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Biomedical subjects

J A Dent

Publications and source records attributed to J A Dent.

At least 19 recordsLinked to original sources
PubMed2006

Dorsal capsulodesis for scapholunate instability--effect on patient disability and wrist pain.

Twenty cases of scapho-lunate instability have been reviewed, to determine the effect of dorsal capsulodesis on disability and wrist pain. The average follow-up was 41 (range 13-63) months. There was a significant improvement in the pre-operative Patient Rated Wrist Evaluation score from 108 (range 18-150) to a postoperative score of 60 (range 0-132). All wrist movements and grip strength were reduced postoperatively but only the reductions in flexion and radial deviation were statistically significant. Seventeen (85%) patients were satisfied with the operation. One patient remained unemployed after surgery. Five patients returned to their normal jobs. This study shows that dorsal capsulodesis should remain an important option in the treatment of scapholunate instability.

Adolescent↗
PubMed2006

What to do about medical students with unsatisfactory consultation skills?

If it is accepted that new doctors must be 'Fit to Practice' in a standard clinical house job, they should be competent in basic communication skills. Although these skills may be assessed as part of a routine OSCE-style exam in the course of the curriculum, the question is raised whether students who fail to demonstrate a minimal level of competence in this area should to be allowed to progress to the next stage of the course and eventually graduate. This paper describes our experiences with introducing 'barrier' stations in communication skills into the OSCE. Students who failed these stations, irrespective of their overall exam performance, undertook remedial studies in a compulsory two-week directed study module followed by a four-station OSCE.

Clinical Competence↗
PubMed2006

Platelet septin complexes form rings and associate with the microtubular network.

BACKGROUND: Septins are important effectors in molecular mechanisms involving membrane partitioning. To date, a growing repertoire of septins in mammals includes 13 different proteins (SEPT1 to SEPT13) that can be classified into four distinct categories based on sequence similarity. AIM: In this study, we document the human platelet septin, SEPT5, as part of a complex composed of multiple septin proteins. RESULTS: Biochemical and immunofluorescent data place the majority of these complexes in the platelet periphery as part of the platelet circumferential band copurifying with the platelet microtubule coil and tubulin. The presence of a prominent platelet septin ring in resting platelets appears to be left intact in the activated platelet, as a similar ring structure is observed following platelet spreading on fibrinogen. The ablation of SEPT5 in the knock-out mouse model had previously been reported to result in a platelet phenotype with aggregation using subthreshold levels of agonist. Speculation on the role of SEPT5 in the platelet-release reaction suggested that SEPT5 regulates platelet function by association with platelet storage granules. We now report that the absence of SEPT5 results in increased ATP release from stimulated platelets. CONCLUSION: These studies document the presence of platelet septin complexes and validate the importance of septins for platelet physiology.

Adenosine Triphosphate↗
PubMed2000

Modeling and functional analysis of the interaction between von Willebrand factor A1 domain and glycoprotein Ibalpha.

Binding of the von Willebrand factor (vWF) A1 domain to the glycoprotein (GP) Ib-IX-V complex mediates platelet adhesion to reactive substrates under high shear stress conditions, a key event in hemostasis and thrombosis. We have now used the known three-dimensional structure of the A1 domain to model the interaction with the GP Ibalpha sequence 271-279, which has previously been implicated in ligand binding. Docking procedures suggested that A1 domain residues in strand beta3 and preceding loop (residues 559-566) as well as in helix alpha3 (residues 594-603) interact with Asp residues 272, 274, 277 and sulfated Tyr residues 278 and 279 in GP Ibalpha. To verify this model, 14 mutant A1 domain fragments containing single or multiple side chain substitutions were tested for their ability to mediate platelet adhesion under flow. Each of the vWF residues Tyr(565), Glu(596), and Lys(599) proved to be strictly required for A1 domain function, which, in agreement with previous findings, was also dependent on Gly(561). Moreover, an accessory functional role was apparent for a group of positively charged residues, including Arg at positions 629, 632, 636 and Lys at positions 643 and 645, possibly acting in concert. There was, however, no evidence from the model that these residues directly participate in forming the complex with GP Ibalpha. These results provide a partial model of the vWF-GP Ibalpha interaction linked to the manifestation of functional activity in platelet adhesion.

Amino Acids↗
PubMed2000

The genetics of ivermectin resistance in Caenorhabditis elegans.

The ability of organisms to evolve resistance threatens the effectiveness of every antibiotic drug. We show that in the nematode Caenorhabditis elegans, simultaneous mutation of three genes, avr-14, avr-15, and glc-1, encoding glutamate-gated chloride channel (GluCl) alpha-type subunits confers high-level resistance to the antiparasitic drug ivermectin. In contrast, mutating any two channel genes confers modest or no resistance. We propose a model in which ivermectin sensitivity in C. elegans is mediated by genes affecting parallel genetic pathways defined by the family of GluCl genes. The sensitivity of these pathways is further modulated by unc-7, unc-9, and the Dyf (dye filling defective) genes, which alter the structure of the nervous system. Our results suggest that the evolution of drug resistance can be slowed by targeting antibiotic drugs to several members of a multigene family.

