Biomedical subjects

E Brown

Publications and source records attributed to E Brown.

At least 73 records · Page 4Linked to original sources

PubMed1999

Attitudes to organ donation among South Asians in an English high street.

In the UK, people of South Asian origin are at more than twice the risk of end-stage renal failure encountered in the Caucasian population but are under-represented among organ donors. Difficulties with matching mean that few donated kidneys are suitable for transplantation to South Asian recipients. A survey of attitudes in 100 South Asian adults was conducted in the main street of Southall, Middlesex. 90 of those questioned were aware of organ transplantation and 69 had heard about donor cards. However, the 16% who carried a donor card was lower than the 28% reported in the general population. The main reason for the low organ donation rate by South Asians seemed to be lack of knowledge, and this could be remedied by more targeting of information in the Asian media.

Adolescent↗

PubMed1999

Variations in calibration for computerized electronystagmography.

The accuracy of the analyses of vestibular test results obtained from a computerized electronystagmography (ENG) system depends on the accuracy with which the system has been calibrated to record the patient's eye movements. The variability of the calibration sensitivity was investigated by analysing the records of 50 consecutive patients who attended for vestibular testing and a study was carried out using 16 volunteer subjects to examine the contributions that time, changes in lighting and subject movement made to this variability. The effect of calibration frequency on the results obtained from caloric testing was also examined by analysing 16 patient records. The mean percentage change in sensitivity between the first two calibrations carried out on patients was found to be -17%, with a standard deviation of 18%. However, there seems to be little baseline drift over time under constant lighting conditions. Changes in lighting have a marked effect, and the adjustment to lighting changes is slow. Gentle movement has little effect. Repeated calibration does not seem to be an effective method to control the calibration-related errors in caloric test results. Careful control of room illumination and the use of adequate adaptation periods to allow patients to adjust to the lighting should help to improve accuracy but, even in the absence of satisfactory calibration, the use of a computerized ENG system can provide valuable diagnostic information.

Adolescent↗

PubMed1999

Hearing-aid-processed tone pips: electroacoustic and ABR characteristics.

The auditory brainstem response (ABR) recorded while wearing a hearing aid may supply supplemental information about the benefit and appropriateness of the hearing aid for certain infants. The purposes of this study were (1) to determine the effects of different output limiting circuits on the acoustics of tone-pip stimuli used for ABR recordings and (2) assess how changes in hearing-aid-processed stimuli affect ABR characteristics. Electroacoustic input/output functions to tone-pip stimuli were constructed for three different output limiting circuits (wide dynamic range compression, output compression, and linear with peak clipping) available in a programmable hearing aid. Wave V latency and amplitude functions were then measured to the same stimuli and hearing aid settings in five normal-hearing adults. Electroacoustic results showed that none of the output limiting circuits, including linear peak clipping, were effectively activated by tone pips compared to the hearing aid performance to continuous tones. Aided wave V latency and amplitude functions were asymptotic to high stimulus levels, suggesting that cochlear output was in saturation.

Acoustics↗

PubMed1998

Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C.

We selected a human colon carcinoma cell line in increasing concentrations of mitoxantrone to obtain a resistant subline, S1-M1-3.2, with the following characteristics: profound resistance to mitoxantrone; significant cross-resistance to doxorubicin, bisantrene, and topotecan; and very low levels of resistance to Taxol, vinblastine, colchicine, and camptothecin. This multidrug resistance (MDR) phenotype, which was not reversed by verapamil or another potent P-glycoprotein (Pgp) inhibitor, CL 329,753, was dependent, in part, upon an energy-dependent drug efflux mechanism. Pgp and the multidrug resistance protein (MRP) were not elevated in the resistant cells relative to the drug-sensitive parent, suggesting that resistance was mediated by a novel pathway of drug transport. A cell-based screen with S1-M1-3.2 cells was used to identify agents capable of circumventing this non-Pgp, non-MRP MDR. One of the active agents identified was a mycotoxin, fumitremorgin C. This molecule was extremely effective in reversing resistance to mitoxantrone, doxorubicin, and topotecan in multidrug-selected cell lines showing this novel phenotype. Reversal of resistance was associated with an increase in drug accumulation. The compound did not reverse drug resistance in cells with elevated expression of Pgp or MRP. We suggest that fumitremorgin C is a highly selective chemosensitizing agent for the resistance pathway we have identified and can be used as a specific pharmacological probe to distinguish between the diverse resistance mechanisms that occur in the MDR cell.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1998

Sodium and ionic strength sensing by the calcium receptor.

