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Biomedical subjects

N Robinson

Publications and source records attributed to N Robinson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis.

OBJECTIVE: To study the expression of chemokine receptors CCR5 and CXCR3 and the Th1/Th2 cytokine balance in children with oligoarticular or polyarticular juvenile idiopathic arthritis (JIA). METHODS: Using 3-color immunofluorescence, we studied the expression of CCR5 and CXCR3 on, and T cell cytokine production by, paired samples of synovial fluid (SF) and peripheral blood (PB) T cells from 20 patients with oligoarticular- or polyarticular-onset JIA. Chemokine and cytokine phenotypes were also compared within the CD45RO+,CD3+ subsets. CCR5 genotypes were confirmed by polymerase chain reaction typing and sequencing. RESULTS: In the majority of samples, the number of T cells that were CCR5+ and CXCR3+ was higher in SF than in PB, and this difference was significant. One child was homozygous for the null A32 CCR5 allele; 4 others had lower expression of CXCR3 in SF than in blood. All samples showed strongly Th1-type cytokine production by synovial T cells compared with that by PB T cells. Both features were also markedly polarized within the synovial CD45RO+ subset compared with PB CD45RO+ T cells. CONCLUSION: The high expression of CCR5 and CXCR3 and high interferon-gamma:interleukin-4 ratios suggest a type 1 phenotype of SF T cells in JIA. The difference between CD45RO+ T cells from SF and from PB suggests that specific activation events have occurred in synovial T cells. We suggest that the highly activated, Th1-type phenotype of T cells within the chronically inflamed joints of children with JIA may reflect specific recruitment events that contribute to the polarization of these cells.

Adolescent↗
PubMed2000

Test methods: anabolics.

In the International Olympic Committee (IOC) accredited laboratories, specific methods have been developed to detect anabolic steroids in athletes' urine. The technique of choice to achieve this is gas-chromatography coupled with mass spectrometry (GC-MS). In order to improve the efficiency of anti-doping programmes, the laboratories have defined new analytical strategies. The final sensitivity of the analytical procedure can be improved by choosing new technologies for use in detection, such as tandem mass spectrometry (MS-MS) or high resolution mass spectrometry (HRMS). A better sample preparation using immuno-affinity chromatography (IAC) is also a good tool for improving sensitivity. These techniques are suitable for the detection of synthetic anabolic steroids whose structure is not found naturally in the human body. The more and more evident use, on a large scale, of substances chemically similar to the endogenous steroids obliges both the laboratory and the sports authorities to use the steroid profile of the athlete in comparison with reference ranges from a population or with intraindividual reference values.

Anabolic Agents↗
PubMed2000

Communication skills training for emergency department senior house officers--a qualitative study.

OBJECTIVE: To identify common weaknesses in senior house officer-patient consultation skills, and evaluate direct observation with feedback and negotiation of educational contracts, as a teaching tool in an emergency department setting. METHOD: Common weaknesses were identified through review of feedback charts by three trained observers. Alteration in clinical and learning behaviour, as well as senior house officer and observer perceptions of the teaching were evaluated qualitatively by a combination of semistructured interviews and focus groups. RESULTS: Several common weaknesses were identified, notably the use of closed questions, and poor negotiation and explanation of treatment plan and follow up. The senior house officers perceived improvement in their clinical practice, welcomed feedback, and subsequently set, though did not complete educational contracts. While comfortable with this style of teaching, the observers felt that it did not make efficient use of teaching time. CONCLUSIONS: This study identifies common weaknesses in the consultation skills of emergency department senior house officers and confirms the need for training in this area. Direct observation is effective in changing behaviour to this end, though self directed learning is not necessarily stimulated. Video recorded consultations with group feedback may be a more effective teaching tool.

Communication↗
PubMed1999

MIG-13 positions migrating cells along the anteroposterior body axis of C. elegans.

