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Biomedical subjects

D W Miller

Publications and source records attributed to D W Miller.

At least 55 records · Page 3Linked to original sources
PubMed2000

Hypophosphatemia in the emergency department therapeutics.

Although hypophosphatemia is relatively uncommon, it may be seen in anywhere from 20% to 80% of patients who present to the ED with alcoholic emergencies, diabetic ketoacidosis (DKA), and sepsis. Severe hypophosphatemia, as defined by a serum level below 1.0 mg/dL, may cause acute respiratory failure, myocardial depression, or seizures. Because hypophosphatemia is not as often treated by ED physicians, becoming familiar with a single intravenous phosphate solution and specific guidelines for phosphate repletion are essential. One mL of the most commonly available phosphate solution (K2PO4) contains 4.4 meq of potassium and 3 mmol (93 mgs) of phosphate. Administering K2PO4 at a rate of 1 mL per hour is almost always a very safe and appropriate treatment for hypophosphatemia. This article provides guidelines for phosphate therapy in hypophosphatemic ED patients including those in DKA, those presenting with alcohol-related complaints including alcoholic ketoacidosis and patients with acute exacerbation of asthma and chronic obstructive pulmonary disease.

Alcoholism↗
PubMed2000

Designing a bridge for consciousness: are criteria for a unification of approaches feasible?

Different intrinsic rules of functioning for body and mind are overemphasized by the mutually exclusive methods of investigation in both consciousness and the sciences. Classical science, alternative and complementary healing, quantum physics, and metaphysics all take drastically different approaches to consciousness research. A bridge is needed to restore the conceptual unity of mind-body. However, the construction of such a bridge paradoxically must rely on consciousness for information. The construction company (Consciousness, Inc.) therefore becomes means and end in the design of the bridge. This piece argues that the methods of each discipline contain research tools and resources to create a bridge that satisfies a unified multidimensional and multidisciplinary conception. The piece further suggests that the framework of the bridge must place consciousness as a partner to physiology in the evolutionary trajectory of life, since problems of survival are a primary consideration in the activity of both. Finally, the piece develops six criteria by which to evaluate the effectiveness of any construction design.

Consciousness↗
PubMed2000

Determination of the air w-value in proton beams using ionization chambers with gas flow capability.

The purpose of this work was to determine the w-value of air for protons using the paired gas method. Several plastic- and magnesium-walled chambers were used with air, synthetic air, nitrogen, and argon flowing gases. Using argon as a reference gas, the w-value of air was measured and ranged from 32.7 to 34.5 J/C for protons with energies encountered in radiotherapy. Using nitrogen as a reference gas, the w-value of air ranged from 35.2 to 35.4 J/C over the same range of proton energies. The w-value was found, at a given energy, to be independent of the ion chamber used. The uncertainty in these measurements was estimated at 5.2% at the 2sigma level. This uncertainty was dominated by the 4.4% uncertainty in the w-value of the reference gas.

Air↗
PubMed2000

Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson's disease.

Mutations in the alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) genes have been linked to some cases of familial Parkinson's disease. To provide insight into how these genes may relate to each other and contribute to the pathology of Parkinson's disease, their expression was examined in normal human brain. Tissue sections from multiple regions of 11 normal human brains were hybridized with radiolabeled and digoxygenin-labeled cRNA probes for alpha-synuclein, parkin, and UCH-L1 mRNA. Expression of each of these three genes was predominantly neuronal. Alpha-synuclein and parkin mRNAs were expressed in a restricted number of brain regions, whereas UCH-L1 mRNA was more uniformly expressed throughout brain. The melanin-containing dopamine neurons of the substantia nigra had particularly robust expression. The expression patterns of alpha-synuclein and parkin mRNAs were similar, suggesting that these two proteins may be involved in common pathways contributing to the pathophysiology of Parkinson's disease.

Aged↗
PubMed2000

T cell adoptive immunotherapy of newly diagnosed gliomas.

