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Biomedical subjects

D A Jones

Publications and source records attributed to D A Jones.

At least 91 records · Page 5Linked to original sources
PubMed1999

Homologues of the Cf-9 disease resistance gene (Hcr9s) are present at multiple loci on the short arm of tomato chromosome 1.

The tomato Cf-4 and Cf-9 genes map at a genetically complex locus on the short arm of chromosome 1 and confer resistance against Cladosporium fulvum through recognition of different pathogen-encoded avirulence determinants. Cf-4 and Cf-9 are members of a large gene family (Hcr9s, Homologues of Cladosporium fulvum resistance gene Cf-9), some of which encode additional distinct recognition specificities. A genetic analysis of the majority of Hcr9s suggests that their distribution is spatially restricted to the short arm of chromosome 1. Two loci of clustered Hcr9 genes have been analyzed physically that mapped distal (Northern Lights) and proximal (Southern Cross) to the Cf-4/9 locus (Milky Way). Sequence homologies between intergenic regions at Southern Cross and Milky Way indicate local Hcr9 duplication preceded cluster multiplication. The multiplication of clusters involved DNA flanking Hcr9 sequences as indicated by conserved lipoxygenase sequences at Southern Cross and Milky Way. The similar spatial distribution of Hcr9 clusters in different Lycopersicon spp. suggests Hcr9 cluster multiplication preceded speciation.

Base Sequence↗
PubMed1999

Avascular necrosis and the Aberdeen splint in developmental dysplasia of the hip.

Between January 1987 and December 1988 there were 7575 births in the Swansea maternity unit. Of these 823 (10.9%) were considered to be at 'high risk' for developmental dysplasia of the hip (DDH). Static ultrasound examination was performed in each case and the results classified on the basis of the method of Graf. A total of 117 type III-IV hips in 83 infants was splinted using the Aberdeen splint. Radiographs of these hips were taken at six and 12 months. Hilgenreiner's measurements of the acetabular angle were made in all cases and the development of the femoral capital epiphysis was assessed by measuring the epiphyseal area. The effect of splintage on the acetabular angle and the epiphyseal area between the normal and abnormal splinted hips was compared. Radiographs of 16 normal infants (32 normal unsplinted hips) were used as a control group. This cohort has now been followed up for a minimum of nine years. There have been no complications as a result of splintage. The failure rate was 1.7% or 0.25 per 1000 live births. No statistical difference was found when comparing the effect of splintage on the acetabular angle and epiphyseal area between normal and abnormal splinted hips and normal unsplinted hips. Our study has shown that while the Aberdeen splint had a definite but small failure rate, it was safe in that it did not produce avascular necrosis. The current conventional view that a low rate of splintage is always best is therefore brought into question if the Aberdeen splint is chosen for the management of neonatal DDH.

Acetabulum↗
PubMed1998

Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model.

Endotoxin (ET)-induced liver failure is characterized by parenchymal cell apoptosis and inflammation leading to liver cell necrosis. Members of the caspase family have been implicated in the signal transduction pathway of apoptosis. The aim of this study was to characterize ET-induced hepatic caspase activation and apoptosis and to investigate their effect on neutrophil-mediated liver injury. Treatment of C3Heb/FeJ mice with 700 mg/kg galactosamine (Gal) and 100 microg/kg Salmonella abortus equi ET increased caspase 3-like protease activity (Asp-Val-Glu-Asp-substrate) by 1730 +/- 140% at 6 h. There was a parallel enhancement of apoptosis (assessed by DNA fragmentation ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay). In contrast, activity of caspase 1 (IL-1beta-converting enzyme)-like proteases (Tyr-Val-Ala-Asp-substrate) did not change throughout the experiment. Caspase 3-like protease activity and apoptosis was not induced by Gal/ET in ET-resistant mice (C3H/HeJ). Furthermore, only murine TNF-alpha but not IL-1alphabeta increased caspase activity and apoptosis. Gal/ET caused neutrophil-dependent hepatocellular necrosis at 7 h (area of necrosis, 45 +/- 3%). Delayed treatment with the caspase 3-like protease inhibitor Z-Val-Ala-Asp-CH2F (Z-VAD) (10 mg/kg at 3 h) attenuated apoptosis by 81 to 88% and prevented liver cell necrosis (< or = 5%). Z-VAD had no effect on the initial inflammatory response, including the sequestration of neutrophils in sinusoids. However, Z-VAD prevented neutrophil transmigration and necrosis. Our data indicate that activation of the caspase 3 subfamily of cysteine proteases is critical for the development of parenchymal cell apoptosis. In addition, excessive hepatocellular apoptosis can be an important signal for transmigration of primed neutrophils sequestered in sinusoids.

