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Biomedical subjects

M D Davis

Publications and source records attributed to M D Davis.

At least 91 records · Page 5Linked to original sources
PubMed1991

Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

A new variant form of hyperphenylalaninemia has recently been discovered in which the patients characteristically excrete 7-biopterin in their urines in addition to the natural 6-biopterin (Curtius, H. Ch., Kuster, T., Matasovic, A., Blau, N. & Dhondt, J.-L. (1988) Biochem. Biophys. Res. Commun. 153, 715-721). This isomer had not been found previously in humans, and although its origin was not established, preliminary evidence suggested that it might be produced from 6-biopterin. We have now found that 7-biopterin can be formed in vitro from (6R)-tetrahydrobiopterin during the hydroxylation of phenylalanine catalyzed by phenylalanine hydroxylase [L-phenylalanine, tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1]. The resulting 7-biopterin was unequivocally identified by the following criteria: preparative isolation and conversion to 7-hydroxymethylpterin following periodate oxidation and borohydride reduction, quantitative conversion to pterin-7-carboxylic acid after oxidation with permanganate, and liquid chromatography/thermospray mass spectrometry. Addition of 4a-carbinolamine dehydratase, an enzyme involved in the regeneration of tetrahydrobiopterin from the pterin carbinolamine intermediate (also called 4a-hydroxytetrahydrobiopterin) formed in the phenylalanine hydroxylase reaction, greatly decreased the amount of the 7-biopterin formed. This result implies that the in vitro formation of 7-biopterin occurs via the nonenzymatic rearrangement of the unstable substrate of the dehydratase, 4a-hydroxytetrahydrobiopterin, and suggests that this new variant of hyperphenylalaninemia may be caused by a lack of 4a-carbinolamine dehydratase activity. A mechanism for the rearrangement is proposed that predicts that other 6-substituted tetrahydropterin substrates of the aromatic amino acid hydroxylases could also give rise to rearranged products from an opening of the pyrazine ring of the corresponding 4a-hydroxytetrahydropterin intermediate.

Animals↗
PubMed1991

Effects of CI-943, a potential antipsychotic drug, and haloperidol on regional brain neurotensin concentrations.

Treatment with efficacious antipsychotic drugs such as haloperidol increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate nucleus of the rat. These increases in NT concentrations may be associated with the therapeutic and/or side effects of these drugs. CI-943, a novel compound without appreciable affinity for dopamine-binding sites, produces behavioral effects in animals, which suggest that it may possess antipsychotic activity. This study evaluated the effects of subchronic treatment (3 weeks) with CI-943 or haloperidol on regional brain NT concentrations in rats. Haloperidol treatment (1 mg/kg) produced significant increases in the concentrations of NT in the nucleus accumbens and caudate nucleus but not in the other brain regions studied. Like haloperidol, CI-943 (40 mg/kg) increased NT concentrations in the nucleus accumbens and caudate but differed in that CI-943 produced significantly greater increases in NT concentration in the caudate than haloperidol and also increased NT content in the substantia nigra/ventral tegmental area and hypothalamus. The regional specificity of the NT alterations produced by chronic treatment with CI-943, a nondopamine receptor ligand, was similar to that previously reported after treatment with multiple doses of methamphetamine.

Animals↗
PubMed1991

Studies on the partially uncoupled oxidation of tetrahydropterins by phenylalanine hydroxylase.