Animals↗
PubMed2000

EAT-20, a novel transmembrane protein with EGF motifs, is required for efficient feeding in Caenorhabditis elegans.

The pharynx of Caenorhabditis elegans is a neuromuscular organ responsible for feeding, concentrating food by its pumping movement. A class of mutants, the eat mutants, are defective in this behavior. We have identified a novel eat gene, eat-20, encoding a unique transmembrane protein with three EGF motifs. Staining with a specific polyclonal antibody reveals that EAT-20 is expressed predominantly in the pharyngeal muscles and a subset of neurons. Some hypodermal cells also express EAT-20. eat-20 mutant animals are starved, have smaller brood sizes, and have prolonged egg-laying periods. The starvation apparently results from pharyngeal pumping defects, including a reduced pumping rate and "slippery pumping," in which the contents of the pharynx sometimes move rostrally. However, electrical activity of eat-20 mutants appears normal by electropharyngeogram.

Amino Acid Sequence↗
PubMed1999

A mutation in the C. elegans EXP-2 potassium channel that alters feeding behavior.

The nematode pharynx has a potassium channel with unusual properties, which allows the muscles to repolarize quickly and with the proper delay. Here, the Caenorhabditis elegans exp-2 gene is shown to encode this channel. EXP-2 is a Kv-type (voltage-activated) potassium channel that has inward-rectifying properties resembling those of the structurally dissimilar human ether-à-go-go-related gene (HERG) channel. Null and gain-of-function mutations affect pharyngeal muscle excitability in ways that are consistent with the electrophysiological behavior of the channel, and thereby demonstrate a direct link between the kinetics of this unusual channel and behavior.

Action Potentials↗
PubMed1999

Contribution of distinct adhesive interactions to platelet aggregation in flowing blood.

Aggregation of blood platelets contributes to the arrest of bleeding at sites of vascular injury, but it can occlude atherosclerotic arteries and precipitate diseases such as myocardial infarction. The bonds that link platelets under flow conditions were identified using confocal videomicroscopy in real time. Glycoprotein (GP) Ibalpha and von Willebrand factor (vWF) acted in synergy with alphaIIbbeta3 and fibrinogen to sustain platelet accrual at the apex of thrombi where three-dimensional growth resulted in increasing shear rates. The specific function of distinct adhesion pathways in response to changing hemodynamic conditions helps to explain hemostatic and thrombotic processes.

Blood Platelets↗
PubMed1998

Post-embryonic expression pattern of C. elegans let-60 ras reporter constructs.

let-60 ras plays roles in the differentiation of several C. elegans tissues (Yochem, J., Sundaram, M., Han, M., 1997. Ras is required for a limited number of cell fates and not for general proliferation in Caenorhabditis elegans. Mol. Cell. Biol. 17, 2716-2722). To understand the transcriptional regulation of ras and to identify new functions for ras in development, we examined expression patterns of let-60::lacZ and let-60::GFP reporter constructs in C. elegans hermaphrodites. Fusion constructs were expressed in vulval precursor cells, sex myoblasts and in cell lineages of the somatic gonad, germline cells (GFP construct only), hypodermis, muscle and nervous system.

Animals↗
PubMed1997

avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.

Ivermectin is a widely used anthelmintic drug whose nematocidal mechanism is incompletely understood. We have used Caenorhabditis elegans as a model system to understand ivermectin's effects. We found that the M3 neurons of the C.elegans pharynx form fast inhibitory glutamatergic neuromuscular synapses. avr-15, a gene that confers ivermectin sensitivity on worms, is necessary postsynaptically for a functional M3 synapse and for the hyperpolarizing effect of glutamate on pharyngeal muscle. avr-15 encodes two alternatively spliced channel subunits that share ligand binding and transmembrane domains and are members of the family of glutamate-gated chloride channel subunits. An avr-15-encoded subunit forms a homomeric channel that is ivermectin-sensitive and glutamate-gated. These results indicate that: (i) an ivermectin-sensitive chloride channel mediates fast inhibitory glutamatergic neuromuscular transmission; and (ii) a nematocidal property of ivermectin derives from its activity as an agonist of glutamate-gated chloride channels in essential excitable cells such as those of the pharynx.

Alternative Splicing↗
PubMed1995

Role of ambulatory care for student-patient interaction: the EPITOME model.