Patients with newly diagnosed gliomas were treated with adoptive transfer of ex vivo activated T lymphocytes, derived from lymph nodes (LNs) draining autologous tumor vaccines, to determine the long-term toxicity of this treatment. Twelve consecutive patients were enrolled: 2 with grade II astrocytoma, 4 with anaplastic gliomas, and 6 with glioblastoma multiforme. Patients were injected intradermally with short-term cultured autologous irradiated tumor cells, admixed with granulocyte macrophage colony-stimulating factor, to stimulate draining LNs. The LN cells were activated with staphylococcal enterotoxin A for 48 h and then cultured in medium containing interleukin 2 for an additional 6-8 days and subsequently transferred i.v. to the patients. The number of cells obtained from the LNs ranged from 9 x 10(7) to 1.1 x 10(9), and the median cell proliferation was 41-fold. The dose of T cells infused ranged from 0.6 to 5.5 x 10(10) with a median of 1.1 x 10(10), the majority of which were CD 4+ (mean, 71%). The entire treatment was performed as outpatient therapy and was associated with a toxicity of grade 2 or less, consisting mainly of fever, nausea, and myalgias during the first 24 h. There were no indications of late adverse events from this treatment even among three patients with follow-up greater than 2 years post T cell transfer. Moreover, four patients demonstrated partial regression of residual tumor. This Phase I clinical trial of adoptive immunotherapy for patients with newly diagnosed malignant gliomas demonstrates feasibility, lack of long-term toxicity, and several objective clinical responses.

Adult↗
PubMed1999

Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique.

PURPOSE: Following adequate therapy, excellent long-term survival rates can be achieved for patients with optic pathway gliomas. Therefore, avoidance of treatment-related functional long-term sequelae is of utmost importance. Optimized sparing of normal tissue is of primary concern in the development of new treatment modalities. The present study compares proton radiation therapy (PRT) with a three-dimensional (3D)-planned multiport photon and a lateral beam photon technique for localized and extensive optic pathway tumors. METHODS AND MATERIALS: Between February 1992 and November 1997, seven children with optic pathway gliomas underwent PRT. For this study, we computed proton, 3D photon, and lateral photon plans based on the same CT data sets, and using the same treatment planning software for all plans. Radiation exposure for normal tissue and discrete organs at risk was quantified based on dose-volume histograms. RESULTS: Gross tumor volume (GTV) ranged from 3.9 cm3 to 127.2 cm3. Conformity index (relation of encompassing isodose to GTV volume) was 2.3 for protons, 2.9 for 3D photons, and 7.3 for lateral photons. The relative increase of normal tissue (NT) encompassed at several isodose levels in relation to NT encompassed by the 95% proton isodose volume was computed. Relative NT volume of proton plan isodoses at the 95%, 90%, 80%, 50%, and 25% isodose level increased from 1 to 1.6, 2.8, 6.4, to a maximum of 13.3. Relative volumes for 3D photons were 1.6, 2.4, 3.8, 11.5, and 34.8. Lateral plan relative values were 6, 8.3, 11.5, 19.2, and 26.8. Analysis for small (<20 cm3) and larger (> 80 cm3) tumors showed that protons encompassed the smallest volumes of NT at all isodose levels. Comparable conformity and high-dose gradient were achieved for proton and 3D photon plans in small tumors. However, with increasing tumor volume and complexity, differences became larger. At the 50% isodose level, 3D photons were superior to lateral photons for small tumors; this advantage was equalized for larger tumors. At the lowest isodose level, 3D photons encompassed the highest amount of NT. Analysis of organs at risk showed that PRT reduced doses to the contralateral optic nerve by 47% and 77% compared to 3D photons and lateral photons, respectively. Reductions were also seen for the chiasm (11% and 16%) and pituitary gland (13% and 16%), with differences at clinically relevant tolerance levels. Furthermore, reduced dose exposure of both temporal lobes (sparing 39% and 54%) and frontal lobes was achieved with PRT. CONCLUSION: PRT offered a high degree of conformity to target volumes and steep dose gradients, thus leading to substantial normal tissue sparing in high- and low-dose areas. It is expected that this will result in decreased long-term toxicity in the maturing child. Advantages of proton versus 3D photon plans became increasingly apparent with increasing target size and tumor complexity. Even in small tumors, conformity of 3D photon irradiation came at the expense of a larger amount of NT receiving moderate to low radiation doses. Lateral photons resulted in inferior dose distribution with high radiation exposure of clinically relevant normal tissues.

