE: To understand better the relationship between heterogeneous receptor damage and the changes in the b-wave of the rod ERG. METHODS: A computational model of the b-wave is used to simulate b-waves from retinas with two regions (a healthier and a more affected region) differing in area and sensitivity. The peak-to-peak amplitudes of the simulated b-waves are fitted with a Naka-Rushton equation, and the parameters log K and Vmax are estimated. Insights gained from these simulations are tested against rod ERGs and rod visual fields from patients with autosomal dominant retinitis pigmentosa (n = 11) and cone-rod dystrophy (n = 17). RESULTS: In the simulated retinas, Vmax decreases when the more affected region of receptors is less sensitive than the healthier region by more than 0.5 log unit. However, the relative change in Vmax does not match the relative area of the more affected region unless this region is depressed by 2.0 log units or more. As the more affected region loses sensitivity, log K at first increases but then decreases and approaches the log K of the healthier region for losses greater than 2.0 log units or so relative to the healthier region. For the patients' data, the simulations predict the general relationships observed between the summary statistics of the visual fields (e.g., area of field and mean of log sensitivity changes in the field) and the changes in log K and Vmax. CONCLUSION: A decrease in Vmax indicates that regions of the patient's retina have lost 0.5 log unit or more of sensitivity. An increase in log K indicates that either the healthiest part of the patient's retina is abnormal by at most delta log K, a large part of the retina has lost considerable sensitivity (i.e., 0.5 to 2.0 log units) but is still contributing to the response, or both.

Adolescent↗
PubMed1994

Rod phototransduction in retinitis pigmentosa: estimation and interpretation of parameters derived from the rod a-wave.

PURPOSE: Relationships between the Lamb and Pugh model of transduction in single rod photoreceptors and the parameters derived from human rod a-waves are examined to evaluate transduction abnormalities in retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). METHODS: ERGs were obtained from 15 patients, 11 with RP and 4 with CRD, and from 15 normal subjects. Rod-only responses were derived from responses to blue (W47B) flashes over a wide range of flash energies by computer-subtracting estimates of the cone contribution. A model of the rod's response was fitted to the a-waves of the rod-only responses as well as to the responses to the blue flashes by estimating three parameters-sensitivity (S), delay (td), and maximum response (RmP3). To assess the limits of the cone contributions to the parameters of the model, ERGs were obtained from two of the patients, two normal subjects, and three additional patients with nondetectable rod responses using white flashes. RESULTS: All patients had significantly decreased values of RmP3, and eight had significantly decreased values of S compared to the control subjects. The values of the parameters estimated from the responses to the blue flashes were reasonably similar to those for the rod-only responses except in patients with nondetectable rod signals. For the white flashes, the estimate of S was considerably larger and the fit of the model noticeably poorer. CONCLUSIONS: The authors reached two conclusions. First, some forms of RP and CRD alter the activation stages of transduction. Transduction appears normal in other patients, despite extensive receptor damage as indicated by markedly reduced RmP3 values. Second, the cone contribution to a blue flash only affects the estimate of the key parameters in patients in whom the rod component is minimal. The cone contribution to a white flash contaminates the fit and the estimate of the parameters in all patients and normal subjects.

Adolescent↗
PubMed1993

Pattern-reversal electroretinographic follow-up of laser photocoagulation for subfoveal neovascular lesions in age-related macular degeneration.

Pattern-reversal electroretinograms were used as an objective measure of macular integrity in a subset of 42 patients who were randomly assigned at enrollment in the Macular Photocoagulation Study to receive laser photocoagulation or no treatment for a subfoveal neovascular lesion. Pattern-reversal electroretinograms were obtained before randomization, three months and six months after randomization, and at six-month intervals randomization, and at six-month intervals thereafter. Responses were obtained to phase-alternating checkerboards of varying check size. Extrapolation of the best-fit regression line relating log-check size to amplitude was used to determine retinal acuity. At each follow-up period, including three months after laser photocoagulation, treated eyes showed less loss in pattern-reversal electroretinographic acuity than untreated eyes. The decline in pattern-reversal electroretinographic acuity in untreated eyes corresponded to the rapid growth in the area of the subfoveal neovascular lesion. The more gradual decline in treated eyes was consistent with an increase in the area of the treatment scar caused by spreading atrophy.

Aged↗
PubMed1993

A leucine to arginine amino acid substitution at codon 46 of rhodopsin is responsible for a severe form of autosomal dominant retinitis pigmentosa.