Animals↗
PubMed1998

Shortening-induced force depression in human adductor pollicis muscle.

1. The effects of single isovelocity shortening contractions on force production of the electrically stimulated human adductor pollicis muscle were investigated in seven healthy male subjects. 2. Redeveloped isometric force immediately following isovelocity shortening was always depressed compared with the isometric force recorded at the same muscle length but without preceding shortening. The maximal isometric force deficit (FD) was (mean +/- S.E.M.) 37 +/- 2% after 38 deg of shortening at 6.1 deg s-1. 3. The FD was positively correlated with angular displacement (r2 > 0.98) and decreased with increasing velocity of the shortening step. Stimulation at 20 Hz instead of 50 Hz reduced absolute force levels during the contractions to about 73% and the FD was decreased to a similar extent. Eighty-nine per cent of the velocity-related variation in the FD could be explained by the absolute force levels during shortening. 4. FD was largely abolished by allowing the muscle to relax briefly (approximately 200 ms), a time probably too short for significant metabolic recovery. 5. At all but the highest velocities there was a linear decline in force during the latter part of the isovelocity shortening phase, suggesting that the mechanisms underlying FD were active during shortening. 6. Our results show that shortening-induced force deficit is a significant feature of human muscle working in situ and is proportional to the work done by the muscle-tendon complex. This finding has important implications for experimental studies of force-velocity relationships in the intact human.

Adult↗
PubMed1998

Why are so many food plants cyanogenic?

A disproportionately large number of the most important human food plants is cyanogenic. The accumulated research of numerous people working in several different disciplines now allows a tenable explanation for this observation. Cyanogenesis by plants is not only a surprisingly effective chemical defence against casual herbivores, but it is also easily overcome by careful pre-ingestion food processing, this latter skill being almost exclusive to humans. Moreover, humans have the physiological ability to detoxify cyanide satisfactorily, given an adequate protein diet. It appears that early in the domestication of crop plants the cyanogenic species would have been relatively free of pests and competitive herbivores, as well as having good nutritional qualities, and thus ideal candidates for cultivation by the first farmers.

Animals↗
PubMed1998

A flax transposon identified in two spontaneous mutant alleles of the L6 rust resistance gene.

Two spontaneous mutant alleles of the L6 flax rust resistance gene, 16-X3A and 16-X117, contain the same transposable element designated dLute (defective Linum usitatissimum transposable element). The element is 314 bp long, 70% AT-rich and, because it contains no extended open reading frame, is probably non-autonomous. It has 14 bp imperfect terminal inverted repeats related to those in the Ac family of plant transposons and, like Ac, causes 8 bp target site duplications upon insertion. Multiple copies of dLute-related sequences exist in the flax genome. Rust resistant revertants were recovered amongst the progeny of both mutants and reversion was associated with excision of dLute. Excision either restored the wild-type L6 sequence or was imprecise, leaving sequence alterations ('footprints') resulting in one to three amino acid alterations in the L6 protein. No phenotypic differences were discerned between plants containing the standard and revertant L6 alleles.

Alleles↗
PubMed1998

Transfusion-related acute lung injury (TRALI) following autologous stem cell transplant for relapsed acute myeloid leukaemia: a case report and review of the literature.