The uncoupled portion of the partially uncoupled oxidation of tetrahydropterins by phenylalanine hydroxylase can be described by the same model as we have recently derived for the fully uncoupled reaction (Davis, M.D. and Kaufman, S. (1989) J. Biol. Chem. 264, 8585-8596). Although essentially no hydrogen peroxide is formed during the fully coupled oxidation of tetrahydrobiopterin or 6-methyltetrahydropterin by phenylalanine hydroxylase when phenylalanine is the amino acid substrate, significant amounts of hydrogen peroxide are formed during the partially uncoupled oxidation of 6-methyltetrahydropterin when para-fluorophenylalanine or para-chlorophenylalanine are used in place of phenylalanine. Similarly, during the partially uncoupled oxidation of the unsubstituted pterin, tetrahydropterin, even in the presence of phenylalanine, hydrogen peroxide formation is detected. The 4a-carbinolamine tetrahydropterin intermediate has been observed during the fully uncoupled tyrosine-dependent oxidations of tetrahydropterin and 6-methyltetrahydropterin by lysolecithin-activated phenylalanine hydroxylase, suggesting that this species is also a common intermediate for uncoupled oxidations by this enzyme.

Animals↗
PubMed1991

Isolation of rat cardiac sarcoplasmic reticulum with improved Ca2+ uptake and ryanodine binding.

The instability of the oxalate-supported Ca2+ uptake activity of rat cardiac sarcoplasmic reticulum (CSR) in ventricular homogenates most likely accounts for the low specific activity of the rate of oxalate-supported Ca2+ uptake in previously reported fractions of isolated rat CSR. We have found that CSR vesicles with improved Ca2+ transport capabilities can be isolated if 1 M KCl is used to stabilize the CSR activity and to allow the extraction of the CSR from the cellular debris. The average rate of Ca2+ uptake by the isolated rat CSR in the presence of 10 mM oxalate at 37 degrees C was 0.45 mumols/min-mg in the absence of CSR Ca2+ channel blockers and 0.87 mumols/min-mg in the presence of 10 microM ruthenium red. The Ca(2+)-dependent ATPase activity under the conditions of oxlate-supported uptake was 1.25 mumols/min-mg and 0.84 mumols/min-mg in the absence and presence of 10 microM ruthenium red, respectively. The rat CSR vesicles bound 3H-ryanodine with a Kd of 1.45 nM and a Bmax of 3.7 pmol mg. The level of phosphorylated intermediate was 0.30 nmol/mg. The values Bmax, EP and Ca(2+)-ATPase activity are from one-third to one-half of those previously reported for isolated canine CSR vesicles. These results suggest that the isolated rat CSR may be quite similar to dog CSR.

Animals↗
PubMed1991

The Wisconsin age-related maculopathy grading system.

A new system for grading age-related maculopathy is described and measures of reliability are reported. A number of characteristics of age-related maculopathy are graded in a semiquantitative fashion from stereoscopic 30 degrees color fundus photographs, using a grid to define subfields, standard circles printed on plastic to assess size and area, and a specially designed lightbox to allow better discrimination of subtle drusen. The degree of exact agreement achieved between two trained graders across a variety of lesions ranged from 67.1% for drusen size to 99.6% for geographic atrophy. Kappa scores ranged from 0.55 (for drusen confluence) to 0.95 for geographic atrophy. This system will be useful in epidemiologic studies and clinical trials.

Aging↗
PubMed1991

The role of CT in the diagnosis and management of childhood pineal region tumours.

As one treatment option for pineal region tumours is based on the accurate prediction of histology by CT, the scans of 11 children with biopsy proven pineal region tumours were reviewed, and poor correlation found with the "classical" appearances previously described. Accurate diagnosis and appropriate treatment are best achieved when CT is combined with serum tumour markers, CSF cytology and tumour biopsy/debulking/resection.

Adolescent↗
PubMed1991

Social class, gay men and AIDS prevention.

The relationship between sexuality, gay communities and class is potentially a very large problem for AIDS prevention. Class is a historical process which interacts with sexuality in ways still little understood. The complexities of modern class structures need full acknowledgement; labour market groupings are internally divided, and cultural privilege and exclusion are important. A community survey in New South Wales of men who have sex with men shows the class selectiveness usual in such research. An exploration of correlates of labour market position, income and education finds few relationships with attachment to milieu except for involvement with gay organisations, and minor differences in broad measures of sexuality but some class differences in HIV risk-taking and some differences in exposure to information and in attitude. An exploration of several cases from a life-history study of working-class gay men shows the impact of class circumstance on the formation of sexual relationships and points to the accessibility of unlabelled homosexual activity in working-class milieux. Research on working-class education points to the importance of curriculum change in overcoming class exclusion, and is moving towards empowerment models of great relevance in AIDS education.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Wisconsin Epidemiologic Study of Diabetic Retinopathy. XII. Relationship of C-peptide and diabetic retinopathy.

