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Matthew Davis

Publications and source records attributed to Matthew Davis.

9 recordsLinked to original sources
PubMed2004

ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver.

BACKGROUND: Two acyl-coenzyme A:cholesterol acyltransferase (ACAT) genes, ACAT1 and ACAT2, have been identified that encode 2 proteins responsible for intracellular cholesterol esterification. METHODS AND RESULTS: In this study, immunohistology was used to establish their cellular localization in human liver biopsies. ACAT2 protein expression was confined to hepatocytes, whereas ACAT1 protein was found in Kupffer cells only. Studies with a highly specific ACAT2 inhibitor, pyripyropene A, in microsomal activity assays demonstrated that ACAT2 activity was highly variable among individual human liver samples, whereas ACAT1 activity was more similar in all specimens. ACAT2 provided the major cholesterol-esterifying activity in 3 of 4 human liver samples examined. CONCLUSIONS: The data suggest that in diseases in which dysregulation of cholesterol metabolism occurs, such as hypercholesterolemia and atherosclerosis, ACAT2 should be considered a target for prevention and treatment.

Adolescent↗
PubMed2003

Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness.

Acyl CoA:cholesterol acyltransferase 1 (ACAT1) and ACAT2 are enzymes responsible for the formation of cholesteryl esters in tissues. While both ACAT1 and ACAT2 are present in the liver and intestine, the cells containing either enzyme within these tissues are distinct, suggesting that ACAT1 and ACAT2 have separate functions. In this study, NBD-cholesterol was used to screen for specific inhibitors of ACAT1 and ACAT2. Incubation of AC29 cells, which do not contain ACAT activity, with NBD-cholesterol showed weak fluorescence when the compound was localized in the membrane. When AC29 cells stably transfected with either ACAT1 or ACAT2 were incubated with NBD-cholesterol, the fluorescent signal localized to the nonpolar core of cytoplasmic lipid droplets was strongly fluorescent and was correlated with two independent measures of ACAT activity. Several compounds were found to have greater inhibitory activity toward ACAT1 than ACAT2, and one compound was identified that specifically inhibits ACAT2. The demonstration of selective inhibition of ACAT1 and ACAT2 provides evidence for uniqueness in structure and function of these two enzymes. To the extent that ACAT2 is confined to hepatocytes and enterocytes, the only two cell types that secrete lipoproteins, selective inhibition of ACAT2 may prove to be most beneficial in the reduction of plasma lipoprotein cholesterol concentrations.

4-Chloro-7-nitrobenzofurazan↗
PubMed2003

High affinity hydroxypiperidine analogues of 4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidine for the dopamine transporter: stereospecific interactions in vitro and in vivo.

In our effort to develop high-affinity ligands for the dopamine transporter which might find potential use as cocaine medication, a polar hydroxy substituent was introduced into the piperidine ring of one of our disubstituted lead analogues derived from 1-[2-(diphenylmethoxy)-ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935). Both cis- and trans-3-hydroxy derivatives were synthesized and the racemic trans isomer, (+/-)-5, was further resolved into two enantiomers. Newly synthesized compounds were characterized for their binding affinity at the dopamine, serotonin, and norepinephrine transporter systems in rat brain. The two enantiomers (+)-5 and (-)-5 exhibited marked differential affinities at the dopamine transporter with (+)-5 being 122-fold more potent than (-)-5 in inhibiting radiolabeled cocaine analogue binding (IC(50); 0.46 vs 56.7 nM) and 9-fold more active for inhibiting dopamine uptake (IC(50); 4.05 vs 38.0 nM). Furthermore, the most active (+)-5 was 22-fold more potent at the dopamine transporter compared to the standard GBR 12909. Absolute configuration of one of the enantiomers was determined unambiguously by X-ray structural analysis. In in vivo locomotor activity studies, the enantiomer (+)-5 and the racemic (+/-)-5, but not (-)-5, exhibited stimulant activity with a long duration of effect. All three compounds, (+)-5, (-)-5, and (+/-)-5, within the dose range tested, partially (50%) but incompletely (80%) produced cocaine-like responses in mice trained to discriminate 10 mg/kg ip cocaine from vehicle. Compound (-)-5 was distinctive in this regard in that, unlike (+)-5 and (+/-)-5, it did not affect locomotor activity yet, but similar to them, was able to engender (albeit incompletely) cocaine-like responses.

Animals↗
PubMed2003

Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.

PURPOSE: To develop consensus regarding clinical disease severity classification systems for diabetic retinopathy and diabetic macular edema that can be used around the world, and to improve communication and coordination of care among physicians who care for patients with diabetes. DESIGN: Report regarding the development of clinical diabetic retinopathy disease severity scales. PARTICIPANTS: A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialties, endocrinology, and epidemiology. METHODS: An initial clinical classification system, based on the Early Treatment Diabetic Retinopathy Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy publications, was circulated to the group in advance of a workshop. Each member reviewed this using e-mail, and a modified Delphi system was used to stratify responses. At a later workshop, separate systems for diabetic retinopathy and macular edema were developed. These were then reevaluated by group members, and the modified Delphi system was again used to measure degrees of agreement. MAIN OUTCOME MEASURES: Consensus regarding specific classification systems was achieved. RESULTS: A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent. If training and equipment allow the screener to make a valid decision, macular edema is further categorized as a function of its distance from the central macula. CONCLUSIONS: There seems to be a genuine need for consistent international clinical classification systems for diabetic retinopathy and diabetic macular edema that are supported with solid evidence. The proposed clinical classification systems provide a means of appropriately categorizing diabetic retinopathy and macular edema. It is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients.

