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Biomedical subjects

R Brown

Publications and source records attributed to R Brown.

At least 415 records · Page 23Linked to original sources
PubMed1994

Transformation properties of the E2a-Pbx1 chimeric oncoprotein: fusion with E2a is essential, but the Pbx1 homeodomain is dispensable.

The t(1;19) chromosomal translocation in acute lymphoblastic leukemias creates chimeric E2a-Pbx1 oncoproteins that can act as DNA-binding activators of transcription. A structural analysis of the functional domains of E2a-Pbx1 showed that portions of both E2a and Pbx1 were essential for transformation of NIH 3T3 cells and transcriptional activation of synthetic reporter genes containing PBX1 consensus binding sites. Hyperexpression of wild-type or experimentally truncated Pbx1 proteins was insufficient for transformation, consistent with their inability to activate transcription. When fused with E2a, the Pbx-related proteins Pbx2 and Pbx3 were also transformation competent, demonstrating that all known members of this highly similar subfamily of homeodomain proteins have latent oncogenic potential. The oncogenic contributions of E2a to the chimeras were localized to transactivation motifs AD1 and AD2, as their mutation significantly impaired transformation. Either the homeodomain or Pbx1 amino acids flanking this region could mediate transformation when fused to E2a. However, the homeodomain was not essential for transformation, since a mutant E2a-Pbx1 protein (E2a-Pbx delta HD) lacking the homeodomain efficiently transformed fibroblasts and induced malignant lymphomas in transgenic mice. Thus, transformation mediated by the chimeric oncoprotein E2a-Pbx1 is absolutely dependent on motifs acquired from E2a but the Pbx1 homeodomain is optional. The latter finding suggests that E2a-Pbx1 may interact with cellular proteins that assist or mediate alterations in gene expression responsible for oncogenesis even in the absence of homeodomain-DNA interactions.

3T3 Cells↗
PubMed1994

DNA-binding and transcriptional regulatory properties of hepatic leukemia factor (HLF) and the t(17;19) acute lymphoblastic leukemia chimera E2A-HLF.

The t(17;19) translocation in acute lymphoblastic leukemias results in creation of E2A-hepatic leukemia factor (HLF) chimeric proteins that contain the DNA-binding and protein dimerization domains of the basic leucine zipper (bZIP) protein HLF fused to a portion of E2A proteins with transcriptional activation properties. An in vitro binding site selection procedure was used to determine DNA sequences preferentially bound by wild-type HLF and chimeric E2A-HLF proteins isolated from various t(17;19)-bearing leukemias. All were found to selectively bind the consensus sequence 5'-GTTACGTAAT-3' with high affinity. Wild-type and chimeric HLF proteins also bound closely related sites identified previously for bZIP proteins of both the proline- and acidic amino acid-rich (PAR) and C/EBP subfamilies; however, E2A-HLF proteins were significantly less tolerant of certain deviations from the HLF consensus binding site. These differences were directly attributable to loss of an HLF ancillary DNA-binding domain in all E2A-HLF chimeras and were further exacerbated by a zipper mutation in one isolate. Both wild-type and chimeric HLF proteins displayed transcriptional activator properties in lymphoid and nonlymphoid cells on reporter genes containing HLF or C/EBP consensus binding sites. But on reporter genes with nonoptimal binding sites, their transcriptional properties diverged and E2A-HLF competitively inhibited activation by wild-type PAR proteins. These findings establish a spectrum of binding site-specific transcriptional properties for E2A-HLF which may preferentially activate expression of select subordinate genes as a homodimer and potentially antagonize expression of others through heteromeric interactions.

Base Sequence↗
PubMed1994

Dynamic moduli of rabbit lung tissue and pigeon ligamentum propatagiale undergoing uniaxial cyclic loading.

In fibrous connective tissue networks, mechanical loads may be transferred from one fiber to the next by friction between slipping fibers (J. Appl. Physiol. 74: 665-681, 1993). Here we tested that hypothesis; it predicts that elastance of fibrous networks increases with increasing frequency, decreases with increasing strain amplitude (delta epsilon), and decreases with tissue swelling by solvent. Similarly, it predicts that hysteresivity (eta) decreases with increasing frequency, increases with increasing delta epsilon, decreases with tissue swelling, and, importantly, exceeds that of isolated fibrous constituents of the matrix. Elastance and eta of two structurally dissimilar connective tissues were measured, the rabbit lung parenchymal strip (a loose collagenous tissue) and the pigeon ligamentum propatagiale (an elastin-rich tissue). Experiments covered the frequency range 0.03125-3.125 Hz. Elastance of lung parenchyma was substantially lower than that of propatagial ligament, increased linearly with the logarithm of frequency, and decreased with delta epsilon; that of ligamentum propatagiale was insensitive to both frequency and delta epsilon. eta of lung parenchyma decreased moderately with increasing frequency and assumed values of approximately 0.1, but eta of ligamentum propatagiale was frequency and delta epsilon invariant and assumed values an order of magnitude smaller. These tissues also showed disparate mechanical responses when exposed to hypertonic bath solutions. Although there were some quantitative differences between predictions and experimental observations, the dynamic behavior of lung parenchyma was generally consistent with that of a network in which load is transferred from one fiber to the next by the agency of friction acting at slipping interface surfaces.

