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R L White

Publications and source records attributed to R L White.

At least 55 records · Page 3Linked 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

Pharmacokinetics of cefepime in patients with thermal burn injury.

The pharmacokinetics of cefepime following administration of a single 2-g dose were evaluated for 12 adult patients with thermal burn injury and suspected or documented infection. Serial blood and urine samples for cefepime concentration determination were obtained for 24 h following drug administration. Serum and urine cefepime concentrations were determined by high-performance liquid chromatography and serum concentrations were fit to a two-compartment pharmacokinetic model. Mean (standard deviation [SD]) age, actual body weight (ABW), percent total body surface area burned, and days postburn at the time of study were 41 (13) years, 84 (22) kg, 36 (17)%, and 9 (3) days, respectively. Mean (SD) measured creatinine clearance (CL(CR)), total clearance (CL(T)), renal clearance (CL(R)), alpha phase half-life, beta phase half-life, and volume of distribution at steady state (V(SS)) were 135 (31) ml/min, 8.8 (2.4) liters/h, 8.1 (2.0) liters/h, 0.33 (0.14) h, 2.8 (0.6) h, and 0.43 (0.10) liters/kg ABW, respectively. Cefepime CL(T) and CL(R) in burn patients were similar to previously reported values for healthy volunteers when normalized by CL(CR). Stepwise multiple regression was used to associate CL(T) with CL(CR) and days postburn (r(2) = 0.861), CL(R) with CL(CR) and days postburn (r(2) = 0.773), nonrenal clearance with percent third-degree (% 3 degrees ) burn and albumin concentration (r(2) = 0.550), and V(SS) only with % 3 degrees burn (r(2) = 0.624). Simulated steady-state serum concentrations obtained by using the patients' pharmacokinetic parameters exceeded the susceptibility interpretive standard (breakpoint) of cefepime for at least 60% of the dosing interval with dosing regimens of 1 g every 8 h (q8h), 2 g q8h, and 2 g q12h. Despite differences in pharmacokinetic parameters between our patients and healthy volunteers, it appears that these dosing regimens may be adequate in similar burn patients.

Adolescent↗
PubMed1999

Colon polyps: a damaged developmental system and a precursor to cancer.

The observation that the attenuated form of adenomatous polyposis coli (AAPC) has a different mutational spectrum in both the adenomatous polyp and the carcinoma than the classical form of APC has led to the hypothesis that AAPC alleles retain some residual APC activity associated with a greatly reduced number of polyps. It is suggested that further progression to carcinoma may be dependent upon either loss of the AAPC allele (loss of heterozygosity), followed by an APC mutation in the wild-type allele, or the occurrence of APC mutations within both the AAPC and wild-type alleles.

Adenomatous Polyposis Coli↗
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↗
PubMed1999

Melanoma-inhibitory activity protein concentrations in blood of melanoma patients treated with immunotherapy.

Melanoma inhibitory activity protein (MIA) has been detected in patients with advanced melanoma. The present study measured the variations in blood concentrations of MIA in 84 patients with AJCC stage II to IV melanoma by ELISA. Patients treated with repeated injections of a polyvalent melanoma vaccine (PMV), interferon-alpha-2b (IFN-alpha2b), or interleukin-2 (IL-2) were followed during treatment duration. Before treatment, patients treated with PMV or IFN-alpha2b had comparable low MIA concentrations, whereas most IL-2-treated patients had higher MIA levels. At the end of treatment, MIA concentrations were higher in patients with progressive disease (PD) than in patients with no clinical evidence of melanoma (NPD) for PMV, IFN-alpha2b, or IL-2 therapy (3.7+/-0.2 vs. 11.5+/-5.4 ng/ml, 3.8+/-0.2 vs. 8.3+/-1.7 ng/ml, and 2.3+/-0.7 vs. 20.2+/-7.4 ng/ml, respectively, P<0.05). In contrast to stable MIA concentrations measured in NPD patients, significant increase in MIA levels were observed in PD patients over time regardless of treatment (P<0.05). In 20 of the 27 patients who had melanoma recurrence or progression, MIA concentrations were above 4.5 ng/ml. Finally, in these 20 patients, MIA concentrations above 4.5 ng/ml were observed prior to clinical evidence of progression (P<0.01).

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↗