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Biomedical subjects

J Brown

Publications and source records attributed to J Brown.

At least 127 records · Page 7Linked to original sources
PubMed2001

Fetal cell grafts provide long-term protection against scrapie induced neuronal loss.

We have transplanted fetal neurons to prolong hippocampal pyramidal cell survival in a mouse scrapie model in which 50% of CA1 pyramidal cells have died by day 180 of the 250-day incubation period. Cells prepared from embryonic PrP deficient mice were intracerebrally injected into infected mice on day 150 and groups killed on day 171 and with terminal disease. Neuron counts and CA1 depth measurements were made on semi-serial sections using an image analysis system. Both grafted groups retained more CA1 neurons than controls injected with medium alone, and showed greater depth of CA1 than controls. This new approach may have potential as a late-stage therapy for TSEs for which there are currently no available treatments.

Animals↗
PubMed2001

Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na(+) channel alpha subunit.

Mutations of amino acid residues in the inner two-thirds of the S6 segment in domain III of the rat brain type IIA Na(+) channel (G1460A to I1473A) caused periodic positive and negative shifts in the voltage dependence of activation, consistent with an alpha-helix having one face on which mutations to alanine oppose activation. Mutations in the outer one-third of the IIIS6 segment all favored activation. Mutations in the inner half of IIIS6 had strong effects on the voltage dependence of inactivation from closed states without effect on open-state inactivation. Only three mutations had strong effects on block by local anesthetics and anticonvulsants. Mutations L1465A and I1469A decreased affinity of inactivated Na(+) channels up to 8-fold for the anticonvulsant lamotrigine and its congeners 227c89, 4030w92, and 619c89 as well as for the local anesthetic etidocaine. N1466A decreased affinity of inactivated Na(+) channels for the anticonvulsant 4030w92 and etidocaine by 3- and 8-fold, respectively, but had no effect on affinity of the other tested compounds. Leu-1465, Asn-1466, and Ile-1469 are located on one side of the IIIS6 helix, and mutation of each caused a positive shift in the voltage dependence of activation. Evidently, these amino acid residues face the lumen of the pore, contribute to formation of the high-affinity receptor site for pore-blocking drugs, and are involved in voltage-dependent activation and coupling to closed-state inactivation.

Amino Acid Substitution↗
PubMed2001

Molecular characterization and ophthalmic investigation of a large family with type 2A Von Hippel-Lindau Disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized. OBJECTIVES: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease. METHODS: A longitudinal clinical study and DNA analysis of 24 family members. RESULTS: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma. CONCLUSIONS: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.

Adrenal Gland Neoplasms↗
PubMed2001

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Adult↗
PubMed2001

Regulation of growth factor induced gene expression by calcium signalling: integrated mRNA and protein expression analysis.

There is considerable indirect evidence that growth factor induced changes in the intracellular concentration of calcium play an important role in the regulation of the mammalian cell cycle. However, the precise mechanism by which this may be achieved remains unclear. Here we show that SKF-96365, an inhibitor of growth factor induced capacitative calcium entry (CCE), inhibits cell cycle progression by preventing entry into S phase. SKF-96365 changes the temporal profile of growth factor induced calcium signalling and recent studies have shown that alterations in the temporal and spatial patterns of calcium signalling can differentially regulate gene expression. We have therefore sought to examine the effect of inhibition of CCE on growth factor induced gene expression during G1. To achieve this we have initiated a combined transcriptomic and proteomic approach to measure CCE regulated gene expression using cDNA arrays and two-dimensional polyacrylamide gel electrophoresis, respectively. The initial results of this on-going analysis are reported here. They reveal that inhibition of CCE influences the expression of 29 genes at the mRNA level and 22 genes at the protein level. We report the identification of the mRNAs whose expression is altered by inhibition of CCE and describe the potential functional significance of some of these changes. The value of integrating a transcriptomic and two-dimensional gel electrophoresis based proteomic approach to studies of gene expression is discussed.

3T3 Cells↗
PubMed2001

HLA-B typing by reference strand mediated conformation analysis using a capillary-based semiautomated genetic analyzer.