To evaluate the extent to which rhodopsin mutations are involved in autosomal dominant forms of retinitis pigmentosa (adRP) we collected DNAs from patients with adRP and screened the rhodopsin coding sequence with single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. This screening revealed a thymidine to guanine transversion at nucleotide 431 (nucleotide sequence numbers as per Genebank) in affected members of one family (RFS04). The nucleotide substitution leads to a missense mutation at the 46th amino acid of rhodopsin. The mutation occurs at an amino acid conserved in mammals and changes the hydrophobic nature of the protein at a transmembrane-spanning region. The mutation causes the substitution of a non-polar hydrophobic amino acid, leucine, for the basic amino acid arginine (Leu46Arg). This nucleotide substitution is unique to the family studied and occurs in the affected individuals in the family. Full-field electroretinograms (ERGs) in four affected members of the family showed nondetectable rod responses at an early age, with markedly reduced cone responses, and a faster than average rate of progression of the phenotype as measured by yearly ERGs.

Adolescent↗
PubMed1993

Red blood cell fatty acid levels in patients with autosomal dominant retinitis pigmentosa.

Fatty acid profiles were determined in red blood cell (RBC), plasma lipids and lipid fractions from 50 patients with autosomal dominant retinitis pigmentosa (ADRP) and 20 normal-sighted controls. In plasma of affected patients, significant increases in omega 6 long-chain derivatives compared to controls resulted in elevated fatty acid unsaturation whereas, in RBCs, significant decreases in the levels of omega 6 and omega 3 long-chain polyunsaturates and a reduced unsaturation index were demonstrated (P < 0.01). The disproportionate levels of long-chain fatty acids in plasma vs. RBCs were consistent with abnormal function of acyl group transfer from plasma lipids to target tissues such as RBCs or, possibly, retina. Metabolic lipid anomalies were evaluated in two sub-groups of patients with ADRP; ten with the highest and ten with the lowest RBC lipid levels of the omega 3 fatty acid, docosahexaenoic acid (DHA). Fatty acid product/precursor relationships in the sub-groups revealed reduced chain elongation and omega 3 fatty acid desaturation associated with reduced ratios of rod-to-cone electroretinographic amplitudes. Based on these results, we suggest that the heterogenic ADRP population includes a sub-group of patients characterized by abnormal fatty acid metabolism that may effect membrane structure and visual function.

Adolescent↗
PubMed1993

Light adaptation of human rod receptors: the leading edge of the human a-wave and models of rod receptor activity.

The human rod receptors can be studied by measuring the leading edge of the rod a-wave of the ERG. Computational models, previously shown to fit the recordings from single rods, are fitted to dark-adapted a-wave responses. A model proposed by Lamb and Pugh [(1992) Journal of Physiology, 499, 719-758] fits slightly better than the traditional models based upon n-stage exponential filters. To test alternative models of rod light adaptation, a-waves were recorded to flashes presented upon steady adapting lights. Steady adapting lights decrease the rods' sensitivity. Human rods must adapt as response compression alone predicts far greater decreases in sensitivity. The evidence suggests that the mechanism(s) of adaptation include a change in the time-course of the rod's response. Human rods appear to adapt in much the same manner as do the rods of other vertebrates.

Adaptation, Ocular↗
PubMed1993

Effects of supplementation with omega 3 long-chain polyunsaturated fatty acids on retinal and cortical development in premature infants.

Deficiency of omega 3 long-chain polyunsaturated fatty acids (LCPUFAs) in vertebrates produces subtle adverse effects on visual and neural function. Preterm infants 1) are deprived of vital intrauterine fat accretion during late pregnancy, 2) must rely solely on formula for fatty acid supplies if not breastfed, and 3) may have limited postnatal desaturase activity. In a study to evaluate the necessity of dietary omega 3 LCPUFAs, preterm infants were fed human milk, corn-oil-based formula (omega 3 fatty acid deficient), soy-oil-based formula (rich in precursor fatty acids), or marine-oil-supplemented formula (containing docosahexaenoic acid). At 36 and 57 wk postconception, the LCPUFA profiles in red blood cell lipids were nearly equivalent in the human-milk and marine-oil groups whereas the corn-oil group had markedly lower values for omega 3 fatty acids. Rod photoreceptor function was significantly less mature in the corn-oil group compared with the human-milk and marine-oil-enriched groups in early postnatal development (36 wk). The corn-oil group also had impaired visual acuity at both 36 and 57 wk. The potential benefit of omega 3 LCPUFA-enriched full-term formula is discussed. The study supports a role for omega 3 LCPUFAs as required nutrients for the optimal maturation of visual and cortical function in preterm infants.

Breast Feeding↗