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Biomedical subjects

S Jones

Publications and source records attributed to S Jones.

At least 271 records · Page 15Linked to original sources
PubMed1998

Out-patient follow-up after total hip replacement in one health region.

A postal survey was carried out of all orthopaedic surgeons in the West Yorkshire Health region enquiring about out-patient follow-up practices after total hip replacement. Follow-up is advised to detect problems that can more effectively be resolved if detected early. A huge variation in the number, timing and nature of appointments following discharge was demonstrated. The total length of follow-up varied between 3 months and indefinite follow-up. The number of visits in the first post-operative year varied between one and four. The considerable variation in post surgery follow-up of these patients has important cost implications. Some patients will have unnecessary appointments whereas others will be inadequately reviewed. Guidance is required on the appropriate review of these patients which will allow early detection of joint failure in a way that is efficient in terms of the time and cost of out-patient follow-up.

Arthroplasty, Replacement, Hip↗
PubMed1997

STAT3 acts as a co-activator of glucocorticoid receptor signaling.

Interleukin-6 (IL-6) and glucocorticoids are important mediators of inflammatory and immunological responses. Glucocorticoids are known to synergistically enhance IL-6-mediated cellular responses. We now show that IL-6 also has a synergistic effect upon glucocorticoid signaling. In particular, IL-6-activated STAT3 associates with ligand-bound glucocorticoid receptor to form a transactivating/signaling complex, which can function through either an IL-6-responsive element or a glucocorticoid-responsive element. These findings reveal a new level of interaction between these two crucial signaling cascades and indicate that activated STAT3 can also act as a transcriptional co-activator without direct association with its DNA binding motif.

Animals↗
PubMed1997

Functional nicotinic ACh receptors on interneurones in the rat hippocampus.

1. Neuronal nicotinic ACh receptors (nAChRs) were studied in the rat hippocampal slice preparation using whole-cell patch-clamp recording techniques. 2. Responses to ACh (100 microM) were detected on inhibitory interneurones in the Ca1 field of the hippocampus proper and in the dentate gyrus, but not on principal excitatory neurones in either region. The different neuronal types were identified based on their morphology and location. 3. ACh excited interneurones in the hippocampus and dentate gyrus in current-clamp recordings. In voltage-clamp recordings, ACh-activated inward currents were recorded from interneurones in the presence of blockers of synaptic transmission and the muscarinic ACh receptor antagonist atropine. The zero current potential for this response to ACh was near 0 mV. 4. The effect of ACh was mimicked by the nAChR-selective agonists nicotine (100 microM) and 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP, 100 microM). The response to ACh was reversibly antagonized by the neuronal nAChR antagonist mecamylamine (10 microM). The nAChR alpha 7 subunit-selective antagonists alpha-bungarotoxin (100 nM) and methyllycaconitine (10 nM) also inhibited the response to ACh. 5. These observations demonstrate the presence of functional nAChRs on inhibitory interneurones in the rat hippocampus. Thus, a novel mechanism by which ACh can regulate neuronal activity in the hippocampus is revealed.

Animals↗
PubMed1997

Potent alpha 4 beta 1 peptide antagonists as potential anti-inflammatory agents.

The migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular cell adhesion molecule-1 (VCAM-1) at inflamed sites. Binding of alpha 4 beta 1 to VCAM-1 initiates firm adhesion of the leukocyte to the vascular endothelium followed by extravasation into the tissue. Monoclonal antibodies generated against either alpha 4 beta 1 or VCAM-1 can moderate this inflammatory response in a variety of animal models. Recently peptides containing a consensus LDV sequence based on the connecting segment-1 (CS-1) of fibronectin and cyclic peptides containing an RCD motif have shown promise in modulating leukocyte migration and inflammation presumably by blocking the interaction of alpha 4 beta 1 with VCAM-1. Here we describe novel, highly potent, cyclic peptides that competitively inhibit alpha 4 beta 1 binding to VCAM-1 and fibronectin at sub nanomolar concentrations. The structure of a representative analog was determined via NMR spectroscopy and used to facilitate optimization of peptide leads. The peptides discussed here utilize similar functional groups as the binding epitope of VCAM-1, inhibit lymphocyte migration in vivo, and are highly selective for alpha 4 beta 1. Furthermore the structure--activity relationships described here have provided a template for the structure-based design of small molecule antagonists of alpha 4 beta 1-mediated cell adhesion processes.

