Unpredictable Sun leaves researchers in the dark.
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Comment↗
Biomedical subjects
David Hughes
Publications and source records attributed to David Hughes.
Modern agrochemical research: a missed opportunity for drug discovery?
The word "agrochemical" has often taken on a pejorative character in the public mind. Some of the negative tone might have coloured the perception of the industry by pharma, together with views on the chemical nature of agrochemicals that seem to be based on older pesticides that date back to the 1950s and 1960s. In this review, we try to address some of these concerns, draw out the similarities between agrochemical and pharmaceutical research and highlight opportunities for drug discovery that are offered by pesticide-related compounds, particularly with regard to herbicides and compounds with leadlike physical properties.
Agrochemicals↗
Monocyte matrix and ADAM metalloproteinase expression in type 2 diabetes after aspirin therapy.
The matrix metalloproteinase system (MMP and the TIMP inhibitors), and the ADAM metalloproteinases, have roles in maintaining vascular plaque stability and the shedding of cell surface molecules, such as TNF-alpha and adhesion molecules; aspirin suppresses MMP expression and ADAM activity from some cell lines in vitro. In a randomised prospective controlled study, we examined peripheral venous monocyte MMP-9, TIMP-1 and ADAM mRNA levels, and protein expression, in subjects with type 2 diabetes (n=10) and controls (n=14) before and after oral aspirin therapy (150mg daily for 14 days) or no active intervention. Baseline monocyte TIMP-1 mRNA levels were significantly lower in the diabetes group (p=0.0014), although monocyte MMP-9 mRNA, and MMP-9 and TIMP-1 protein expression after culture did not differ significantly between groups. Plasma MMP-9 (p=0.027) and TIMP-1 (p=0.016) concentrations were significantly greater, and the ratio of plasma TIMP-1:MMP-9 concentrations significantly lower, in the diabetes group (p=0.023). ADAM mRNA levels did not differ significantly between groups and oral aspirin therapy had no significant effect on any variable. Type 2 diabetes is characterised by reduced monocyte TIMP-1 mRNA levels, and a lower plasma MMP-9 to TIMP-1 protein ratio compared to controls, a pattern that would promote coronary plaque instability if reproduced within vascular plaque. Monocyte ADAM mRNA levels do not differ between group and oral aspirin has no significant effect on these variables.
ADAM Proteins↗
BAP1 and breast cancer risk.
BAP1 whose protein interacts with BRCA1 was analysed in a series of 47 French familial breast cancer cases negatively tested for BRCA1/2 mutations. The lack of detection of deleterious mutations suggests that BAP1 is not a high risk breast cancer predisposing gene. However, a common identified variant, rs123602, may be tested in sporadic cases as candidate for moderate risk.
Adult↗
When monomers are preferred: a strategy for the identification and disruption of weakly oligomerized proteins.
Oligomerization is important for the structure and function of many proteins, but frequently complicates their characterization. It is often desirable to obtain the protein in monomeric form. Here, we report a strategy that allows the generation of monomers from weakly associated oligomers but does not require knowledge of the three-dimensional structure of the protein. The dynamics of protein association are used in solution NMR spectroscopy to identify regions of the polypeptide chain that are likely to be responsible for the interaction. Protein sequence analysis further refines the selection, as conserved sites with moderate hydrophobicity are targeted for modification. Gel filtration and activity assays straightforwardly reveal the consequences of the change and are used to screen for the desired mutants. The strategy is demonstrated for the Rac1 binding domain of plexin-B1. A monomeric variant is generated which preserves the Rac1 binding activity and the wild-type protein structure.
Amino Acid Sequence↗
Challenging the representations of cancer pain: experiences of a multidisciplinary pain management group in a palliative care unit.
OBJECTIVE: This article describes how a Multidisciplinary Pain Management Group was set up in a palliative care unit, and outlines the ways that the group works with different patients. We place these comments in the context of the wider representations of pain. METHODS: Our observations of patients seen by the multidisciplinary team. RESULTS: We tentatively propose that where the patient's pain has certain characteristics it may require a different approach. Patients who are older, with a lengthy treatment history, may require a different input than younger patients, who may have a number of factors that further complicate their experience of pain. We use our extensive experience with mesothelioma patients to draw a further important distinction between this patient group and other patients. SIGNIFICANCE OF RESEARCH: Our observations suggest the need to allow sufficient time for intensive psychological work to be done with mesothelioma patients in order for pharmacological interventions to be effective.
