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Biomedical subjects

F Crawford

Publications and source records attributed to F Crawford.

At least 55 records · Page 3Linked to original sources
PubMed1999

A systematic review of treatments for the painful heel.

OBJECTIVE: To establish the efficacy for treatments of pain on the plantar aspect of the heel. METHODS: Systematic review of the published and unpublished literature. Electronic search of Medline, BIDS and the Cochrane database of clinical trials. An assessment of the quality of the reporting was made of studies included in the review. MAIN OUTCOME MEASURE: patients' pain scores. STUDY SELECTION: randomized controlled trials, published or unpublished, that evaluated treatments used for plantar heel pain. Foreign language papers were excluded. RESULTS: Eleven randomized controlled trials were included in the review. These evaluated some of the most frequently described treatments (steroid injections and orthoses) and some experimental therapies (extracorporeal shock wave therapy and directed electrons). The methodological assessment scores of the published trials were low; small sample sizes and failure to conceal the treatment allocation from study participants prevents more definitive statements about the efficacy of treatments. In 10 of the included trials, patients in both the intervention and control arms reported improved pain scores at the final outcome measure. CONCLUSIONS: Although much has been written about the treatment of plantar heel pain, the few randomized controlled trials involve small populations of patients and do not provide robust scientific evidence of treatment efficacy.

Fasciitis↗
PubMed1999

Steroid injection for heel pain: evidence of short-term effectiveness. A randomized controlled trial.

OBJECTIVES: To compare the effectiveness of a steroid injection (25 mg/ml prednisolone acetate) with a local anaesthetic control in the treatment of heel pain and to determine any advantage for patients' comfort of using a posterior tibial nerve block to anesthetize the heel prior to infiltration. METHODS: A double-blind randomized controlled trial using a 2 x 2 design in a hospital-based rheumatology clinic. Subjects comprised 106 patients with heel pain referred by general practitioners and other rheumatologists working in Camden and Islington Health Authority. MAIN OUTCOME MEASURES: heel pain reduction at 1, 3 and 6 months, and patient comfort at the time of injection. All outcomes were measured using a 10 cm visual analogue scale. RESULTS: A statistically significant reduction in pain was detected at 1 month (P=0.02) in favour of steroid injection, but thereafter no differences could be detected. Patient comfort was not significantly affected by anaesthesia of the heel (P=0.5). CONCLUSIONS: A steroid injection can provide relief from heel pain in the short term. There appears to be no increase in patient comfort from anaesthetizing the heel prior to infiltration.

Adult↗
PubMed1999

Bioequivalence study of two morphine extended release formulations after multiple dosing in healthy volunteers.

AIM: Two extended release (ER) formulations of morphine sulphate (30 mg each), Oramorph SR (test) and a marketed reference formulation (MST Mundipharma Retardtabletten), were investigated for their relative bioavailability at steady-state: METHODS: The study was designed as a single-centre, open-label, two-period crossover, pharmacokinetic comparison in 28 healthy male volunteers and was completed in 23 subjects. The determination of morphine and its metabolite morphine-6-glucuronide in plasma was done by HPLC with electrochemical detection after solid-phase extraction. RESULTS: Under steady-state conditions in the first dosing interval, mean maximum plasma concentrations for morphine were 19.1 ng/ml (CV% 41) for Oramorph SR 30 mg and 19.1 ng/ml (CV% 33) for MST-30 Mundipharma Retardtabletten. Geometric mean AUC(0-12) values were calculated as 108 ngxh/ml (CV% 40) for Oramorph SR 30 mg and as 118 ng x h/ml (CV% 30) for the reference formulation. The plasma concentrations of the major metabolite, morphine-6-glucuronide, were found to be generally in a higher range compared to the parent compound. The 90% confidence intervals of test to reference ratios calculated for all relevant parameters (AUC, C(max), PTF) for both the parent compound and morphine-6-glucuronide were all within the limits of 80 - 125%. The most frequent adverse events (AE > 10%) during Oramorph SR 30 mg treatment were headache (36%), dizziness (18%), nausea (21%), vomiting (21%) and pruritus (11%). During treatment with MST-30 Mundipharma Retardtabletten, the most frequent AEs were headache (29%), dizziness (13%), nausea (29%) and vomiting (29%). CONCLUSION: The results demonstrate bioequivalence of Oramorph SR 30 mg and MST-30 Mundipharma Retardtabletten.