Animals↗
PubMed1997

Comparison of in vitro and in vivo infectivity of different clade B HIV-1 envelope chimeric simian/human immunodeficiency viruses in Macaca mulatta.

The use of HIV-1 env/SIVmac chimeric viruses expressing divergent HIV-1 envelopes of clinical isolates, facilitates homologous and heterologous evaluation of various recombinant HIV-1 envelope vaccine candidates in lower primates. In this study we compare the in vitro and in vivo infectivity, via intravenous (IV) and intravaginal (IVAG) routes of infection, of stocks of chimeric viruses expressing env from four different clade B HIV-1 isolates. The TCID50/ml was 7.1 x 10(4), 1.0 x 10(4), 6.3 x 10(4), and 1.2 x 10(3) for SHIVsf13, SHIVHan2, SHIVNM-3rn, and SHIVW6.1D, respectively, with a MID50/ml upon IV inoculation of 3.2 x 10(3), 3.2 x 10(4), 3.2 x 10(4), and 3.2 x 10(3), respectively. The same SHIVsf13 stock was infectious after IVAG administration, requiring a 300-fold higher virus dose. Plasma antigenemia and cell-associated viremia were generally highest at weeks 2 or 4 after infection and decreased to subdetectable levels after 8-12 weeks. All infected animals tested developed anti-HIV-1 gp120 antibodies. Inoculated virus dose showed no (linear) quantitative correlation with cellular virus load, duration of viremia, plasma antigenemia, and anti-gp120 antibody titers. No significant changes in peripheral blood CD4 cell levels were observed and none of the animals has shown evidence of disease progression to date (i.e., 13 months postinfection). Four in vivo passages of cell-associated SHIVW6.1D did not result in increased virulence. Vaccine development studies in macaques monkeys have become feasible with the use of various clade B HIV-1 env SHIV chimeras.

Animals↗
PubMed1997

Prediction of protein-protein interaction sites using patch analysis.

A method for defining and analysing a series of residue patches on the surface of protein structures is used to predict the location of protein-protein interaction sites. Each residue patch is analysed for six parameters; solvation potential, residue interface propensity, hydrophobicity, planarity, protrusion and accessible surface area. The method involves the calculation of a relative combined score that gives the probability of a surface patch forming protein-protein interactions. Predictions are made for the known structures of protomers from 28 homo-dimers, large protomers from 11 hetero-complexes, small protomers from 14 hetero-complexes, and antigens from six antibody-antigen complexes. The predictions are successful for 66% (39/59) of the structures and the remainder can usually be rationalized in terms of additional interaction sites.

Antigens↗
PubMed1997

Analysis of protein-protein interaction sites using surface patches.

Protein-protein interaction sites in complexes of known structure are characterised using a series of parameters to evaluate what differentiates them from other sites on the protein surface. Surface patches are defined in protomers from a data set of 28 homo-dimers, 20 different hetero-complexes (segregated into large and small protomers), and antigens from six antibody-antigen complexes. Six parameters (solvation potential, residue interface propensity, hydrophobicity, planarity, protrusion and accessible surface area) are calculated for the observed interface patch and all other surface patches defined on each protein. A ranking of the observed interface, relative to all other possible patches, is calculated. With this approach it becomes possible to analyse the distribution of the rankings of all the observed patches, relative to all other surface patches, for each data set. For each type of complex, none of the parameters were definitive, but the majority showed trends for the observed interface to be distinguished from other surface patches.

Animals↗
PubMed1997

CATH--a hierarchic classification of protein domain structures.

