Biomedical subjects

J Brown

Publications and source records attributed to J Brown.

At least 361 records · Page 20Linked to original sources

PubMed1997

Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates.

The internalizing anti-Le(y) monoclonal antibody (MAb) BR64 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to the DOX and either a disulfide or thioether bond to the MAb. The resulting disulfide (BR64-SS-DOX) and thioether (BR64-S-DOX) conjugates were evaluated for stability, potency, and antigen-specific activity in both in vitro and in vivo model systems. The BR64-SS-DOX conjugates demonstrated antigen-specific activity both in vitro and when evaluated against antigen-expressing, DOX-sensitive human carcinoma xenografts. However, the stability and potency of disulfide conjugates were poor, and in vivo activity superior to unconjugated DOX was seen only at doses approaching the maximum tolerated dose. Furthermore, BR64-SS-DOX conjugates were not active against antigen-expressing, DOX-insensitive colon tumor xenografts. In contrast, the BR64-S-DOX conjugates demonstrated good stability both in vitro and in vivo. The increased stability of the BR64-S-DOX conjugates resulted in the delivery of more biologically active DOX to tumors with a concomitant increase in potency and efficacy over that which could be achieved with either unconjugated DOX or BR64-SS-DOX conjugates. Delivery of DOX by BR64-SS-DOX conjugates resulted in complete regressions and cures of both DOX-sensitive lung xenografts and DOX-intensitive colon tumor xenografts. These results demonstrate the importance of linker stability when delivering drugs such as DOX to carcinomas via internalizing antibodies and are likely to have direct relevance to the clinical utility of MAb-directed delivery.

Animals↗

PubMed1997

Clinical and genetic analysis of a family affected with dominant optic atrophy (OPA1)

OBJECTIVES: To refine the dominant optic atrophy locus, OPA1, on chromosome 3q and to characterize the phenotype of a 6-generation family pedigree affected with this disease. METHODS: Fifty-six family members had a complete eye examination. Clinical records of an additional 3 patients were reviewed. Goldmann perimetry and a 21-chip subtest of the Farnsworth-Munsell 100-Hue test were performed on selected patients. Affected patients, unaffected siblings, and potentially informative spouses were genotyped with short tandem repeat polymorphisms located on chromosome 3. The genotypic data were subjected to linkage analysis. RESULTS: Thirty-four family members were found to be clinically affected. Most experienced vision loss (20/40 or poorer) in the first decade of life. Most (9 of the 16 eyes) progressed to 20/800 or poorer visual acuity by age 60 years, while 2 patients maintained visual acuities of 20/40 at that age. Affected patients had a 2- to 10-fold increase in the error score of a 21-chip subtest of the Farnsworth-Munsell 100-Hue test compared with age-matched unaffected family members. The optic nerve examination revealed temporal pallor and excavation in all affected individuals. Linkage analysis revealed significant lod scores with 9 markers. The highest lod score, 10.1 (theta = 0) [corrected], was obtained with marker D3S2305. Analysis of recombinants narrowed the disease interval to approximately 3.8 centimorgans, flanked by D3S3669 (centromeric) and D3S1305 (telomeric). CONCLUSIONS: Most patients affected with dominant optic atrophy in this family progressed to legal blindness by middle age. Color vision testing is a sensitive method for detection of affected patients. The dominant optic atrophy locus, OPA1, has been refined by the identification of new flanking markers: D3S3669 (centromeric) and D3S1305 (telomeric).

Adolescent↗

PubMed1997

Baroreflex dysfunction after nasopharyngectomy and bilateral carotid isolation.

Baroreflex dysfunction (BRD) is an uncommon but perplexing clinical entity that occurs after an operation performed in the head and neck. Cases of BRD have occasionally been reported after bilateral carotid endarterectomies and in rare brain-stem tumors. We describe, for the first time to our knowledge, BRD in a patient after nasopharyngectomy and bilateral carotid isolation for recurrent nasopharyngeal carcinoma.

Anti-Arrhythmia Agents↗

PubMed1997

Fragmentation of complex carbohydrates following ionization by matrix-assisted laser desorption with an instrument fitted with time-lag focusing.

