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Biomedical subjects

D G Birch

Publications and source records attributed to D G Birch.

At least 37 records · Page 2Linked to original sources
PubMed2000

Impact of early dietary intake and blood lipid composition of long-chain polyunsaturated fatty acids on later visual development.

BACKGROUND: In contrast to human milk, current infant formulas in the United States do not contain omega3 and omega6 long-chain polyunsaturated fatty acids. This may lead to suboptimal blood lipid fatty acid profiles and to a measurable diminution of visual function in developing term infants. The need for docosahexaenoic acid and arachidonic acid supplementation in the infant diet was evaluated in a double-blind, randomized clinical trial. METHODS: Healthy term infants were randomized to diets of (1) commercial formula, (2) docosahexaenoic acid-enriched formula (0.35% of total fatty acids), or (3) docosahexaenoic acid- (0.36%) and arachidonic acid- (0.72%) enriched formula. Eighty-seven infants completed the 17-week nutritional trial, and 58 were observed until 52 weeks of life. A reference group was exclusively breast fed for at least 17 weeks (n = 29). Outcome measures included electroretinographic responses, visual evoked potentials, and blood fatty acid analysis in infants at birth and at 6, 17, and 52 weeks of age. RESULTS: Commercial formula-fed infants had 30% to 50% lower content of docosahexaenoic acid in total red blood cell lipids during the 17-week feeding trial compared with breastfed infants. Significant differences persisted at the 1-year follow-up. Arachidonic acid content was consistently reduced in the commercial formula group by 15% to 20%. Infants fed long-chain polyunsaturated fatty acid-enriched formulas had docosahexaenoic acid and arachidonic acid blood lipid profiles resembling those of human milk-fed infants. Infants receiving this enriched formula had more mature electroretinographic responses than commercial formula-fed infants at 6 weeks of age. Human milk-fed and docosahexaenoic acid-enriched formula-fed infants had better visual acuity than commercial formula-fed infants at both 17 and 52 weeks of age. Early (17-week) fatty acid profiles in blood lipids were correlated with later (52-week) visual function development in study infants. CONCLUSIONS: Results from this clinical trial demonstrate that long-chain polyunsaturated fatty acid supplementation of formula in term infants produces blood lipid fatty acid profiles that are similar to those observed in breast-fed infants. This supplementation leads to better visual function later in life (i.e., 1 year of age) than that shown by infants fed commercial formula.

Arachidonic Acid↗
PubMed2000

Visual phenotype in patients with Arg41Gln and ala196+1bp mutations in the CRX gene.

Our aim was to describe the visual function characteristics of affected members from two unrelated families with different dominant mutations in the CRX gene. Standard full-field ERGs and high-intensity a-wave series were obtained. In addition, in most subjects, dark-adapted (DA) thresholds, color vision function (arrangement tests), and static perimetry were assessed. A point mutation in codon 41 of the CRX gene (Arg41Gln) was identified in family members from the RFS087 family who were tested on several occasions since 1983. Depending on age, affected members showed varying degrees of acuity loss, normal or slightly elevated DA thresholds, reduced cone a- and b-wave amplitudes, normal or minimally delayed cone b-wave implicit times, and normal rod and cone phototransduction gain parameters. An insertion mutation (Ala196+1bp) was found in two members of another family (RFS014). Affected members showed reduced visual acuity, normal or slightly elevated DA thresholds, relatively preserved rod ERG and substantially reduced or undetectable cone ERG, and normal rod phototransduction gain parameters. The Arg41Gln was associated with a late-onset, slowly progressing mild form of cone-rod dystrophy with cone loss but preserved rod and cone sensitivity until later in life. The Ala196+1bp mutation was associated with an early-onset, severe form of cone-rod dystrophy similar to that described in the original CORD2 family (Evans et al., Arch Ophthalmol 1995;113:195-201).

