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Biomedical subjects

B Carlson

Publications and source records attributed to B Carlson.

At least 19 recordsLinked to original sources
PubMed2004

Kinetics and mechanism of degradation of epothilone-D: an experimental anticancer agent.

The objective of this study was to investigate the stability and the degradation pathway of epothilone-D (Epo-D), an experimental anticancer agent. In pH range 4-9, Epo-D displayed pH-independent stability and the highest stability was observed at pH 1.5-2 where its thiazole group is protonated. Increasing the pH >9 or <1.5 resulted in an increase in the degradation rate. Epo-D contains an ester group that can be hydrolyzed. The formation of the hydrolytic product was confirmed by the nuclear magnetic resonance (NMR), fast atom bombardment mass spectroscopy and liquid chromatography/mass spectroscopy/mass spectroscopy techniques. The largely sigmoidal pH-rate profile is not consistent with the normal pH dependency of ester hydrolysis involving an addition/elimination mechanism. Hence, a hydrolysis mechanism through a carbonium ion was suggested. At pH 4 and 7.4, no buffer catalysis was observed (0.01, 0.02, and 0.05 M buffers) and no significant deuterium kinetic solvent isotope effect was noted. The degradation was very sensitive to changes in the dielectric constant of the solvents as significant enhancement in the stability was observed in buffer-acetonitrile and 0.1 M (SBE)7m-beta-cyclodextrin solutions compared with just buffer, suggesting that the rate-determining step in the degradation pathway involved formation of a polar transition state. Mass spectral analysis of the reaction run in 18O water was consistent with incorporation of the 18O in the alcohol hydroxyl rather than the carboxylate group. These observations strongly support the carbonium ion mechanism for the hydrolysis of Epo-D in the pH range 4-9. A pKa value of 2.86 for Epo-D was estimated from the fit of the pH-rate profile. This number was confirmed independently by the changes in ultraviolet absorbance of Epo-D as a function of pH (pKa 3.1) determined at 25 degrees C and the same ionic strength.

Antineoplastic Agents↗
PubMed2001

Interactions between dopamine D1 receptors and gamma-aminobutyric acid mechanisms in substantia nigra pars reticulata of the rat: neurochemical and behavioral studies.

RATIONALE: Several studies have shown that dopamine D1 agonists act on forebrain dopamine terminal regions to exert many of their behavioral effects. Yet, there is also a large number of D1 receptors in the substantia nigra pars reticulata (SNr), and these receptors are located mainly on terminals of gamma-aminobutyric acid (GABA)-ergic striatonigral neurons. OBJECTIVE: The present studies were undertaken to determine the behavioral and neurochemical effects of local administration of the D1 agonist SKF 82958 and to study the interactions between D1 and GABA mechanisms in SNr. METHODS: Microdialysis methods were used to characterize the effect of SKF 82958 on extracellular GABA, and several experiments studied the effects of nigral D1 stimulation on motor activity and investigated the behavioral significance of D1/GABA interactions in SNr. RESULTS: Local infusion of 10(-6) M SKF 82958 increased extracellular levels of SNr GABA, and this effect was blocked by co-infusion of the D1 antagonist SCH 23390. Bilateral SNr injections of SKF 82958 increased locomotor activity, and this effect was blocked by the GABA-A antagonist bicuculline. Intranigral bicuculline reduced motor activity, while the GABA-A agonist muscimol increased various motor activities in a manner similar to SKF 82958. CONCLUSIONS: The present results suggest that the D1 agonist SKF 82958 acts on D1 receptors in SNr to increase extracellular levels of GABA, and the increase in motor activity produced by nigral D1 stimulation is dependent on stimulation of GABA-A receptors. D1/GABA interactions in SNr are important for the modulation of basal ganglia output, which may have important implications for Parkinson's disease.

Animals↗
PubMed2001

Image-based dose planning of intracavitary brachytherapy: registration of serial-imaging studies using deformable anatomic templates.

