Search PubMed⌕ Search

Biomedical subjects

D B Miller

Publications and source records attributed to D B Miller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Racial socialization and racial identity: can they promote resiliency for African American adolescents?

Although there is a rich body of research on resiliency, much of the literature fails to include minority youths or does not take into consideration their distinctive racial and environmental circumstances. Additionally, limited attention has been given to protective factors that are unique to nonmajority populations. This article posits that racial socialization and racial identity protect urban African American adolescents against some of the harmful effects of a discriminatory environment. These factors are hypothesized to influence academic achievement-an indicator of resiliency that has been used in many studies. A theoretical framework is provided that combines character development in a hostile environment, bicultural identity, and urban stress models. Implications for practice and future research are discussed.

Adaptation, Psychological↗
PubMed1998

Thermoregulation in rats exposed perinatally to dioxin: core temperature stability to altered ambient temperature, behavioral thermoregulation, and febrile response to lipopolysaccharide.

Recent studies have shown that perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) alters thermoregulatory function in adult rats and hamsters, indicated by a reduced body temperature during the animal's nocturnal phase. The present study was designed to assess the behavioral thermoregulation, ability to develop a fever, and thermoregulatory stability as a function of ambient temperature (Ta) in rats exposed perinatally to TCDD. Pregnant Long-Evans rats were exposed on gestational day (GD) 15 to 1 microg TCDD/kg (po). The male offspring were implanted with transmitters to monitor core temperature (Tc) and motor activity (MA). The 24-h pattern of core temperature was affected by TCDD exposure, characterized by a reduced nocturnal Tc. At some ages, the diurnal Tc of the TCDD group was elevated. This dysfunction in temperature regulation was most apparent at 7 and 11 mo of age. The 24-h pattern of MA was also altered by TCDD. The hypothermic effects of TCDD were most pronounced at cooler Ta values of 10 to 22 degrees C. In contrast, behavioral thermoregulation, assessed by measuring the selected Ta and Tc of rats in a temperature gradient, was unaffected by TCDD. The ability to develop a fever following administration of lipopolysaccharide (LPS) endotoxin (Escherichia coli; 50 microg/kg) was accentuated in the TCDD-treated animals. The data confirm a nocturnal hypothermia in rats prenatally exposed to TCDD. However, the normal behavioral regulation of Tc suggests that hypothalamic thermoregulatory centers are not permanently altered. The accentuated fever in TCDD animals shows possible functional alterations in the neuroimmune and/or thermoregulatory axes involved in fever.

Administration, Oral↗
PubMed1998

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.

Amphetamines↗
PubMed1998

The impact of gender and estrogen on striatal dopaminergic neurotoxicity.

The reproductive properties of estrogen are well established, but it is now evident that this steroid hormone has substantial modulatory capabilities in nonreproductive systems. For example, estrogen may be neuroprotective as Alzheimer's disease progresses more slowly in women receiving hormone replacement therapy, and Parkinson's disease affects more men than women. Gender affects both the functional biochemical responses of the nigral-striatal pathway to dopaminergically active compounds. To begin to evaluate the possible neuroprotective effects of estrogen in this pathway, we first determined if gender affected dopaminergic striatal neurotoxicity induced by two different neurotoxicants, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Both agents induced greater neurotoxicity in males than females as evidenced by greater striatal dopamine (DA) depletions. An examination of striatal levels of 1-methyl-4-phenylpyridium ion (MPP+) following MPTP treatment established that the observed gender differences were not due to metabolic/pharmacokinetic variables. The neurotoxicity of MPTP was then examined in ovariectomized (OVX) mice. Estrogen replacement reduced the DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletions as well as the glial fibrillary acidic protein (GFAP) elevation induced by MPTP, which indicates that estrogen has neuroprotective properties in this model of striatal dopaminergic neurotoxicity. Surprisingly, estrogen supplementation did not protect against the neurotoxic effects of MPTP in intact 2-yr-old intact female mice, suggesting that low endogenous levels of estrogen may provide neuroprotection.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Synthesis and preliminary evaluation of MP-2269: a novel, nonaromatic small-molecule blood-pool MR contrast agent.

A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugating a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yielded spin-lattice relaxivities (R1) for MP-2269 of 6.2, 20.0 and 26.1 mM(-1)sec(-1) in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate significant binding of the agent to blood proteins. At a dose of 45 micromol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (approximately 70% in 24 h by this mode). The LD50 value of MP-2269 is approximately 3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiography.

Animals↗
PubMed1998

Low velocity impact, vehicular damage and passenger injury.

