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R Reynolds

Publications and source records attributed to R Reynolds.

At least 19 recordsLinked to original sources
PubMed2002

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease.

The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P <0.0001), accounting for 11.6% of overall variance observed. Among them are candidate genes for cardiovascular pathophysiology (apolipoprotein-species and NOS), inflammatory response (TNF receptor and CD14), and cell-cycle control (p53 and p53-associated protein). Our results emphasize the need to account for complex multi-gene influences and interactions when assessing the molecular pathology of multifactorial medical entities.

Angioplasty, Balloon, Coronary↗
PubMed2001

Disturbed oligodendrocyte development and recovery from hypomyelination in a c-myc transgenic mouse mutant.

The complexity of interactions underlying the elaboration of myelin has been extensively demonstrated. We provide evidence that signals promoting myelination are not confined to the normal developmental time window for myelination and persist well into adult life. The 2-50 mutant, described previously, carries a c-myc transgene regulated by a myelin basic protein promoter. This mutant is characterised by severe hypomyelination and abnormal oligodendrocytes in early life, followed by loss of the phenotype and normal longevity. We show that c-myc expression in early oligodendrocyte development results in a substantial reduction of cells of this lineage. However, apparent complete recovery, associated with loss of c-myc expression, axonal survival, and gradual myelin accumulation, is observed by 4 months of age. Thus, stimulation of myelination continues during adult life until normal myelin levels are established. We propose that this mutant may contribute to the characterisation of oligodendrocyte responses to myelinating signals.

Age Factors↗
PubMed2001

Aeolian dust in Colorado Plateau soils: nutrient inputs and recent change in source.

Aeolian dust (windblown silt and clay) is an important component in arid-land ecosystems because it may contribute to soil formation and furnish essential nutrients. Few geologic surfaces, however, have been characterized with respect to dust-accumulation history and resultant nutrient enrichment. We have developed a combination of methods to identify the presence of aeolian dust in arid regions and to evaluate the roles of this dust in ecosystem processes. Unconsolidated sandy sediment on isolated surfaces in the Canyonlands region of the Colorado Plateau differs greatly in mineralogical and chemical composition from associated bedrock, mainly aeolian sandstone. Detrital magnetite in the surficial deposits produces moderately high values of magnetic susceptibility, but magnetite is absent in nearby bedrock. A component of the surficial deposits must be aeolian to account for the abundance of magnetite, which formed originally in far-distant igneous rocks. Particle-size analysis suggests that the aeolian dust component is typically as much as 20-30%. Dust inputs have enriched the sediments in many elements, including P, Mg, Na, K, and Mo, as well as Ca, at sites where bedrock lacks calcite cement. Soil-surface biologic crusts are effective dust traps that apparently record a change in dust sources over the past several decades. Some of the recently fallen dust may result from human disturbance of land surfaces that are far from the Canyonlands, such as the Mojave Desert. Some land-use practices in the study area have the potential to deplete soil fertility by means of wind-erosion removal of aeolian silt.

Colorado↗
PubMed2001

Respiratory responses of normal and vestibular defective human subjects to rotation in the yaw and pitch planes.

We evaluated the contribution of the semicircular canals to autonomic responses to rotation in 12 normal subjects and three labyrinthine defective patients. Respiration, heart rate, arterial blood pressure and blood flow in the finger were recorded during 60 degrees /s steps of constant velocity rotation. Rotation was performed in the dark about a vertical axis: (I) with head upright for yaw stimulation of horizontal canals; (II) head tilted chin down and rotated laterally to stimulate the vertical canals in both face-forwards and backwards directions. In normal subjects, rotation in the pitch plane elicited an increase in respiratory frequency due to a shortening of the time for expiration, whilst patients had inconsistent responses. We conclude that vertical semicircular canal activity exerts a regulatory drive on respiration in human subjects.