Adult↗
PubMed1999

Disruption of a retinal guanylyl cyclase gene leads to cone-specific dystrophy and paradoxical rod behavior.

One of two orphan photoreceptor guanylyl cyclases that are highly conserved from fish to mammals, GC-E (or retGC1) was eliminated by gene disruption. Expression of the second retinal cyclase (GC-F) as well as the numbers and morphology of rods remained unchanged in GC-E null mice. However, rods isolated from such mice, despite having a normal dark current, recovered from a light flash markedly faster. Unexpectedly, the a- and b-waves of electroretinograms (ERG) from dark-adapted null mice were suppressed markedly. Cones, initially present in normal numbers in the retina, disappeared by 5 weeks, based on ERG and histology. Thus, the GC-E-deficient mouse defines a model for cone dystrophy, but it also demonstrates that morphologically normal rods display paradoxical behavior in their responses to light.

Adaptation, Ocular↗
PubMed1999

Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice.

Rim protein (RmP) is an ABC transporter of unknown function in rod outer segment discs. The human gene for RmP (ABCR) is affected in several recessive retinal degenerations. Here, we characterize the ocular phenotype in abcr knockout mice. Mice lacking RmP show delayed dark adaptation, increased all-trans-retinaldehyde (all-trans-RAL) following light exposure, elevated phosphatidylethanolamine (PE) in outer segments, accumulation of the protonated Schiff base complex of all-trans-RAL and PE (N-retinylidene-PE), and striking deposition of a major lipofuscin fluorophore (A2-E) in retinal pigment epithelium (RPE). These data suggest that RmP functions as an outwardly directed flippase for N-retinylidene-PE. Delayed dark adaptation is likely due to accumulation in discs of the noncovalent complex between opsin and all-trans-RAL. Finally, ABCR-mediated retinal degeneration may result from "poisoning" of the RPE due to A2-E accumulation, with secondary photoreceptor degeneration due to loss of the RPE support role.

ATP-Binding Cassette Transporters↗
PubMed1999

Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview.

Retinal degeneration is an early consequence of the group of lysosomal storage diseases collectively referred to as the neuronal ceroid lipofuscinoses (NCLs). This review details specialized techniques that have evolved for retinal assessment in patients with hereditary retinal degeneration. A standard ERG protocol is described for assessing rod- and cone-mediated function. Standardization will be crucial for planning and implementing multicenter trials as rational therapeutic intervention becomes available. In recent years, there has been a dramatic increase in knowledge of the molecular biological bases of retinitis pigmentosa and allied retinal degenerations. Rather than attempting a comprehensive summary, this review stresses the concepts of genetic, allelic, and clinical heterogeneity, which have obvious parallels in the NCLs. Many of the mutations that cause retinal degeneration are in genes that encode photoreceptor cascade proteins; others are in genes that encode photoreceptor structural proteins. Recent advances in linking the retinal degeneration slow (RDS) and ATP-binding cassette transporter retina (ABCR) genes to a variety of disease phenotypes will be summarized. Clinical heterogeneity even among family members with the same mutation raises the possibility that modifying factors, either genetic or environmental, could influence the severity of the disease. Here, we focus on vitamin A and docosahexaenoic acid, two potential nutritional modifiers that have received considerable attention in recent years.

Child↗
PubMed1999

Fatty acid profile of buccal cheek cell phospholipids as an index for dietary intake of docosahexaenoic acid in preterm infants.

