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Biomedical subjects

Robert M Douglas

Publications and source records attributed to Robert M Douglas.

13 recordsLinked to original sources
PubMed2006

Enhancement of vision by monocular deprivation in adult mice.

Plasticity of vision mediated through binocular interactions has been reported in mammals only during a "critical" period in juvenile life, wherein monocular deprivation (MD) causes an enduring loss of visual acuity (amblyopia) selectively through the deprived eye. Here, we report a different form of interocular plasticity of vision in adult mice in which MD leads to an enhancement of the optokinetic response (OKR) selectively through the nondeprived eye. Over 5 d of MD, the spatial frequency sensitivity of the OKR increased gradually, reaching a plateau of approximately 36% above pre-deprivation baseline. Eye opening initiated a gradual decline, but sensitivity was maintained above pre-deprivation baseline for 5-6 d. Enhanced function was restricted to the monocular visual field, notwithstanding the dependence of the plasticity on binocular interactions. Activity in visual cortex ipsilateral to the deprived eye was necessary for the characteristic induction of the enhancement, and activity in visual cortex contralateral to the deprived eye was necessary for its maintenance after MD. The plasticity also displayed distinct learning-like properties: Active testing experience was required to attain maximal enhancement and for enhancement to persist after MD, and the duration of enhanced sensitivity after MD was extended by increasing the length of MD, and by repeating MD. These data show that the adult mouse visual system maintains a form of experience-dependent plasticity in which the visual cortex can modulate the normal function of subcortical visual pathways.

Animals↗
PubMed2006

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus.

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

Animals↗
PubMed2006

Cognitive deficits in rats after forebrain cholinergic depletion are reversed by a novel NO mimetic nitrate ester.

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons.

Acetylcholine↗
PubMed2005

Effect of chronic continuous or intermittent hypoxia and reoxygenation on cerebral capillary density and myelination.

Chronic hypoxia, whether continuous (CCH) or intermittent (CIH), occurs in many neonatal pathological conditions, such as bronchopulmonary dysplasia and obstructive sleep apnea. In this study, we explored the effect of CCH and CIH on cerebral capillary density and myelination. We subjected CD-1 mice starting at postnatal day 2 to either CCH 11% oxygen (O(2)), or CIH 11% O(2) (4-min cycles), for periods of 2 and 4 wk followed by reoxygenation for 4 wk. Mice were deeply anesthetized and perfused. Brains were removed to fixative for 24 h, then paraffin-embedded. Coronal brain sections were taken for analysis. Immunocytochemistry for glucose transporter 1 was used to assess angiogenesis, and Luxol fast blue and fluoromyelin stains were used to assess myelination. Capillary density increased after 2-wk exposure to CIH and CCH. By 4 wk, capillary density increased in both CIH and CCH by 25% and 47%, respectively, in cortex and by 29% and 44%, respectively, in hippocampus (P < 0.05). There was a decrease in myelination in the corpus callosum of mice exposed to CIH (75% of control) and CCH (50% of control) (P < 0.05). Reoxygenation reversed the increased capillary density seen in CCH to normoxic values. However, dysmyelination that occurred in CCH-exposed mice did not show any improvement upon reoxygenation. We conclude that neonatal chronic hypoxia 1) induces brain angiogenesis, which is reversible with reoxygenation, and 2) irreversibly reduces the extent of myelination in the corpus callosum. This potential irreversible effect on myelination in early life can, therefore, have long-term and devastating effects.

Animals↗
PubMed2004

Quantification of spatial vision in the Royal College of Surgeons rat.

PURPOSE: To examine how spatial vision deteriorates in the RCS rat over time as a background to experimental studies aimed at limiting photoreceptor degeneration. METHODS: The Visual Water Task was used to quantify the grating acuity of pigmented dystrophic RCS rats as they aged and to compare both grating acuity and contrast sensitivity in nondystrophic RCS rats with those parameters in normal pigmented laboratory rats (Long-Evans). RESULTS: Nondystrophic rats had grating acuities and contrast sensitivity functions that were similar to those obtained from Long-Evans rats. The grating acuity of dystrophic rats deteriorated from 80% of normal at 1 month of age to blindness by 11 months. Acuity declined rapidly to 0.32 cyc/deg over the first 4 months, with a slower decline thereafter. CONCLUSIONS: Robust measures of vision can be achieved in RCS rats using the Visual Water Task, and with this test, no visual dysfunction can be detected in the background strain. The course of functional deterioration in dystrophic rats is highly predictable, allowing the approach to be used to explore the substrates of the deterioration in vision and to monitor the effects of therapeutic retinal interventions on spatial vision.