Low velocity motor vehicle accidents are a source of injury to many people every year, but the existence of these injuries is often challenged in the courts. The question raised is: "If the vehicle did not suffer any damage, how could the occupant become injured?" This paper reviews the pertinent literature and explains the mechanism of injury. The factors influencing the probability of injury are discussed. Fallacies of research methodology are explored as they relate to "real" victims.

Acceleration↗
PubMed1998

The HMG-CoA reductase inhibitor atorvastatin increases the fractional clearance rate of postprandial triglyceride-rich lipoproteins in miniature pigs.

We have previously shown in vivo that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin decreases hepatic apolipoprotein B (apoB) secretion into plasma. To test the hypothesis that atorvastatin modulates exogenous triglyceride-rich lipoprotein (TRL) metabolism in vivo, an oral fat load (2 g fat/kg body wt) containing retinol (50 000 IU) was given to 6 control miniature pigs and to 6 animals after 28 days of treatment with atorvastatin 3 mg. kg-1. d-1. A multicompartmental model was developed by use of SAAM II and kinetic analysis performed on the plasma retinyl palmitate (RP) data. Peak TRL (d<1.006 g/mL; Sf>20) triglyceride concentrations were decreased 29% by atorvastatin, and the time to achieve this peak was delayed (5.2 versus 2.3 hours; P<0.01). The TRL triglyceride 0- to 12-hour area under the curve was decreased by 24%. In contrast, atorvastatin treatment had no effect on peak TRL RP concentrations, time to peak, or its rate of appearance into plasma; however, the TRL RP 0- to 12-hour area under the curve was decreased by 20%. Analysis of the RP kinetic parameters revealed that the TRL fractional clearance rate was increased significantly, 1.4-fold (3.093 versus 2.276 pools/h; P=0.012), with atorvastatin treatment. The percent conversion of TRL RP from the rapid-turnover to the slow-turnover compartment was decreased by 47% with atorvastatin treatment. The TRL RP fractional clearance rate was negatively correlated with very low density lipoprotein apoB production rate measured in the fasting state (r=-0.49). Thus, although atorvastatin had no effect on intestinal TRL assembly and secretion, plasma TRL clearance was significantly increased, an effect that may relate to a decreased competition for removal processes by hepatic very low density lipoprotein.

Animals↗
PubMed1998

Clinical pharmacokinetics of fibric acid derivatives (fibrates).

Beginning with the description of clofibrate in 1962, derivatives of fibric acid (fibrates) have been used clinically to treat dyslipidaemias. Subsequently, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate and long-acting forms of gemfibrozil, fenofibrate and bezafibrate have been developed. Clinically, this class of drugs appears to be most useful in lipoprotein disorders characterised by elevations of very low density lipoprotein and plasma triglycerides, which are often accompanied by reductions in high density lipoprotein (HDL) levels. The principal effects are a reduction in triglyceride and increase in HDL levels, with increases in the activity of hepatic lipase and lipoprotein lipase. There is some reduction of low density lipoprotein (LDL), lipoprotein (a), fibrinogen and uric acid. As a class, these drugs are generally well absorbed from the gastrointestinal tract (immediate-acting fenofibrate being the exception) and display a high degree of binding to albumin. Fibrates are metabolised by the hepatic cytochrome P450 (CYP) 3A4. All members of this class are primarily excreted via the kidneys and display some increase in plasma half-life in individuals with severe renal impairment. The long-acting forms of gemfibrozil and bezafibrate have pharmacokinetic properties similar to those of their immediate-acting parent compounds. The long-acting form of fenofibrate, produced by the process of micronisation, has increased oral bioavailability with less variability in absorption compared with the immediate-acting form of fenofibrate. Drug interactions are seen with other drugs that share a high degree of binding to albumin or are metabolised by CYP3A4. Clinically the most important and most commonly reported drug interactions are with HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin and fluvastatin), warfarin, cyclosporin and oral hypoglycaemic agents [including metformin, tolbutamide and glibenclamide (glyburide)]. The main potential for drug interactions is with drugs or compounds that are metabolised by or affect CYP3A4, including imidazoles, grapefruit juice, erythromycin, mibefradil and others.

Anticholesteremic Agents↗
PubMed1998

Oxidized type IV hypertriglyceridemic VLDL-remnants cause greater macrophage cholesteryl ester accumulation than oxidized LDL.