Child↗
PubMed1999

Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.

The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.

Acrylic Resins↗
PubMed1999

Elevated expression of endoglin, a component of the TGF-beta-receptor complex, correlates with proliferation of tumor endothelial cells.

Endoglin/CD105 is a membrane protein involved in the TGF-beta receptor signalling pathway. Endoglin expression has been reported to be selective for a few cell types, in particular endothelial cells, although a number of conflicting reports have been published. In this study, we performed a detailed analysis of endoglin expression in human lung tumors and different tumor and endothelial cell lines, employing reverse-transcriptase-polymerase-chain reaction as well as immunoblotting and immunohistochemistry using verified antibodies to endoglin. Our data show a clearly preferential expression of both endoglin mRNA and protein in endothelial cells. In tumors, endoglin expression was strongly elevated in the angiogenic endothelium at the tumor edges. In agreement with this observation, we find a clear correlation between endoglin expression and markers of proliferation, such as cyclin A and Ki-67, suggesting that endoglin expression is linked to cell-cycle regulation. These findings not only resolve some of the discrepancies in the literature, but also provide the basis for further applications making use of its selective localization and expression in the tumor vasculature.

Antigens, CD↗
PubMed1999

Enzyme specificity under dynamic control: a normal mode analysis of alpha-lytic protease.

We have used alpha-lytic protease as a model system for exploring the relationship between the internal dynamics of an enzyme and its substrate specificity. The wild-type enzyme is highly specific for small substrates in its primary specificity pocket, while the M190A mutant has a much broader specificity, efficiently catalyzing cleavage of both large and small substrates. Normal modes have been calculated for both the wild-type and the mutant enzyme to determine how internal vibrations contribute to these contrasting specificity profiles. We find that for the atoms lining the walls of the specificity pocket, the wild-type normal modes have a more symmetric character, with the walls vibrating in phase, and the size of the pocket remaining relatively fixed. This is in agreement with X-ray crystallographic data on conformational substates trapped at 120 K. In contrast, we find that in the mutant, the binding pocket normal modes have a more antisymmetric character, with the walls vibrating out of phase, and the pocket able to expand and contract. These results suggest that the internal vibrations of a molecule may play an important role in determining substrate binding and specificity. A small change in protein structure can have a significant effect on the pattern of molecular vibrations, and thus on enzymatic properties, even if the overall amplitudes of the vibrations, as measured by NMR relaxation or crystallographic B-factors, remain largely unchanged.

Magnetic Resonance Spectroscopy↗
PubMed1999

Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-alpha exposure.

TNF-alpha is a cytokine that produces increased permeability in the peripheral vasculature; however, little is known about the effects of TNF-alpha on the blood-brain barrier (BBB). Using primary cultured bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB, this study shows that TNF-alpha produces a reversible increase in the permeability of the brain microvessel endothelial cells. The BBMEC monolayers were pre-treated with 100 ng/ml of TNF-alpha for periods ranging from 2 to 12 hours. Permeability was assessed using three molecular weight markers, fluorescein (376 MW), fluorescein-dextran (FDX-4400; 4400 MW), and FDX-70000 (MW 70000). The permeability of BBMEC monolayers to all three fluorescent markers was increased two-fold or greater in the TNF-alpha treatment group compared to control monolayers receiving no TNF-alpha. Significant changes in permeability were also observed with TNF-alpha concentrations as low as 1 ng/ml. These results suggest that TNF-alpha acts directly on the brain microvessel endothelial cells in a dynamic manner to produce a reversible increase in permeability. Exposure of either the lumenal or ablumenal side of BBMEC monolayers to TNF-alpha resulted in similar increases in permeability to small macromolecules, e.g. fluorescein. However, when a higher molecular weight marker was used (e.g. FDX-3000), there was a greater response following lumenal exposure to TNF-alpha. Together, these studies demonstrate a reversible and time dependent increase in brain microvessel endothelial cell permeability following exposure to TNF-alpha. Such results appear to be due to TNF's direct interaction with the brain microvessel endothelial cell.