Adolescent↗
PubMed1998

Soluble Alzheimers beta-amyloid constricts the cerebral vasculature in vivo.

Bilateral temporoparietal hypoperfusion has been frequently observed early in the Alzheimer's disease (AD) process. An increased beta-amyloid (Abeta) peptide is believed to play a central role in the pathogenesis of AD. In vitro experiments have shown that freshly solubilized Abeta enhances constriction of cerebral and peripheral vessels. We propose that in vivo the Abeta vasoactive property may contribute to cerebral hypoperfusion of AD patients. To test this hypothesis, we intra-arterially infused freshly solubilized Abeta -40 in rats and observed changes in cerebral blood flow and cerebrovascular resistance using fluorescent microspheres. We found that infusion of Abeta in vivo resulted in a decreased blood flow and increased vascular resistance specifically in cerebral cortex but not in heart or kidneys. These data suggest that Abeta has a direct and specific constrictive effect on cerebral vessels in vivo, which may contribute to the cerebral hypoperfusion observed early in the AD process.

Alzheimer Disease↗
PubMed1998

Alzheimer's beta-amyloid vasoactivity: identification of a novel beta-amyloid conformational intermediate.

The beta-amyloid (A beta) peptide has previously been shown to enhance phenylephrine or endothelin-1 induced constriction of aortic rings in vitro. The characteristics of A beta vasoactivity (dose, fragment length, timing) suggest that the mechanism is distinct from A beta cytotoxicity. To identify which properties of A beta determine its biological activity on vessels, we investigated a number of A beta analogues and fragments, individually and in combination, including those that are known to be associated with Alzheimer's disease (A beta(1-42)) and hereditary cerebral hemorrhage with amyloidosis--Dutch type (A beta(22Q)(1-40)). The vasoactivity appears to be related to the conformation adopted by the peptide in solution. The beta-pleated sheet rich A beta(1-42) and A beta(22Q)(1-40) were each less vasoactive than the mainly random coil wild type A beta(1-40). However, the most vasoactive A beta peptides were combinations which contain mixtures of random coil and beta-sheet structure. The finding that peptides containing low or high levels of beta-pleated conformation are less vasoactive than those containing intermediate amounts of this structural motif allows us to propose the existence of a transitional form between random coil and beta-pleated that is the vasoactive species of A beta. This is the first time that A beta conformational intermediates have been identified and a biological activity associated with them.

Amyloid beta-Peptides↗
PubMed1998

Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40.

Accumulating evidence suggests that beta-amyloid (Abeta)-induced inflammatory reactions may partially drive the pathogenesis of Alzheimer's disease (AD). Recent data also implicate similar inflammatory processes in cerebral amyloid angiopathy (CAA). To evaluate the roles of Abeta in the inflammatory processes in vascular tissues, we have tested the ability of Abeta to trigger inflammatory responses in cultured human vascular cells. We found that stimulation with Abeta dose-dependently increased the expression of CD40, and secretion of interferon-gamma (IFN-gamma) and interleukin-1beta (IL-1beta) in endothelial cells. Abeta also induced expression of IFN-gamma receptor (IFN-gammaR) both in endothelial and smooth muscle cells. Characterization of the Abeta-induced inflammatory responses in the vascular cells showed that the ligation of CD40 further increased cytokine production and/or the expression of IFN-gammaR. Moreover, IL-1beta and IFN-gamma synergistically increased the Abeta-induced expression of CD40 and IFN-gammaR. We have recently found that Abeta induces expression of adhesion molecules, and that cytokine production and interaction of CD40-CD40 ligand (CD40L) further increase the Abeta-induced expression of adhesion molecules in these same cells. These results suggest that Abeta can function as an inflammatory stimulator to activate vascular cells and induces an auto-amplified inflammatory molecular cascade, through interactions among adhesion molecules, CD40-CD40L and cytokines. Additionally, Abeta1-42, the more pathologic form of Abeta, induces much stronger effects in endothelial cells than in smooth muscle cells, while the reverse is true for Abeta1-40. Collectively, these findings support the hypothesis that the Abeta-induced inflammatory responses in vascular cells may play a significant role in the pathogenesis of CAA and AD.