The relationship between plasma C-peptide and the frequency and severity of diabetic retinopathy was examined in a population-based study in Wisconsin in 1984-1986. Individuals with younger- (n = 835) and older- (n = 940) onset diabetes were included. C-peptide was measured by radioimmunoassay with Heding's M1230 antiserum. Retinopathy was determined from stereoscopic fundus photographs. The highest frequencies and most severe retinopathy were found in insulin-using individuals with undetectable or low plasma C-peptide (less than 0.3 nM), whereas the lowest frequencies of retinopathy were found in older-onset overweight individuals not using insulin. In older-onset individuals using insulin, having no detectable C-peptide was significantly associated with the presence of proliferative retinopathy. Otherwise, within each group (younger onset using insulin, older onset using insulin, and older onset not using insulin), after controlling for other characteristics associated with retinopathy, there was no relationship between higher levels of C-peptide and lower frequency of or less severe retinopathy.

C-Peptide↗
PubMed1989

Evidence for the formation of the 4a-carbinolamine during the tyrosine-dependent oxidation of tetrahydrobiopterin by rat liver phenylalanine hydroxylase.

In the presence of phenylalanine and molecular oxygen, activated phenylalanine hydroxylase catalyzes the oxidation of tetrahydrobiopterin. The oxidation of this tetrahydropterin cofactor also proceeds if the substrate, phenylalanine, is replaced by its product, tyrosine, in the initial reaction mixture. These two reactions have been defined as coupled and uncoupled, respectively, because in the former reaction 1 mol of phenylalanine is hydroxylated for every mole of tetrahydrobiopterin oxidized, whereas in the latter reaction there is no net hydroxylation of tyrosine during the oxidation of the tetrahydropterin. During the course of the coupled oxidation of tetrahydrobiopterin, a pterin 4a-carbinolamine intermediate can be detected by ultraviolet spectroscopy (Kaufman, S. (1976) in Iron and Copper Proteins (Yasunobu, K. T., Mower, H. F., and Hayaishi, O., eds) pp. 91-102, Plenum Publishing Corp., New York). Dix and Benkovic (Dix, T. A., and Benkovic, S. J. (1985) Biochemistry 24, 5839-5846) have postulated that the formation of this intermediate only occurs when the oxidation of the tetrahydropteridine is tightly coupled to the concomitant hydroxylation of the aromatic amino acid. However, during the tyrosine-dependent uncoupled oxidation of tetrahydrobiopterin by phenylalanine hydroxylase, we have detected the formation of a spectral intermediate with ultraviolet absorbance that is essentially identical to that of the carbinolamine. Furthermore, this absorbance can be eliminated by the addition of 4a-carbinolamine dehydratase, an enzyme which catalyzes the dehydration of the 4a-carbinolamine. Quantitation of this intermediate suggests that there are two pathways for the tyrosine-dependent uncoupled oxidation of tetrahydrobiopterin by phenylalanine hydroxylase because only about 0.3 mol of the intermediate is formed per mol of the cofactor oxidized.

Animals↗
PubMed1989

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years.