The calcium-sensing receptor (CaR) is activated by small changes in extracellular calcium [Ca2+]o) in the physiological range, allowing the parathyroid gland to regulate serum [Ca2+]o; however, the CaR is also distributed in a number of other tissues where it may sense other endogenous agonists and modulators. CaR agonists are polycationic molecules, and charged residues in the extracellular domain of the CaR appear critical for receptor activation through electrostatic interactions, suggesting that ionic strength could modulate CaR activation by polycationic agonists. Changes in the concentration of external NaCl potently altered the activation of the CaR by external Ca2+ and spermine. Ionic strength had an inverse effect on the sensitivity of CaR to its agonists, with lowering of ionic strength rendering the receptor more sensitive to activation by [Ca2+]o and raising of ionic strength producing the converse effect. Effects of osmolality could not account for the modulation seen with changes in NaCl. Other salts, which differed in the cationic or anionic species, showed shifts in the activation of the CaR by [Ca2+]o similar to that elicited by NaCl. Parathyroid cells were potently modulated by ionic strength, with addition of 40 mM NaCl shifting the EC50 for [Ca2+]o inhibition of parathyroid hormone by at least 0.5 mM. Several CaR-expressing tissues, including regions of the brain such as the subfornical organ and hypothalamus, could potentially use the CaR as a sensor for ionic strength and NaCl. The Journal guidelines state that the summary should be no longer than 200 words.

Adenosine Triphosphate↗

PubMed1998

Role of the gamma chain Ala-Gly-Asp-Val and Aalpha chain Arg-Gly-Asp-Ser sites of fibrinogen in coaggregation of platelets and fibrinogen-coated beads.

Fibrinogen (Fg) mediates platelet aggregation and adhesion to artificial surfaces. The carboxyl terminus of the gamma chain of Fg (residues AGDV at gamma408-411) is known to play an exclusive role in platelet aggregation, while there is no known role for the consensus RGD sites in the Aalpha chain. In this study, we used flow cytometry to measure the coaggregation (CA) of platelets with Fg-coated beads, and investigated which domains in surface-immobilized Fg support platelet adhesion. CA of platelets with Fg-beads was nearly abolished in the presence of 4A5, a monoclonal antibody (mAb) whose epitope includes AGDV, while Z69/8, a mAb that also binds to the gamma chain carboxyl terminus but does not cover AGDV, had little effect. When beads were coated with recombinant Fg (rFg) lacking AGDV, CA was similarly abolished. In contrast, beads coated with Fg that lacked the RGDS site, supported platelet CA as did intact Fg. These results were confirmed in experiments that measured the binding of activated soluble glycoprotein IIb and IIIa (GPIIbIIIa), the platelet membrane glycoprotein complex known to be the Fg receptor, to immobilized Fg. This binding was inhibited by mAb 4A5, but not by mAb Z69/8. Binding was totally retained when beads were coated with Fg lacking RGDS, but was completely lost when beads were coated with Fg lacking AGDV. These results demonstrated that the AGDV sequence on the carboxyl terminus of the gamma chain of Fg plays an exclusive role in platelet adhesion to surface-immobilized Fg, while the carboxyl terminus of the Aalpha chain, including a consensus RGD site, is not required.

Antibodies, Monoclonal↗

PubMed1998

Primary structure of ovine fibroblast growth factor-1 deduced by protein and cDNA analysis.

