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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 271 records · Page 15Linked to original sources
PubMed1996

Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase--deficient severe combined immunodeficiency disease patients.

Peripheral blood (PB) CD34+ cells mobilized by granulocyte colony-stimulating factor (G-CSF) administration are potentially useful for transplantation and as a target of gene transfer for therapy of hematopoietic disorders. Efficient harvest and planning for clinical use of PB CD34+ cells ideally requires foreknowledge of the expected mobilization kinetics and yield. We developed a sensitive flow cytometric assay for accurately enumerating CD34+ cells throughout the range seen at baseline to peak mobilization. We used this assay to assess the kinetics of G-CSF-mediated mobilization of CD34+ cells to PB in normal volunteers and in patients with chronic granulomatous disease (CGD) or adenosine deaminase (ADA)-deficient severe combined immunodeficiency disease (SCID). Two dose levels of G-CSF were examined (5 and 10 micrograms/kg/d for 7 days). Both doses were well tolerated. For normal subjects and patients an increase in PB CD34+ cells was first detected only preceding the third dose of G-CSF (day 3), peaked transiently on day 5 or 6, and then decreased thereafter despite additional doses of G-CSF. With 32 normal volunteers mean peak CD34+ cell counts were 57 and 76 cells/mm2 of blood (5 and 10 micrograms doses, respectively), whereas for 18 CGD patients the mean peaks were 31 and 40 cells/mm2 of blood. For 2 ADA-deficient SCID patients studied at a G-CSF dose of 5 micrograms/kg/d, the average peak was 16 cells/mm2 of blood. For both of these patient groups mobilization of CD34+ cells to PB was impaired compared with similarly treated normal subjects (P < .05). By contrast to the kinetics of the CD34+ cell mobilization, the absolute neutrophil count (ANC) increased markedly by 6 hours after the first dose of G-CSF and then increased steadily through day 8. At days 5 and 6 (peak mobilization of CD34+ cells) the mean ANC of CGD and ADA patients was only slightly lower ( < or = 15%) than that seen with normal subjects, whereas the difference in CD34+ cell mobilization was > 48%. Thus, ANC is not a reliable surrogate to predict peak PB CD34+ cell counts and direct enumeration of PB CD34+ counts should be undertaken in decisions regarding timing and duration of apheresis to harvest a specific number of these cells. Finally, unexpected, but significant differences in the PB CD34+ cell mobilization between normal subjects and patients with inherited disorders can occur and underscores the importance of establishing the expected mobilization of PB CD34+ cells in the planning of treatment approaches using these cells.

Adenosine Deaminase↗
PubMed1996

Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?

Mutations in the heavy chain complementarity determining region 2 (CDR2) of the phosphocholine-specific T15 Ab can have a dramatic effect on the ability of the Ab to bind Ag. A panel of multisite mutants that had lost detectable binding to phosphocholine-containing Ags was previously created by saturation mutagenesis of the CDR2 region of T15. Based on the predicted importance of amino acid changes represented in the multisite mutants, we have created single-site mutations, yielding a panel of Abs with which to test 17 of the 19 CDR2 residues. Of the 17 positions examined, only one, Arg52, is intolerant to change, yielding a nonbinder phenotype even with conservative amino acid replacement. Mutation at two other sites, Ala50 and Tyr55, can yield a nonbinder phenotype depending on the amino acid replacement. Single-site mutations of the remaining 14 positions allowed retention of binding ability. Thus, except for positions 50, 52, and 55, multiple mutations must be introduced into the CDR2 region to create a nonbinder phenotype. We provide a newly refined model of T15, illustrating the structure and the interactions of the CDR2 region. Our results imply that introduction of point mutations would not normally delete Ag-binding ability until two or more mutations had accumulated. This would minimize potentially harmful effects of somatic mutation on Ig V region genes and improve the chance of survival for an Ab such as T15, which in its unmutated form is already well suited to bind Ag.

Amino Acid Sequence↗
PubMed1996

Binding of phenylphosphocholine-carrier conjugates to the combining site of antibodies maintains a conformation of the hapten.

The structural basis of the binding of phenylphosphocholine haptens to antibodies was studied. This was done by preparing antibodies and testing binding to conjugates of phenylphosphocholine. The choice of haptens was made in order to evaluate the contribution of the carrier to binding, and its effect on hapten conformation in the active site. Thus, phosphocholine (PC) was diazophenyl-linked to tyrosine or histidine as single amino acid carriers and to tripeptides or octapeptides containing tyrosine or histidine as central amino acids to which PC was attached. Relative affinity was assessed by inhibition enzyme-linked immunosorbent assay (ELISA) and binding constants were determined by fluorescence quenching. Fluorinated haptens were used to determine the kinetics of binding using 19F nuclear magnetic resonance. The transferred nuclear Overhauser effect was used to characterize conformation of the bound hapten. We had previously shown that nitrophenylphosphocholine unlinked to carrier is bound in the active site as a bent structure [Bruderer, U., Peyton, D. H., Barbar, E., Fellman, J. H., & Rittenberg, M. B. (1992) Biochemistry 31, 584-589]. We show here that this same bent conformation is retained in the active site regardless of the neighboring carrier or the conformation of the hapten in the unbound conjugate. The presence of the carrier residues in the bound state does, however, influence affinity.