We have previously shown that very low density lipoproteins (VLDL, Sf 60-400) from subjects with type IV hyperlipoproteinemia (HTG-VLDL) will induce appreciable cholesteryl ester accumulation in cultured macrophages (J774A.1). The present study examined whether copper-mediated oxidative modification of HTG-VLDL and their remnants would further enhance cholesteryl ester accumulation in J774A.1 cells. Incubation with oxidized VLDL-remnants caused the greatest increase in cellular cholesteryl ester concentrations (54-fold) relative to control cells (P = 0.001). HTG-VLDL and VLDL-remnants each induced similar increases in cholesteryl ester levels (32.3- and 35.8-fold, respectively; both P = 0.001), whereas incubation with oxidized HTG-VLDL brought about only a 20.6-fold increase in cholesteryl ester concentrations (P = 0.014). The increase in cellular cholesteryl ester concentrations induced by oxidized VLDL-remnants was significantly higher (P < or = 0.04) than that induced by all other lipoproteins tested including low density lipoprotein (LDL) and oxidized LDL which caused a 6.7- and a 35.1-fold increase (P < or = 0.0002 for both), respectively. Unlike HTG-VLDL and to a lesser extent VLDL-remnants, uptake of oxidized VLDL and oxidized VLDL-remnants did not require catalytically active, cell secreted lipoprotein lipase. Co-incubation with polyinosine, which blocks binding to the type I scavenger receptor, completely inhibited the cholesteryl ester accumulation induced by oxidized HTG-VLDL, oxidized VLDL-remnants and oxidized LDL (P < or = 0.02). We conclude that oxidation of VLDL-remnants significantly enhances macrophage cholesteryl ester accumulation compared to either HTG-VLDL, VLDL-remnants, or oxidized LDL. Uptake of oxidized VLDL and oxidized VLDL-remnants does not require catalytically active lipoprotein lipase, and involves a receptor that can be competed for by polyinosine.

Animals↗
PubMed1997

Secondary prevention for ischemic heart disease. Relative numbers needed to treat with different therapies.

Secondary prevention of ischemic heart disease refers to the process of preventing further morbidity and reducing mortality rates in patients with clinical manifestations of the disease. Twenty-five large randomized, clinical trials addressing mortality rates and cardiovascular morbidity in patients with established ischemic heart disease are reviewed. Broadly defined, these were trials of aspirin and antiplatelet agents, anticoagulants, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, lowering of cholesterol levels, exercise rehabilitation, and diet or vitamins. In trials using warfarin sodium, timolol maleate, propranolol hydrochloride, captopril, ramipril, and simvastatin and 2 diet studies, statistically significant improvements in total mortality rates were seen. Most other studies showed non-significant reductions in total mortality rates, with statistically significant reductions in 1 or more measures of cardiovascular morbidity. The methods necessary for the reader to calculate the number (of patients) needed to treat for other studies are also reviewed. The uses and limitations of the number needed to treat as a method to compare studies of different interventions in similar populations are discussed.

Adrenergic beta-Antagonists↗
PubMed1997

Uptake of type III hypertriglyceridemic VLDL by macrophages is enhanced by oxidation, especially after remnant formation.

We previously showed that hypertriglyceridemic VLDL (HTG-VLDL, Sf 60 to 400) from subjects with type III (E2/E2) hyperlipoproteinemia do not induce appreciable cholesteryl ester (CE) accumulation in cultured macrophages (J774A.1). In the present study, we examined whether oxidation of type III HTG-VLDL would enhance their uptake by J774A.1 cells. Type III HTG-VLDL were oxidized as measured by both conjugated-diene formation and increased electrophoretic mobility on agarose gels. Both LDL and type III HTG-VLDL undergo oxidation, albeit under different kinetic parameters. From the conjugated-diene curve, type III HTG-VLDL, compared with LDL, were found to have a 6-fold longer lag time, to take 6-fold longer to reach maximal diene production, and to produce a 2-fold greater amount of dienes but at half the rate (all P < .005). Incubation of macrophages with either native type III HTG-VLDL or LDL (50 micrograms lipoprotein cholesterol/mL media for 16 hours) caused small increases (4-fold and 2.7-fold, respectively) in cellular CE levels relative to control cells (both P = .0001). After 24 hours of CuSO4 exposure, we found that oxidized type III HTG-VLDL and LDL caused a 9.4-fold and 10.5-fold increase, respectively, in cellular CE levels (P = .0001). We next examined whether extending the exposure period for type III HTG-VLDL to CuSO4 beyond 24 hours would further enhance its ability to induce macrophage CE accumulation. After 48 hours of CuSO4 exposure, type III HTG-VLDL and LDL caused 21.3-fold and 11.6-fold increases, respectively, in cellular CE levels (P = .0001). The cellular CE loading achieved with 48 hour-oxidized type III HTG-VLDL was significantly higher than either 24 hour-oxidized type III HTG-VLDL (2.3-fold, P = .003) or 48 hour-oxidized LDL (1.8-fold, P = .012). There was no significant difference between the CE loading achieved by incubation of cells with either 24 hour-oxidized type III HTG-VLDL, 24 hour-oxidized LDL, or 48 hour-oxidized LDL (P > or = .518). In this study, we also examined whether partial lipolysis (19% to 50% triglyceride hydrolysis) of type III HTG-VLDL to produce remnants would increase the susceptibility of the lipoprotein to oxidative modification and subsequent cellular CE loading. Forty-eight hour-oxidized type III VLDL-remnants stimulated CE accumulation 30.4-fold over baseline (P = .0001). In contrast, nonoxidized type III VLDL-remnants caused the same very low level of CE loading as did native type III HTG-VLDL (P = .680). The increase in cellular CE levels achieved with 48 hour-oxidized type III VLDL-remnants was significantly higher than that achieved with 48 hour-oxidized type III HTG-VLDL (P = .047). In conclusion, we have shown that oxidized type III HTG-VLDL will induce macrophage CE accumulation well above levels achieved with oxidized LDL. In addition, we also showed that by forming a VLDL-remnant before oxidative modification, we can further enhance macrophage CE accumulation. These results provide a potential mechanism for the atherogenicity of type III HTG-VLDL and their remnants.