The amino acid sequence of full-length ovine fibroblast growth factor-1 (FGF-1) was determined by a combination of protein and cDNA sequencing. FGF-1 cDNA analysis indicated that ovine kidney cells express mRNAs encoding both full-length FGF-1 and a truncated FGF-1 variant. An overall comparison of the ovine FGF-1 primary sequence to the eight species studied to date revealed a high degree of conservation, with ovine FGF-1 sharing 90 and 95% sequence identity with human FGF-1 and bovine FGF-1, respectively. Additionally, the FGF-1 proteins from the various species have conserved cysteine residues at positions 30 and 97 and contain acetylated amino-terminal alanine residues. Mass spectrometry analysis confirmed that the blocking group of ovine FGF-1 is also consistent with that of an acetyl-moiety. In contrast to the other FGF-1 proteins, the 154 residue primary sequence of ovine FGF-1 contains three unique amino acid differences: Arg9, Arg44, and Ile123. Ovine FGF-1, unlike human FGF-1, is a potent mitogenic factor for NIH 3T3 fibroblasts in the absence of heparin. In the presence of exogenous heparin, the mitogenic activity of ovine FGF-1 is potentiated slightly.

3T3 Cells↗

PubMed1998

Evidence for a neurotensin receptor in rat serosal mast cells.

OBJECTIVE AND DESIGN: The ability of neurotensin (NT) at nmolar levels to stimulate exocytosis of the mast cell suggested that it could play a role in neuro-immune-endocrine interactions. The inhibition by a specific receptor antagonist of NT's mast cell stimulation suggested the presence of a specific mast cell NT receptor. We have here employed several probes to determine if a specific neurotensin receptor was present on rat serosal mast cells. MATERIAL: Serosal mast cells were isolated from the peritoneal and pleural cavities of male Sprague-Dawley rats. METHODS: Immunocytochemistry with an antibody raised against the C-terminal peptide of the neurotensin receptor was utilized. The same antibody was employed in immunoblotting following SDS gel electrophoresis of mast cell extracts. An RNA probe for ribonuclease protection assays (RPA) was prepared using the rat brain neurotensin receptor cDNA and polymerase chain reaction was carried out using primers based on the rat brain neurotensin receptor sequence. RESULTS: Mast cells showed specific staining with the anti-neurotensin receptor antibody and this same antibody revealed a protein on SDS gels migrating as a 70 kDa species. Ribonuclease protection assays revealed the predicted protected fragment at approximately 450 bp while PCR amplification gave a major product at 843 bp. CONCLUSIONS: These results indicate that a specific neurotensin receptor is present on the rat mast cell.

Animals↗

PubMed1998

"Depression" increases "craving" for sweet rewards in animal and human models of depression and craving.

This study consisted of two experiments, one in rats and one in human volunteers, that used the identical progressive ratio (PR) operant procedure. In both experiments, responding was reinforced under a progressively increasing work requirement, and different groups of subjects received reinforcers that varied in sweetness. In experiment 1, rats were subjected to chronic mild stress, a well-validated animal model of depression. Performance under the PR schedule increased in subjects reinforced with conventional precision pellets (which contain 10% sucrose) or very sweet pellets, but not in subjects reinforced with sugar-free pellets. In experiment 2, volunteers were subjected to a depressive musical mood induction. Performance under the PR schedule increased in subjects reinforced with chocolate buttons, but not in subjects reinforced with with buttons made from the relatively unpalatable chocolate substitute carob. In experiment 2, depressive mood induction also increased chocolate craving, as measured by a novel questionnaire, and there were significant correlations between chocolate craving and chocolate-reinforced PR performance. These results suggest that performance under the PR schedule provides a measure of craving rather than reward, and that craving for sweet rewards is increased by depressive mood induction in both animal and human models. Implications for the interpretation of pharmacological studies using the PR procedure are also discussed.

Adult↗

PubMed1998

Children with autism fail to orient to naturally occurring social stimuli.

Children with autism were compared to developmentally matched children with Down syndrome or typical development in terms of their ability to visually orient to two social stimuli (name called, hands clapping) and two nonsocial stimuli (rattle, musical jack-in-the-box), and in terms of their ability to share attention (following another's gaze or point). It was found that, compared to children with Down syndrome or typical development, children with autism more frequently failed to orient to all stimuli, and that this failure was much more extreme for social stimuli. Children with autism who oriented to social stimuli took longer to do so compared to the other two groups of children. Children with autism also exhibited impairments in shared attention. Moreover, for both children with autism and Down syndrome, correlational analyses revealed a relation between shared attention performance and the ability to orient to social stimuli, but no relation between shared attention performance and the ability to orient to nonsocial stimuli. Results suggest that social orienting impairments may contribute to difficulties in shared attention found in autism.