Attitude of Health Personnel↗
IT-driven patient safety at the heart of radiology service improvement.
Patient safety is a fundamental requirement of modern health-care systems and the application of information technology (IT) to this activity should have improvements in the area as one of its goals. Indeed, ensuring that the diagnostic IT strategy is optimized, for example, the use of IT in service redesign or data analysis, forms one of the main platforms for the National Framework for Service Improvement in Radiology. This paper presents both the concept behind and the results of a project that has been under way in the UK involving St Helens and Knowsley NHS Trust and IRS Ltd concerned with implementing effective IT-driven scientific support in the field of medical radiation protection. Locally developed software is employed in assessing, managing, and analysing patient dose data arising from X-ray examinations performed in the busy department of a large district general hospital (DGH). Such data are analysed in a variety of ways, for example, over time and according to location (department or X-ray room). This analysis not only provides a measure of performance against nationally agreed dose reference levels (DRLs) but also enables a detailed analysis of any variations as well as the establishment of local DRLs (performance indicators). This process provides quantitative input to management strategies aimed at service improvement. Such strategies are geared towards the support of the Ionizing Radiations (Medical Exposures) Regulations 2000 as well as implementation of quality-management principles at the heart of radiology practices.
Cooperative Behavior↗
Four-year data after pediatric renal transplantation: a randomized trial of tacrolimus vs. cyclosporin microemulsion.
This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.
Adolescent↗
Staff reports of setting events associated with challenging behavior.
This study sought to identify the setting events reported by care staff as more and less likely to be associated with the challenging behaviors of people with intellectual disabilities. Sixty-five staff working with 22 individuals were interviewed using an inventory of putative setting events. Findings were collated to allow identification of those events reported to be associated with increased and decreased likelihood of challenging behavior. Some events were reported as strongly associated with the occurrence of challenging behavior, some as strongly associated with its absence, some as largely "inert," and many as idiosyncratically associated with occurrence, absence, or inertness. Different categories of setting events contributed different relative amounts to reported variation in challenging behavior. The use of the inventory described here, or modified versions, may be a useful way of identifying relationships between setting events and challenging behaviors, which suggest ways in which routine service provision might be modified to help prevent challenging behavior.
Adult↗
Preparation of colloidal gold probes.
This chapter describes the production of immunogold probes for use in immunocytochemistry at the light and electron microscope levels. The protocols provide sufficient detail to enable workers to produce immunogold probes in their own laboratories. Reagents and equipment required should be readily accessible in most modern immunochemistry facilities. The protocols include descriptions of gold sol production and subsequent gold labeling of probes such as antisera. The chapter notes give suggestions for the quality control of particle production, approaches for optimizing gold probe use, and details of the latest technological advances, such ultrasmall gold particle technology.
Animals↗
Immunogold probes in light microscopy.
Since their introduction 60 yr ago, immunolabeling procedures for use in light microscopy have become increasingly sophisticated, with greater levels of sensitivity and versatility. This chapter reviews the range of immunocytochemical procedures now available, discussing the attributes of each method that must be considered when choosing the most appropriate approach for the tissue target concerned. The immunogold silver staining technique is described in detail because the method has many advantages over rival labeling procedures, including its dual applicability at the light and electron microscope levels.
Animals↗
Resolution of temporal lobe epilepsy and MRI abnormalities after coiling of a cerebral aneurysm.
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Diagnosis, Differential↗
Demonstration of vertebral and disc mechanical torsion in adolescent idiopathic scoliosis using three-dimensional MR imaging.