Alzheimer Disease↗
PubMed1998

The -491A/T apolipoprotein E promoter polymorphism association with Alzheimer's disease: independent risk and linkage disequilibrium with the known APOE polymorphism.

The epsilon4 allele of the apolipoprotein E gene (APOE) has repeatedly been associated with increased risk for Alzheimer's disease (AD). Bullido and colleagues recently identified a polymorphism in the promoter region of the APOE gene (-491A/T) and found that -491A homozygosity predicted AD independently of APOE epsilon4. Since the -491A/T polymorphism and the known APOE polymorphism must be in tight linkage disequilibrium, and the later polymorphism is know to be associated with the disease, we wished to determine to what extent this linkage disequilibrium explained the -491A/T polymorphism association with Alzheimer's disease. We genotyped a community-based control sample (n = 132) and a clinic-based Alzheimer's disease sample (n = 190) for the known APOE and -491A/T polymorphisms, and find that, while the -491A/T polymorphism confers some independent risk for AD, linkage disequilibrium between the known APOE and -491A/T polymorphic sites explains most of the -491A association. Furthermore, when considering the known APOE and -491A/T polymorphisms alone, APOE epsilon4 status is the best predictor of the disease.

Aged↗
PubMed1998

The butyrylcholinesterase gene is neither independently nor synergistically associated with late-onset AD in clinic- and community-based populations.

The K variant of the butyrylcholinesterase gene (BChE) was recently found to occur at an increased frequency in a late onset Alzheimer's disease (AD) population, specifically in individuals carrying the epsilon4 allele of the apolipoprotein E (APOE) gene. This suggested synergy between these two genes resulting in an increased risk of late-onset AD. We have genotyped 62 community-based and 329 clinic-based AD cases, and 201 community-based controls at BChE and APOE and find no independent association between BChE and AD nor interaction with APOE in risk for AD in either our clinic or community-based samples.

Aged↗
PubMed1998

T cell positive selection by a high density, low affinity ligand.

Interaction of the alpha beta T cell receptor (TCR) with major histocompatibility (MHC) molecules occupied with any of a large collection of peptides derived from self proteins is a critical step in driving T cell "positive" selection in the thymus. Interaction with this same pool of self-peptide/MHC ligands deletes T cells with potential self-reactivity. To examine how T cells survive both of these processes to form a self-tolerant mature repertoire, mice were constructed whose entire class II MHC IEk specific repertoire was positively selected on a single peptide covalently attached to the IEk molecule. In these mice T cells were identified that could respond to a variant of the positively selecting peptide bound to IEk. The affinities of the TCRs from these T cells for the positively selecting ligand were extremely low and at least 10-fold less than those for the activating ligand. These results support the theory that positive selection is driven by TCR affinities lower than those involved in T cell deletion or activation and that, if present at high concentration, even very low affinity ligands can positively select.

Amino Acid Sequence↗
PubMed1998

Characteristics of the in vitro vasoactivity of beta-amyloid peptides.