Adult↗
PubMed2001

Galactose metabolism in normal human lymphoblasts studied by (1)H, (13)C and (31)P NMR spectroscopy of extracts.

The development of tools to follow and quantitate the fate of galactose in mammalian cells is crucial to the study and understanding of the inherited disorders of galactose metabolism. In this study we incubated normal human lymphoblasts with 1- or 2-(13)C galactose for 2.5 or 5 h and prepared TCA extracts of the cells. The various galactose metabolites were identified and quantified using a combination of proton, carbon and phosphorus NMR spectra. Galactose-1-phosphate (gal-1P), uridine diphosphogalactose, uridine diphosphoglucose and galactitol were present in the extracts. Average levels for gal-1P were around 10 nmol/mg protein and for uridine diphosphoglucose, uridine diphosphogalactose and galactitol in the range of 0.5-2 nmol/mg protein. Galactonate was never found in any conditions. Percentage labeling could be estimated for gal-1P and for the ribose carbons of AMP. The labeling agrees with a conversion of galactose to glucose through the Leloir pathway.

Carbon Isotopes↗
PubMed2001

Expression of QKI proteins and MAP1B identifies actively myelinating oligodendrocytes in adult rat brain.

We have studied developing oligodendrocytes in tissue sections as they initiate myelination and have found that the transition from premyelinating oligodendrocytes into myelin-bearing cells is accompanied by a dramatic upregulation in expression of the RNA binding QKI proteins. We show that in mature oligodendrocytes in culture, the localization of cytoplasmic QKI isoforms requires an intact cytoskeleton. Together with previous observations, this indicates that cytoplasmic QKI proteins facilitate movement of mRNAs to myelin via the cytoskeleton. In the adult rat brain, we found that a subset of oligodendrocytes displays characteristics of actively myelinating cells seen during development, i.e., connections to myelin sheaths and elevated levels of QKI proteins and also MAP1B. These observations suggest that instead of merely maintaining myelin, oligodendrocytes in the normal adult CNS are capable of responding to demands for new myelin sheaths. This has important implications for the prospect of repair of myelin in demyelinating conditions such as multiple sclerosis.

Age Factors↗
PubMed2001

Evidence for alternate galactose oxidation in a patient with deletion of the galactose-1-phosphate uridyltransferase gene.

The persistent, dietary-independent elevation of galactose metabolites in patients with galactose-1-phosphate uridyltransferase (GALT) deficiency is probably secondary to de novo synthesis of galactose. Relatively constant steady-state levels of galactose metabolites in patients also suggest that non-GALT metabolic pathways must function to dispose of the galactose synthesized each day. The discovery of a patient with a rare deletion of the GALT gene provided a unique opportunity to examine the availability of any alternate galactose oxidative capacity both in vivo and in vitro. Utilizing genomic DNA from the patient, Southern blot data demonstrated that 10 of the 11 GALT exons were homozygously deleted. By measurement of 13CO2 in expired air for up to 24 h after an oral bolus of [1-13C]galactose, it was demonstrated that 17% of the galactose was metabolized, a value comparable to the 3-h elimination rate in a control subject. Furthermore, lymphoblasts prepared from the patient could also convert [1-14C]galactose to 14CO2. This unique study provides the first unambiguous evidence that another pathway exists in man that can be responsible for galactose disposal. Further knowledge of this alternate galactose oxidative route and its regulation may aid in formulating new strategies for the treatment of galactosemia.

Blotting, Southern↗
PubMed2001

Galactose metabolism in mice with galactose-1-phosphate uridyltransferase deficiency: sucklings and 7-week-old animals fed a high-galactose diet.

