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Biomedical subjects

J Mundy

Publications and source records attributed to J Mundy.

At least 19 recordsLinked to original sources
PubMed2006

The imaginary line method is not reliable for identification of prosthetic heart valves on AP chest radiographs.

OBJECTIVE: To examine the utility of four criteria for distinguishing aortic from mitral valve prostheses on supine anteroposterior (AP) chest x rays in critically ill patients. MATERIALS AND METHODS: Two reviewers independently examined the post operative chest X-rays (CXR) of all patients undergoing either an aortic or mitral valve replacement over a 32 month period, in a blinded fashion. They applied four criteria to each film. For each criterion a sensitivity and specificity of differentiating the valve positions correctly was calculated for each reviewer, as well as a kappa statistic for inter-observer agreement between the two reviewers. RESULTS: Two hundred and twenty seven CXR's were evaluated by each of the reviewers. There were 174 aortic and 53 mitral valve replacements. There was a high level of inter-observer agreement for all four criteria applied (kappa values 0.785 to 0.966). Criterion one (imaginary line method) could be applied by both reviewers to less than 50% of CXR's, and when applied was specific but not sensitive. The other three criteria could be applied by both reviewers to approximately 80% of films. Criterion 2 (orientation method) was sensitive but not specific. Criteria 3 (valve orifice method) and 4 (perceived direction of blood flow method) were both highly sensitive and specific and are therefore the best methods. CONCLUSIONS: The well known imaginary line method is of limited value when identifying prosthetic valve positions on supine AP CXR's. We advocate the use of the "valve orifice" method or the "perceived direction of blood flow" method to gain valuable information regarding the presence and position of prosthetic heart valves.

Aortic Valve↗
PubMed2005

Functional and prognostic implications of left ventricular contractile reserve in patients with asymptomatic severe mitral regurgitation.

OBJECTIVE: To evaluate contractile reserve (CR) determined by exercise echocardiography in predicting clinical outcome and left ventricular (LV) function in asymptomatic severe mitral regurgitation (MR). DESIGN: Cohort study. SETTING: Regional cardiac centre. PATIENTS AND OUTCOME MEASURES: LV volumes and ejection fraction (EF) were measured at rest and after stress in 71 patients with isolated MR. During follow up (mean (SD) 3 (1) years), EF and functional capacity were serially assessed and cardiac events (cardiac death, heart failure, and new atrial fibrillation) were documented. RESULTS: CR was present in 45 patients (CR+) and absent in 26 patients (CR-). Age, resting LV dimensions, EF, and MR severity were similar in both groups. Mitral surgery was performed in 19 of 45 (42%) CR+ patients and 22 of 26 (85%) CR- patients. In patients undergoing surgery, CR was an independent predictor of follow up EF (p = 0.006) and postoperative LV dysfunction (EF < 50%) persisted in five patients, all in the CR- group. Event-free survival was lower in surgically treated patients without CR (p = 0.03). In medically treated patients, follow up EF was preserved in those with intact CR but progressively deteriorated in patients without CR, in whom functional capacity also deteriorated. CONCLUSIONS: Evaluation of CR by exercise echocardiography may be useful for risk stratification and may help to optimise the timing of surgery in asymptomatic severe MR.

Chronic Disease↗
PubMed2001

Two differentially regulated Arabidopsis genes define a new branch of the DFR superfamily.

Two tandem genes were identified on Arabidopsis chromosome II (AtCRL1 and AtCRL2) encoding proteins with homology to members of the dihydroflavonol-4-reductase (DFR) superfamily. The encoded CRL1 and CRL2 proteins share 87% mutual amino acid sequence identity whereas their promoter regions are highly divergent, suggesting differential regulation of the CRL genes. Phylogenetic analysis placed CRL1 and CRL2 in a separate branch of the DFR superfamily. Northern blotting showed strong AtCRL1 induction by abscisic acid (ABA), drought, and heat shock, and high expression level in seeds, thus resembling the expression pattern of late embryogenic abundant ABA-responsive genes. Differential expression of the two genes during plant development was confirmed in plants expressing transcriptional fusions between the two promoters and the Escherichia coli beta-glucuronidase reporter gene. This showed that, whereas high expression of AtCRL1 in mature seeds declines during subsequent vegetative growth, transcriptional activity from the AtCRL2 promoter increases during vegetative growth. Expression of both genes is restricted to vascular tissue. Based upon their homology to proteins involved in lignin synthesis, we propose that AtCRL2 is involved in generating conducting tissue late in development, while AtCRL1 is involved in vascular tissue differentiation and/or synthesis in the germinating embryos.