Diabetic Retinopathy↗
PubMed2002

Primates highly responsive to dietary cholesterol up-regulate hepatic ACAT2, and less responsive primates do not.

The role of liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT enzyme within primate hepatocytes, as a regulator of the hypercholesterolemia induced by dietary cholesterol was studied. At the end of low and high cholesterol diet periods, liver biopsies were taken from cynomolgus monkeys, a species highly responsive to dietary cholesterol, and less responsive African green monkeys. Liver cholesterol and cholesteryl ester concentrations were highest in cynomolgus monkeys fed cholesterol, despite the fact that in order to induce equivalent hypercholesterolemia, dietary cholesterol levels were 50% lower than was fed to green monkeys. Hepatic cholesteryl oleate secretion rate, measured during liver perfusion as an indicator of ACAT activity, was significantly higher in cynomolgus monkeys. Liver microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys than in green monkeys. The responses of ACAT2 were compared with those of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass was significantly correlated to microsomal total ACAT activity in both species; ACAT1 mass was less well correlated. Dietary cholesterol induced a significant 3-fold increase of ACAT2 protein mass in cynomolgus monkeys, a much greater increase than was found for mRNA abundance; neither ACAT2 mRNA nor protein was diet-responsive in green monkeys. In cynomolgus monkeys but not in green monkeys, liver free cholesterol concentrations were elevated when cholesterol was fed and were correlated with ACAT2 protein levels. The data suggest a mechanism whereby the elevation of hepatic free cholesterol concentrations by dietary cholesterol, seen only in cynomolgus monkeys, resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor.

Animals↗
PubMed2002

Preliminary results of a nonrandomized, multicenter, open-label study of patient satisfaction after treatment with combination benzoyl peroxide/clindamycin topical gel for mild to moderate acne.

BACKGROUND: Assessments of patient satisfaction are needed to determine treatment-related improvement in acne from the patient's perspective. OBJECTIVES: The aims of this study were to assess patient satisfaction, drug efficacy, and the social aspects of quality of life after treatment with benzoyl peroxide/clindamycin topical gel in patients who were dissatisfied with their previous acne treatment regimens. METHODS: This nonrandomized, open-label, multicenter study was open to patients aged > or = 12 years who were dissatisfied with their previous acne treatments. Patients applied topical benzoyl peroxide/clindamycin gel twice daily for 8 weeks. Patient satisfaction was assessed on an 11-point analog scale (0 = not satisfied; 10 = very satisfied). The social effects of acne were assessed using a 9-question acne quality of life (AQOL) scale, and treatment efficacy was assessed using the global acne grading system (GAGS). Safety and tolerability were monitored continuously through self-reporting and patient questioning. RESULTS: Preliminary results were gathered for 257 patients. Relative to baseline, patients were significantly more satisfied after 8 weeks of treatment with benzoyl peroxide/ clindamycin gel (P < 0.001). The mean overall cumulative AQOL score improved significantly among 249 patients aged > or = 12 years (P < 0.001), but the clinical relevance of this finding is unknown. The mean GAGS score decreased from 15.9 (SD = 6.0) at baseline to 8.2 (SD = 5.7) at week 8 (P < 0.001). The most common adverse events were dry skin and skin irritation. CONCLUSIONS: These preliminary results suggest that patients who are dissatisfied with their current acne regimen may be more satisfied after treatment with benzoyl peroxide/clindamycin gel. However, more definitive conclusions can be drawn only following the completion of the study.

Acne Vulgaris↗
PubMedDate not supplied

Rates of maternal depression in pediatric emergency department and relationship to child service utilization.

This cross-sectional study aimed to (a) identify rates and correlates of untreated elevated depression in mothers of young children in a pediatric emergency department (ED) setting and (b) examine the association of depression and other key variables to child healthcare use. Mothers (n=176) bringing their child (<age 7) to the pediatric ED completed a screening survey assessing depression, demographic information, and select child healthcare information. Up to 31% of mothers screened evidenced elevated depression, and most were not being treated (78%). Elevated depression was related to both missed pediatric outpatient visits and greater use of pediatric ED services. Thus, the pediatric ED setting may provide the opportunity to identify mothers whose depressive symptoms have been obstacles to seeking routine primary care for their children. Detection of maternal depression in pediatric settings using a screening tool accompanied by appropriate follow through may be a reasonable strategy to improve health outcomes for both the mother and her child.

Adult↗