The beta-amyloid (A beta 1-40) peptide has previously been shown to enhance phenylephrine contraction of aortic rings in vitro. We have employed a novel observation, that A beta peptides enhance endothelin-1 (ET-1) contraction, to examine the relationship between vasoactivity and potential amyloidogenicity of A beta peptides, the role played by free radicals and calcium in the vasoactive mechanism, and the requirement of an intact endothelial layer for enhancement of vasoactivity. Rings of rat aortae were constricted with ET-1 before and after addition of amyloid peptide and/or other compounds, and a comparison was made between post- and pre-treatment contractions. In this system, vessel constriction is consistently dramatically enhanced by A beta 1-40, is enhanced less so by A beta 1-42, and is not enhanced by A beta 25-35. The endothelium is not required for A beta vasoactivity, and calcium channel blockers have a greater effect than antioxidants in blocking enhancement of vasoconstriction by A beta peptides. In contrast to A beta-induced cytotoxicity, A beta-induced vasoactivity is immediate, occurs in response to low doses of freshly solubilized peptide, and appears to be inversely related to the amyloidogenic potential of the A beta peptides. We conclude that the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. Although free radicals appear to modulate the vasoactive effects, the lack of requirement for endothelium suggests that loss of the free radical balance (between NO and O2-) may be a secondary influence on A beta enhancement of vasoconstriction. These effects of A beta on isolated vessels, and reported effects of A beta in cells of the vasculature, suggest that A beta-induced disruption of vascular tone may be a factor in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Although the mechanism of enhanced vasoconstriction is unknown, it is reasonable to propose that in vivo contact of A beta peptides with small cerebral vessels may increase their tendency to constrict and oppose their tendency to relax. The subclinical ischemia resulting from this would be expected to up-regulate beta APP production in and around the vasculature with further increase in A beta formation and deposition. The disruptive and degenerative effects of such a cycle would lead to the complete destruction of cerebral vessels and consequently neuronal degeneration in the affected areas.

Alzheimer Disease↗
PubMed1998

Role of peroxynitrite in the vasoactive and cytotoxic effects of Alzheimer's beta-amyloid1-40 peptide.

Increasing evidence implicates oxidative stress as partially responsible for the neurodegenerative process of Alzheimer's disease (AD). Recent reports show an increased production of nitrotyrosine in AD brains, suggesting that peroxynitrite is produced in excess in this disease. Furthermore, incidence of cerebral amyloid angiopathy in AD cases is very frequent (83%), strongly suggesting a vascular component of AD pathogenesis. We have evaluated the hypothesis that peroxynitrite could be responsible for mediating the cytotoxicity and vasoactivity induced by the amyloid-beta1-40 (Abeta) peptide. Rat brain endothelial cells (RBE-4) appear to be sensitive to Abeta-induced toxicity but not to the cytotoxicity induced by peroxynitrite. Addition of Cu/Zn superoxide dismutase to cell culture media, which is only able to clear extracellular superoxide, was not effective in blocking Abeta-induced toxicity. However, we were able to partially block Abeta-induced cytotoxicity by using Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP) which dismutes superoxide intracellularily. Yet, MnTBAP was not able to prevent the vasoactivity triggered by Abeta. Moreover, addition of peroxynitrite to rat aortae did not modulate the vasotension induced by Abeta. We conclude that intracellular superoxide radicals may contribute to Abeta-induced cytotoxicity. Our results also indicate that peroxynitrite does not significantly contribute to Abeta-induced cytotoxicity in rat brain endothelial cells (RBE-4) or vasoactivity in rat aortae. These results suggest that therapeutic efforts aimed at removal of reactive oxygen species with SOD is unlikely to be beneficial for treatment of Abeta-induced endothelial dysfunction. However, compounds that clear free radicals intracellularly may well be beneficial.

Alzheimer Disease↗
PubMed1998

Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes.

Multimeric soluble MHC class II molecules stably occupied with covalently attached peptides bind with appropriate specificity to T cell hybridomas and T cells from T cell receptor transgenic mice. There is a direct correlation between soluble T cell receptor affinity for monomeric MHC/peptide and level of binding of multimeric MHC/peptide to T cells. While binding of the multimeric MHC/peptide complex is proportional to T cell receptor affinity and expression level, there is little influence of T cell CD4.

Amino Acid Sequence↗
PubMed1998

Crystal structure of mouse H2-M.

H2-M (HLA-DM in humans) resides in an acidic endosomal compartment, where it facilitates the loading of antigenic peptides into the peptide-binding groove of class II MHC. The crystal structure of a soluble form of H2-M has been solved to 3.1 A resolution, revealing a heterodimer with structural similarities to the MHC family of proteins. In contrast to its antigen-presenting cousins, the membrane distal alpha helices of H2-M pack closely together, occluding most of the binding groove except for a single large pocket near the center. The structure of H2-M has several unique features that may play a role in its function as a molecular chaperone and peptide exchange factor.

Amino Acid Sequence↗
PubMed1998

Evidence into practice, experimentation and quasi experimentation: are the methods up to the task?