A fatal case of transfusion-related acute lung injury (TRALI) in a child post-autologous stem cell transplant for relapsed acute myeloid leukaemia is described. The implicated product was a single unit platelet concentrate containing anti-HLA A2 and granulocyte-specific anti-NA1 antibodies. The recipient typed as HLA A2/A2, NA1/NA1. This is the first reported case of TRALI following a transplant procedure for a haematological condition. It is also unusual in that the patient failed to make a full recovery and that two relevant leucocyte antibodies of clear specificity were identified in the donor plasma. The literature relating to the pathophysiology, clinical sequelae and management of TRALI is reviewed.

Acute Disease↗
PubMed1998

Ownership and use of assistive devices amongst older people in the community.

AIMS: To determine the ownership and use of various assistive devices by older people living at home. METHOD: A random sample of 1405 elderly people aged 65 years and over, in three health authorities, were asked about ownership and use of a number of disability aids, spectacles and hearing aids. RESULTS: 74% of respondents owned one or more aid, 97% had spectacles and 16% a hearing aid. The most commonly owned assistive devices were a non-slip bath mat (50%), a walking stick (24%) and a bath rail (21%). Many severely disabled people, however, had no aids. For example, 75% had no stair rail, 68% had no lavatory rail and 46% had no non-slip bath mat. Most of the equipment owned was used. Walking frames and wheelchairs were used more by those over 75, as were all bathroom and lavatory appliances. Gender influenced the use of some aids, with more women using their walking frames and bathroom rails than men. CONCLUSION: Our study confirms that ownership and use of aids varies with age, gender, living arrangements and disability. Very disabled people need but do not own certain basic and relatively inexpensive appliances. Community services currently aim to promote autonomy and independence in elderly people in the community. This may be facilitated and enhanced by provision of appropriate equipment and increasing awareness of the value of assistive devices among elderly people, informal carers and health- and social-care professionals. Knowledge of who owns and uses various items of equipment may help improve strategic planning.

Aged↗
PubMed1998

The tomato Cf-5 disease resistance gene and six homologs show pronounced allelic variation in leucine-rich repeat copy number.

The tomato Cf-2 and Cf-5 genes confer resistance to Cladosporium fulvum and map to a complex locus on chromosome 6. The Cf-5 gene has been isolated and is predicted to encode a largely extracytoplasmic protein containing 32 leucine-rich repeats (LRRs), resembling the previously isolated Cf-2 gene, which has 38 LRRs. Three haplotypes of this locus from Lycopersicon esculentum, L. pimpinellifolium, and L. esculentum var cerasiforme were compared, and five additional homologs of Cf-5 were sequenced. All share extensive sequence identity, particularly within the C-terminal portions of the predicted proteins. In striking contrast to the Cf-9 gene family, six of seven homologs in the Cf-2/Cf-5 gene family vary in LRR copy number, ranging from 25 to 38 LRRs. Cf-5 and one adjacent homolog differ by only two LRRs. Recombination events that vary the LRR copy number in this region could provide a mechanism for the generation of new specificities for recognition of different ligands. A recombination breakpoint between the Cf-2 and Cf-5 loci was fully characterized and shown to be intragenic.

Alleles↗
PubMed1998

Caspase activation in MCF7 cells responding to etoposide treatment.

Studies of the biochemical mechanisms evoked by conventional treatments for neoplastic diseases point to apoptosis as a key process for elimination of unwanted cells. Although the pathways through which chemotherapeutics promote cell death remain largely unknown, caspase proteases play a central role in the induction of apoptosis in response to a variety of stimuli including tumor necrosis factor, fas ligand, and growth factor deprivation. In this article, we demonstrate the induction of caspase protease activity in MCF7 human breast carcinoma cells exposed to the topoisomerase inhibitor, etoposide. Caspase protease activity was assessed by incubating cell lysates with the known caspase substrates, acetyl-L-aspartic-L-glutamic-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin or acetyl-L-tyrosyl-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin. We observed maximal cleavage of acetyl-L-aspartic-L-glutamic-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin within 6 hr following etoposide addition, a time that precedes cell death. In contrast, acetyl-L-tyrosyl-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin was resistant to cleavage activity. This substrate cleavage specificity implies that a caspase-3-like protease is activated in response to DNA damage. Consistent with the lysate protease activity, an intracellular marker of caspase activation, poly-ADP ribose polymerase (PARP), was cleaved in a concentration- and time-dependent manner after etoposide-treatment. PARP cleavage followed caspase activation and reached maximum cleavage between 12 and 16 hr. Incubation of the cells with the peptidic caspase inhibitor z-valine-alanine-asparagine-CH2F prevented caspase activation, inhibited PARP cleavage, and inhibited cell death. Thus, etoposide killing of MCF7 cells requires a caspase-3-like protease.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Modeling developmental changes in strength and aerobic power in children.