Journal Article↗
PubMed2001

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases.

The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration. The short half-life of the tracer and its availability from a 62Zn/62Cu generator enabled short-interval repeat PET scans on patients in a single imaging session. Distribution of tracer within the liver was imaged in a single view using a PET camera with rotating large-area detectors. By optimisation of the acquisition protocol, it was possible to acquire sufficient data to produce good-quality images and to quantify tracer uptake with an accuracy of <10%. Reproducibility of the imaging method was assessed in a single patient in whom three consecutive 62Cu-PTSM PET scans were obtained, and in whom no vascular manipulation was performed. Sets of scans (before, during and immediately after a 45-min AII infusion) were obtained in nine patients to assess blood flow changes associated with prolonged vascular manipulation. Significant individual responses, varying in both the magnitude and the duration of flow change, were observed in the majority of cases (7/11 lesions; 7/9 patients). These findings illustrate the potential of 62Cu-PTSM and PET for pharmacological studies. The wide range of individual patient responses to AII infusion suggests that PET blood flow assessment would be of value for selecting patients in whom this procedure may be effective.

Algorithms↗
PubMed2001

A recombinase-mediated transcriptional induction system in transgenic plants.

We constructed and tested a Cre-loxP recombination-mediated vector system termed pCrox for use in transgenic plants. In this system, treatment of Arabidopsis under inducing conditions mediates an excision event that removes an intervening piece of DNA between a promoter and the gene to be expressed. The system developed here uses a heat-shock-inducible Cre to excise a DNA fragment flanked by lox sites, thereby generating a constitutive GUS reporter gene under control of the CaMV 35S promoter. Heat-shock-mediated excision of several, independent lines resulted in varying degrees of recombination-mediated GUS activation. Induction was shown to be possible at essentially any stage of plant growth. This single vector system circumvents the need for genetic crosses required by other, dual recombinase vector systems. The pCrox system may prove particularly useful in instances where transgene over-expression, or under-expression by antisense, would otherwise affect embryo, seed or seedling viability.

Acetyltransferases↗
PubMed2001

Gibberellin response mutants identified by luciferase imaging.

The gibberellin (GA) 20-oxidase encoded by Arabidopsis GA5 catalyzes the synthesis of active GAs. GA5 is a regulatory step in GA biosynthesis as GA5 mRNA levels are negatively regulated by its bioactive GA products. A fusion between the GA5 promoter and the firefly luciferase reporter (GA5-LUC) was shown to be similarly regulated, indicating GA feedback of GA5 occurs at the transcriptional level. The fidelity of the GA5-LUC reporter permitted a fusion genetic screen to identify mutants altered in transgene expression. This bioimaging screen identified two types of recessive mutants with increased LUC activity and apparent GA-related growth phenotypes, a dwarf (lue1) and two late flowering mutants (fpa1-3 and fpa1-4). Mutant progeny exhibited altered levels of LUC and of endogenous GA5 and other GA-regulated mRNAs. SSLP-based mapping localized lue1 to chromosome I near the ga2 locus, although complementation analyzes showed that lue1 is not allelic to ga2. Mapping and complementation analyzes showed that the late flowering mutants are allelic to fpa1. This provides genetic evidence for crosstalk between the autonomous and gibberellin-dependent flowering pathways.

Arabidopsis↗
PubMed2001

A magnetic resonance study of complicated early childhood convulsion.