BACKGROUND: Protein evolution gives rise to families of structurally related proteins, within which sequence identities can be extremely low. As a result, structure-based classifications can be effective at identifying unanticipated relationships in known structures and in optimal cases function can also be assigned. The ever increasing number of known protein structures is too large to classify all proteins manually, therefore, automatic methods are needed for fast evaluation of protein structures. RESULTS: We present a semi-automatic procedure for deriving a novel hierarchical classification of protein domain structures (CATH). The four main levels of our classification are protein class (C), architecture (A), topology (T) and homologous superfamily (H). Class is the simplest level, and it essentially describes the secondary structure composition of each domain. In contrast, architecture summarises the shape revealed by the orientations of the secondary structure units, such as barrels and sandwiches. At the topology level, sequential connectivity is considered, such that members of the same architecture might have quite different topologies. When structures belonging to the same T-level have suitably high similarities combined with similar functions, the proteins are assumed to be evolutionarily related and put into the same homologous superfamily. CONCLUSIONS: Analysis of the structural families generated by CATH reveals the prominent features of protein structure space. We find that nearly a third of the homologous superfamilies (H-levels) belong to ten major T-levels, which we call superfolds, and furthermore that nearly two-thirds of these H-levels cluster into nine simple architectures. A database of well-characterised protein structure families, such as CATH, will facilitate the assignment of structure-function/evolution relationships to both known and newly determined protein structures.

Databases, Factual↗
PubMed1997

Low vitamin D status is common among elderly Dunedin women.

AIMS: To review vitamin D status and the relationship of serum 25-hydroxyvitamin D levels to hip bone mineral density in a group of healthy elderly women living independently in their own homes in Dunedin. METHODS: Thirty-eight elderly subjects (> 70 years of age) were studied. Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured by radioimmunoassay in summer and winter. Femoral neck bone mineral density was measured by dual x-ray energy absorptiometry. RESULTS: Hip density was correlated with serum 25(OH)D levels at study entry. In summer, 10 of 38 patients (26.3%) had serum 25(OH)D levels below the reference range for healthy adults (40-185 nmol/L). Six patients subsequently withdrew from the study. In winter, 22 of the remaining 32 women (68.8%) had serum 25(OH)D values below the reference range. Subjects with low 25(OH)D values were given halibut oil tablets (400 IU vitamin D3 per day) to improve their serum 25(OH)D levels. CONCLUSIONS: Vitamin D deficiency is common among elderly women with a high risk of fracture who live in southern New Zealand. This is most marked in the winter months. Vitamin D replacement is cheap and effective and should be considered in patients over 70 years of age who have a high risk of fracture and who live in temperate climates.

Absorptiometry, Photon↗
PubMed1997

The construction and evaluation of SIV/HIV chimeras that express the envelope of European HIV type 1 isolates.

The molecular construction of SIV/HIV-1 chimeric viruses (or SHIVs), provides a means of infecting macaques with immunodeficiency viruses that express the envelope protein of HIV-1. However, to date, most SHIVs produced express the envelope of isolates of HIV-1 that have been passaged repeatedly in T cell lines. We have taken SHIV-4 and replaced an NheI-AvrII fragment that encompasses the gp120 region and the extracellular portion of gp41 with the equivalent region of two European isolates of HIV-1 (ACH320.3.1 and HIV-1Han-2). Neither of these viruses had been passaged in T cell lines for prolonged periods prior to molecular cloning. Virus stocks were prepared of both SHIV constructs. In vitro, the relative ability of each clone to replicate in four T cell lines mirrored closely the pattern observed with the parental virus donating the envelope sequences. In vivo, only one of the chimeric viruses was infectious in cynomolgus macaques and its recovery was transient. The factors that affect the replication of SHIVs in vitro and in vivo are discussed.

Animals↗
PubMed1997

A comparison of semantic memory in vascular dementia and dementia of Alzheimer's type.