The application of reference strand conformation analysis (RSCA) to HLA-A typing using the ABI PRISM 310 capillary based genetic analyzer has recently been described. This study outlines the development and validation of capillary RSCA for HLA-B typing. Mobility values for 93 HLA-B alleles were defined following electrophoresis of known controls through the system. Three fluorescently labelled references, labelled with three different dyes can be electrophoresed simultaneously. The technique was validated by comparing results from 296 cord blood donors with those obtained using reverse SSO. Following capillary RSCA 14.5% of samples required confirmatory typing, compared with a repeat rate of 5.1% following reverse SSO. In samples where no other typing was necessary there was 100% correlation between the two methods. Capillary RSCA for HLA-B typing is quick, easy to implement, and with the introduction of new FLRs and gel matrices has the potential to evolve into a high resolution typing method.

Alleles↗
PubMed2001

Cardiac arrest during surgery and ventilation in the prone position: a case report and systematic review.

We present a case report of successful resuscitation following cardiac arrest in a patient undergoing surgery in the prone position. A systematic review of the literature identified 22 further cases. Risk factors for intra-operative cardiac arrest in patients in the prone position include: cardiac abnormalities in patients undergoing major spinal surgery, hypovolaemia, air embolism, wound irrigation with hydrogen peroxide, poor positioning and occluded venous return. Cardiac arrest is also a risk in the increasing number of patients with acute respiratory distress syndrome ventilated in the prone position. Management of prone cardiac arrest may be improved by identification of high-risk patients, careful patient positioning, use of invasive monitoring and placement of self-adhesive defibrillator paddles. Suitable techniques for cardiopulmonary resuscitation including methods for chest compression, defibrillation and the management of air embolism are discussed.

Blood Loss, Surgical↗
PubMed2001

Assessment of pretest risk for venous thromboembolic disease.

The news, therefore, is somewhat pessimistic. Empiric estimate appears to be fairly good in stratifying risk groups for PE but suffers from a lack of standardization, as well as poor sensitivity and specificity. Multiple attempts to standardize pretest risk have used several different but usually overlapping variables, and none appears yet to be much better than simple clinical estimate--the very scale they were trying to replace. The clinician therefore must assess whether, on the basis of what has been published so far, there is any convincing reason to move from an empiric to a score-based prediction system. Apart from the clear advantage of standardization, the score-based systems are varied, not agreed on, and usually clumsy to use in a busy ED. Until one prediction system has been shown to be both easy to remember and use in clinical practice, and to be more accurate than an empiric score, emergency physicians should continue to use their own practice-based empiric system. DVT can be safely, quickly, and accurately diagnosed in the ED, and for most cases there is no need to use a prediction rule. Suspected PE continues to be a complex entity to evaluate and diagnose in the ED, and none of the objective prediction rules have yet been able to improve the difficult task of the ED evaluation of the patient with suspected PE.

Humans↗
PubMed2001

The impact of a community mobilization project on health-related knowledge and practices in Cameroon.

The analyses presented in this paper document the impact of a community mobilization effort in Cameroon. Between 1997 and 1998, a local non-governmental organization worked with community associations, Njangi, in one urban and one rural location to promote knowledge and positive practices concerning family planning, sexually transmitted diseases, and treatment of common childhood diseases. Based on a multi-tiered structure, the project involved selecting and training two prominent and influential members of each community as "relais" or middlemen. The "relais" then trained mobilizers from participating Njangis to provide relevant information and help to mobilize their fellow members in favor of the positive attitudes and practices promoted by the project. The project was evaluated using baseline and follow-up measurement of pertinent indicators, and service statistics. Results suggest that the intervention had significant influence in the rural location with noticeable positive effects on knowledge and practices of family planning, knowledge and attitudes about HIV/AIDS and STIs, and use of health services. In the urban location, for programmatic and extraneous factors, the intervention was not effective. The paper discusses the lessons learnt from the intervention and offers pertinent suggestions for replicating the intervention in rural settings.

Adolescent↗
PubMed2001

Workplace tobacco policy: progress on a winding road.

This is a report of a pre- and post-intervention telephone survey to track changes in workplace tobacco policy in Pima County, Arizona, from 1997 to 1999. During this period, an extensive effort was made to assist workplaces to establish and enforce formal tobacco use policies. A random sample of 1134 workplaces, stratified by workforce size, was surveyed in 1997. Complete interviews were conducted with 934 (82.4%) workplaces. All 934 workplaces were contacted for the follow-up survey that was conducted in 1999. Of these, 824 (88.2%) completed follow-up surveys. The analyses presented were conducted on businesses that were included in both the baseline and follow-up surveys, and that reported having at least one employee on-site (n = 813). Tobacco policies and smoke-free policies were more likely to be found in larger businesses and businesses with a predominantly female workforce. There was no clear policy progression from having no policy, to having a policy, to becoming smoke-free. There was a small but significant overall decrease (4.8%) in the proportion of businesses having policies in the last two years. We found that 10.3% (75) of businesses that had policies in 1997 had dropped their policies by 1999, and that 13.4% (73) of worksites that were smoke-free in 1997 retained tobacco policies but were not smoke-free in 1999. However, formalization of policy in writing and the number of enforcement strategies utilized increased. These findings suggest that efforts to encourage businesses to establish workplace tobacco policies must be sustained even after policies have been established.