Mice deficient in galactose-1-phosphate uridyltransferase (GALT) demonstrate abnormal galactose metabolism but no obvious clinical phenotype. To further dissect the pathways of galactose metabolism in these animals, galactose oxidation and metabolite levels were studied in 16-day-old sucklings and the effect of a 4 week prior exposure to a 40% glucose or 40% galactose diet was determined in 7-week-old mice. Suckling GALT-deficient (G/G) mice slowly oxidized [1-14C]galactose to 14CO2, 4.0% of the dose when fed and 7.9% when fasted compared to normal animals 38.3 and 36.4% in 4 h, respectively. Plasma of G/G sucklings contained 11.1 mM galactose and erythrocyte galactose 1-phosphate levels were 28.2 and 31.9 mg/dl packed cells. Galactose, galactitol, galactonate, and galactose 1-phosphate were found in G/G suckling mouse tissues. The tissue galactose concentrations were 10% or less of that in plasma, suggesting that there was limited cellular entry of galactose. In 7-week-old fasted mice with 4 weeks prior exposure to glucose or galactose-containing diet, 4-h oxidation was 12.9 and 15.0% of the administered radiolabeled galactose, respectively. Normal animals oxidized 33.9 and 37.9% of the dose when fed the same diets, respectively. The ability of G/G mice to oxidize galactose in the absence of GALT activity suggests the presence of alternate metabolic pathways for galactose disposition. G/G mice fed the galactose-free 40% glucose diet had erythrocyte galactose 1-phosphate levels ranging from 6.4 to 17.7 mg/dl packed cells and detectable galactose and galactose metabolites in tissues, suggesting that these animals endogenously produced galactose. The plasma of 40% galactose-fed G/G mice contained 9.1 mM galactose with red blood cell galactose 1-phosphate averaging 43.6 mg/dl. Tissues of these animals also contained high levels of galactose and galactose 1-phosphate. Liver contained over 4 micromol/g galactonate but little galactitol. Despite the elevated galactose and galactose 1-phosphate, the animals tolerated the high-galactose diet and were indistinguishable from normal animals, exhibiting no manifestations of galactose toxicity seen in human GALT-deficient galactosemia. The data suggest that high galactose 1-phosphate levels do not cause galactose toxicity and that high galactitol in combination with galactose 1-phosphate may be a prerequisite. Absence of GALT appears necessary but insufficient to produce human galactosemic phenotype.

Animals↗
PubMed2001

The response of adult oligodendrocyte progenitors to demyelination in EAE.

Cells with the phenotypic characteristics of oligodendrocyte progenitors (NG2+/PDGF alpha R+/O4+) are found throughout the adult mammalian CNS in numbers similar to microglia. They are a reactive glial cell population and respond to demyelination by increasing in number, thereby repopulating the lesion site with cells capable of differentiating into remyelinating oligodendrocytes. Direct evidence that they differentiate into remyelinating cells is missing, although this is the most likely scenario. Cells with the same phenotype are found in normal human CNS tissue and also in chronic MS lesions. Further studies on this intriguing cell type are necessary in order to understand the molecular signals involved in their reaction to injury, particularly in multiple sclerosis.

Animals↗
PubMed2001

The oligodendrocyte precursor cell in health and disease.

Adult oligodendrocyte precursor cells (OPCs) make up around 5-8% of the glial cell population in the CNS. Their function in the undamaged CNS is largely unknown, but their processes are in contact with nodes of Ranvier and synapses, suggesting a regulatory role at these structures. The cells divide slowly, and constitute approximately 70% of cells labelled following a pulse injection of bromodeoxyuridine. In the injured CNS the cells form a reactive glial population that undergoes hypertrophy and mitosis, probably driven by a variety of growth factors and cytokines. In response to demyelination they divide and are thought to differentiate to provide new oligodendrocytes to replace those that have been lost. However, remyelination fails during the later stages of multiple sclerosis, and it is not clear whether this is as a result of a depletion of adult OPCs, inhibition within the glial scar, or damage to the axons that prevents myelination. Adult OPCs are also activated and proliferate following other forms of CNS damage, such as mechanical injury, excitotoxicity and viral infection. The cells produce several of the chondroitin sulphate proteoglycans that might inhibit axon regeneration.