Matrix-assisted laser desorption/ionization time-of-flight spectra of carbohydrates recorded with an instrument using time-lag focusing (delayed extraction) were found to exhibit fragment ions, whereas, in the non time-lag-focusing mode, fragment ions were not observed. Fragment ions consisted both of glycosidic and cross-ring cleavage products whose absolute, but not relative abundance increased with the delay time and indicated that they were formed within the ion source. Only the glycosidic cleavage ions were present in post-source decay spectra and their abundance was inversely correlated with the delay time. The results indicated that the cross-ring cleavages were predominately the products of fast reactions whereas the glycosidic cleavages occurred over a longer time frame.

Carbohydrate Sequence↗

PubMed1997

Influence of inhaled corticosteroids and dietary intake on bone density and metabolism in patients with moderate to severe asthma.

OBJECTIVES: Compare the effect of high doses of inhaled corticosteroids on bone loss in subjects with moderate to severe asthma or mild asthma, and examine the influence of dietary intake on bone metabolism. DESIGN: A survey on the effects of corticotherapy and nutrition on bone density was conducted in 74 subjects currently being treated for asthma in the asthma clinic of Hôpital Laval (Sainte-Foy, Quebec, Canada). Fifty-eight subjects completed the study (attrition rate = 15%). MAIN OUTCOME MEASURES: In all subjects expiratory volumes were determined and urinary analysis was conducted for hydroxyproline, calcium, phosphorus, and cortisol levels. Osteocalcin, calcium, phosphorus, cortisol, alkaline phosphatase, and gamma-glutamyltransferase levels were measured in blood samples. Bone density of the lumbar spine was determined by means of dual-energy x-ray absorptiometry. Nutrition evaluation was based on a 3-day food diary analyzed using progiciel Nutri 91. The nutritional parameters examined were calcium; phosphorus; magnesium; zinc; vitamins A, C, and D; protein; total fiber; oxalates; energy; caffeine; and alcohol in relation to bone density. SUBJECTS: Thirty-one patients with moderate to severe asthma who had been taking more than 1,000 micrograms beclomethasone per day or the equivalent for more than 2 years and 27 patients with mild asthma who were taking less than 500 micrograms beclomethasone per day or the equivalent. STATISTICAL ANALYSES PERFORMED: Four-factor analysis of variance with hierarchized interactions of four levels, Duncan's test, Pearson correlation coefficients. RESULTS: Blood levels of osteocalcin and protein intake were lower in patients with moderate to severe asthma than in those with mild asthma (P < .05). Significant correlations (P < .02) were observed between bone density and calcium intake (r = .40), phosphorus intake (r = .35), protein intake (r = .30), and serum alkaline phosphatase level (r = -.30). Bone density was not significantly different between the two groups of patients with asthma. APPLICATIONS: A follow-up of patients with asthma who are taking inhaled corticosteroids is needed to assess bone density, osteocalcin levels, and dietary intakes of calcium. Verify if osteocalcin level decreases over time in patients with moderate to severe asthma, monitor possible modifications in bone density, and verify if the correlation between dietary calcium and bone density is maintained.

Absorptiometry, Photon↗

PubMed1997

Frequency of optic disc or parapapillary nerve fiber layer drusen in retinitis pigmentosa.

PURPOSE: To determine the frequency and characteristics of optic disc and parapapillary nerve fiber layer drusen in patients with retinitis pigmentosa and to attempt to document any differences in the frequency within different genetic subtypes of retinitis pigmentosa. METHODS: This retrospective case series reviewed 117 patients with autosomal-dominant, 84 with autosomal-recessive, and 61 with X-linked recessive forms of retinitis pigmentosa. Color fundus photographs were reviewed independently by three investigators. The presence of optic disc or parapapillary nerve fiber layer drusen was documented only when all three observers concurred as to their presence. The number (isolated or multiple), site (disc, parapapillary, or both), and bilaterality (unilateral or bilateral) were noted in each patient. RESULTS: Optic disc or parapapillary nerve fiber layer drusen or both were observed in 11 patients (9.4%) with autosomal-dominant, 6 patients (7.1%) with autosomal-recessive, and 7 patients (11.5%) with X-linked recessive types of retinitis pigmentosa. The differences in the observed frequencies were not statistically significant (P = 0.67). Overall, the frequency of optic nerve head or parapapillary drusen or both in 262 patients with retinitis pigmentosa was 9.2%. CONCLUSION: In a large population of patients with retinitis pigmentosa, our findings suggest that approximately 10% are likely to show optic nerve fiber layer drusen involving the optic disc or parapapillary regions or both. The frequency does not vary significantly between different genetic subtypes.