Arizona↗
PubMed2001

A novel HLA allele, B*4104, identified in a cord blood donor.

Results from a number of HLA typing methods prompted the DNA sequencing (SBT) of a cord blood sample at the HLA-B locus. A novel HLA-B allele, B*4104, was identified. This was confirmed by sequencing the mother of the cord blood unit for HLA-B.

Alleles↗
PubMed2001

Changes in general health and musculoskeletal outcomes in the workforce of a hospital undergoing rapid change: a longitudinal study.

This article aimed to examine changes in general health and time with back pain and neck pain and to identify predictors of any such changes. Hospital workers were studied longitudinally with surveys in 1995, 1996, and 1997 (N = 712). Back and neck pain were reported only at the 2nd and 3rd surveys. There was a significant decline in general health and significant increases in time with neck pain and back pain. Predictors of changes in these outcomes were mainly work-related variables (initial or change values), such as job interference with family, job influence, work psychological demands, and hours worked.

Adult↗
PubMed2001

The use of panoramic radiography in a dental accident and emergency department.

OBJECTIVES: To determine the rate of appropriate requests for panoramic radiography (PR) in a Dental Accident and Emergency Department and the implications for patient dose. METHODS: Two hundred and seventy-one requests for PR during July 1998 were assessed by two dental radiologists and categorised as appropriate or inappropriate based on established selection criteria. Incidental findings that might alter patient management were also noted. RESULTS: One hundred and fifty-seven requests (58%) were considered appropriate and 114 (42%) inappropriate. The most common inappropriate request was to assess disease localised to one or two teeth. Dental students were involved in 186 requests and 76 of these (41%) were inappropriate. The estimated saving in collective radiation dose over the month of the study if appropriate radiographs had been taken, would have been approximately 540 microSv, a reduction of 70%. Three out of 114 (3%) inappropriate, PRS showed minor incidental findings. CONCLUSIONS: A considerable proportion of requests for PR were inappropriate. In most of these cases, periapical radiographs would have provided more detail with less radiation dose. The large number of inappropriate requests involving dental students has implications for educators. The use of local selection criteria based on currently accepted guidelines would have reduced the dose substantially.

Decision Making↗
PubMed2001

Leucine suppresses acid-induced protein wasting in L6 rat muscle cells.

BACKGROUND: Metabolic acidosis induces protein wasting in skeletal muscle cells, accompanied by decreased glycolysis and compensatory increased consumption of other metabolic fuels, implying that protein wasting arises from fuel starvation and might be rectified by fuel supplements. Design To test this hypothesis, total protein and protein degradation (release of 14C-phenylalanine) were measured in L6 skeletal muscle cells cultured in Eagle's Minimum Essential Medium at pH 7.1-7.5 for 3 days with metabolic inhibitors or metabolic fuel supplements. RESULTS: Inducing metabolic fuel starvation with inhibitors (1 mmol L(-1) 2-deoxyglucose or 0.1 mmol L(-1) KCN [potassium cyanide]) failed to stimulate protein degradation or net protein wasting under nonacidaemic conditions (pH 7.5). Conversely metabolic fuel supplements (1 mmol L(-1) octanoate, pyruvate or alanine) failed to increase the protein content of the cultures at any pH tested, in spite of significant consumption of the fuels by the cells. Only leucine (1-3 mmol L(-1)) increased protein content and suppressed protein degradation in opposition to the catabolic effect of acidaemia (pH 7.1). Conclusion Leucine exerts a beneficial anabolic effect on cultured skeletal muscle cells in the face of metabolic acidaemia. The failure of other metabolic fuels to do this, and of the metabolic inhibitors to exert a catabolic effect, suggests that leucine acts as a specific modulator of protein turnover and not as a nonspecific source of carbon for oxidation as a fuel.

Acidosis↗