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Biomedical subjects

R L White

Publications and source records attributed to R L White.

At least 19 recordsLinked to original sources
PubMed1999

The nerve-electrode interface of the cochlear implant: current spread.

One of the fundamental facets of the cochlear implant that must be understood to predict accurately the effect of an electrical stimulus on the auditory nerve is the nerve-electrode interface. One aspect of this interface is the degree to which current delivered by an electrode spreads to neurons distant from it. This paper reports a direct mapping of this current spread using recordings from single units from the cat auditory nerve. Large variations were seen in the degree to which the different units are selective in responding to electrodes at different positions within the scala tympani. Three types of units could be identified based on the selectiveness of their response to the different electrodes in a linear array. The first type of unit exhibited a gradual increase in threshold as the stimulating site was moved from more apical to more basal locations within the scala tympani. The second type of unit exhibited a sharp local minimum, with rapid increases in threshold in excess of 6 dB/mm in the vicinity of the minimum. At electrode sites distant from the local minima the rate of change of the threshold approached that of the first type of units. The final type of unit also demonstrated a gradual change in threshold with changing electrode position, however, two local minima, one apical and one basal, could be identified. These three types are hypothesized to correspond to units which originate apical to the electrode array, along the electrode array and basal to the electrode array.

Acoustic Stimulation↗
PubMed1999

A pilot study of the efficacy of constant-infusion ceftazidime in the treatment of endobronchial infections in adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the efficacy of constant-infusion ceftazidime (CTZ) with that of traditional intermittent dosing in a pilot trial. DESIGN: Prospective, crossover trial. SUBJECTS: Five adults with cystic fibrosis requiring intravenous antibiotic therapy for pulmonary exacerbations of the disease. INTERVENTIONS: Patients were initially treated with standard CTZ 2 g 3 times/day for 10 days. At the next hospitalization patients were crossed over and CTZ was administered as a constant infusion at a rate determined to achieve a serum concentration 6.6 times the minimum inhibitory concentration (MIC) of the least susceptible Pseudomonas aeruginosa isolate. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of CTZ were determined, as were MICs for all P. aeruginosa isolates. Outcome parameters of interest were changes with therapy in white blood cell count, P aeruginosa density in sputum, and pulmonary function test results. Differences in these parameters for the two forms of administration were not significant. With the exception of one patient who received 6 g/day with both regimens, the average reduction in dosage with the constant infusion was 50%. CONCLUSION: These preliminary data suggest that constant-infusion CTZ may be as safe and efficacious as intermittent dosing.

Adult↗
PubMed1998

BRCA1 is associated with the centrosome during mitosis.

Centrosomes and their associated microtubules direct events during mitosis and control the organization of animal cell structures and movement during interphase. The centrosome replicates during the cell cycle, directs the assembly of bipolar mitotic spindles, and plays an important role in maintaining the fidelity of cell division. Recently, tumor suppressors such as p53 and retinoblastoma protein pRB have been localized to the centrosome in a cell cycle-dependent manner. Immunofluorescence microscopy and analysis of isolated centrosomes now provide evidence that BRCA1 protein, a suppressor of tumorigenesis in breast and ovary, also is associated with centrosomes during mitosis. Our results indicate that BRCA1 localizes with the centrosome during mitosis and coimmunoprecipitates with gamma-tubulin, a centrosomal component essential for nucleation of microtubules. Furthermore, gamma-tubulin associates preferentially with a hypophosphorylated form of BRCA1.

Animals↗
PubMed1998

Evaluation of adsorption preconcentration/capillary zone electrophoresis/nanoelectrospray mass spectrometry for peptide and glycoprotein analyses.