OBJECTIVE: Methodological review of evaluations of interventions intended to help health professionals provide more effective and efficient health care, motivated by the current experience of NHS Research and Development in England. Emphasis upon the forms of research appropriate to different stages in the development and evaluation of interventions, the use of experimental and quasi experimental designs, the methods used in systematic reviews and meta analyses. METHOD: A proposed development process is derived from that used in the development of drugs. The strengths and weaknesses of different experimental and quasi experimental designs are derived from published methodological literature and first principles. Examples are drawn from the literature. RESULTS: Like pharmaceuticals, implementation interventions need to go through several stages of development before they are evaluated in designed experiments. Where there are practical reasons that make random allocation impossible in quantitative evaluations, quasi experimental methods may provide useful information, although these studies are open to bias. It is rare for a single study to provide a complete answer to important questions, and systematic reviews of all available studies should be undertaken. Meta analytic techniques go some way towards countering the low power of many existing studies, reduce the risk of bias, and avoid the subjective approaches that may be found in narrative reviews. CONCLUSIONS: The initiative taken by NHS Research and Development in examining methods to promote the uptake of research findings is welcome, but will only prove helpful if careful attention is paid to the different stages of the development process, and different research approaches are used appropriately at different stages.

Humans↗
PubMed1997

The vasoactivity of A beta peptides.

We have demonstrated that freshly solubilized A beta peptides can enhance vasoconstriction by phenylephrine or endothelin of isolated rat aorta. Concentrations of peptide producing these effects (100 nM-1 microM) are much lower than those requiring toxicity to endothelial cells in culture, and effects are immediate, not requiring the prolonged time periods for aggregation necessary in A beta cell culture toxicity experiments. Pre-treatment with SOD diminishes the enhancement of vasoconstriction by A beta peptides, suggesting that the effects are partly mediated via a decrease in the nitric oxide/superoxide ratio. Enhancement of endothelin vasoconstriction is observed with A beta 1-40 and A beta 1-42, but not with A beta 25-35 even at 5 microM, again suggesting the mechanism of A beta vasoactivity is distinct from that of A beta cytotoxicity. These observations raise the possibility that A beta peptides in contact with the cerebrovasculature could result in vasoconstriction, hypoperfusion and oxygen free radical imbalance contributing to the neurodegeneration of AD.

Amyloid beta-Peptides↗
PubMed1997

No association between the low density lipoprotein receptor-related protein (LRP) gene and late-onset Alzheimer's disease in a community-based sample.

It is now commonly known that possession of the epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for both familial and sporadic Alzheimer's disease (AD), in a dose-dependent way. Other genes that may play a role in AD, either through independent association with the disease or through modification of the existing APOE risk, have been reported with conflicting results. One such gene, the low density lipoprotein receptor-related protein (LRP) gene, was recently reported by two groups to be associated with AD, although the groups identified different risk-conferring alleles. Both studies were based on clinic-derived AD populations (one American, one French), and both reported only marginally significant results. We have genotyped a community-based AD and control population at this LRP polymorphism and find no association between the variants at that polymorphism and the occurrence of AD. Further, despite the biochemical relationship between LRP and the ApoE protein, we find no significant statistical interaction between the alleles at these loci.

Age of Onset↗
PubMed1997

APOE is linked to Alzheimer's disease in a large pedigree.

Although previous association studies have demonstrated that the APOE4 allele is a risk factor for Alzheimer's disease (AD), its value for the prediction of AD in individuals is <100%. The limited predictive value of epsilon4 is also seen in multiply affected families where the epsilon4 allele is not tightly linked to AD. We analyzed a large pedigree multiply affected with AD by lod score linkage analysis at the known loci associated with AD. In this pedigree, the APOE/APOCI gene area was linked to the development of AD, while no linkage was detected to any of the other loci known to be associated with the disease. In this family, then, the inheritance of an epsilon4 allele is highly associated with the early development of the disease (mean age of onset, 62 years), and is a good predictor of disease. However, given the wealth of evidence for association, but not linkage, of APOE4 to AD, we believe this finding suggests that another factor (or factors) interact(s) with APOE to precipitate early disease, and produce positive linkage results. The nature of this factor presently remains unknown.

Age of Onset↗