Population-based epidemiologic data on the incidence and progression of diabetic retinopathy are important in medical counseling and rehabilitative services and for developing approaches to preventing diabetic retinopathy. We performed a population-based study in southern Wisconsin of insulin-taking diabetic persons diagnosed before 30 years of age. Of the 271 who had no retinopathy at the first visit, 160 (59%) developed it by the time they were reexamined four years later, and 75 (11%) of the 713 free of proliferative diabetic retinopathy developed it. Overall, worsening of retinopathy occurred in 41% of the population, whereas improvement occurred in only 7%. The incidence of proliferative retinopathy rose with increasing duration until 13 to 14 years of diabetes, thereafter remaining between 14% and 17%. These incidence data underscore the need for careful ophthalmologic follow-up of these people.

Adolescent↗
PubMed1989

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more.

The four-year incidence and progression of retinopathy were investigated in a population-based sample of people with diabetes diagnosed at 30 years of age or older. For insulin users, 73 (47%) of the 154 who did not have any retinopathy at the first visit developed it in the four-year interval, and 31 (7%) of the 418 free of proliferative retinopathy developed it. Worsening of retinopathy occurred in a total of 34% (142/418). For nonusers of insulin, corresponding rates were 34% (110/320) for incidence of any retinopathy, 2% (11/486) for developing proliferative retinopathy, and 25% (121/486) for worsening. These population-based data clearly indicate the risk of retinopathy worsening in a short interval (four years) in a large proportion of people with older-onset diabetes, a group previously thought to be relatively protected from retinopathy. Such patients who make up the largest proportion of diabetic patients in the United States need examination when diabetes is first diagnosed and regular follow-up.

Adult↗
PubMed1989

The Wisconsin epidemiologic study of diabetic retinopathy. XI. The incidence of macular edema.

As part of a population-based study of diabetes mellitus, the 4-year incidence of macular edema and its relationship to various risk factors was examined in a group of younger onset insulin-taking persons (n = 610) and older onset persons (n = 652). The presence of macular edema at the baseline and follow-up examinations was determined from gradings of stereoscopic fundus photographs. The overall incidence of macular edema in the younger onset group was 8.2% (50/610); in the group of older onset persons using insulin, 8.4% (23/273) and in the group of those not using insulin, 2.9% (11/379). The incidence of macular edema was associated with higher level of glycosylated hemoglobin, longer duration of diabetes, and more severe retinopathy at the baseline examination in both younger and older onset groups. These data provide accurate population-based estimates of incidence of macular edema, and suggest that the level of glycemia is a significant risk factor for the development of macular edema.

Adolescent↗
PubMed1989

The validity and reliability of photographic documentation of proliferative vitreoretinopathy.

The Silicone Study is a multicentered, randomized surgical trial designed to compare the tamponade effectiveness of silicone oil versus long-acting gas in the treatment of proliferative vitreoretinopathy (PVR) by vitrectomy and associated techniques. Fundus photographs are taken to provide documentation of the anatomic status of eyes proposed for entry and are graded at an independent Reading Center. This article describes the protocol for photographic documentation of PVR as a continuum of increasing pathology, in which the pathology may only be present in the anterior retina, and the retina is usually highly elevated. In a validity and reliability study, agreement between photographic and clinical observation within one step was obtained for 88% of the eyes; intra- and inter-observer agreement within one step was 85 and 80%, respectively. Differences between the surgeon's grade and the Reading Center's were caused about equally by disagreement regarding extent of fixed folds and width of the funnel. Rarely did peripheral folds not visible in the photographs appear to be the sole explanation of the disagreement. Differences among readers were concerned mainly with differentiation of true full-thickness fixed folds from folds due to simple redundancy of the detached retina. These results demonstrate that complicated retinal detachment (RD) can be photographically documented and independently assessed.

Clinical Trials as Topic↗
PubMed1989

Is blood pressure a predictor of the incidence or progression of diabetic retinopathy?