Animals↗
PubMed1999

Conformal proton therapy for early-stage prostate cancer.

OBJECTIVES: To assess the effect of proton radiation on clinical and biochemical outcomes for early prostate cancer. METHODS: Three hundred nineteen patients with T1-T2b prostate cancer and initial prostate-specific antigen (PSA) levels 15.0 ng/mL or less received conformal radiation doses of 74 to 75 cobalt gray equivalent with protons alone or combined with photons. No patient had pre- or post-treatment hormonal therapy until disease progression was documented. Patients were evaluated for biochemical disease-free survival, PSA nadir, and toxicity; the mean and median follow-up period was 43 months. RESULTS: Overall 5-year clinical and biochemical disease-free survival rates were 97% and 88%, respectively. Initial PSA level, stage, and post-treatment PSA nadir were independent prognostic variables for biochemical disease-free survival: a PSA nadir 0.5 ng/mL or less was associated with a 5-year biochemical disease-free survival rate of 98%, versus 88% and 42% for nadirs 0.51 to 1.0 and greater than 1.0 ng/mL, respectively. No severe treatment-related morbidity was seen. CONCLUSIONS: It appears that patients treated with conformal protons have 5-year biochemical disease-free survival rates comparable to those who undergo radical prostatectomy, and display no significant toxicity. A Phase III randomized dose-escalation trial is underway to define the optimum radiation dose for early-stage prostate cancer.

Follow-Up Studies↗
PubMed1999

Sumatriptan treatment for migraine in a health maintenance organization: economic, humanistic, and clinical outcomes.

This study was undertaken to assess the impact of 12 months of sumatriptan therapy (6 mg subcutaneously) for migraine on health care use, health-related quality of life, productivity, patient satisfaction with the medication, and clinical efficacy in a health maintenance organization (HMO). One hundred forty-eight patients received open-label sumatriptan for 12 months for the treatment of migraine. Medical records were reviewed to obtain information on the frequency of migraine-related health care use during the 12 months before and during sumatriptan treatment. Patients completed questionnaires on their productivity at work, health-related quality of life, and satisfaction with medication at baseline and after 3, 6, and 12 months of sumatriptan treatment. For each migraine, patients recorded pain severity scores before and after taking sumatriptan and the time between dosing and onset of meaningful relief. Sumatriptan was associated with significant reductions in migraine-related use of general outpatient services, telephone calls, urgent care services, and emergency department visits (P < 0.05); a significant increase in the use of pharmacy services (P < 0.05); and significant and sustained improvements in health-related quality-of-life scores compared with baseline (P < 0.001). Patients lost significantly less time from work and were significantly more satisfied with sumatriptan compared with their usual therapy (P < 0.05). Two hours after dosing, 81% of patients experienced reduction of moderate or severe pain to mild or no pain, and 90% of all patients experienced meaningful relief of pain. The use of sumatriptan for 12 months in an HMO was associated with reductions in health care use and improved health-related quality of life, productivity, and patient satisfaction with medication.

Adult↗
PubMed1999

Modeling economic evaluations of pharmaceuticals: manipulation or valuable tool?

Controversy surrounds the use of models in economic evaluations of pharmaceuticals. Many believe that modeling is a way of manipulating results and is not credible, whereas others consider modeling a valuable tool in economic evaluations. The purpose of this article is to provide a historical perspective on modeling, focus on the controversy and policy implications of using models, and review the suggested framework and guidelines for modeling practices. Models can be used to extrapolate beyond intermediate end points, predict costs and consequences of alternative therapies, generalize data to other settings, pose questions instead of providing answers when no data exist, design an evaluation to reduce uncertainty, and perform direct comparisons that are not currently available. We believe that a useful model should document the detailed inner workings, assumptions, and inherent bias during production (and at publication time), so that its reviewers and users can evaluate the appropriateness of the model's outcomes. The acceptability of models in the future rests with the researchers constructing them. If constructed appropriately, modeling economic evaluations is not a manipulation but rather a valuable tool.