Amino Acid Sequence↗
PubMed1996

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium.

PURPOSE: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Adult↗
PubMed1996

A man with "shrub leg".

A 39-year-old man with confirmed HIV infection of six years' duration presented with painful swelling of his right lower leg. Two weeks earlier, he had scratched the leg on a shrub.

AIDS-Related Opportunistic Infections↗
PubMed1996

Pain palliation with strontium-89 in children with metastatic disease.

We report two cases of children with metastatic bone disease who received strontium-89 intravenously. An 11-year-old boy with stage IV neuroblastoma received 50 microCi/kg of strontium-89. He had a good response, and his pain abated to the point that he could be taken off IV Dilaudid and was discharged from the hospital. A 7-year-old girl with the diagnosis of squamous cell carcinoma of the lung disclosed minimal increased uptake on a bone scan. Following the strontium-89 therapy, she did not have any significant improvement in pain, probably due to the minimal osteoblastic activity evidenced by the minimal abnormalities on the bone scan. Until this report there has been no reported case of using strontium-89 in the treatment of children with metastatic disease.

Analgesics, Opioid↗
PubMed1996

Screening for Wilms' tumor in children with high-risk congenital syndromes: considerations for an intervention trial.

Screening for cancer in children is uncommon. However, in children with congenital syndromes associated with Wilms' tumor, conditions exist that potentially make screening effective. This select population of children 1) are relatively easily identified; 2) have a high incidence of Wilms' tumor; 3) if identified before development of Wilms' tumor, may have a decrement in morbidity/mortality; and 4) are amenable to a simple and acceptable screening technology, renal sonography exams. Many clinicians have recommended screening for cancer in children with congenital syndromes associated with Wilms' tumor. However, neither costs nor effectiveness of such recommendations have been evaluated systematically. The strongest evidence for or against Wilms' tumor screening in this select population would be provided by a randomized screening trial. Prior to undertaking such a trial, the key parameters that dominate the cost and effectiveness of screening should be identified. Simulation models, such as cost effectiveness analysis, offer a starting point for deciding whether cancer screening is appropriate, and if so, under what set of conditions. We review basic conditions required for a successful screening trial in children with syndromes that are at increased risk of Wilms' tumor. We also discuss the use of cost-effectiveness analysis as a preliminary step in determining the feasibility of an intervention trial.

Child↗
PubMed1996

Neural network modeling of the hippocampal formation spatial signals and their possible role in navigation: a modular approach.

Cells throughout the hippocampal formation show striking spatial firing correlates as a rat navigates through space. These cells are thought to play a critical role in orchestrating the navigational abilities of the animals, since damage to the hippocampal formation causes spatial learning deficits. Here, we present a theoretical framework aimed at explaining how the different spatial signals are generated, as well as how they may help guide navigational behavior. Earlier work from our laboratory has presented a simple model for how the location-related signals exhibited by hippocampal place cells could be generated, based on convergent sensory information. Here, the results of this work are combined with two more recent models, to provide a more comprehensive theoretical framework. Specifically, we present 1) A neural network model of head direction cells, based on the idea that the directional signals are generated using a path integration mechanism. Cells which combine directional and angular head velocity information project onto the head direction cells, to "update" the current directional signal. This model reproduces the basic phenomenon of direction-specific firing, as well as the anticipatory nature of this firing, reported for some head direction cells. 2) A network simulation of how the hippocampal spatial signals could be used to orchestrate instrumental learning. Here, place and directional signals converge onto motor cells, each of which are thus driven to fire to specific combinations of location and directional heading. Each active motor cell generates a small leftward or rightward "step" of the simulated animal. When the simulated goal is encountered, recently active synapses are strengthened, so that goal-directed trajectories are "stamped in". We have found these models useful in helping to clarify our thinking about the proposed theoretical principles, as well as in generating testable predictions.

Animals↗
PubMed1996

Structural features unique to enteric adenoviruses.

Enteric adenoviruses are important agents of pediatric gastroenteritis. Characterization of monoclonal antibodies against human adenovirus 41 (h-41) identified an epitope of interest on protein VI, an internal virion protein. The epitope is common to enteric adenoviruses (subgenus A: h-12, h-18, h-31 and subgenus F: h-40, h-41) but is not shared by non-enteric serotypes (subgenera B, C, D or E). By expressing random oligonucleotide fragments of the protein VI gene as T7 gene 10 fusion proteins in the pTope vector (Novagen), the epitope was mapped within the central domain of protein VI, to the region corresponding to aa 114-125 of the Ad2 protein. Identification of this epitope reflects the close evolutionary relationship of subgenus A and subgenus F adenoviruses and draws attention to structural features of enteric adenoviruses as potential determinants of tropism. Furthermore, this epitope may be valuable for identification of enteric adenoviruses in clinical specimens.