The C. elegans Q neuroblasts and their descendants migrate along the anteroposterior (A/P) body axis to positions that are not associated with any obvious landmarks. We find that a novel protein, MIG-13, is required to position these cells correctly. MIG-13 is a transmembrane protein whose expression is restricted to the anterior and central body regions by Hox gene activity. MIG-13 functions non-cell autonomously within these regions to promote migration toward the anterior: loss of mig-13 activity shifts the Q descendants toward the posterior, whereas increasing the level of MIG-13 shifts them anteriorly in a dose-dependent manner. Our findings suggest that MIG-13 is a component of a global A/P migration system, and that the level of MIG-13 determines where along the body axis these migrating cells stop.

Amino Acid Sequence↗
PubMed1999

Treatment choice and quality of life in patients with choroidal melanoma.

OBJECTIVE: To determine if quality of life differs between patients with choroidal melanoma treated with enucleation and those treated with radiation therapy. MATERIALS AND METHODS: Patients treated for choroidal melanoma at 5 Midwest centers were asked to participate. There were 65 participants treated with enucleation and 82 treated with radiation therapy. Quality of life was assessed using the Medical Outcome Study Short Form 36 and the National Eye Institute Visual Function Questionnaire and by the Time-Tradeoff interview method. RESULTS: The average length of follow-up was 4.9 years for the group treated with radiation therapy and 6.3 years for the group treated with enucleation (P = .05). After adjusting for age, sex, years of follow-up, and the number of chronic conditions, there were few differences in any of the quality-of-life measures by treatment status. Participants in the group treated with radiation therapy were more likely to have higher (better) scores on the Vitality and Mental Component subscales of the Medical Outcome Study Short Form 36 than participants treated with enucleation. There were no differences on the National Eye Institute Visual Function Questionnaire or the Time-Tradeoff measures of quality of life. CONCLUSION: Choice of treatment for choroidal melanoma does not seem to be associated with large differences in quality of life in long-term follow-up.

Aged↗
PubMed1999

The use of focus group methodology--with selected examples from sexual health research.

This paper describes in detail the use of the focus group approach in research. The following issues are discussed: when, why and how focus group methods are used, their advantages and disadvantages and how data are analysed. Selected examples from four research studies on sexual health using this methodology are reported together with some of the problems experienced with their use. The importance of using focus groups in qualitative research is addressed and an argument is suggested for their more general use.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Characteristics of ischemic and peri-ischemic regions during ventricular fibrillation in the canine heart.

INTRODUCTION: Although premature beats originating in areas of ischemia have been shown to be important in initiating ventricular fibrillation (VF), the participation of the ischemic zone in maintenance of VF has not been investigated. METHODS AND RESULTS: Ten normal dogs underwent induction of two separate episodes of VF, before and 10 minutes after left anterior descending coronary artery ligation. Ischemic VF was allowed to occur spontaneously or was induced by burst pacing after 10 minutes of ischemia. Unipolar epicardial electrograms were recorded using an 8 x 14 plaque electrode array (interelectrode distance 2.5 mm) placed over the anterior wall. Activation during VF was characterized by VF cycle length (CL) and wavefront organization based on linking analysis of epicardial activation directions at adjacent sites. Individual plaque sites were separated into regions based on electrogram morphology during ischemia: R1 = no ischemia; R2 = mild-to-moderate ischemia (minor ST elevation and QRS widening); and R3 = severe ischemia (marked ST elevation and QRS widening). Percent conduction block was calculated based on the percent of cycles during which sites were not activated during VF. There were no significant differences noted in mean CL or mean percent conduction block in the peri-ischemic region R1 compared to the same region under nonischemic (control) conditions. During ischemia, the mean CL was noted to increase in R2 from 111+/-14 msec (control) to 128+/-29 msec (ischemia) and in R3 from 113+/-14 msec (control) to 150+/-42 msec (ischemia) (P < 0.05). The percentage conduction block in R2 increased from 6%+/-11% (control) to 14%+/-16% (ischemia) and in R3 from 4%+/-6% (control) to 44%+/-21% (ischemia) (P < 0.05). Linking analysis revealed no significant changes in VF organization at distances of 2.5 mm in regions R1 and R2 under both control and ischemic conditions. Premature beats initiating fibrillation originated at the border between the normal and mildly ischemic zones. CONCLUSIONS: (1) Some VF characteristics are altered in ischemic regions including a longer VFCL and greater percentage of functional block. (2) VF characteristics are unchanged in immediately adjacent nonischemic myocardium. (3) Although the ischemic zone may be involved in the initiation of VF and has unique activation characteristics during VF, it does not affect VF characteristics in the adjacent nonischemic zone, suggesting that it may not play a major role in VF maintenance.