Animals↗
PubMed1994

Epidural pain management in the postrhizotomy patient.

The authors report a randomized double-blind prospective study comparing epidural morphine 80 micrograms/kg to epidural morphine 80 micrograms/kg plus butorphanol 40 micrograms/kg in children undergoing rhizotomy. Up to 50% of children receiving epidural morphine alone will experience side effects of nausea, vomiting, pruritus, urinary retention or respiratory depression. The addition of the narcotic agonist-antagonist butorphanol virtually eliminated these side effects without compromising analgesia or causing undue sedation. Parent satisfaction was greater than 90%.

Butorphanol↗
PubMed1994

An outbreak of diarrhea due to verotoxin-producing Escherichia coli in the Canadian Northwest Territories.

In the summer of 1991 a large outbreak of Escherichia coli O157:H7 associated diarrhea occurred in 6 Inuit communities in the Canadian Northwest Territories. The total population of these communities is 5,292. Of the 521 individuals who developed diarrhea, 152 (29%) were positive for E. coli O157:H7 on stool culture or positive by verotoxin analysis. Median age was 6 years. The attack rate for children < 1 year was 43% in the major affected community of Arviat. Hemolytic-uremic syndrome (HUS) developed in 22 cases, and 2 patients died. Asymptomatic stool carriage of verotoxin-producing E. coli (VTEC) 2-5 weeks after diarrheal illness was noted in 4/28 persons followed prospectively. Epidemic curves, case-control studies and phage type testing suggested person-to-person transmission. The original source of infection was not identified, though a food source was suspected. VTEC were detected in 6 food samples (minced beef and caribou) taken from retail outlets and homes. Primary prevention of infection through health education and promotion activities, as well as long-term follow-up of HUS survivors, are indicated in this population.

Adolescent↗
PubMed1994

A brief history of psychiatric classification. From the ancients to DSM-IV.

We are now at an interesting crossroads in the history of psychiatric nosology. There have been many oscillations over time between etiologic and descriptive models, between lumping and splitting, and between categorical and dimensional systems. It is unfortunate, but inevitable, that most of the etiologic models of the past have been based on unproven and unprovable theories. Like its predecessors, DSM-IV is a descriptive system, and it too gradually will be replaced by an etiologic model--one, it is hoped, that is more scientifically valid than previous attempts at etiologic explanation. This will be an important step for the profession, for scientific understanding, and for the patient.

Europe↗
PubMed1994

Recent applications of a computer based modelling system for biomechanical interactions.

We discuss developments in our previously reported system for the modelling of the biomechanical interaction between people and products. The mass properties of the artefact are obtained and used to construct a computer model which includes both an android modelling the user and the product. This system developed as part of of a continuing collaboration, initially focussed on design methodologies in rehabilitation engineering. A description of the techniques used is given in our paper and related to ergonomics and occupational biomechanics after validating the approach in a pilot study we subsequently proposed to include a wider range of consumer products while continuing the work on rehabilitation engineering. Examples from case studies are investigated and used to refine the technique. These progressed from a heavy concrete breaker through to the design of domestic electrical; appliances, in the latter work although the loadings are not excessive in general use there are situations, especially those involving specific users such as elderly people, in which the design of the product may be inappropriate In each case we construct a model from the anthropometric data and refine the model where necessary to take into account special constraints imposed on the user. Recent results together with refinements to our technique are discussed.

Biomechanical Phenomena↗
PubMed1994

Transabdominal needle embryofetoscopy: a new technique paving the way for early fetal therapy.