OBJECTIVES: The relation between complicated early childhood convulsion (ECC) and adult epilepsy is unclear, although a history of complicated ECC is obtainable in half of adults with epilepsy associated with hippocampal sclerosis. It is not known if the ECC is a marker of pre-existing brain damage or is itself harmful to the developing brain. The objective of the study was to assess the extent of structural brain abnormality present soon after a first complicated early childhood convulsion with a view to obtaining data which might contribute to an understanding of whether such abnormalities were likely to be pre-existing or caused by the convulsion. METHODS: Children under the age of 5 years were recruited into the study after their first complicated febrile or non-febrile ECC. None had previously experienced an epileptic seizure. All underwent MRI of the brain within 14 days. Hippocampal volumes and T2 relaxation times were measured. The results were compared with a neurological control group of children without gross structural abnormalities of the neocortex undergoing MRI of the brain for reasons other than epilepsy. RESULTS: Eighteen patients and 10 control subjects were recruited into the study. One patient was subsequently excluded because of EEG and clinical evidence of benign childhood epilepsy. Nine patients had volumetric evidence of significant hippocampal volume asymmetry (3 SD from the mean of the control group), although in only three of these was the asymmetry apparent on visual inspection of the MRI. Three patients had extrahippocampal neuropathology. None of the control subjects had significant hippocampal volume asymmetry (p<0.001). T2 relaxometry showed no evidence that postictal hippocampal oedema contributed to the asymmetry. CONCLUSIONS: There is a high prevalence of structural brain abnormalities in children within 2 weeks of the first complicated early childhood convulsion, including significant hippocampal asymmetry unrelated to oedema. This does not exclude a damaging effect of complicated ECC on the brain, but suggests that in at least some patients the complicated ECC is the result of pre-existing brain abnormalities.

Brain↗
PubMed2001

Control of specific gene expression by gibberellin and brassinosteroid.

We identified a recessive, brassinolide-insensitive mutant caused by a deletion allele (bri1-201) of the brassinosteroid (BR) receptor BRI1. The bri1-201 mutant displayed altered expression levels of genes differentially regulated by gibberellin (GA). RNA-blot analysis revealed that BR and GA antagonistically regulate the accumulation of mRNAs of the GA-responsive GASA1 gene, as well as the GA-repressible GA5 gene. Expression studies with cycloheximide indicated that the antagonistic effects of GA and BR on GA5 require de novo protein synthesis. Reporter transgene analyses and RNA-blot analysis showed that BR and GA modulate GA5 expression, at least in part, at the transcriptional level, and that the signals are independent and subtractive.

Arabidopsis↗
PubMed2000

Arabidopsis map kinase 4 negatively regulates systemic acquired resistance.

Transposon inactivation of Arabidopsis MAP kinase 4 produced the mpk4 mutant exhibiting constitutive systemic acquired resistance (SAR) including elevated salicylic acid (SA) levels, increased resistance to virulent pathogens, and constitutive pathogenesis-related gene expression shown by Northern and microarray hybridizations. MPK4 kinase activity is required to repress SAR, as an inactive MPK4 form failed to complement mpk4. Analysis of mpk4 expressing the SA hydroxylase NahG and of mpk4/npr1 double mutants indicated that SAR expression in mpk4 is dependent upon elevated SA levels but is independent of NPR1. PDF1.2 and THI2.1 gene induction by jasmonate was blocked in mpk4 expressing NahG, suggesting that MPK4 is required for jasmonic acid-responsive gene expression.

Alleles↗
PubMed2000

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.

Cholesterol, HDL↗
PubMed2000

Arabidopsis ATP A2 peroxidase. Expression and high-resolution structure of a plant peroxidase with implications for lignification.

Lignins are phenolic biopolymers synthesized by terrestrial, vascular plants for mechanical support and in response to pathogen attack. Peroxidases have been proposed to catalyse the dehydrogenative polymerization of monolignols into lignins, although no specific isoenzyme has been shown to be involved in lignin biosynthesis. Recently we isolated an extracellular anionic peroxidase, ATP A2, from rapidly lignifying Arabidopsis cell suspension culture and cloned its cDNA. Here we show that the Atp A2 promoter directs GUS reporter gene expression in lignified tissues of transgenic plants. Moreover, an Arabidopsis mutant with increased lignin levels compared to wild type shows increased levels of ATP A2 mRNA and of a mRNA encoding an enzyme upstream in the lignin biosynthetic pathway. The substrate specificity of ATP A2 was analysed by X-ray crystallography and docking of lignin precursors. The structure of ATP A2 was solved to 1.45 A resolution at 100 K. Docking of p-coumaryl, coniferyl and sinapyl alcohol in the substrate binding site of ATP A2 were analysed on the basis of the crystal structure of a horseradish peroxidase C-CN-ferulic acid complex. The analysis indicates that the precursors p-coumaryl and coniferyl alcohols are preferred by ATP A2, while the oxidation of sinapyl alcohol will be sterically hindered in ATP A2 as well as in all other plant peroxidases due to an overlap with the conserved Pro-139. We suggest ATP A2 is involved in a complex regulation of the covalent cross-linking in the plant cell wall.