The relationship between blood pressure and the 4-year incidence and progression of diabetic retinopathy was examined in a population-based study in Wisconsin. Younger- (n = 891) and older-onset (n = 987) persons participating in baseline and follow-up examinations were included. Blood pressure was measured using the Hypertension Detection and Follow-up Program protocol. Retinopathy was determined from stereoscopic fundus photographs. In the younger-onset group, comparing the highest with the lowest quartile of systolic blood pressure, the relative risk for developing any diabetic retinopathy was 1.8 and for diastolic blood pressure it was 1.2; for progression of diabetic retinopathy, it was 1.1 and 1.3 for systolic and diastolic blood pressure, respectively. After controlling for other risk variables, systolic blood pressure remained a significant predictor of the incidence of diabetic retinopathy; diastolic blood pressure was of borderline significance in predicting progression in the younger-onset group. Blood pressure was not related to incidence or progression of retinopathy either in the older-onset group using insulin or the older-onset group not using insulin.

Age Factors↗
PubMed1989

Factors associated with visual outcome after photocoagulation for diabetic retinopathy. Diabetic Retinopathy Study Report #13.

Six risk factors for severe visual loss despite panretinal (scatter) photocoagulation were identified by analyzing data collected during the first 5 years after randomization in the Diabetic Retinopathy Study. Proportional hazards regression revealed NVD (neovascularization on/around the optic disc) to be the most important risk factor. The risk of severe visual loss rose with increasing NVD, hemorrhages/microaneurysms, retinal elevation, proteinuria, and hyperglycemia and fell with increasing "treatment density." These results are similar to previous DRS findings on untreated eyes. The importance of "treatment density" as an independent predictor of visual outcome is a new finding and lends support to the common clinical practice of repeating photocoagulation if initial treatment does not reduce or stabilize retinal neovascularization.

Aged↗
PubMed1988

The tyrosine-dependent oxidation of tetrahydropterins by lysolecithin-activated rat liver phenylalanine hydroxylase.

In the presence of tyrosine, phenylalanine hydroxylase, which has been activated with lysolecithin, catalyzes the oxidation of tetrahydrobiopterin at a rate 10-20% that of the parallel reaction with phenylalanine. Unlike the reaction with phenylalanine, there is no net concomitant hydroxylation of tyrosine, although the amino acid is still a necessary component. Tyrosine appears to form an abortive complex with the activated enzyme, the pterin cofactor and molecular oxygen. The Km for tetrahydrobiopterin is identical for the reactions with phenylalanine and tyrosine, whereas the Km for tyrosine is approximately 3 1/2 times greater than the Km for phenylalanine. The tyrosine-dependent oxidation of tetrahydrobiopterin proceeds at both pH 6.8 and 8.2 and shows a similar dependence on the pH as that of the physiological reaction. Tetrahydrobiopterin can be replaced by the artificial cofactor, 6-methyltetrahydropterin, in the tyrosine-dependent oxidation at both pH 6.8 and 8.2. As in the parallel reaction with phenylalanine, both the Km for the cofactor and the Km for the aromatic amino acid increase with this substitution.

Animals↗
PubMed1988

Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy.

The relationship between hyperglycemia, measured by glycosylated hemoglobin at the initial examination, and the four-year incidence and progression of diabetic retinopathy was examined in a population-based study in Wisconsin. Younger- (n = 891) and older-onset (n = 987) persons participating in baseline and follow-up examinations were included. Glycosylated hemoglobin was measured by microcolumn. Retinopathy was determined from stereoscopic fundus photographs. In the younger-onset group, comparing the highest with the lowest quartile of glycosylated hemoglobin, the relative risk for developing any diabetic retinopathy was 1.9; for proliferative retinopathy, 21.8; and for progression, 4.0. Among older-onset persons taking insulin, the corresponding relative risks were 1.9, 4.0, and 2.1. Among older-onset persons not taking insulin, relative risks were 4.0 for any retinopathy and 6.2 for progression. A positive relationship between incidence and progression of retinopathy and glycosylated hemoglobin remained after controlling for duration of diabetes, age, sex, and baseline retinopathy. These data suggest a strong and consistent relationship between hyperglycemia and incidence and progression of retinopathy.

Adult↗