Animals↗
PubMed2000

Effect of community-based interventions on high-risk drinking and alcohol-related injuries.

CONTEXT: High-risk alcohol consumption patterns, such as binge drinking and drinking before driving, and underage drinking may be linked to traffic crashes and violent assaults in community settings. OBJECTIVES: To determine the effect of community-based environmental interventions in reducing the rate of high-risk drinking and alcohol-related motor vehicle injuries and assaults. DESIGN AND SETTING: A longitudinal multiple time series of 3 matched intervention communities (northern California, southern California, and South Carolina) conducted from April 1992 to December 1996. Outcomes were assessed by 120 general population telephone surveys per month of randomly selected individuals in the intervention and comparison sites, traffic data on motor vehicle crashes, and emergency department surveys in 1 intervention-comparison pair and 1 additional intervention site. INTERVENTIONS: Mobilize the community; encourage responsible beverage service; reduce underage drinking by limiting access to alcohol; increase local enforcement of drinking and driving laws; and limit access to alcohol by using zoning. MAIN OUTCOME MEASURES: Self-reported alcohol consumption and driving after drinking; rates of alcohol-related crashes and assault injuries observed in emergency departments and admitted to hospitals. RESULTS: Population surveys revealed that the self-reported amount of alcohol consumed per drinking occasion declined 6% from 1.37 to 1. 29 drinks. Self-reported rate of "having had too much to drink" declined 49% from 0.43 to 0.22 times per 6-month period. Self-reported driving when "over the legal limit" was 51% lower (0. 77 vs 0.38 times) per 6-month period in the intervention communities relative to the comparison communities. Traffic data revealed that, in the intervention vs comparison communities, nighttime injury crashes declined by 10% and crashes in which the driver had been drinking declined by 6%. Assault injuries observed in emergency departments declined by 43% in the intervention communities vs the comparison communities, and all hospitalized assault injuries declined by 2%. CONCLUSION: A coordinated, comprehensive, community-based intervention can reduce high-risk alcohol consumption and alcohol-related injuries resulting from motor vehicle crashes and assaults. JAMA. 2000;284:2341-2347.

Accidents, Traffic↗
PubMed2000

NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors?

Antibodies against the chondroitin sulphate proteoglycan, NG2, are increasingly being used to identify the widespread population of oligodendrocyte progenitor cells in the adult mammalian CNS. However, the specificity of this marker and the role of NG2-expressing cells in CNS function are still open to question. In this review we consider the evidence that NG2(+) cells in the CNS are part of the oligodendrocyte lineage and whether they can give rise to new oligodendrocytes following demyelination. In both the developing and mature rodent CNS, NG2(+) cells express the established oligodendrocyte lineage marker PDGF-alphaR and from P7, the late progenitor antigen O4, which persists in immature oligodendrocytes. They do not express markers of other CNS populations, such as OX42 or GFAP, at any developmental age. NG2(+) cells represent the major cycling cell population in the normal adult rat CNS, suggesting they have stem cell-like properties. NG2 immunoreactivity is upregulated as a result of physical, viral, excitotoxic and inflammatory insults to the CNS. Following demyelination NG2(+) cell number increases in the immediate vicinity of the lesion and rapid remyelination ensues. NG2 expression has also been investigated in human tissue. Multi-process bearing cells, which morphologically resemble those identified with antibodies against O4, persist in chronically demyelinated multiple sclerosis lesions.

Animals↗
PubMed2000

A mouse model of galactose-induced cataracts.

Galactokinase (GK; EC 2.7.1.6) is the first enzyme in the metabolism of galactose. In humans, GK deficiency results in congenital cataracts due to an accumulation of galactitol within the lens. In an attempt to make a galactosemic animal model, we cloned the mouse GK gene (Glk1) and disrupted it by gene targeting. As expected, galactose was very poorly metabolized in GK-deficient mice. In addition, both galactose and galactitol accumulated in tissues of GK-deficient mice. Surprisingly, the GK-deficient animals did not form cataracts even when fed a high galactose diet. However, the introduction of a human aldose reductase transgene into a GK-deficient background resulted in cataract formation within the first postnatal day. This mouse represents the first mouse model for congenital galactosemic cataract.