Attention↗

PubMed1998

Effect of intermittent urethral catheterization and oxybutynin bladder instillation on urinary continence status and quality of life in a selected group of spinal cord injury patients with neuropathic bladder dysfunction.

OBJECTIVES: A comparative assessment of (i) urinary continence status, (ii) quality of life, and (iii) sexuality in spinal cord injury patients prior to, and during intermittent catheterization with adjunctive intravesical oxybutynin therapy (Cystin: manufactured by Leiras Oy. Helsinki, Finland). SETTING: A hospital, and community-based study of selected adult, male, spinal cord injury patients registered with the Regional Spinal Injuries Centre, Southport. PATIENTS: Seven patients (mean age: 44.3 years) suffering from neuropathic bladder due to suprasacral spinal cord lesion of traumatic aetiology, and well settled in the community in the north-west of England were the subjects of this study. Before commencing the intermittent catheterization regime, these patients were on penile sheath drainage. INTERVENTION: Intermittent urethral catheterization was performed with sterile, single-use Nelaton catheters 5-6 times a day with intravesical instillation of oxybutynin 5 mg in 30 ml. 1-3 times a day for periods ranging from 14 to 30 months. OUTCOME MEASURES: Assessment of urinary continence, sexuality, and quality of life was made (i) at the outset before any intervention, (ii) during intermittent catheterization regime, and (iii) when the patients were using the oxybutynin bladder instillation along with intermittent catheterization. RESULTS: Initially all the seven patients were constantly wearing penile sheaths and leg bags. When these patients performed intermittent catheterization 5-6 times in 24 h, they attempted to discard the penile sheath during the day but they were experiencing mild to moderate urine leak between catheterization. They were compelled to wear penile sheaths during night. Subsequently, five patients took oxybutynin by mouth, but developed an unacceptable degree of side-effects necessitating discontinuation of the medication. Following commencement of intravesical oxybutynin therapy, all of them were able to discard the penile sheaths and leg bags during the day as well as during the night. However, on waking-up after a full night's sleep, three patients found dampness of their undergarments 1-2 times per week. None of the patients experienced side-effects attributable either to the intermittent catheterization procedure, or to the intravesical oxybutynin therapy. The number of episodes of urinary infection requiring antibiotic therapy was 0.08/patient/month. All the seven patients noticed a remarkable improvement in the quality of life because they had achieved a high degree of continence. All the seven patients commented on the improved sense of their own sexuality which was attributed to (i) absence of incontinence episodes, (ii) improved self-image, and (iii) not wearing penile sheaths and leg bags. CONCLUSION: These seven spinal cord injury patients achieved socially acceptable continence with improved quality of life, and enhanced sexuality with the intermittent urethral catheterization regime and intravesical oxybutynin therapy.

Adult↗

PubMed1998

Prospective evaluation of magnetic resonance cholangiography to detect common bile duct stones before laparoscopic cholecystectomy.

BACKGROUND: With the advent of laparoscopic cholecystectomy, endoscopic retrograde cholangiography (ERC) is frequently employed before operation to detect common bile duct stones. However, this is an invasive technique with recognized complications. This study evaluated the accuracy of magnetic resonance cholangiography (MRC) to detect choledocholithiasis in selected patients before laparoscopic cholecystectomy. METHODS: Patients scheduled for elective laparoscopic cholecystectomy, with risk factors for common bile duct stones, underwent MRC followed by ERC or peroperative cholangiography. RESULTS: Over a 2-year period 40 patients were studied. MRC had a sensitivity of 88 per cent, specificity of 93 per cent, positive predictive value of 78 per cent and negative predictive value of 97 per cent for the detection of common bile duct stones. CONCLUSION: MRC is a simple non-invasive method for preoperative screening for common bile duct stones in at-risk patients. In this study it would have reduced the need for ERC by three-quarters.