Animals↗
PubMed1997

Fear of AIDS and Homophobia Scales: additional estimates of reliability and validity.

Psychometric properties of the Fear of AIDS Scale and the Homophobia Scale from 85 heterosexual undergraduates (and 44 gay, lesbian, and bisexual undergraduates) were estimated. Responses on the Homophobia Scale were internally consistent (alpha = .88), had 4% standard error of measurement, and scores differed by subjects' sexual orientation. Responses to Fear of AIDS Scale were moderately internally consistent (alpha = .75), had 12% standard error, and were significantly different for the two groups. Scores on the tests were correlated .66. Researchers must assess the relationship between scores on these measures.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Multiple malignant meningiomas in a young cat.

A 2-year-old cat was presented with generalised muscle tremors and progressive fore- and hindlimb ataxia, 5 months after the initiation of chemotherapy for thymic lymphoma. The lymphoma was treated with combination chemotherapy (cyclophosphamide, vincristine and prednisolone), which resulted in remission. The neurological signs progressed to paralysis and the cat subsequently died. On autopsy, multiple meningiomas were diagnosed, which is an unusual finding. It is possible that the lymphoma chemotherapy resulted in the development of the multiple meningiomas as secondary malignancies.

Animals↗
PubMed1997

Transient hyperammonaemia in an adult German shepherd dog.

A 3-year-old male German shepherd dog was presented with severe generalised seizures. The dog was protein-intolerant and showed severe hyperammonaemia on ammonia stimulation. The hyperammonaemic state was present for at least 6 weeks and then spontaneously resolved. No obvious cause (liver disease, portocaval shunts, urea cycle enzyme deficiencies, drug therapy or urinary tract obstruction) could be identified. It is possible that this dog had a variation of transient hyperammonaemic syndrome, described in man and recently in a juvenile Irish wolfhound, that extended into adulthood.

Ammonia↗
PubMed1997

Uptake of hypertriglyceridemic very low density lipoproteins and their remnants by HepG2 cells: the role of lipoprotein lipase, hepatic triglyceride lipase, and cell surface proteoglycans.

Hypertriglyceridemic very low density lipoproteins (HTG-VLDL, S(f) 60-400) are not taken up by HepG2 cells. However, addition of bovine milk lipoprotein lipase (LPL) at physiological concentrations markedly stimulates uptake. In the present study, we determined whether: a) LPL catalytic activity is required for uptake, b) LPL functions as a ligand, and c) cell surface hepatic triglyceride lipase (HL) and/or proteoglycans are involved. Incubation of HepG2 cells with HTG-VLDL plus LPL (8 ng/ml) increased cellular cholesteryl ester (CE) 3.5-fold and triglyceride (TG) 6-fold. Heat-inactivation of LPL abolished the effect. Addition of tetrahydrolipstatin (THL, an LPL active-site inhibitor) to HTG-VLDL + LPL, inhibited the cellular increase in both CE and TG by greater than 90%. Co-incubation of HTG-VLDL + LPL with heparin, heparinase, or heparitinase, blocked CE accumulation by 70%, 48%, and 95%, respectively, but had no effect on the increase in cellular TG. Pre-treatment of cells with 1 mM 4-methylumbelliferyl-beta-D-xyloside, (beta-xyloside) to reduce cell surface proteoglycans inhibited the increase in CE induced by HTG-VLDL + LPL by 78%. HTG-VLDL remnants, prepared in vitro and isolated free of LPL activity, stimulated HepG2 cell CE 2.8-fold in the absence of added LPL, a process inhibited with THL by 66%. Addition of LPL (8 ng/ml) to remnants did not further enhance CE accumulation. HepG2 cell HL activity, released by heparin, was inhibited 95% by THL. The amount of HL activity and immunoreactive mass, released by heparin, was reduced 50-60% in beta-xyloside-treated cells. These results indicate that physiological concentrations of LPL promote HepG2 cell uptake of HTG-VLDL primarily due to remnant formation and that LPL does not play a major role as a ligand. HL activity and cell surface proteoglycans significantly enhance the subsequent uptake of VLDL remnants.