Adenoviridae Infections↗
PubMed1996

New Zealand health care financing 'reforms' perceived ideological context.

Health sector financing reforms that have been ongoing over the last decade in most developed countries are rooted in philosophical terms in the ideology of economic rationalism. The ideology suggests that it is possible to artificially create markets for activities in contexts where markets do not develop naturally, and that the creation of these artificial markets leads to resource allocations that are both more efficient and more equitable than historical arrangements. The application of the ideology to New Zealand's health sector has generated some benefit--for example, a more rational approach to influencing the decisions of self-interest health care providers; but it has also generated some costs--for example, on ideological grounds it has brought into question the non-market rationales for maintaining a national health service system.

Financing, Government↗
PubMed1996

Differential effects of reduced muscle use (hindlimb unweighting) on skeletal muscle with aging.

The changes in hindlimb muscle mass, fiber area and contractile tension that occurred with two weeks of reduced weight-bearing (HU) were of greater magnitude in 6-month-old as opposed to 36-month-old rats. The pattern of change following HU for young and old animals differed, which may indicate that multiple mechanisms are responsible for the observed changes. The majority of old rats had difficulty with ambulation following unweighting, suggesting that the functional consequences of reduced weight-bearing are greater in old than in young animals. One hour of weight-bearing during HU attenuated the decline in SOL fiber atrophy, muscle mass and Po, but had no apparent effect on the GAST, PL or EDL. The reduction in Po with HU was not due, except for the old PL, to changes at the neuromuscular junction.

Aging↗
PubMed1996

Localization of anti-CENP antibodies and alphoid sequences in acentric heterochromatin in a breast cancer cell line.

Karyotype alterations are a hallmark of cancer cells. Of particular interest to our laboratory are the inactive centromeres and blocks of heterochromatin devoid of the accompanying centromere. When purified or monospecies anticentromere proteins (CENP) antibodies or the whole serum from scleroderma (crest) patients are applied to human chromosomes, the centromere region exhibits the label. When we treated MDA 435 cells with the anti-CENP-A, anti-CENP-B, or the whole serum, the label was apparent on heterochromatin pericentric to the active and inactive centromeres. Moreover, blocks of heterochromatin not associated with any centromere also exhibited the label. Anti-CENP-C, however, is more strictly confined to the centromere in discrete dots and is not detected on any region except the sites of active centromeres. Distribution of alpha sequences also shows a pattern compatible with its distribution in the heterochromatin. Apparently, the use of anti-CENP-A and anti-CENP-B antibodies or alphoid DNA may not detect either the centromere (primary constriction) or the kinetochore; CENP-C may be an exception.

Autoantibodies↗
PubMed1996

Implementing national standards for cancer pain management: program model and evaluation.

The purpose of this quasi-experimental (pre and posttest) study was to test a model pain management program (PMP) to implement the American Pain Society (APS) quality assurance standards for the management of acute and chronic cancer pain using a continuous quality improvement (CQI) approach to improve professionals' knowledge and skills, patient satisfaction, and to identify areas needing improvement. The sample consisted of 1210 nurse responses and 698 interviews of patients with pain during hospitalization at a major urban cancer center. The PMP provided a structure (standards), educational opportunities, and training in CQI methods. Outcome measures included a patient evaluation questionnaire and concerns checklist; nurse knowledge, attitude and barriers questionnaire; and focus groups to identify areas needing improvement. Significant improvements were found in patients' satisfaction, nurses' knowledge and attitude scores, and reductions in nurses' perceptions of barriers. Focus groups revealed the need for improved communication among disciplines about pain and better assessment of patients unable to self-report. The program met its goal of implementing the APS standards, educating nurses, and identifying "system" problems, and improving overall patient satisfaction.

Evaluation Studies as Topic↗
PubMed1996

Dirichlet mixtures: a method for improved detection of weak but significant protein sequence homology.

We present a method for condensing the information in multiple alignments of proteins into a mixture of Dirichlet densities over amino acid distributions. Dirichlet mixture densities are designed to be combined with observed amino acid frequencies to form estimates of expected amino acid probabilities at each position in a profile, hidden Markov model or other statistical model. These estimates give a statistical model greater generalization capacity, so that remotely related family members can be more reliably recognized by the model. This paper corrects the previously published formula for estimating these expected probabilities, and contains complete derivations of the Dirichlet mixture formulas, methods for optimizing the mixtures to match particular databases, and suggestions for efficient implementation.

Algorithms↗