In undergraduate medical education, a shift away from in-patient teaching towards greater use of the ambulatory care setting is occurring. This paper looks at what effect this change in emphasis might have on students' clinical competence. A log-book approach was used to study final-year orthopaedic students' opportunities to interact with patients in the wards and out-patient clinics at the University of Dundee Medical School. Students perceived that similar opportunities to interact with patients to develop and improve their clinical skills were provided by both settings. The study showed that much greater use could be made of both settings for clinical skills teaching. While students were not enthusiastic about the log-book approach, it stimulated their thinking. It is concluded that student opportunities to develop clinical skills will not be adversely affected by the trend towards ambulatory care teaching. There should be more clinical teaching in the out-patient setting.

Ambulatory Care↗
PubMed1994

Comparison of student learning in the out-patient clinic and ward round.

In undergraduate medical education there is a trend away from ward-based teaching towards out-patient and community-based teaching. To study the potential effects of this altered emphasis on student learning, a pilot group of final-year medical students at the University of Dundee was asked to keep individual structured log-books. These contained details of patients seen during their 3-week orthopaedic attachment in both a ward and out-patient setting. A comparison of perceived learning in the two settings showed that students learned more from attending an out-patient clinic than a ward round, but did not make full use of the learning potential of either. The setting did not particularly influence the balance of learning as categorized here but only the ward round supplied experience of surgical complications. The amount of learning taking place in an out-patient clinic was influenced by student ability, measured by examination performance, but not by clinic work-load. The implications of increased use of out-patient clinics and the advantages and disadvantages of the approach employed are discussed. It is concluded that in the situation studied student learning in the outpatient setting is as good as or superior to the ward setting but should not totally replace it.

Ambulatory Care↗
PubMed1994

Vimentin's tail interacts with actin-containing structures in vivo.

The tail domain of the intermediate filament (IF) protein vimentin is unnecessary for IF assembly in vitro. To study the role of vimentin's tail in vivo, we constructed a plasmid that directs the synthesis of a 'myc-tagged' version of the Xenopus vimentin-1 tail domain in bacteria. This polypeptide, mycVimTail, was purified to near homogeneity and injected into cultured Xenopus A6 cells. In these cells the tail polypeptide co-localized with actin even in the presence of cytochalasin. Two myc-tagged control polypeptides argue for the specificity of this interaction. First, a similarly myc-tagged lamin tail domain localizes to the nucleus, indicating that the presence of the myc tag did not itself confer the ability to co-localize with actin (Hennekes and Nigg (1994) J. Cell Sci. 107, 1019-1029). Second, a myc-tagged polypeptide with a molecular mass and net charge at physiological pH (i.e. -4) similar to that of the mycVimTail polypeptide, failed to show any tendency to associate with actin-containing structures, indicating that the interaction between mycVimTail and actin-containing structures was not due to a simple ionic association. Franke (1987; Cell Biol. Int. Rep. 11, 831) noted a similarity in the primary sequence between the tail of the type I keratin DG81A and vimentin. To test whether the DG81A tail interacted with actin-containing structures, we constructed and purified myc-tagged DG81A tail polypeptides. Unexpectedly, these keratin tail polypeptides were largely insoluble under physiological conditions and formed aggregates at the site of injection. While this insolubility made it difficult to determine if they associated with actin-containing structures, it does provide direct evidence that the tails of vimentin and DG81A differ dramatically in their physical properties. Our data suggest that vimentin's tail domain has a highly extended structure, binds to actin-containing structures and may mediate the interaction between vimentin filaments and microfilaments involved in the control of vimentin filament organization (Hollenbeck et al. (1989) J. Cell Sci. 92, 621; Tint et al. (1991) J. Cell Sci. 98, 375).

Actins↗
PubMed1993

Disulfide bond requirements for assembly of the platelet glycoprotein Ib-binding domain of von Willebrand factor.

von Willebrand factor (vWF) is a multimeric glycoprotein of plasma and the subendothelial matrix that interacts with specific platelet receptors to establish platelet adhesion at a site of vascular injury. The vWF domain containing the platelet receptor glycoprotein Ib-binding site can be expressed in heterologous cells as a recombinant homodimeric fragment that mediates platelet-platelet interaction, analogous to multimeric vWF. The recombinant domain, r116, contains 7 Cys residues within its 290-residue monomeric subunit paired in an unidentified intra- and intermolecular disulfide bond arrangement. In this report we define the disulfide bond-dependent framework of r116 that provides the domain with its essential structural features that support dimer formation and the generation of a disulfide bond-dependent epitope. The results demonstrate that a triplet of Cys residues at positions 459, 462, and 464 are essential for efficient dimer formation. An intramolecular Cys509/Cys695 disulfide loop is required for generating a functional dimeric molecule, and monomeric molecules containing a Cys509/Cys695 intramolecular disulfide bond are unable to support ristocetin-mediated platelet aggregation. The disulfide arrangement in r116 is similar, if not identical, to the proposed arrangement within the corresponding region of plasma vWF, and these studies document the inherent Cys-dependent maturation of an isolated vWF domain.

Disulfides↗