Animals↗
PubMed1999

Platelet IIb/IIIa antagonists followed by delayed stent implantation. A new treatment for vein graft lesions containing massive thrombus.

The percutaneous treatment of saphenous vein graft lesions containing angiographically massive thrombus is associated with a high risk of distal embolisation and no-reflow. The optimal management for these lesions remains unclear and a challenge to the interventional cardiologist. Five cases are described in whom the risks of percutaneous angioplasty were felt to be excessive owing to a high thrombus load. Each case was treated with a bolus and infusion of abciximab (ReoPro; Eli Lilly-a platelet glycoprotein IIb/IIIa receptor antagonist) at least 24 hours before further angiography. Repeat angiography of the culprit vein graft, following treatment with abciximab alone, demonstrated a major reduction in the thrombus score and the presence of TIMI 3 flow in each case. Immediately following repeat angiography, angioplasty with stent insertion was performed successfully with no distal embolisation or no-reflow phenomenon. This staged approach, with abciximab used alone to reduce thrombus load, is a new treatment for vein graft lesions containing massive thrombus.

Abciximab↗
PubMed1999

A novel (6S)-4,6-dimethyldodeca-2E,4E-dienoyl ester of phomalactone and related alpha-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity.

A series of novel 6-substituted 5,6-dihydro-5-hydroxy-alpha-pyrone esters, 1 approximately 3, isolated from fermentations of a Phomopsis sp. (Xenova culture collection no. X22502) have been identified as inhibitors of lipopolysaccharide (LPS)-induced cytokine production. These include the (6S)-4,6-dimethyldodecadien-2E,4E-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2E-enoic acid moiety at the 6-position of the alpha-pyrone ring. (6S)-4,6-Dimethyl-2E,4E-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited LPS-induced tumour necrosis factor alpha (TNFalpha) production by U937 cells and LPS-induced interleukin 1beta (IL-1beta) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selective for IL-1beta relative to TNFalpha. The inhibition of IL-1beta production by 1 involved a post-translational mechanism of action at the level of IL-1beta secretion as demonstrated by the lack of an effect on cell-associated IL-1beta production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.

Dose-Response Relationship, Drug↗
PubMed1998

Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene.

Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.

Amino Acid Sequence↗
PubMed1998

Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaB and stabilization of calcium homeostasis.