The use of an on-line adsorption preconcentrator coupled with capillary zone electrophoresis/nanoelectrospray mass spectrometry (PC/CZE/nESMS) is described for the analysis of peptides and protein digests. The investigation was focused on the production of disposable preconcentrators made of large particle size (40 microns irregular packing), thereby eliminating the use of a retaining frit without loss of performance. These preconcentration devices were made of commercially available components which can be easily interfaced to current CZE/nESMS systems. Practical issues such as the composition of the stationary phase, the elution volume and sample breakthrough and carry-over were evaluated in order to optimize the analytical performance of this technique. Under optimized elution conditions, the PC/CZE/nESMS technique provided separation efficiencies in excess of 100,000 theoretical plates for a sample loading of 8 microliters. Sample carry-over was minimized by proper reconditioning of the preconcentrator prior to the CZE separation. Alternatively, the sample carry-over resulting from small elution volumes could be used advantageously to provide multiple analyses from a single injection of sample. The application of this technique is demonstrated for the analysis of proteolytic peptides from a Bauhinia purpurea lectin at a concentration level of 30 nM. Further structural information was obtained using on-line tandem mass spectrometry to elucidate the structure of N-linked glycans and the amino acid sequences of the glycopeptides.

Adsorption↗
PubMed1998

Comprehensive human genetic maps: individual and sex-specific variation in recombination.

Comprehensive human genetic maps were constructed on the basis of nearly 1 million genotypes from eight CEPH families; they incorporated >8,000 short tandem-repeat polymorphisms (STRPs), primarily from Généthon, the Cooperative Human Linkage Center, the Utah Marker Development Group, and the Marshfield Medical Research Foundation. As part of the map building process, 0.08% of the genotypes that resulted in tight double recombinants and that largely, if not entirely, represent genotyping errors, mutations, or gene-conversion events were removed. The total female, male, and sex-averaged lengths of the final maps were 44, 27, and 35 morgans, respectively. Numerous (267) sets of STRPs were identified that represented the exact same loci yet were developed independently and had different primer pairs. The distributions of the total number of recombination events per gamete, among the eight mothers of the CEPH families, were significantly different, and this variation was not due to maternal age. The female:male ratio of genetic distance varied across individual chromosomes in a remarkably consistent fashion, with peaks at the centromeres of all metacentric chromosomes. The new linkage maps plus much additional information, including a query system for use in the construction of reliably ordered maps for selected subsets of markers, are available from the Marshfield Website.

Chromosome Mapping↗
PubMed1998

Effectiveness of positron emission tomography for the detection of melanoma metastases.

OBJECTIVE: The purpose of this study was to determine the sensitivity, specificity, and clinical utility of 18F 2-fluoro-2-deoxy-D-glucose (FDG) total-body positron emission tomography (PET) scanning for the detection of metastases in patients with malignant melanoma. SUMMARY BACKGROUND DATA: Recent preliminary reports suggest that PET using FDG may be more sensitive and specific for detection of metastatic melanoma than standard radiologic imaging studies using computed tomography (CT). PET technology is showing utility in the detection of metastatic tumors from multiple primary sites including breast, lung, lymphoma, and melanoma. However, little information is available concerning the general utility, sensitivity, and specificity of PET scanning of patients with metastatic melanoma. METHODS: One hundred three PET scans done on 76 nonrandomized patients having AJCC stage II to IV melanoma were prospectively evaluated. Patients were derived from two groups. Group 1 (63 patients) had PET, CT (chest and abdomen), and magnetic resonance imaging (MRI; brain) scans as a part of staging requirements for immunotherapy protocols. Group 2 (13 nonprotocol patients) had PET, CT, and MRI scans as in group 1, but for clinical evaluation only. PET scans were done using 12 to 20 mCi of FDG given intravenously. Results of PET scans were compared to CT scans and biopsy or cytology results. RESULTS: PET scanning for the detection of melanoma metastases had a sensitivity of 94.2% and a specificity of 83.3% compared to 55.3% and 84.4%, respectively, for CT scanning. Factors that produced false-positive PET scans were papillary carcinoma of the thyroid (1), bronchogenic carcinoma (1), inflamed epidermal cyst (1), Warthin's tumor of the parotid gland (1), surgical wound inflammation (2), leiomyoma of the uterus (1), suture granuloma (1), and endometriosis (1). The four false-negative scans were thought to be due to smaller (<0.3 to 0.5 cm) and diffuse areas of melanoma without a mass effect. CONCLUSIONS: PET scanning is extremely sensitive (94.2%) and very specific (83.3%) for identifying metastatic melanoma, particularly in soft tissues, lymph nodes, and the liver. A number of second primary or metastatic tumors and an inflammatory response can also be localized by PET. This observation mandates a close clinical correlation with positive PET and emphasizes the importance of establishing a tissue diagnosis. False-negative scans in the presence of metastases are rare (4% of scans). Metastases < or =5 mm in diameter may not image well. PET is superior to CT in detecting melanoma metastases and has a role as a primary strategy in the staging of melanoma.