Adolescent↗

PubMed1997

ED evaluation of transient global amnesia.

Transient global amnesia is an unusual syndrome involving a transient memory loss and inability to form new memories, without affecting other cognitive functions. Although the patient often lacks insight into the problem, the syndrome is very frightening for family members, who frequently present to the ED. The evaluation of the syndrome is the subject of some controversy. This review presents current understanding about the causes of transient global amnesia and an approach to the ED evaluation of the syndrome.

Amnesia↗

PubMed1997

Analysis of acetate counter ion and inorganic impurities in pharmaceutical drug substances by capillary ion electrophoresis with conductivity detection.

Capillary electrophoresis with conductivity detection is a versatile new method for the analysis of counter ions in pharmaceutical drug substances. It is a sensitive and linear technique for determining inorganic ions and short chain carboxylic acids such as acetate. Both acetate counter ion and inorganic impurities can be separated and determined in the same assay.

Acetates↗

PubMed1997

Long-term effects and costs of brief behavioural dietary intervention for patients with diabetes delivered from the medical office.

This study evaluated the 12-month follow-up results and costs of a personalized, medical office-based intervention focused on behavioral issues related to dietary self-management. Two hundred and six adults having diabetes attending an internal medicine outpatient clinic visit were randomized to either Usual Care or to Brief Intervention. The single session intervention involved touchscreen computer-assisted assessment that provided immediate feedback on key barriers to dietary self-management, goal setting and problem-solving counselling. Follow-up components included phone calls and videotape intervention relevant to each participant. Brief Intervention produced significantly greater improvement than Usual Care on multiple measures of change in dietary behaviour (e.g., covariate adjusted difference of 2.2% of calories from fat; p = 0.023) and on serum cholesterol levels (covariate adjusted difference of 15 mg/dl; p = 0.002) at 12-month follow-up. There were also significant differences favouring intervention on patient satisfaction (p < 0.02) but not on HbA1c levels. The costs of intervention ($137 per patient) were modest relative to many commonly used practices.

Computer-Assisted Instruction↗

PubMed1997

The effect of intravenous ketorolac given intraoperatively versus postoperatively on outcome from gynecologic abdominal surgery.

STUDY OBJECTIVES: To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy. DESIGN: Prospective, randomized, placebo-controlled study. PATIENTS: 248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy. INTERVENTIONS: General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded. MEASUREMENTS AND MAIN RESULTS: VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones. CONCLUSIONS: Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.

Adult↗

PubMed1997

Infertility treatment and multiple birth rates in Britain, 1938-94.

Trends in multiple birth rates are thought to have been substantially affected by subfertility treatments in the last 25 years, but there are few quantitative assessments of this. This paper examines trends in twin and higher multiple birth rates separately in Scotland, England and Wales and compares their course with corresponding multiple birth rates in the Oxford Record Linkage Study area, where the proportions following subfertility treatment are documented. National data on prescriptions for subfertility treatments reinforce the view that they have had a major effect on the trends, and currently perhaps 60% of triplet and higher order births and 15% of twins follow their use in Britain.

Birth Rate↗

PubMed1997

Characterization of Salmonella dublin and Salmonella typhimurium (Copenhagen) isolates from cattle.

Eight Salmonella typhimurium (Copenhagen) and eight Salmonella dublin isolates from cattle were compared by their antibiotic resistance patterns, by their production of colicin, aerobactin, haemolysin and capsule, by their possession of transmissible R plasmids and the spvC gene, and by their ability to invade and replicate within cultured epithelial cells. The two groups differed in their antibiotic resistance profiles, with more of the host-adapted S. dublin isolates resistant to tetracycline than were the non-host-adapted S. typhimurium (Copenhagen) group, but more of the S. typhimurium (Copenhagen) isolates resistant to the other antibiotics tested. None of the isolates produced colicin, but all produced aerobactin. One isolate in each group was encapsulated. All of the S. typhimurium (Copenhagen) and S. dublin isolates contained plasmids, and all of them contained the spvC-homologous sequences. Four of the S. typhimurium (Copenhagen) isolates were able to transfer an R plasmid to a recipient organism by conjugation. One of the five S. dublin isolates, which showed resistance to some of the antibiotics tested, was able to transfer an R plasmid by conjugation. Both groups of isolates invaded cultured epithelial cells to a similar degree after 1 h, but the S. dublin isolates reached significantly higher levels within the cells than did S. typhimurium (Copenhagen) after 9 h. This ability may, in part, explain the association of S. dublin with more severe forms of salmonellosis and prolonged carrier states. Further study of the intracellular growth of these isolates seems warranted.