Cheek cells (buccal epithelia) were utilized as a noninvasive index of fatty acid status in a study of the effects of n-3 long chain polyunsaturated fatty acid supplementation on visual function in preterm infants. The fatty acid profile of cheek cell phospholipids was directly correlated with the dietary docosahexenoic acid (DHA) intake of infants receiving: (i) primarily human milk; (ii) n-3 fatty acid-deficient, corn oil-based, commercial formula (CO); (iii) alpha-linolenic acid-enriched, soy oil-based, commercial formula; or (iv) experimental formula enriched with soy and marine oils providing a DHA level equivalent to that in human milk. In a subset of infants with complete cheek cell fatty acid profiles and visual function assessments, preterm infants at both 36 wk (n = 63) and 57 wk (n = 45) postconceptional age had significantly (P < 0.0005) reduced cheek cell phospholipid DHA levels in the n-3-deficient, CO-fed group compared to the other diet groups. The DHA content in cheek cell phospholipids was highly correlated (P < 0.0005) with that of both red blood cell lipids and plasma phospholipids at the 36- and 57-wk time points. The DHA content in cheek cell lipids of infants at 36 wk was significantly correlated with electroretinographic responses (r = -0.29; P < 0.03) and visual acuity (r = -0.31; P < 0.02) as measured by visual-evoked potentials (VEP). Cheek cell DHA was highly correlated (r= -0.57; P < 0.0005) with VEP acuity at the 57-wk time point. These results suggest that the fatty acid profile of cheek cells is a valid index of essential fatty acid status, can be monitored frequently, and is associated with functional parameters in infants.

Cheek↗
PubMed1999

Yearly rates of rod and cone functional loss in retinitis pigmentosa and cone-rod dystrophy.

OBJECTIVE: To provide the first measures of the relative rates of rod and cone functional loss in patients with retinitis pigmentosa (RP) or cone-rod dystrophy (CRD). DESIGN: Five-year, prospective natural history study. PARTICIPANTS: Ninety-six patients (67 with RP and 29 with CRD) retaining measurable rod-mediated visual function and 5 normal subjects were tested at baseline and annually for 4 consecutive years. MAIN OUTCOME MEASURES: Tests of visual function included visual acuity, dark-adaptation thresholds, dark-adapted static perimetry, and rod and cone computer-averaged electroretinograms (ERGs), which were obtained over a range of retinal illuminances. Intervisit variability for each measure was obtained in a subset of patients who were tested twice within a 2-month interval and was used to determine whether an individual patient had shown progression, regression, or no change over a particular study interval. RESULTS: Over a 4-year interval, a significant number of patients with RP (60%) and CRD (62%) showed a decline in cone ERG amplitude. For rod ERG amplitude, the percentage of patients with RP or CRD showing progression was 64% and 45%, respectively. Although visual acuity, dark-adapted threshold, and rod visual field area also declined significantly over the 4-year period, the mean rate of change and the numbers of patients showing progression on these measures were lower than those for ERG measures. On specialized ERG testing, the yearly change in rod ERG threshold in RP was greater than the yearly change in cone ERG threshold, and the rate of progression varied significantly among inheritance types. For patients with CRD, the yearly change in rod threshold was comparable to the yearly change in cone ERG threshold. CONCLUSIONS: This study helps to define the natural progression of rod-mediated and cone-mediated functional loss in patients with RP and CRD.

Adolescent↗
PubMed1999

Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration that affects approximately 1 in 3500 people worldwide. Recently we identified the gene responsible for the RP1 form of autosomal dominant retinitis pigmentosa (adRP) at 8q11-12 and found two different nonsense mutations in three families previously mapped to 8q. The RP1 gene is an unusually large protein, 2156 amino acids in length, but is comprised of four exons only. To determine the frequency and range of mutations in RP1 we screened probands from 56 large adRP families for mutations in the entire gene. After preliminary results indicated that mutations seem to cluster in a 442 nucleotide segment of exon 4, an additional 194 probands with adRP and 409 probands with other degenerative retinal diseases were tested for mutations in this region alone. We identified eight different disease-causing mutations in 17 of the 250 adRP probands tested. All of these mutations are either nonsense or frameshift mutations and lead to a severely truncated protein. Two of the eight different mutations, Arg677X and a 5 bp deletion of nucleotides 2280-2284, were reported previously, while the remaining six mutations are novel. We also identified two rare missense changes in two other families, one new polymorphic amino acid substitution, one silent substitution and a rare variant in the 5'-untranslated region that is not associated with disease. Based on this study, mutations in RP1 appear to cause at least 7% (17/250) of adRP. The 5 bp deletion of nucleotides 2280-2284 and the Arg677X nonsense mutation account for 59% (10/17) of these mutations. Further studies will determine whether missense changes in the RP1 gene are associated with disease, whether mutations in other regions of RP1 can cause forms of retinal disease other than adRP and whether the background variation in either the mutated or wild-type RP1 allele plays a role in the disease phenotype.