The present study examined two contrasting multilevel model structures to describe the developmental (longitudinal) changes in strength and aerobic power in children: 1) an additive polynomial structure and 2) a multiplicative structure with allometric body size components. On the basis of the maximum log-likelihood criterion, the multiplicative "allometric" model was shown to be superior to the additive polynomial model when fitted to the data from two published longitudinal studies and to provide more plausible solutions within and beyond the range of observations. The multilevel regression analysis of study 1 confirmed that aerobic power develops approximately in proportion to body mass, m1/3. The analyses from study 2 identified a significant increase in quadriceps and biceps strength, in proportion to body size, plus an additional contribution from age, centered at about peak height velocity (PHV). The positive "age" term for boys suggested that at PHV the boys were becoming stronger in the quadriceps and biceps in relation to their body size. In contrast, the girls' age term was either negligible (quadriceps) or negative (biceps), indicating that at PHV the girls' strength was developing in proportion to or, in the case of the biceps, was becoming weaker in relation to their body size.

Adolescent↗
PubMed1998

Molecular, genetic and physiological analysis of Cladosporium resistance gene function in tomato.

Characterization of the DNA sequence of 4 tomato leaf mould disease resistance genes (Cf-2, Cf-4, Cf-5 and Cf-9) leads to the prediction that they encode C-terminally membrane anchored glycopeptides with many extracytoplasmic leucine rich repeats (LRRs). The N terminal LRRs are variable between the Cf-genes, suggesting a role in specificity, and the C terminal LRRs are more conserved, suggesting a role in signal transduction. Genetic analysis has revealed several Rcr genes that are required for Cf-gene function; their isolation will help us understand how Cf-genes work. Cf-9 confers responsiveness to pathogen-encoded Avr9 peptide on introduction to tobacco. Tobacco suspension cultures carrying the Cf-9 gene produce reactive oxygen species in response to Avr9 peptide, whereas untransformed cultures do not. The significance of these observations is discussed.

Cladosporium↗
PubMed1997

Novel disease resistance specificities result from sequence exchange between tandemly repeated genes at the Cf-4/9 locus of tomato.

Tomato Cf genes confer resistance to C. fulvum, reside in complex loci carrying multiple genes, and encode predicted membrane-bound proteins with extracytoplasmic leucine-rich repeats. At least two Cf-9 homologs confer novel C. fulvum resistance specificities. Comparison of 11 genes revealed 7 hypervariable amino acid positions in a motif of the leucine-rich repeats predicted to form a beta-strand/beta-turn in which the hypervariable residues are solvent exposed and potentially contribute to recognition specificity. Higher nonsynonymous than synonymous substitution rates in this region imply selection for sequence diversification. We propose that the level of polymorphism between intergenic regions determines the frequency of sequence exchange between the tandemly repeated genes. This permits sufficient exchange to generate sequence diversity but prevents sequence homogenization.

Amino Acid Sequence↗
PubMed1997

Phosphorylation of growth factor receptor binding protein-2 by pp60c-src tyrosine kinase.