Aging↗
PubMed2004

Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system.

PURPOSE: To develop a simple, rapid method of quantifying the spatial vision of mice. METHODS: A rotating cylinder covered with a vertical sine wave grating was calculated and drawn in virtual three-dimensional (3-D) space on four computer monitors facing to form a square. C57BL/6 mice standing unrestrained on a platform in the center of the square tracked the grating with reflexive head and neck movements. The spatial frequency of the grating was clamped at the viewing position by repeatedly recentering the cylinder on the head. Acuity was quantified by increasing the spatial frequency of the grating until an optomotor response could not be elicited. Contrast sensitivity was measured at spatial frequencies between 0.03 and 0.35 cyc/deg. RESULTS: Grating acuity was measurable on the day of eye opening (postnatal day [P]15: mean acuity, 0.031 cyc/deg) and reached a maximum (approximately 0.4 cyc/deg) by P24. A peak in the contrast sensitivity function emerged on P16 (4.7, or 21% contrast at 0.064 cyc/deg). The peak remained at 0.064 cyc/deg and climbed to a maximum sensitivity of 24.5, or 4% contrast, by P29. Acuity was obtained in each mouse in <10 minutes, and a detailed contrast sensitivity curve was generated in approximately 30 minutes. CONCLUSIONS: The virtual optomotor system provides a simple and precise method for rapidly quantifying mouse vision. Behavioral measures of vision in mice are essential for interpreting the results of experiments designed to reveal the cellular and molecular mechanisms of vision and visual development and for evaluating potential treatments for visual diseases.

Animals↗
PubMed2004

Psychophysical indexes of temporal processing abnormalities in children with developmental dyslexia.

Children with dyslexia and children progressing normally in reading performed several perceptual tasks to determine (a) the psychophysical measures that best differentiate children with dyslexia from children with average reading abilities; (b) the extent of temporal processing deficits in a single, well-defined group of children with dyslexia; and (c) the co-occurrence of visual and auditory temporal processing deficits in children with dyslexia. 4 of our 12 psychophysical tasks indicated differences in temporal processing ability between children with dyslexia and children with good reading skills. These included 2 auditory tasks (dichotic pitch perception and FM tone discrimination) and 2 visual tasks (global motion perception and contrast sensitivity). The battery of 12 tasks successfully classified 80% of the children into their respective reading-level groups. Within the group of children with dyslexia who had temporal processing deficits, most were affected in either audition or vision; few children were affected in both modalities. The observed deficits suggest that impaired temporal processing in dyslexia is most evident on tasks that require the ability to synthesize local, temporally modulated inputs into a global percept and the ability to extract the resultant global percept from a noisy environment.

Adolescent↗
PubMed2003

Developmental plasticity of mouse visual acuity.

Monocular deprivation in mice between postnatal days 19 and 32 has been reported to significantly shift ocular dominance within the binocular region of primary visual cortex; however, it is not known whether visual deprivation in mice during this physiologically defined critical period also results in amblyopia, as it does in other mammals. We addressed this uncertainty by psychophysically assessing in adulthood (postnatal day 70 or older) the grating acuity of normal and monocularly deprived mice, using the Visual Water Task. The visual acuity of mice tested with their nondeprived eyes was equivalent to that of normal mice ( approximately 0.5 cycles/degree); however, acuity measured with eyes monocularly deprived of vision transiently between postnatal days 19 and 32 was reduced by over 30% ( approximately 0.31 cycles/degree). Identical binocular deprivation produced a significant, but smaller, decrease in acuity ( approximately 0.38 cycles/degree). The effects of monocular and binocular deprivation were long lasting and occurred only if visual deprivation occurred between postnatal days 19 and 32. These data indicate that the deleterious effects of early visual deprivation on visual acuity in mice are similar to those reported in other mammals, and together with electrophysiological evidence of ocular dominance plasticity, suggest that the mechanisms of mouse visual plasticity are fundamentally the same as that in other mammals. Therefore, the mouse is probably a good model for investigating the basic cellular and molecular mechanisms underlying visual developmental plasticity and amblyopia.

Age Factors↗
PubMed2003

Changing GPs' antibiotic prescribing: a randomised controlled trial.