Diagnostic Errors↗
PubMed1997

Antibiotic resistance in Streptomyces lividans: fluorescence assay for streptogramin B lyase.

A fluorescence assay for streptogramin B lyase, an enzyme that confers resistance to streptogramin B antibiotics, has been developed. The antibiotic substrates are fluorescent and the linear peptide products formed in the lyase-catalyzed reaction are relatively nonfluorescent. The assay has potential for assessing bacterial resistance to streptogramin B antibiotics and will be utilized to direct the purification of streptogramin B lyase from bacterial extracts.

Anti-Bacterial Agents↗
PubMed1997

Nuclear and cytoplasmic localizations of the adenomatous polyposis coli protein.

Mutation of the adenomatous polyposis coli (APC) gene is an early step in the initiation of colon cancer. Because the distribution pattern of a protein within the cell can provide important clues as to function, we have used a combination of immunofluorescence microscopy and biochemical fractionation to determine the location of APC protein in epithelial cells. Immunofluorescence microscopy placed full-length APC protein in both the nucleus and the cytoplasm. The nuclear APC protein was concentrated in discrete subnuclear regions, including nucleoli, whereas the cytoplasmic APC protein concentrated at the leading edge of migrating cells. Colocalization of APC protein with rRNA confirmed a nucleolar localization. These immunocytochemical findings have been supported by cell fractionation, which demonstrated that full-length APC protein was located in both the membrane/cytoskeletal and the nuclear fractions.

Adenomatous Polyposis Coli Protein↗
PubMed1997

Probing the substrate specificity of an enzyme catalyzing inactivation of streptogramin B antibiotics using LC-MS and LC-MS/MS.

LC-MS and LC-MS/MS analyses indicated that an enzyme responsible for inactivating the antibiotic etamycin is specific for streptogramins and acts on both type B-I and B-II streptogramin subgroups. No enzymatic activity was detected for other cyclodepsipeptides such as surfactins and viscosin. It was demonstrated using analogs of etamycin that the picolinyl moiety is essential to obtain enzyme-generated ring-opened compounds. Because the picolinyl moiety is also essential for the biological activity of streptogramins, it is proposed that this residue is a distinctive topographic feature in the binding of this group of antibiotics to enzyme active sites.

Chromatography, Liquid↗
PubMed1997

Comparative bactericidal activity of ceftazidime against isolates of Pseudomonas aeruginosa as assessed in an in vitro pharmacodynamic model versus the traditional time-kill method.

Bactericidal activity, historically assessed by in vitro tests which employ fixed drug concentrations, may also be evaluated in in vitro pharmacodynamic models in which in vivo pharmacokinetics and bacterial growth conditions can be simulated. However, systematic comparisons between the two methods are lacking. We evaluated the bactericidal activities of ceftazidime, at two different concentration/MIC ratios (C/MICs), against 10 clinical isolates of Pseudomonas aeruginosa in a two-compartment model with continuous-infusion conditions and a 2-h half-life. These values were compared to those determined by traditional 24-h time-kill (TTK) methods at the same C/MICs. Bactericidal activities were compared by using area under the colony count-time curves. Antibiotic exposure (area under the drug concentration-time curve) was also evaluated. Although bactericidal activity appeared greater by the TTK method (P = 0.05), when it was normalized for drug exposure, these differences disappeared (P = 0.2). This disparity was likely due to differences in drug exposure in the TTK method and in the peripheral compartment of the model (site of bacteria) over the first 8 h of the experiment, during which the antibiotic accumulated to target concentrations. This suggests that the bactericidal effects with constant antibiotic concentrations are similar in the two methods; however, this may not hold true with fluctuating drug concentrations. Further, results from the pharmacodynamic model may theoretically be more relevant, as in vivo pharmacokinetics and bacterial growth conditions call be more faithfully simulated.