Growth factor receptor binding protein-2 (GRB2) couples growth factor receptor activation to the p21-ras nucleotide exchange factor son-of-sevenless. Both GRB2 and son-of-sevenless display phosphorylation in cells treated with growth factors and may be subject to feed back regulation in mitogen-stimulated cells. Herein, we demonstrate that pp60c-src can utilize GRB2 as a substrate. NIH 3T3 fibroblasts overexpressing pp60v-src contained high levels of phosphorylated GRB2. In comparison, control fibroblasts contained phosphorylated GRB2 only after stimulation with platelet-derived growth factor. Analysis of GRB2 immune complexes isolated from fibroblasts stimulated with PDGF or transformed by pp60v-src revealed a kinase activity capable of phosphorylating GRB2 in vitro. Incubation of native or recombinant GRB2 with purified pp60c-src provided additional support for pp60c-src as the kinase for GRB2. Deletion mutants of GRB2 demonstrated that pp60c-src phosphorylated GRB2 on a tyrosine residue (residue 160) located between the SH2 domain and carboxyl terminal SH3 domain. Mutation of tyrosine 160 to phenylalanine abolished phosphorylation of GRB2 by pp60c-src. We conclude that Src finds GRB2 a suitable substrate in vitro and may phosphorylate GRB2 in cells responding to platelet-derived growth factor.

3T3 Cells↗
PubMed1997

Processing of [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P in xenograft bearing Nu/Nu mice.

[D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P is a broad-spectrum neuropeptide growth factor antagonist that has exhibited in vitro activity against a range of human cancer cell lines. The fate of this compound in vivo following i.p. administration at 12 micrograms/g to nu/nu mice bearing the H69 small-cell lung cancer xenograft has been studied. Metabolism was confined to the C-terminus producing [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P acid and [D-Arg1,D-Phe5,D-Trp7,9]substance P(1-10). The peptide had a long half-life in plasma (45.9 min) and became widely distributed among the tissues studied with the highest accumulation observed in the liver (AUC 1102 micrograms/g x min) and the lowest in the brain (5 micrograms/g x min). Uptake into the tumor xenograft was poor (AUC 189 micrograms/g x min); however, uptake into the lungs was much greater (AUC 507 micrograms/g x min), offering encouragement that therapeutic concentrations may be targeted to primary lung tumors.

Animals↗
PubMed1997

The cortisol response to psychological stress in temporomandibular dysfunction.

The salivary cortisol response to psychological stress and its relationship to psychological variables was examined in 36 female temporomandibular dysfunction (TMD) sufferers and 39 female control participants. Saliva samples were taken at baseline, after completion of a modified version of the Trier Social Stress Test, and after rest. Participants also completed a battery of measures, including Visual Analog Scales for measuring pain intensity and disability and a number of established psychological scales. The TMD group showed a significantly higher cortisol response to experimental stress than the control group. Closer examination of the data revealed that the TMD group was heterogeneous and composed of a group that hypersecreted cortisol in response to stress (Hi-SC TMD group) and another group whose cortisol response was not significantly different from the control group (Lo-SC TMD group). The Lo-SC TMD group showed significant negative relationships between cortisol response and self-reported symptoms of both anxiety and depression, plus significantly more use of the Praying or Hoping coping strategy on the Coping Strategies Questionnaire. A dual relationship between TMD symptoms and the stress response is proposed. First, a biological predisposition to TMD is suggested by the stress response in the Hi-SC TMD group. Second, both psychological and biological variables appear to be important factors in those TMD patients who respond to stress with low cortisol secretion.

Adaptation, Psychological↗
PubMed1997

Preclinical studies on the broad-spectrum neuropeptide growth factor antagonist G.

1. Antagonist G is a broad-spectrum neuropeptide growth factor antagonist that inhibits the growth of small cell lung cancer (SCLC) cells both in vitro and in vivo. 2. Antagonist G is metabolized in peripheral tissues by a chymotrypsin-like serine carboxypeptidase causing C-terminal deamidation and removal of the methionine residue. 3. The metabolites of Antagonist G retain neuropeptide antagonist properties and are thought to contribute to the parent peptide's antitumor activity. 4. Pharmacokinetic studies following systemic (IP) administration to nude mice revealed that the tissue distribution of Antagonist G is likely to be determined by vascular permeability. 5. Preclinical toxicology studies have been completed, and we have now started a phase I clinical trial.

Animals↗