Adult↗
PubMed1999

Current popularity of pneumatic retinopexy.

PURPOSE: To compare the popularity of pneumatic retinopexy (PR) in 1997 with its popularity in 1990 among retinal specialists. METHODS: In 1997, a survey was mailed to the 1994-1995 members of the Retina or Vitreous Societies who lived in the United States or Canada, asking how they would manage a hypothetical retinal detachment. The choices were limited to PR, segmental scleral buckling, scleral bucking with encircling, primary vitrectomy, and Lincoff balloon. The results of the survey were compared with those previously reported by a similar survey in 1990. RESULTS: The majority (55%) of respondents selected PR, which is a twofold increase over those who preferred it in 1990 (odds ratio 2.08; 95% confidence interval 1.53, 2.85). The popularity of PR was inversely proportional to the length of time the respondents had been in practice. If the eye with the hypothetical detachment had pseudophakia, only 30% of respondents selected PR. If the eye had additional tears, vitreous hemorrhage, or lattice degeneration, only about one-sixth preferred PR. CONCLUSION: Pneumatic retinopexy was much more popular in 1997 than it was in 1990. Its popularity continues to be influenced by the age of the surgeon and by the complexity of the detachment.

Data Collection↗
PubMed1998

Rod photoresponses in 6-week and 4-month-old human infants.

Rod-only electroretinograms (ERGs) were recorded from 6-week and 4-month-old normal human infants. The leading edge of the rod a-wave was fitted with a model of the activation phase of phototransduction to provide estimates of S (a sensitivity parameter) and RmP3 (the maximum saturated photoreceptor response) at each of the investigated ages. Both S and RmP3 increased over the first postnatal months but followed different developmental time courses with S approaching adult-like values sooner than RmP3. The changes in S and RmP3 can be interpreted within the context of a model incorporating the combined effects of increased levels of rhodopsin and the changing structure of the rod outer segment during development.

Aging↗
PubMed1998

Evidence for genetic heterogeneity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by disturbed or absent night vision; its clinical features may also include myopia, nystagmus, and impaired visual acuity. X-linked CSNB is clinically heterogeneous, and it may also be genetically heterogeneous. We have studied 32 families with X-linked CSNB, including 11 families with the complete form of CSNB and 21 families with the incomplete form of CSNB, to identify genetic-recombination events that would refine the location of the disease genes. Critical recombination events in the set of families with complete CSNB have localized a disease gene to the region between DXS556 and DXS8083, in Xp11.4-p11.3. Critical recombination events in the set of families with incomplete CSNB have localized a disease gene to the region between DXS722 and DXS8023, in Xp11.23. Further analysis of the incomplete-CSNB families, by means of disease-associated-haplotype construction, identified 17 families, of apparent Mennonite ancestry, that share portions of an ancestral chromosome. Results of this analysis refined the location of the gene for incomplete CSNB to the region between DXS722 and DXS255, a distance of 1.2 Mb. Genetic and clinical analyses of this set of 32 families with X-linked CSNB, together with the family studies reported in the literature, strongly suggest that two loci, one for complete (CSNB1) and one for incomplete (CSNB2) X-linked CSNB, can account for all reported mapping information.

Female↗
PubMed1998

A novel locus (RP24) for X-linked retinitis pigmentosa maps to Xq26-27.