Aldehyde Reductase↗
PubMed2000

Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria.

BACKGROUND: Fexofenadine is a nonsedating antihistamine approved for treatment of seasonal allergic rhinitis. OBJECTIVE: This dose-finding study assessed the safety and efficacy of fexofenadine in chronic idiopathic urticaria. METHODS: The 4-week, double-blind, randomized, placebo-controlled study included patients diagnosed with chronic urticaria who had moderate to severe pruritus. Patients received twice daily oral doses of placebo or fexofenadine HCl (20, 60, 120, or 240 mg) at 7 AM and 7 PM. Patients recorded scores for pruritus severity and number of wheals (over the previous 12 hours) in a daily diary. Efficacy variables included mean daily changes from baseline in pruritus severity, number of wheals, and interference with sleep and daily activities due to urticaria. RESULTS: Patients (N = 418) from 37 investigative sites were included. All four fexofenadine HCl doses were statistically superior to placebo (P < or = .0115) for reducing pruritus and number of wheals scores over the 4-week treatment period. There were greater reductions in urticaria symptoms in the 60 mg fexofenadine HCl group than in the 20 mg group, while similar reductions were observed in the 60, 120, and 240 mg dose groups. Additionally, patients receiving fexofenadine experienced significantly less interference with sleep and daily activities than patients receiving placebo (P < or = .0014). Adverse events occurred with similar incidence in all treatment groups, with no dose-related increases in any event. CONCLUSIONS: Fexofenadine HCl significantly reduced pruritus severity, number of wheals, and interference with sleep and normal daily activities in patients with chronic urticaria compared with placebo. Twice-daily doses of 60 mg or greater were most effective.

Adolescent↗
PubMed2000

Selecting SNPs in two-stage analysis of disease association data: a model-free approach.

For large numbers of marker loci in a genomic scan for disease loci, we propose a novel 2-stage approach for linkage or association analysis. The two stages are (1) selection of a subset of markers that are 'important' for the trait studied, and (2) modelling interactions among markers and between markers and trait. Here we focus on stage 1 and develop a selection method based on a 2-level nested bootstrap procedure. The method is applied to single nucleotide polymorphisms (SNPs) data in a cohort study of heart disease patients. Out of the 89 original SNPs the method selects 11 markers as being 'important'. Conventional backward stepwise logistic regression on the 89 SNPs selects 7 markers, which are a subset of the 11 markers chosen by our method.

Algorithms↗
PubMed2000

Characterization of a novel D1S80 pseudoallele.

During a D1S80 population study conducted for databasing purposes in the New York City Ashkenazi Jewish population, eight out of 96 samples were typed with a band corresponding to the position of a #15 allele. In seven of the eight samples, three bands appeared. Further investigation was needed to explain the high frequency of an allele considered so rare that it is not included in the commercially provided allelic ladder. After extraction of the putative D1S80 15-repeat amplicon band from the 6% polyacrylamide genotyping gel, the amplicon bands were reamplified with D1S80 primers. After retyping as putative 15 alleles, these samples underwent Southern hybridization with a D1S80 locus-specific probe followed by DNA sequence analysis. Sequence analysis revealed that these bands did not arise from true D1S80 15 alleles. However, the PCR product was of a size that fell within the allelic ladder region corresponding to the 15 band and contained end sequences with strong homology to the D1S80 primers. An alignment search of the sequenced product revealed that a portion of the amplicons contained 72% identity to a known gene. These results emphasize the importance of sequencing analysis when questions arise about the authenticity of an allele.

Alleles↗
PubMed2000

Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics.

Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia.

Age Factors↗