Arabidopsis↗
PubMed2000

Promiscuous and specific phospholipid binding by domains in ZAC, a membrane-associated Arabidopsis protein with an ARF GAP zinc finger and a C2 domain.

Arabidopsis proteins were predicted which share an 80 residue zinc finger domain known from ADP-ribosylation factor GTPase-activating proteins (ARF GAPs). One of these is a 37 kDa protein, designated ZAC, which has a novel domain structure in which the N-terminal ARF GAP domain and a C-terminal C2 domain are separated by a region without homology to other known proteins. Zac promoter/beta-glucuronidase reporter assays revealed highest expression levels in flowering tissue, rosettes and roots. ZAC protein was immuno-detected mainly in association with membranes and fractionated with Golgi and plasma membrane marker proteins. ZAC membrane association was confirmed in assays by a fusion between ZAC and the green fluorescence protein and prompted an analysis of the in vitro phospholipid-binding ability of ZAC. Phospholipid dot-blot and liposome-binding assays indicated that fusion proteins containing the ZAC-C2 domain bind anionic phospholipids non-specifically, with some variance in Ca2+ and salt dependence. Similar assays demonstrated specific affinity of the ZAC N-terminal region (residues 1-174) for phosphatidylinositol 3-monophosphate (PI-3-P). Binding was dependent in part on an intact zinc finger motif, but proteins containing only the zinc finger domain (residues 1-105) did not bind PI-3-P. Recombinant ZAC possessed GTPase-activating activity on Arabidopsis ARF proteins. These data identify a novel PI-3-P-binding protein region and thereby provide evidence that this phosphoinositide is recognized as a signal in plants. A role for ZAC in the regulation of ARF-mediated vesicular transport in plants is discussed.

ADP-Ribosylation Factors↗
PubMed2000

Caleosins: Ca2+-binding proteins associated with lipid bodies.

We have previously identified a rice gene encoding a 27 kDa protein with a single Ca2+-binding EF-hand and a putative membrane anchor. We report here similar genes termed caleosins, CLO, in other plants and fungi; they comprise a multigene family of at least five members in Arabidopsis (AtClo1-5). Northern hybridization demonstrated that AtClo2-4 mRNAs levels were low in various tissues, while AtClo1 mRNA levels were high in developing embryos and mature seeds. Analysis of transgenic Arabidopsis plants expressing the GUS reporter under control of the AtClo1 promoter showed strong levels of expression in developing embryos and also in root tip cells. Antibodies raised against AtCLO1 were used to detect caleosin in cellular fractions of Arabidopsis and rapeseed. This indicated that caleosins are a novel class of lipid body proteins, which may also be associated with an ER subdomain.

Abscisic Acid↗
PubMed2000

Fusion genetic analysis of gibberellin signaling mutants.

A fusion genetic strategy was used to identify gibberellin (GA) signaling mutants in transgenic Arabidopsis expressing the beta-glucuronidase (GUS) and firefly luciferase (LUC) reporter genes under control of the GA-responsive GASA1 promoter. Initial analyses determined the spatial and temporal patterns of reporter expression, and showed that reporter induction by GA was antagonized by ABA. gamma-Irradiated M2 progeny with altered reporter activities were identified by LUC bioimaging followed by GUS assays and northern hybridization of the endogenous GASA1 mRNA. Genetic analysis showed that three mutants, which overexpressed both reporters and endogenous GASA1, were caused by recessive (goe1 and goe2, for GASA over-expressed) and semi-dominant (goe3) mutations at different loci. These mutants are altered in their sensitivity to GA and the GA biosynthetic inhibitor paclobutrazol, and in the expression of several GA signaling related genes.

Base Sequence↗
PubMed1999

Target genes and regulatory domains of the GAMYB transcriptional activator in cereal aleurone.