Clinical Trials as Topic↗
PubMed1999

Using semantic constraints to help verify the completeness of a computer-based clinical guideline for childhood immunization.

The paper describes Commander, a prototype computer program designed to help verify the completeness of a computer-based clinical practice guideline built using if then rules. It also describes the application of Commander to a guideline for childhood immunization. Commander is designed to help identify incomplete rule sets, where there are clinically meaningful conditions to which the guideline does not respond. To allow this, the user defines semantic constraints, in the form of if-then statements, which indicate combinations of conditions which are not meaningful. In an iterative process, Commander takes the guideline rules, together with an increasingly refined set of constraints and helps focus in on any combinations of conditions to which the guideline does not respond. When applied to the clinical guideline for childhood immunization, Commander was able to dramatically reduce the number of potential combinations of conditions for consideration and also identified several areas of incompleteness in the rules.

Child↗
PubMed1999

Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers.

PURPOSE: Using monolayers of human pancreatic adenocarcinoma cells (Panc-1) that express multidrug resistance-associated protein (MRP), the present work investigates the effects of Pluronic block copolymers on the functional activity of MRP. METHODS: The studies examined the accumulation and efflux of the MRP selective probe fluorescein (FLU) in Panc-1 cell monolayers with and without Pluronic P85 (P85), Pluronic L81 (L81) and Pluronic F108 (F108). RESULTS: Treatment of Panc-1 cells with P85 resulted in concentration-dependent increases in FLU accumulation and elimination of FLU sequestration in vesicular compartments in these cells. The effects of P85 were selective for FLU in the Panc-1 cell monolayers. Inhibition of MRP-mediated transport was dependent on the composition of Pluronic block copolymer: the more hydrophobic copolymer had the greater effect on FLU uptake in Panc-1 monolayers (L81 > P85 > F108). CONCLUSIONS: This paper demonstrates for the first time that Pluronic block copolymers inhibit multidrug resistance-associated protein (MRP). The similarities in the effects of Pluronic block copolymers on MRP and P-glycoprotein drug efflux systems suggest that a single unifying mechanism may explain the inhibition observed.

ATP-Binding Cassette Transporters↗
PubMed1999

Pluronic P85 increases permeability of a broad spectrum of drugs in polarized BBMEC and Caco-2 cell monolayers.

PURPOSE: Previous studies demonstrated that inhibition of P glycoprotein (P-gp) by Pluronic P85 (P85) block copolymer increases apical (AP) to basolateral (BL) transport of rhodamine 123 (R123) in the polarized monolayers of bovine brain microvessel endothelial cells (BBMEC) and Caco-2 cells. The present work examines the effects of P85 on the transport of fluorescein (Flu), doxorubicin (Dox), etoposide (Et), taxol (Tax), 3'-azido-3'-deoxythymidine (AZT), valproic acid (VPA) and loperamide (Lo) using BBMEC and Caco-2 monolayers as in vitro models of the blood brain barrier and intestinal epithelium respectively. METHODS: Drug permeability studies were performed on the confluent BBMEC and Caco-2 cell monolayers mounted in Side-Bi-Side diffusion cells. RESULTS: Exposure of the cells to P85 significantly enhanced AP to BL permeability coefficients of Flu, Tax, Dox and AZT in both cell models. Further, P85 enhanced AP to BL transport of Et, VPA and Lo in Caco-2 monolayers. No changes in the permeability coefficients of the paracellular marker mannitol were observed in the presence of the copolymer. CONCLUSIONS: P85 increases AP to BL permeability in BBMEC and Caco-2 monolayers with respect to a broad panel of structurally diverse compounds, that were previously shown to be affected by P-gp and/ or multidrug resistance associated protein (MRP) efflux systems. Broad specificity of the block copolymer effects with respect to drugs and efflux systems appears to be a valuable property in view of developing pharmaceutical formulations to increase drug accumulation in selected organs and overcome both acquired and intrinsic drug resistance that limits the effectiveness of many chemotherapeutic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats.

The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.

Animals↗