Cholangiography↗

PubMed1998

In vitro activity of hepatitis B virus polymerase: requirement for distinct metal ions and the viral epsilon stem-loop.

Hepadnaviruses have a complex replication cycle which includes reverse transcription of the pregenomic RNA. The initial step in this process in hepatitis B virus (HBV) requires the viral polymerase to engage a highly stable region of secondary structure within the pregenomic RNA termed the epsilon stem-loop. While reverse transcriptases belonging to the retrovirus family use a specific cellular tRNA as primer, HBV polymerase utilizes a tyrosine residue located within its own N terminus. Therefore, the first deoxyribonucleotide is covalently coupled to HBV polymerase prior to extension of the DNA strand by conventional reverse transcription. We have expressed HBV polymerase in a baculovirus and following purification have found it to be active with respect to protein-priming and reverse transcription of copurified RNA. Importantly, we found both of these processes to be critically dependent on the presence of the epsilon stem-loop. The metal ion preferences of HBV polymerase were also investigated for both the protein-priming and reverse transcription activities of this enzyme. Reverse transcription was dependent on magnesium, with an optimal concentration of 5 mM. However, protein-priming was strongly favoured by manganese ions and was optimal at a concentration of 1 mM. Thus, using manganese as sole source of metal ions our activity assay is restricted to the protein-priming event and will allow the search for novel antivirals specifically blocking this unique mechanism.

Animals↗

PubMed1998

Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer.

PURPOSE: To evaluate the efficacy of an abbreviated treatment plan consisting of two cycles of chemotherapy plus thoracic irradiation in a population of limited-stage small-cell lung cancer (LSCLC) patients who were elderly, infirm, or noncompliant with standard-duration therapy. PATIENTS AND METHODS: Fifty-five LSCLC patients (median age, 73) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Both regimens were administered at conventional full dose. Thoracic irradiation (20 to 30 Gy) was delivered concurrently with EP. RESULTS: Complete response occurred in 28 patients (51%) and partial response in 21 (38%). The median survival time was 54 weeks; the 2-year survival rate was 28% and the actual 5-year survival rate was 18%. Three patients died of toxicity. CONCLUSION: Elderly, infirm, or noncompliant LSCLC patients who are unable to receive standard-duration chemotherapy may have useful palliation and potential for long-term survival with abbreviated chemotherapy (two cycles) and thoracic irradiation.

Aged↗

PubMed1998

Strategies for environmental monitoring of toxin producing phantom dinoflagellates in the Chesapeake.

Toxin-producing estuarine dinoflagellates have been linked with the occurrence of fish kills and the development of a novel clinical illness syndrome among persons exposed to waters during fish kill events. The prototype organism of this group, Pfiesteria piscicida, has an extremely complex life cycle, making traditional methods used for environmental monitoring of harmful algal blooms less reliable. The response to fish kill events and the occurrence of human illness in Maryland in 1997 is reviewed, with particular emphasis on problems in organism detection. Current and anticipated classical and molecular methodologies for the detection of Pfiesteria and Pfiesteria-like organisms are reviewed. Development of these capabilities will be of critical importance in defining the epidemiology of human illness related to environmental exposure to Pfiesteria, and in developing public health strategies to predict and prevent such illness.

Animals↗

PubMed1998

c-fos and c-jun mRNA expression in activated cord and adult lymphocytes: an analysis by Northern hybridization.