This study was designed to demonstrate and measure mechanical torsion in patients with adolescent idiopathic scoliosis using three-dimensional magnetic resonance (MR) imaging. Ten patients with adolescent idiopathic scoliosis were imaged with three-dimensional MR imaging, and the data post-processed through multiplanar reconstruction to produce images angled through individual endplates. Transverse rotation was measured at each endplate and these measurements used to calculate the amount of vertebral and disc mechanical torsion present. A test object was imaged in order to validate the measurement technique. Mechanical torsion was demonstrated within the vertebral bodies and discs of the imaged subjects, with vertebral mechanical torsion contributing on average 45% of the overall transverse plane deformity. It is concluded that deformation occurs in the transverse plane within the vertebrae and discs of subjects with idiopathic scoliosis, and a significant proportion of the rotation present in the scoliotic spine occurs as a result of plastic deformation within the vertebrae themselves. We believe that this is the first systematic demonstration of mechanical torsion in idiopathic scoliosis.
Adolescent↗
A hypothetical anti-neoplastic mechanism associated to reserve cells.
Reserve-stem cells, the permanent cells of body tissues, are thought to be the progenitor cells of cancer. This concept originates from the assumption that accumulation of somatic mutations necessary for malignant transformation can only take place in cellular targets with a prolonged life span. The progeny of reserve cells entering the differentiative pathway would be protected from potential critical mutations happening later than the reserve cell stage by normal cell population replacement unless possible targets would escape the replacement process by further mutations extending the cell's life span, impairment of physiological apoptosis. The existence of a mechanism for maintenance of genetic integrity in stem/reserve cells has previously been proposed. This mechanism differs from already identified DNA repair systems and, potentially, could prevent malignant transformation at the reserve cell stage, counteracting the expected high propensity of stem/reserve cells to neoplastic proliferation. Here, we show some histopathological observations suggesting that an anti-cancer mechanism might be associated to reserve/stem cells and that it could be responsible for huge differences in cancer incidence between closely related body sites. Furthermore, primary impairment of this protective mechanism might characterize the oncogenic pathway responsible for tumors of primitive cells. Several features of the histopathological observations presented lead us to propose that the underlying molecular mechanism may involve the telomere complex.
Animals↗
6-azapyrimidine-2'-deoxy-4'-thionucleosides: antiviral agents against TK+ and TK- HSV and VZV strains.
The synthesis of a series of novel 1-(2-deoxy-4-thio-beta-D-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides is described. X-ray crystallographic data of the thymidine derivative allowed conformational analysis, which indicated a twist (3T2) sugar conformation. Hydrogen-bonded assemblies for the crystal structure were determined using PLATON software to allow further interpretation of the crystal packing and base interactions. The 6-azapyrimidine nucleosides described were evaluated against a range of viral strains. The thymidine analogue showed pronounced activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and vaccinia virus. This compound lost only 5- to 10-fold of its antiviral activity against thymidine kinase (TK)-deficient HSV-1 and VZV strains. These observations suggest that the compounds may not entirely depend on viral TK-catalyzed phosphorylation for antiviral activity and/or use an alternative metabolic activation pathway, and/or display a unique mechanism of antiviral action by the unmetabolized nucleoside analogue.
Animals↗
Mechanistic evidence for an alpha-oxoketene pathway in the formation of beta-ketoamides/esters via Meldrum's acid adducts.
A practical, one-pot process for the preparation of beta-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Meldrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of beta-keto amides from acyl Meldrum's acids occurs via alpha-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated alpha-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.
Journal Article↗
Acetyl-CoA carboxylase alpha gene and breast cancer susceptibility.
The identification of an interaction between BRCA1 and acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in lipid synthesis, led us to investigate the role of ACCalpha in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCalpha alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron-exon junctions, 5'UTR, 3'UTR (untranslated regions) and the promoter regions of the ACCalpha gene. Two possibly disease-associated ACCalpha variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCalpha coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACCalpha haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (odds ratio = 3.10, 95% confidence interval 1.87-5.14, P < 0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACCalpha gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCalpha alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCalpha gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCalpha in tumour susceptibility and development.
Acetyl-CoA Carboxylase↗
Fatal emphysematous gastritis in a 2-year-old child with chronic renal failure.
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Child, Preschool↗