Animals↗

PubMed1997

Spreading and retention of vaginal formulations in post-menopausal women as assessed by gamma scintigraphy.

PURPOSE: In this paper we report on the first scintigraphic evaluation of vaginal dosage forms in post-menopausal women. To date, almost nothing is known about the in vivo performance of pharmaceutical formulations in the human vagina, which is a major deficiency in the rational design of drug delivery systems for both existing and new indications. METHODS: The vaginal spreading and clearance of a radiolabelled pessary formulation and Replens (polycarbophil) gel, was assessed in six healthy, post-menopausal female volunteers over a six hour period using the technique of gamma scintigraphy. RESULTS: In five out of the six subjects studied, clearance of the two formulations exhibited very little intra-subject variation. However, there was considerable inter-subject variability in clearance; in Subject 5 circa 80% of the products were retained whilst in Subject 2 less than 2% was present at the end of the six hour imaging period. Importantly, there was no evidence to suggest that either of the formulations dispersed material beyond the cervix, into the uterus, in any of the subjects studied. CONCLUSIONS: The lack of significant retention of these products in most of the volunteers has obvious implications for the delivery of therapeutic agents. This study shows that gamma scintigraphy is an invaluable technique with which to assess novel formulations aimed at optimising retention in the vagina for topical or systemic drug delivery.

Administration, Intravaginal↗

PubMed1997

Colonic spread of three rectally administered mesalazine (Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy.

BACKGROUND: Rectal administration of enemas, foams and suppositories is the most efficient method of delivering locally-acting drugs to the distal colon, sigmoid colon and rectum. Healthy volunteers provide an effective population to compare different formulations for rectal drug delivery. However, there is still only limited comparative information available on the dispersion of such dosage forms in human subjects. Therefore, the objective of this scintigraphic study was to compare colonic spread of an enema, a rectal foam and a suppository formulation in healthy volunteers. METHODS: This was a randomized, crossover study in eight healthy male volunteers. Each received Pentasa rectal formulations as either a 100 mL suspension enema (1 g mesalazine), one actuation of a non-CFC propellant rectal foam (1 g mesalazine in 5 mL concentrate, expanding to 40 mL on actuation), or one suppository (1 g mesalazine) on three separate occasions. The spread of the radiolabelled formulations was assessed over a 4-h period by gamma scintigraphy. RESULTS: The formulations were retained by all subjects for the whole of the 4-h imaging period. The enema spread to the splenic flexure in 7 out of 8 subjects, but was retained in the rectum and sigmoid colon in one individual. The foam spread as far as the descending colon in four subjects. In the remaining individuals the foam was retained in the rectum and sigmoid colon. The spread of the suppository was limited and confined to the rectum. CONCLUSIONS: The findings of this study are consistent with previous research and support the intended clinical uses of the enema, foam and suppository formulations to treat distal ulcerative colitis, proctosigmoiditis and proctitis, respectively. The results highlight the potential of gamma scintigraphy in providing in vivo 'proof of concept' data to help verify the targeting of pharmaceutical products to their intended site of delivery.

Administration, Rectal↗

PubMed1997

Human minisatellite MS32 (D1S8) displays somatic but not germline instability in transgenic mice.