Two genetic loci, RP2 and RP3, for X-linked retinitis pigmentosa (XLRP) have been localized to Xp11.3-11.23 and Xp21.1, respectively. RP3 appears to account for 70% of XLRP families; however, mutations in the RPGR gene (isolated from the RP3 region) are identified in only 20% of affected families. Close location of XLRP loci at Xp and a lack of unambiguous clinical criteria do not permit assignment of genetic subtype in a majority of XLRP families; nonetheless, in some pedigrees, both RP2 and RP3 could be excluded as the causative locus. We report the mapping of a novel locus, RP24, by haplotype and linkage analysis of a single XLRP pedigree. The RP24 locus was identified at Xq26-27 by genotyping 52 microsatellite markers spanning the entire X chromosome. A maximum LOD score of 4.21 was obtained with DXS8106. Haplotype analysis assigned RP24 within a 23-cM region between the DXS8094 (proximal) and DXS8043 (distal) markers. Other chromosomal regions and known XLRP loci were excluded by obligate recombination events between markers in those regions and the disease locus. Hemizygotes from the RP24 family have early onset of rod photoreceptor dysfunction; cone receptor function is normal at first, but there is progressive loss. Patients at advanced stages show little or no detectable rod or cone function and have clinical hallmarks of typical RP. Mapping of the RP24 locus expands our understanding of the genetic heterogeneity in XLRP and will assist in development of better tools for diagnosis.

Chromosome Mapping↗
PubMed1998

Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants.

The need for a dietary supply of docosahexaenoic acid (DHA) and arachidonic aid (AA) in term infants was evaluated in a double-masked randomized clinical trial of the effects of supplementation of term infant formula with DHA (0.35% of total fatty acids) or with DHA (0.36%) and AA (0.72%) on visual acuity development. One hundred and eight healthy term infants were enrolled in the study; 79 were exclusively formula-fed from birth (randomized group) and 29 were exclusively breast-fed (gold standard group). Infants were evaluated at four time points during the first 12 mo of life for blood fatty acid composition, growth, sweep visual evoked potential (VEP) acuity, and forced choice preferential looking acuity. Supplementation of term infant formula with DHA or with DHA and AA during the first 4 mo of life yields clear differences in total red blood cell (RBC) lipid composition. Supplementation of term infant formula with DHA or with DHA and AA also yields better sweep VEP acuity at 6, 17, and 52 wk of age but not at 26 wk of age, when acuity development reaches a plateau. The RBC lipid composition and sweep VEP acuity of supplemented infants was similar to that of human milk-fed infants, whereas the RBC lipid composition and sweep VEP acuity of unsupplemented infants was significantly different from human milk-fed infants. Differences in acuity among diet groups were too subtle to be detected by the forced choice preferential looking protocol. Infants in all diet groups had similar rates of growth and tolerated all diets well. Thus, early dietary intake of preformed DHA and AA appears necessary for optimal development of the brain and eye of the human infant.

Arachidonic Acid↗
PubMed1997

In-utero and post-delivery supplementation of motor neuron degeneration mutant mice with polyunsaturated fatty acids does not alter the clinical or pathological course.

We have studied the effects of polyunsaturated fatty acid (PUFA) supplementation in utero and throughout life in mnd mutant mice, a proposed model for juvenile neuronal ceroid lipofuscinosis (CLN-3). Unlike our earlier in-vitro studies in humans with CLN-3, and in-vitro studies in CLN-3 lymphoblasts, we saw no beneficial effects in electroretinographic, electron microscopic or clinical studies in the mnd mice. Electron microscopy of brain revealed a pattern which was not consistent with the characteristic ceroid patterns in CLN-3. Our data suggest that the mnd mouse is not responsive to PUFA supplementation and may not be an appropriate animal model for CLN-3.

Animals↗
PubMed1997

Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa.