PURPOSE: To demonstrate that high-dimensional voxel-to-voxel transformations, derived from continuum mechanics models of the underlying pelvic tissues, can be used to register computed tomography (CT) serial examinations into a single anatomic frame of reference for cumulative dose calculations. METHODS AND MATERIALS: Three patients with locally advanced cervix cancer were treated with CT-compatible intracavitary (ICT) applicators. Each patient underwent five volumetric CT examinations: before initiating treatment, and immediately before and after the first and second ICT insertions, respectively. Each serial examination was rigidly registered to the patient's first ICT examination by aligning the bony anatomy. Detailed nonrigid alignment for organs (or targets) of interest was subsequently achieved by deforming the CT exams as a viscous-fluid, described by the Navier-Stokes equation, until the coincidence with the corresponding targets on CT image was maximized. In cases where ICT insertion induced very large and topologically complex rearrangements of pelvic organs, e.g., extreme uterine canal reorientation following tandem insertion, a viscous-fluid-landmark transformation was used to produce an initial registration. RESULTS: For all three patients, reasonable registrations for organs (or targets) of interest were achieved. Fluid-landmark initialization was required in 4 of the 11 registrations. Relative to the best rigid bony landmark alignment, the viscous-fluid registration resulted in average soft-tissue displacements from 2.8 to 28.1 mm, and improved organ coincidence from the range of 5.2% to 72.2% to the range of 90.6% to 100%. Compared to the viscous-fluid transformation, global registration of bony anatomy mismatched 5% or more of the contoured organ volumes by 15-25 mm. CONCLUSION: Pelvic soft-tissue structures undergo large deformations and displacements during the external-beam and multiple-ICT course of radiation therapy for locally advanced cervix cancer. These changes cannot be modeled by the conventional rigid landmark transformation method. In the current study, we found that the deformable anatomic template registration method, based on continuum-mechanics models of deformation, successfully described these large anatomic shape changes before and after ICT. These promising modeling results indicate that realistic registration of the cumulative dose distribution to the organs (or targets) of interest for radiation therapy of cervical cancers is achievable.

Algorithms↗
PubMed2001

The challenges of conducting clinical research: one research team's experiences.

Conducting clinical research is an exciting and a rewarding endeavor. Each project is unique and, because of this uniqueness, research studies require considerable planning. Regardless of all the upfront planning, challenges will occur throughout the life of the study. Clinical research projects are rife with obstacles that range from the lack of administrative and physician support to subject attrition. Some of the challenges, such as subject dropout, are not unexpected, whereas other unanticipated issues can blindside a research team. This case study examines several such challenges experienced in one longitudinal study and presents the solutions engineered by the research team to keep the project on track.

Cardiac Output, Low↗
PubMed2001

Antibody against surface-bound C5a peptidase is opsonic and initiates macrophage killing of group B streptococci.

The capsular polysaccharides of group B streptococci (GBS) are a primary focus of vaccine development. Immunogenicity and long-lasting protection are best achieved by conjugating polysaccharides to a T-cell-dependent protein antigen. Streptococcal C5a peptidase (SCPB) is a conserved surface protein that is expressed by all streptococcal serotypes tested to date, and it is a possible carrier protein that could itself induce a protective immune response. Clearance of GBS from lungs, mucosal surfaces, or blood probably depends on the opsonophagocytic response of tissue-specific macrophages and polymorphonuclear leukocytes (PMNs). In this study, we examined the potential of antibody directed against SCPB from a serotype II strain to enhance the capacity of mouse bone marrow macrophages (from primary cultures) and human PMNs in whole blood to kill GBS in vitro. Our experiments demonstrated that Streptococcus serotypes Ia, Ib, II, III, and V, preopsonized with anti-SCPB antibody, were killed more rapidly by cultured macrophages and PMNs in whole blood than were nonopsonized GBS. The increased rate of killing was accompanied by an increased macrophage oxidative burst. Furthermore, opsonization was serotype transparent. Immunization with SCPB conjugated to capsular polysaccharide type III produced polysaccharide-specific antibodies. It is interesting that this antiserum promoted serotype-independent killing of streptococci. These data support the use of SCPB in a GBS polysaccharide conjugate vaccine. SCPB not only enhanced the immunogenicity of polysaccharide components of the vaccine, but it might also induce additional serotype-independent protective antibodies.

Adhesins, Bacterial↗
PubMed2000

Which patients with heart failure respond best to multidisciplinary disease management?

BACKGROUND: Multidisciplinary disease management approaches have been shown to decrease resource use in selected samples of patients with heart failure. We remain uncertain regarding the effectiveness of this approach in a general heart failure population and who can be expected to benefit most. The purpose of this study was to test the effectiveness of a multidisciplinary disease management intervention in an unselected population of patients with heart failure and to determine if subgroups could be identified in which the intervention is most effective. METHODS AND RESULTS: Two hundred forty patients with heart failure who were matched on preadmission functional status, comorbidity, and age participated in a quasi-experimental clinical trial. Half (n = 120) were given a multidisciplinary disease management intervention, whereas the other half (n = 120) received usual care. Data on acute care resource use were collected 3 and 6 months after enrollment. No intervention effect was seen in the primary analysis. When the data were analyzed by preadmission functional status (I to IV), acute care resource use was lower in the class II intervention patients. Class I intervention patients had a 288% increase in total costs and a 14-fold increase in heart failure costs. A model of predictor variables explained 17.2% of the variance in heart failure readmission at 3 months. CONCLUSIONS: An intervention of this type and intensity is recommended primarily for functional class II heart failure patients. Increases in cost in class I patients may have resulted from improved access to care.

Activities of Daily Living↗