Area Under Curve↗
PubMed1997

In vitro pharmacodynamics of ceftazidime against Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The concentration/MIC (C/MIC) ratio maximizing the bactericidal activity of ceftazidime against 10 Pseudomonas aeruginosa isolates from cystic fibrosis patients was identified. Bactericidal activity was assessed by determining the percent difference in the area under the killing curve at each C/MIC ratio for all of the isolates from that of their growth control. The percent effect at each C/MIC ratio was fitted to a sigmoidal Emax model with maximum bactericidal activity defined as the C/MIC ratio that produced an effect that was 90% of the Emax. Our results suggest that at least some isolates may require higher C/MIC ratios than previously reported for maximal activity.

Ceftazidime↗
PubMed1997

Colon cancer. Molecular biology of the APC protein.

The discovery of a tumor suppressor gene opens a new pathway to discovery of the fundamental mechanisms that underlie tumor initiation and progression. An inherited tumor suppressor gene is of special interest in that it defines a step in the tumorigenesis pathway that can be rate limiting in development of that tumor type. In the case of colon cancer, we were fortunate in identifying an inherited tumor suppressor gene, the APC gene, that plays a major etiologic role in both the inherited disease, familial adenomatous polyposis (FAP), and in sporadic colon polyps. Characterization of the molecular biology of that gene, and the underlying mechanisms that result in the development of colon tumors, could provide new approaches to both colon cancer diagnostics, therapeutics and chemopreventives. We have embarked, therefore, on a series of exploratory studies designed to provides clues to possible functional roles for the APC protein. We have found through immunocytochemistry that APC protein is distributed throughout the cell, in both the cytoplasm and nucleus. Furthermore, within the nucleus much of the APC protein seems associated with the nucleoli. The cytoplasmic label is distributed in a punctate pattern, with concentrations at the leading edge of migrating cells at the ends of microtubules. Furthermore, following an extraction of the cells that leaves behind primarily cytoskeletal and nuclear scaffold structures, we see strong APC staining of these structures. The yeast two-hybrid system has offered a number of potentially interacting partners for APC, including a new binding site for alpha-tubulin. These results, and others recent discoveries concerning APC, suggest a rather global role for APC protein, modulating cellular activity and signal transduction pathway from the cell periphery to the nucleus.

Adenomatous Polyposis Coli Protein↗
PubMed1996

Stability of ceftazidime sodium and teicoplanin sodium in a peritoneal dialysis solution.

The stability of ceftazidime sodium and teicoplanin sodium separately and in combination in a peritoneal dialysis (PD) solution was studied. PD solutions containing ceftazidime 100 micrograms/mL (as the sodium salt), teicoplanin 25 micrograms/mL (as the sodium salt), or ceftazidime 100 micrograms/mL plus teicoplanin 24 micrograms/mL were prepared in triplicate for each of two conditions: condition A, storage at 25 degrees C (room temperature) for 24 hours, then at 37 degrees C for eight hours; and condition B, storage for seven days at 4 degrees C, followed by 16 hours at 25 degrees C and 8 hours at 37 degrees C. The dialysis solution used was Dianeal PD-2 with 1.5% dextrose. Samples were removed at intervals and analyzed by stability-indicating high-performance liquid chromatography. Under condition A, ceftazidime sodium alone was stable for 24 hours at 25 degrees C but only 2 hours when then heated to 37 degrees C. Under condition B, ceftazidime sodium alone was stable throughout the observation period. Teicoplanin sodium alone was stable throughout the observation periods under both conditions. In combination, the drugs were stable if initially refrigerated and then brought to room temperature one week later, but were unstable when initially stored at 25 degrees C. No visual changes were noted, and pH did not vary substantially. Ceftazidime 100 micrograms/mL (as the sodium salt) and teicoplanin 25 micrograms/mL (as the sodium salt) combined in a PD solution were unstable when first kept at 25 degrees C before storage at 37 degrees C. The drugs in the combination remained stable when the solution was kept at 4 degrees C before storage at 37 degrees C.

Anti-Bacterial Agents↗