The RPGR (retinitis pigmentosa GTPase regulator) gene for RP3, the most frequent genetic subtype of X-linked retinitis pigmentosa (XLRP), has been shown to be mutated in 10%-15% of European XLRP patients. We have examined the RPGR gene for mutations in a cohort of 80 affected males from apparently unrelated XLRP families, by direct sequencing of the PCR-amplified products from the genomic DNA. Fifteen different putative disease-causing mutations were identified in 17 of the 80 families; these include four nonsense mutations, one missense mutation, six microdeletions, and four intronic-sequence substitutions resulting in splice defects. Most of the mutations were detected in the conserved N-terminal region of the RPGR protein, containing tandem repeats homologous to those present in the RCC-1 protein (a guanine nucleotide-exchange factor for Ran-GTPase). Our results indicate that mutations either in as yet uncharacterized sequences of the RPGR gene or in another gene located in its vicinity may be a more frequent cause of XLRP. The reported studies will be beneficial in establishing genotype-phenotype correlations and should lead to further investigations seeking to understand the mechanism of disease pathogenesis.

Carrier Proteins↗
PubMed1997

Light reduction and the electroretinogram of preterm infants.

AIMS: To examine the effects of light on retinal development and function in preterm infants as measured by the electroretinogram (ERG). Secondary outcomes included visual acuity testing, the incidence of retinopathy of prematurity, and general wellbeing, reflected in feeding tolerance, rate of weight gain, and length of hospital stay. METHODS: Eligibility criteria for enrollment were birthweight < or = 1250 g and gestational age < or = 31 weeks. Sixty one infants were randomly allocated by 6 hours after birth to a control or treatment group which wore 97% light filtering goggles for a minimum of four weeks or until the infant reached 31 weeks postmenstrual age. RESULTS: There were no significant differences between the two groups in the numbers of electroretinograms performed at 36 weeks of postmenstrual age. Although the sample size was not large enough to exclude clinically important differences in secondary outcomes, no significant differences were observed between the groups in visual acuity testing at 4-6 months corrected age, incidence of retinopathy of prematurity, weight gain, or length of stay. CONCLUSION: These data support the safety and feasibility of this intervention. A much larger study will be needed to determine whether light reduction to the eyes of very low birthweight infants will reduce the incidence of retinopathy of prematurity or enhance general well-being.

Electroretinography↗
PubMed1997

Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors.

PURPOSE: In this study, the authors present the biochemical, morphologic, and physiological analyses of a transgenic mouse model for retinal degeneration slow (RDS)-mediated retinitis pigmentosa caused by a proline 216 to leucine (P216L) amino acid substitution in rds/peripherin. METHODS: The authors assembled a mutant rds transgene that encodes rds/peripherin with a P216L substitution. Transgenic mice were generated on wild-type (+/+), heterozygous (rds-/+), and homozygous (rds-/rds-) null genetic backgrounds. These mice were analyzed biochemically, by light and electron microscopy, and by electroretinography. RESULTS: In P216L-transgenic mice on a +/- background, the authors observed expression-level-dependent photoreceptor degeneration and outer-segment shortening. Expression of the P216L transgene on an rds-/+ background resulted in more severe photoreceptor degeneration and outer-segment dysplasia than seen in nontransgenic rds-/+ mutants. Severely dysplastic outer segments were detectable in P216L transgenics on an rds-/rds-null background. The reduction in b-wave amplitudes by electroretinography were well correlated with the degree of photoreceptor degeneration, but not outer-segment dysplasia in these different rds mutants. CONCLUSIONS: The phenotype in P216L-transgenic mice on an rds-/+ genetic background probably is caused by a combination of two genetic mechanisms: a direct dominant effect of the P216L substituted protein, and a reduction in the level of normal rds/peripherin. The expression pattern of the normal and mutant genes in these animals is similar to that predicted for humans with RDS-mediated autosomal-dominant retinitis pigmentosa. These mice may thus be considered an animal model for this disease.

Animals↗