OBJECTIVE: To explore the feasibility of using a newly devised needle endoscope to conduct transabdominal first-trimester endoscopy for both embryonic visualization and blood sampling. METHODS: Following informed consent, 12 patients at 8-12 weeks' gestation undergoing first-trimester termination were invited to participate in this study. Transabdominal needle embryofetoscopy was also performed in one continuing pregnancy. A specially designed 16-gauge, double-barrel instrument sheath equipped with 0.8-mm fiberoptic endoscope and a customized 27-gauge heparinized needle were passed transabdominally under ultrasound guidance through the uterine wall and into the exocoelomic space. RESULTS: Using first-trimester transabdominal needle embryofetoscopy, we were able to identify the normal anatomical landmarks of the embryo and were also able to gain access to the embryonic circulation by advancing the 27-gauge needle into the umbilical vessels. In addition, we were able to infuse indigo carmine dye into the fetal circulation of three subjects. Needle embryofetoscopy was also used in a continuing pregnancy for prenatal diagnosis. CONCLUSION: Our experience establishes the feasibility of first-trimester transabdominal needle embryofetoscopy for embryonic visualization and access to the circulation. This new development is expected to serve as a basis for further studies attempting to diagnose and treat congenital diseases in early pregnancy.

Abdomen↗
PubMed1993

Increased accumulation of p53 protein in cisplatin-resistant ovarian cell lines.

We have examined p53 protein levels in cell lines selected for resistance to the chemotherapeutic drug cis-diamminedichloroplatinum (II), cisplatin. The majority of the independent cisplatin-resistant clones isolated by a single selection with cisplatin from the ovarian tumour cell line A2780 showed increased levels of p53 protein compared to the parental cell line. Elevated p53 protein levels were also observed in cisplatin-resistant ovarian human tumour lines isolated after multiple exposures to cisplatin (A2780/cp70 and OVIP/DDP). Direct PCR sequencing of p53 cDNAs showed that both the A2780/cp70 and the parental A2780 cell lines had a wild-type p53 gene sequence. The OVIP and OVIP/DDP lines both had a heterozygous mutation at codon 126. Cell-cycle analysis after gamma-irradiation or cisplatin treatment showed evidence of a G1/S and G2/M cell-cycle checkpoint in both A2780/cp70 and the sensitive parental cell lines. However, the resistant cell line A2780/cp70 showed less inhibition of DNA synthesis after gamma-irradiation than the sensitive cell line. Transfection of a mutant p53 gene construct (containing a mutation at codon 143, val to ala) into the A2780/cp70 resistant cells conferred a significantly increased sensitivity to cisplatin, suggesting that p53 is a direct determinant of cisplatin resistance in these cells. However, expression of this mutant p53 in the A2780 cells did not affect sensitivity.

Cell Cycle↗
PubMed1993

The experience of a single Australian paediatric oncology unit. 1000 patients 1964-1987.

OBJECTIVE: To determine the survival for children with malignant disease diagnosed in the period 1964-1987 and treated in a single paediatric oncology unit. DESIGN: Records of patients treated by the Department of Haematology and Oncology at the Prince of Wales Children's Hospital were reviewed to determine the survival of children with cancer according to decade of diagnosis and diagnostic group. PATIENTS: Patients were eligible for the study if referred for treatment at or soon after diagnosis of malignancy. One thousand patients were treated during the study period. There were 363 with acute lymphoblastic leukaemia (ALL), 126 with tumours of the central nervous system (CNS), 86 with acute non-lymphoblastic leukaemia (ANLL), 81 with lymphoma, 79 with neural crest tumours, 69 with renal tumours, 66 with bone sarcomas, 53 with soft tissue sarcomas, and 77 with various other diagnoses. Age range was one day to 20.75 years. INTERVENTIONS: Treatment included surgery, radiotherapy and chemotherapy in a variety of protocols. RESULTS: Ten-year survival for the 1960s, 1970s and 1980s was 15%, 51% and 64% respectively (P < 0.001), excluding tumours of the CNS. From 1985 onwards, actual survival at five years has been 79%. Survival from Wilms' tumour and Hodgkin's disease remained high throughout the study period, and significant improvement in survival occurred with ALL, non-Hodgkin's lymphoma (NHL) and osteogenic sarcoma. Survival remained poor with neuroblastoma and ANLL. CONCLUSIONS: Significant improvement in outcomes for childhood malignancy has been achieved over the last three decades, with five-year survival currently at 79% (excluding tumours of the CNS). Some diagnostic groups have had only small improvements in outcome and require new strategies.

Adolescent↗
PubMed1993

Distribution and characterization of neuropeptide FF-like immunoreactivity in the rat nervous system with a monoclonal antibody.