A randomised controlled trial involving 54 general practitioners (GPs) was conducted in Canberra, Australian Capital Territory from September 1997 to November 1999. In the first year of the study, 24 GPs, who constituted the active arm of the intervention group, were involved in the consideration of evidence and the development and implementation of a set of clinical guidelines for the treatment of acute respiratory infections. These guidelines were then endorsed in a meeting together with specialist colleagues. In the second year of the study the group of GPs who had been acting as controls, received a moderate intervention consisting of a brief educational event and distribution of the locally developed guidelines. We obtained data from January 1997 to December 1999 from the Health Insurance Commission on prescribing rates for 40 of the doctors in the study. The rate of prescribing was calculated as the number of antibiotic prescriptions per 100 Medicare services. The average yearly prescribing decreased significantly in the intensive intervention group and increased in the moderate intervention group, (p=0.026). A mixed effects longitudinal time series model was fitted to the data to account for seasonal variation of antibiotic prescribing and trends over time. The intensive intervention group significantly reduced their antibiotic prescribing over time compared to the moderate intervention group, (p<0.001). This study has shown that an intensive intervention in which general practitioners were actively engaged in development and consideration of the evidence base for the guidelines resulted in a significant fall in general antibiotic prescribing.

Adult↗
PubMed2002

Variation in visual acuity within pigmented, and between pigmented and albino rat strains.

Many researchers assume that laboratory rats have poor vision, and accordingly, that they need not consider differences in the visual function of rats as a consequence of strain or experience. Currently, it is not specifically known whether rat domestication has negatively affected the visual function of laboratory rat strains, what the effects of strain albinism are on rat visual function, or whether there are strain differences in the visual function of laboratory rats that are independent of pigmentation. In order to address these questions, we measured psychophysically the vertical grating acuity of three pigmented (Dark Agouti, Fisher-Norway, Long-Evans) and three albino (Fisher-344, Sprague-Dawley, Wistar) strains of laboratory rats, and compared their acuity with that of wild rats. The grating thresholds of Dark Agouti, Long-Evans and wild strains clustered around 1.0 cycle/degree (c/d) and did not significantly differ from one another. Fisher-Norway rats, however, had a significantly higher threshold of 1.5 c/d. The grating thresholds of Fisher-344, Sprague-Dawley, and Wistar strains, which were clustered around 0.5 c/d, were significantly lower than those of the pigmented strains. These data demonstrate that there is significant strain variability in the visual function of laboratory rats. Domestication of Long-Evans and Dark Agouti strains does not appear to have compromised visual acuity, but in the case of Fisher-Norway rats, selective breeding may have enhanced their acuity. Strain selection associated with albinism, however, appears to have consistently impaired visual acuity. Therefore, a consideration of strain differences in visual function should accompany the selection of a rat model for behavioral tasks that involve vision, or when comparing visuo-behavioral measurements across rat strains.

Albinism↗
PubMed2002

Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study.

OBJECTIVE: To examine the relation between use of antibiotics in a cohort of preschool children and nasal carriage of resistant strains of pneumococcus. DESIGN AND PARTICIPANTS: Prospective cohort study over two years of 461 children aged under 4 years living in Canberra, Australia. MAIN OUTCOME MEASURES: Use of drugs, respiratory symptoms, and visits to doctors were documented in a daily diary by parents of the children during 25 months of observation. Isolates of pneumococci, which were cultured from nasal swabs collected approximately six monthly, were tested for antibiotic resistance. RESULTS: From the four swab collections 631 positive pneumococcal isolates from 461 children were found, of which 13.6% were resistant to penicillin. Presence of penicillin resistant pneumococci was significantly associated with children's use of a beta lactam antibiotic in the two months before each swab collection (odds ratio 2.03 (95% confidence interval 1.15 to 3.56, P=0.01)). The odds ratio of the association remained >1 (though did not reach significance at the 0.05 level) for use in the six months before swab collection. The association was seen in children who received only penicillin or only cephalosporin antibiotics in that period. The odds ratio was 4.67 (1.29 to 17.09, P=0.02) in children who had received both types of beta lactam in the two months before their nasal swab. The modelled odds of carrying penicillin resistant pneumococcus was 4% higher for each additional day of use of beta lactam antibiotics in the six months before swab collection. CONCLUSIONS: Reduction in beta lactam use could quickly reduce the carriage rates of penicillin resistant pneumococci in early childhood. In view of the propensity of these organisms to be spread among children in the community, the prevalence of penicillin resistant organisms may fall as a consequence.

Anti-Bacterial Agents↗