Animals↗
PubMed1996

Neurotoxicity of d-amphetamine in the C57BL/6J and CD-1 mouse. Interactions with stress and the adrenal system.

Substantial evidence suggests that stress can alter the general toxicological properties of the substituted amphetamines (AMPs) as well as their psychostimulant properties. Research concerning the interactions between stress and the neurotoxicity associated with the AMPs is, however, limited. Our previous work demonstrated that a variety of AMPs, including d-METH, d-MDA, d-MDMA but not d-FEN are able to damage dopaminergic elements of the striatum as shown by decreases in dopamine and tyrosine hydroxylase. The neurotoxic capabilities of these AMPs appear linked to their hyperpyrexic actions as diverse manipulations able to block AMP-induced hyperthermia are also neuroprotective. Surprising, since stress usually potentiates the actions of the AMPs, it is our finding that restraint, a commonly used stressor, is protective against the injurious actions of all neurotoxic AMPs evaluated to date. In the mouse restraint acts to elevate blood levels of corticosterone (CORT) by activating the hypothalamic-pituitary-adrenal (HPA) axis as well as inducing a profound hypothermia. The role CORT may play in the neuroprotective actions of restraint, if any, is unknown. Here, data is presented showing the impact of several HPA axis manipulations, including restraint, supplementation with CORT in the drinking water and removal of CORT by adrenalectomy (ADX) on the striatal dopaminergic neurotoxicity of d-AMP. As strain is known to be a powerful determinant of the actions of stress an essential element of these experiments was the evaluation of both an inbred, C57BL/6J and outbred, CD-1, mouse strain. Exposure to d-AMP caused hyperthermia and substantial striatal dopaminergic neurotoxicity in both strains suggesting that an elevation in body temperature is as important a component of the neurotoxicity of d-AMP, as it is of the other neurotoxic AMPs. Restraint was equally effective in both strains and completely blocked the hyperthermia and striatal neurotoxicity induced by d-AMP. CORT supplementation, evaluated in only the C57BL/6J mouse at dosages not capable of involuting either the thymus or the spleen, did not alter d-AMP-induced neurotoxicity. Although the immune system organs of the two strains responded differentially to the removal of CORT, ADX provided equivalent partial protection against the loss of dopaminergic elements in striatum for both strains. Adrenal status clearly affects d-AMP neurotoxicity but the interaction is complex. Future work should examine the roles of the cortical and medullary components of the adrenal gland in the neuroprotective actions of ADX. A precise assessment of the role of circulating CORT In the neurotoxicity of the AMPs will require additional work in which a wider range of CORT dosages, including those capable of involuting thymus and spleen, are evaluated.

Adrenal Cortex Hormones↗
PubMed1995

Comparison of recombinant cyclooxygenase-2 to native isoforms: aspirin labeling of the active site.

The search for isoform-specific enzyme inhibitors has been the focus of much recent research effort. Towards this goal, human recombinant cyclooxygenase-2 (EC 1.14.99.1, prostaglandin H synthase) was expressed in insect cells and purified to > 98% purity. Recombinant enzyme was characterized both by physical methods and activity measurements and shown to be fully active with kinetic properties similar to native COX-2 and COX-1. After detergent extraction, the enzyme had hydrodynamic properties indistinguishable from native bovine COX-1 and corresponded to the enzyme dimer as measured with size-exclusion chromatography. Peptide mapping via Lys-C protease identified a site of N-linked glycosylation and the aspirin covalent modification site. In the presence of heme, aspirin-specifically acetylated Ser-516. The enzyme will be suitable for biophysical studies and may lead to isoform-specific enzyme inhibitors.

Amino Acid Sequence↗