GAMYB is an MYB transcription factor which is expressed in cereal aleurone cells in response to gibberellin (GA). HvGAMYB binds to the TAACAAA box of a high-pl alpha-amylase gene promoter and transcriptionally activates its expression. In this study, we examined the role of HvGAMYB in activating expression of other GA-regulated genes encoding hydrolytic enzymes. In transient expression experiments, HvGAMYB transactivated expression of reporter genes fused to a low-pl alpha-amylase gene promoter, an EII (1-3, 1-4)-beta-glucanase gene promoter and a cathepsin B-like protease promoter. HvGAMYB DNA binding specificity was determined using a PCR-based random site selection using HvGAMYB fusion protein isolated from E. coli. The deduced consensus closely resembled gibberellin response elements in alpha-amylase promoters. Functional analysis of HvGAMYB by transient expression of C terminal HvGAMYB deletions in barley aleurone cells identified two transcriptional activation domains (TADs) which function in transcriptional regulation of both high- and low-pl alpha-amylase promoters. The same TADs were identified using a heterologous yeast expression system. Together, these results indicate that HvGAMYB has two TADs. These domains are C-terminal to its DNA-binding domain.

Base Sequence↗
PubMed1999

A bacterial haloalkane dehalogenase gene as a negative selectable marker in Arabidopsis.

The dhlA gene of Xanthobacter autotrophicus GJ10 encodes a dehalogenase which hydrolyzes dihalo- alkanes, such as 1, 2-dichloroethane (DCE), to a halogenated alcohol and an inorganic halide (Janssen et al. 1994, Annu. Rev. Microbiol. 48, 163-191). In Xanthobacter, these alcohols are further catabolized by alcohol and aldehyde dehydrogenase activities, and by the product of the dhlB gene to a second halide and a hydroxyacid. The intermediate halogenated alcohols and, in particular, the aldehydes are more toxic than the haloalkane substrates or the pathway products. We show here that plants, including Arabidopsis, tobacco, oil seed rape and rice, do not express detectable haloalkane dehalogenase activities, and that wild-type Arabidopsis grows in the presence of DCE. In contrast, DCE applied as a volatile can be used to select on plates or in soil transgenic Arabidopsis which express dhlA. The dhlA marker therefore provides haloalkane dehalogenase reporter activity and substrate dependent negative selection in transgenic plants.

Arabidopsis↗
PubMed1999

Thyroglobulin antibodies in differentiated thyroid cancer.

A retrospective review of patients with differentiated thyroid cancer (DTC) who were seen between 1984 and 1996 at the Royal Marsden Hospital identified 40 patients with serum thyroglobulin antibodies (TgAb). These antibodies can interfere with the immunoradiometric assay for serum thyroglobulin (Tg) used at this hospital, with resulting underestimation of the Tg level. A review of the case notes was carried out to ascertain the clinical significance of TgAb. The median follow-up from diagnosis of DTC was 26 months (range 3-401). The median age at diagnosis of DTC was 50 years (range 13-83). Patients were grouped according to the TgAb titre (high titre: TgAb >1/100, n = 28; low titre TgAb <1/100, n = 12). Thirteen patients relapsed, 11 in the high titre group and two in the low titre group. Sites of recurrence were: neck (n = 9), lung (n = 5), bone (n = 4) and brain (n = 2). No patient in the high titre group showed an elevated Tg with recurrence. One patient in the low titre group showed a Tg response to recurrence. Overall, the Tg assay failed to detect 92% of recurrences. Eight patients in the high titre group developed TgAb, apparently in response to tumour progression. In a third patient in the low titre group, the TgAb also acted as a 'tumour marker'. Thus, overall TgAb acted as a tumour marker in nine of the 40 (22.5%) patients in whom it was detected, and in nine of the 470 (1.9%) patients on follow-up during this time period. The overall survival of the whole group was 69% at 10 years. For patients with papillary carcinoma (n = 34) overall survival was 78% at 10 years. Laboratories should report routinely the presence of TgAb, with a caution indicating the direction of possible error (which depends on the assay used). Clinicians should appreciate that Tg measurements are unreliable in the presence of TgAb and that the development of TgAb can indicate active tumour.

Adenocarcinoma, Follicular↗