BACKGROUND AND OBJECTIVES: To further analyze the neonatal immune response to an antigenic challenge such as blood transfusion, c-fos and c-jun mRNA expression were analyzed in twelve in-vitro-stimulated normal cord blood and ten in-vitro-stimulated normal adult peripheral blood lymphocyte samples. MATERIALS AND METHODS: Lymphocyte samples were stimulated by either the mitogen phytohemagglutinin (PHA) or the monoclonal antibody alphaCD3. Proliferation rate and Northern blot hybridization were employed. RESULTS: Cord lymphocytes revealed a greater proliferation rate with PHA and alphaCD3 than adult lymphocytes (p = 0.0081 and 0.0023, respectively). In addition, Northern blot analysis of cord and adult samples revealed similar maximal increases in c-fos (99+/-15 and 126+/-11%, p = 0.0126) and c-jun (123+/-9 and 185+/-38%, p = 0.0291) mRNA expression, respectively, as early as 15 min post-alphaCD3 stimulation. Adult lymphocytes showed an equivalent increase in mRNA expression of c-fos and c-jun (140+/-25 and 155+/-31%) at 30 min post-PHA stimulation, while cord lymphocyte maximum c-fos and c-jun expression (82+/-6 and 142+/-12%) occurred at 15 min post-PHA stimulation (c-fos, p = 0.0354; c-jun, p = 0.0112). CONCLUSION: Although cord lymphocyte proliferation rates were significantly greater than those of adult lymphocytes following stimulation, lymphocyte activation, as analyzed by c-fos and c-jun mRNA expression, appears similar in both cord and adult samples. We conclude that cord lymphocyte activation exhibits an adult-type profile.

Adult↗

PubMed1997

The AGDV residues on the gamma chain carboxyl terminus of platelet-bound fibrinogen are needed for platelet aggregation.

It has been clear that only the carboxyl terminus of fibrinogen (Fg) gamma chain is required for the initial binding of Fg from solution to its GPIIbIIIa (glycoprotein IIb and IIIa) receptor on activated platelets, whereas the two RGD sites on the A alpha chain do not play any role. In this study, we examined the role of these three putative adhesive domains on Fg already bound to its receptors in mediating platelet aggregation. Activated platelets were first incubated with Fg to let the Fg bind, then with monoclonal antibodies (mAb) to block the putative adhesive domains, and the platelet suspension was then sheared or stirred to induce aggregation. The mAb 4A5, which recognizes the last four amino acid residues (AGDV) in a dodecapeptide (H12) on the carboxyl terminus of the Fg gamma chain, markedly inhibited platelet aggregation. Z69/8, a mAb whose epitope is also on the dodecapeptide but does not recognize the AGDV residues, did not have any inhibitory effect on aggregation. The anti-RGDS and anti-RGDF mAbs did not affect both macro- and micro-aggregation at all, whether tested singly or together. These results demonstrate that, similar to the situation for the initial binding of soluble Fg, only the gamma chain carboxyl terminus with the AGDV residues are needed for platelet-bound Fg to support aggregation, while the RGD sites on the A alpha chain do not seem to be required.

Antibodies, Monoclonal↗

PubMed1997

CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion.

BACKGROUND: Adhesion of leukocytes to the extracellular matrix and to other cells is mediated by members of the integrin family of adhesion molecules. Src family kinases are activated upon integrin-mediated adhesion. In lymphocytes, CD45 is a leukocyte-specific transmembrane protein tyrosine phosphatase that activates Src family kinases associated with B-cell and T-cell antigen receptor signaling by constitutive dephosphorylation of the inhibitory carboxy-terminal tyrosine phosphorylation site. Here, we show that CD45 is also important in downregulating the kinase activity of Src family members during integrin-mediated adhesion in macrophages. RESULTS: We found that CD45 colocalized with beta2 integrin and the Src family kinase p53/56(lyn) to adhesion sites in bone marrow-derived macrophages. Macrophages from CD45(-/-) mice were unable to maintain integrin-mediated adhesion. In adherent macrophages, absence of CD45 led to the hyperphosphorylation and hyperactivation of p56/59(hck) and p53/56(lyn), but not of p58(c-fgr). CD45 directly inactivated p59(hck) but not p56(lck) in transient transfection assays. Furthermore, coexpression of CD45 with p59(hck) or p56(lyn) containing a tyrosine to phenylalanine mutation at the carboxy-terminal negative regulatory site resulted in decreased tyrosine phosphorylation of the Src family member kinases due to dephosphorylation of the potentiating tyrosine phosphorylation site within the kinase domain. CONCLUSIONS: Using primary bone marrow macrophages, these studies demonstrate that CD45 regulates Src family kinases and is required to maintain macrophage adhesion. CD45 decreases Src family kinase activity by dephosphorylating the tyrosine residue located within the kinase domain.

Animals↗