Human minisatellite MS32 (D1S8) shows instability both in the germline and, at much lower levels, in somatic DNA. To investigate factors that influence somatic and germline mutation, large cosmid-based constructs containing MS32 were introduced into mice, bred to homozygosity and tested for instability in blood and sperm. Analysis of single copy and multicopy transgenic lines revealed somatic mutants occurring at a frequency comparable with that seen in man. As in humans, these mutants arose mainly by simple intra-allelic duplications and deletions. In contrast, analysis of sperm DNA from four different transgenic lines showed no trace of the complex recombination-based germline instability seen in man, even using PCR-based approaches capable of detecting very rare mutants. These data provide further evidence that germline and somatic mutation at human minisatellite MS32 occur via distinct pathways, that a major barrier exists to the transfer of germline instability from humans to mice and that the mouse germline appears to be protected from mitotic instability of the type seen in blood.

Alleles↗

PubMed1997

Children's perception of, and attitude towards, unfamiliar peers with facial port-wine stains.

Evaluated children's perception of, and attitude towards, unfamiliar peers with facial port-wine stains (PWS). Participants (ages 8 to 11 years) from three grades were shown videoclips of the same 6 children, 3 of whom (2 girls and 1 boy) were seen with a (fake) PWS by participants from one grade. Participants from different grades saw a different 1 of these 3 children with a PWS. Participants thought PWS would attract staring and teasing; for the boy it would cause self-pity and, for one of the girls, it would make getting a boyfriend more difficult, but the stain did not significantly affect participants' assessment of the attractiveness and character or willingness to interact/become friendly with the children on the video. Possible reasons for this discrepancy are discussed.

Attitude↗

PubMed1997

D-penicillamine reduces renal injury in the remnant model of chronic renal failure in the rat.

BACKGROUND: Glomerulosclerosis and interstitial fibrosis, which are cardinal features of the end-stage kidney, result from accumulation of extracellular matrix proteins, particularly collagen, in the glomerular mesangium and renal interstitium. This study examined the effect of D-penicillamine (DPC), which inhibits collagen deposition, on disease progression in the remnant kidney. METHODS: Two groups of 10 rats underwent two-thirds nephrectomy and were pair-fed 20% casein paste (Gp 1) or the same paste supplemented with 90 mg/kg body wt per day of DPC (Gp 2). Two further groups of five non-nephrectomized animals also received 20% casein paste either alone (Gp 3) or supplemented with DPC (Gp 4). In a further experiment, systolic blood pressure was compared at 1 and 4 weeks after nephrectomy in eight DPC-treated remnants and eight untreated controls. RESULTS: Gp 2 developed significantly less proteinuria than Gp 1 (41 +/- 9 vs 142 +/- 33 mg/24 h at 6 weeks, P < 0.005; 136 +/- 36 vs 282 +/- 59 mg/24 h at 12 weeks, P < 0.05). At sacrifice after 12 weeks, glomerular filtration rates were higher (1.34 +/- 0.08 vs 1.07 +/- 0.1 ml/min, P < 0.05), kidney total collagen content was lower (14.9 +/- 1.5 vs 26.9 +/- 5.4 mg/kidney, P < 0.05) and glomerular abnormalities, interstitial fibrosis and lymphocytic infiltration were less marked in Gp 2 compared with Gp 1. DPC had no effect on protein excretion, total kidney collagen or GFR in non-nephrectomized rats, and did not influence the early rise in blood pressure seen after two-thirds nephrectomy. CONCLUSIONS: These findings demonstrate that DPC reduces renal injury in the remnant kidney, and raise the possibility of a therapeutic role for DPC in the treatment of patients with chronic renal failure.

Animals↗

PubMed1997

A blending of health strategies in a community-based nursing center.

In today's changing healthcare climate, there is a need for a paradigm shift from a goal-driven model of care to a resource-driven model of care. This proposal describes a nursing center model that attempts to create a framework involving the community in determining the priority of its healthcare needs. Although it is desirable to offer all services to all people, it is apparent that costs will play a major role in determining service availability. Participation, support, and cost-effective outcomes are likely to be greater if residents of the community are involved in the services and programs provided. The advanced practice nurse (APN) is well suited to assist communities in determining priorities and meeting health needs in a cost-effective manner. The proposal submitted is based on a theoretical foundation that articulates a nursing framework and includes specific examples of services provided. It is flexible and can be adapted to any community. Modern scientific care, alternative therapies, education, and programs specific to the community's needs are also discussed. The presentation offers a nursing care delivery model in the community and discusses phases of implementation that have been initiated.

Community Health Centers↗