Mutations in the presenilin-1 (PS-1) gene account for approximately 50% of the cases of autosomal dominant, early onset, inherited forms of Alzheimer's disease (AD). PS-1 is an integral membrane protein expressed in neurons and is localized primarily in the endoplasmic reticulum (ER). PS-1 mutations may promote neuronal degeneration by altering the processing of the beta-amyloid precursor protein (APP) and/or by engaging apoptotic pathways. Alternative processing of APP in AD may increase production of neurotoxic amyloid beta-peptide (Abeta) and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPPalpha). In differentiated PC12 cells expressing an AD-linked PS-1 mutation (L286V), sAPPalpha activated the transcription factor NF-kappaB and prevented apoptosis induced by Abeta. Treatment of cells with kappaB decoy DNA blocked the antiapoptotic action of sAPPalpha, demonstrating the requirement for NF-kappaB activation in the cytoprotective action of sAPPalpha. Cells expressing mutant PS-1 exhibited an aberrant pattern of NF-kappaB activity following exposure to Abeta, which was characterized by enhanced early activation of NF-kappaB followed by a prolonged depression of activity. Blockade of NF-kappaB activity in cells expressing mutant PS-1 by kappaB decoy DNA was associated with enhanced Abeta-induced increases of [Ca2+]i and mitochondrial dysfunction. Treatment of cells with sAPPalpha stabilized [Ca2+]i and mitochondrial function and suppressed oxidative stress by a mechanism involving activation of NF-kappaB. Blockade of ER calcium release prevented (and stimulation of ER calcium release by thapsigargin induced) apoptosis in cells expressing mutant PS-1, suggesting a pivotal role for ER calcium release in the proapoptotic action of mutant PS-1. Finally, a role for NF-kappaB in preventing apoptosis induced by ER calcium release was demonstrated by data showing that sAPPalpha prevents thapsigargin-induced apoptosis, an effect blocked by kappaB decoy DNA. We conclude that sAPPalpha stabilizes cellular calcium homeostasis and protects neural cells against the proapoptotic action of mutant PS-1 by a mechanism involving activation of NF-kappaB. The data further suggest that PS-1 mutations result in aberrant NF-kappaB regulation that may render neurons vulnerable to apoptosis.

Amyloid beta-Peptides↗
PubMed1998

Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function.

Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid beta-peptide (Abeta). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Abeta, and potentiated by mutant PS-1, were suppressed in calbindin-overexpressing cells. Impairment of mitochondrial function by Abeta (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by calbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

Amyloid beta-Peptides↗
PubMed1998

Social deprivation and mortality in adults with diabetes mellitus.

To investigate the relationship between measures of social deprivation and mortality in adults with diabetes, data from 2104 randomly selected adults (> 16 years of age) with Type 1 and Type 2 diabetes mellitus from 8 hospital out-patient departments were analysed. A total of 38% of subjects had Type 1 (diagnosed before the age of 36 years and treated with insulin), 55% were male and 85% Caucasian. During a follow-up period (mean (SD) of 8.4 (0.9) years), 293 (14%) of the subjects died, the most commonly recorded cause of death being cardiovascular disease. Duration adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for Type 1 and Type 2 subjects. The mortality rates for men were higher than for women (Type 1: OR 1.27, CI 0.61-2.62; Type 2: OR 1.79, CI 1.27-2.52); were higher for those of lower vs higher social class (Type 1: OR 1.34, CI 0.61-2.96; Type 2: OR 2.0, CI 1.41-2.85); and were higher for those who left school before 16 years of age compared to those who left school at or after 16 years of age (Type 1: OR 3.98, CI 1.96-8.06; Type 2: OR 2.86, CI 1.93-4.25). Subjects who were unemployed had a higher mortality rate than those employed at the time of the study (Type 1: OR 3.10, CI 1.67-5.79; Type 2: OR 2.88, CI 2.12-3.91) and those living in council housing had a greater mortality than those who were living in other types of housing (Type 1: OR 2.57, CI 1.35-4.91, Type 2: OR 2.76, CI 2.05-3.73). Also for both Type 1 and Type 2 subjects mortality was significantly higher in those subjects who had a least one diabetic complication at baseline and reported one or more hospital admissions in the previous year and in Type 2 subjects with poor glycaemic control. After adjusting for duration of diabetes, hospital admissions, and the presence of diabetic complications, being unemployed, male, in poor glycaemic control (Type 2 only), and less educated were significant risk factors for mortality (p<0.001). These results suggest that there are important indicators of social deprivation which predict mortality over and above diabetic health status itself. Locally targeted action will be required if these inequalities in health experienced by people with diabetes are to be reduced.

Adolescent↗