Monoclonal antibodies against neuropeptide FF were produced and characterized. The antibodies are directed and highly specific to neuropeptide FF, and reactivity requires the C-terminal dipeptide of neuropeptide FF (Arg-Phe-NH2). Tissue extracts from bovine spinal cord, rat spinal cord and hypothalamus were analysed by high-pressure liquid chromatography coupled with radioimmunoassay using the characterized monoclonal antibody. Only one immunoreactive peptide was detected and it coeluted with authentic neuropeptide FF. Using this highly specific monoclonal antibody, the distribution of neuropeptide FF-like immunoreactivity was further studied by indirect immunohistochemistry. Immunoreactivity was seen in two major cell groups in the rat brain. The largest cell group was located in the medial hypothalamus between the dorsomedial and ventromedial nuclei. The other one was found in the nucleus of the solitary tract. Fibres immunoreactive for neuropeptide FF were located in the lateral septal nucleus, amygdala, different hypothalamic areas, nucleus of the solitary tract, ventral medulla, trigeminal complex and the dorsal horn of the spinal cord. Spinal and sympathetic ganglia were non-reactive. No neuropeptide FF immunoreactivity was seen in the gut autonomic nervous system or endocrine cells. The results show that neuropeptide FF-like immunoreactivity has a clearly more limited distribution in the nervous system than typical brain-gut peptides.

Amino Acid Sequence↗
PubMed1993

Odor-induced sexual maturation and expression of c-fos in the olfactory system of juvenile female mice.

Exposure to the urine or soiled bedding odors of novel adult males is known to accelerate puberty in juvenile female mice. To determine what part of the olfactory system is activated by these odors, the expression of c-fos in the main olfactory bulb (MOB) and the accessory olfactory bulb (AOB) of juvenile female mice was examined after their exposure to male-soiled bedding, peppermint odor or their own bedding. Fos-like immunoreactivity was found throughout the AOB of the juvenile female mice exposed to the bedding odors of adult males for 3 h. In contrast, dense staining was found in the granular cell layer of the MOB of mice exposed to peppermint odors for 3 h, whereas mice exposed to their own bedding failed to show immunostaining in the AOB and only slight or no staining in the MOB. These results indicate that social odors stimulate the expression of c-fos in the AOB while non-social odors activate the MOB. This method allows the identification of individual cells activated by the different odors and will be useful in locating other areas of the brain involved in the neuroendocrine changes underlying odor-induced precocious puberty.

Animals↗
PubMed1993

Advancement of multiple myeloma from diagnosis through plateau phase to progression does not involve a new B-cell clone: evidence from the Ig heavy chain gene.

The Ig heavy chain (IgH) gene was used as a marker to investigate clonal succession and the origin of the neoplastic cell in multiple myeloma. The polymerase chain reaction (PCR) was used to amplify a section of the rearranged IgH gene at diagnosis and at progression in 21 patients who had exhibited a plateau phase. A monoclonal PCR product was seen for 16 of the patients and the product present at progression was of the same molecular weight as that at diagnosis. This finding suggests that the IgH rearrangement present at diagnosis and progression was the same. This was confirmed by sequencing the IgH gene in 10 patients. The IgH genes were found to be hypermutated at diagnosis, but no further hypermutation occurred during the course of the disease. The results provide evidence that the neoplastic cell in myeloma may originate as a memory B cell, plasmablast, or plasma cell, and suggest that progression beyond the plateau phase is not caused by clonal succession.

B-Lymphocytes↗
PubMed1993

The reliability of optimization under dose-volume limits.

PURPOSE: An optimization algorithm improves the distribution of dose among discrete points in tissues, but tolerance depends on the distribution of dose across a continuous volume. This report asks whether an exact algorithm can be completed when enough points are taken to accurately model a dose-volume constraint. METHODS AND MATERIALS: Trials were performed using a 3-dimensional model of conformal therapy of lung cancer. Trials were repeated with different limits placed on the fraction of lung which could receive > 20 Gy. Bounds were placed on cord dose and target dose inhomogeneity. A mixed integer algorithm was used to find a feasible set of beam weights which would maximize tumor dose. Tests of feasibility and optimality are introduced to check the solution accuracy. RESULTS: Solutions were optimal for points used to model tissues. An accuracy of 3-4% in a volume condition could be obtained with models of 450-600 points. The error improved to 2% with 800 points to model the lung. Solution times increased six-fold at this level of accuracy. CONCLUSION: The mixed integer method can find optimum weights which respect dose-volume conditions in usually acceptable times. If constraints are violated by an excessive amount, the optimization model should be rerun with more points.

Algorithms↗