OBJECTIVE: To determine whether semantic memory is impaired in vascular dementia and to assess the utility of semantic memory measures in differentiating vascular dementia from dementia of Alzheimer's type (DAT). DESIGN: Case-control study. PATIENTS: Ten patients with Cambridge Mental Disorders in the Elderly (CAMDEX) diagnosis of 'definite' mild or moderate vascular dementia (mean age 77) were individually matched with 10 patients with a CAMDEX diagnosis of 'definite' DAT on the basis of age, education, sex, premorbid IQ (as measured by the National Adult Reading Test) and performance on the Cambridge Cognitive Examination (CAMCOG). In addition, 10 age, sex and education matched volunteer or relative controls were assessed. OUTCOME MEASURES: A detailed semantic memory test battery consisting of five subtests: category fluency, picture naming, picture sorting, word-picture matching and generation of verbal definitions. RESULTS: Compared to normal controls, both patient groups were impaired on all subtests of the semantic battery with the exception of the word-picture matching test. No differences were found between the vascular dementia and DAT groups on any of the measures. CONCLUSIONS: Impairment of semantic memory is a feature of both vascular dementia and DAT. Tests of semantic memory appear, therefore, of little value in differentiating between these two major causes of dementia. Further work is required to determine whether the nature of the processing deficit is the same in these conditions.

Aged↗
PubMed1997

The dopamine transporter: a crucial component regulating dopamine transmission.

The dopamine system is implicated in the control of locomotion, cognition, and endocrine function. The relative contribution of the various dopamine-related components is not well established mainly because drugs that target the dopaminergic system often lack selectivity. The in vivo gene inactivation procedure, or knockout, enables the creation of new strains of mice lacking a specific gene. This technique has been applied recently to inactivate the expression of the plasma membrane dopamine transporter. Here we summarize the main findings obtained with these transgenic mice carrying this "genetic defect," leading to a better understanding of the relative contribution of the dopamine transporter regarding locomotor activity, regulation of the expression of peptides under the control of dopaminergic activity, and responses to various drugs targeting the dopamine system. Our results establish not only the central importance of the transporter as the key element controlling dopamine levels in the brain, but also its role as an obligatory target for the behavioral and biochemical action of amphetamine and cocaine. In addition, the genetically altered mice offer a unique model to test the specificity and selectivity of dopamine transporter-acting drugs and may provide important new concepts related to the clinical and social implications of conditions such as Parkinson's disease, schizophrenia, and drug addiction.

Amphetamines↗
PubMed1997

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Its binding motif for alpha 4 beta 7 and role in experimental colitis.

The integrin alpha 4 beta 7 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) are molecules involved in the normal recirculation of lymphocytes between the blood and the gastrointestinal tract. These molecules may play a complementary and significant role in animal models of colitis. We have investigated the structural interaction between alpha 4 beta 7 and MAdCAM-1. Site-directed mutagenesis studies of the MAdCAM-1 molecule has led to the identification of the amino acid residue (LDT) in the loop between beta strands C and D of the Ig-superfamily-like folds being involved in the adhesive and cell activation functions of MAdCAM-1 with alpha 4 beta 7.

Amino Acid Sequence↗
PubMed1997

P19 cells differentiate into glutamatergic and glutamate-responsive neurons in vitro.

The neurotransmitter L-glutamate has been associated with a number of developmental events within the central nervous system including synaptogenesis and the refinement of topographically ordered neural maps. As a model for studying such events at the molecular level, we have examined the expression of glutamate and glutamate receptors in neurons that develop from P19 cells in response to retinoids. We report here that many P19-derived neurons do contain glutamate in secretory vesicles and that this glutamate appears to function as a neurotransmitter. The neurotransmitter GABA is also present in these cultures and both glutamate and GABA appeared to co-localize in some neuronal processes. Both neurotransmitters were released from the neurons in response to membrane depolarization. These neurons also express various glutamate receptor subunits including GluR1, GluR4 and NMDAR1 as detected by immunological methods. Using whole-cell patch-clamping, we have recorded spontaneous postsynaptic potentials which increase in both amplitude and frequency with time in culture and which are sensitive to the glutamate antagonist kynurenic acid Thus, P19-derived neurons mature in culture and form electrically active neural networks involving glutamate and glutamate receptors.

Animals↗
PubMed1997

Effects of hydroxyurea administration on the body weight, body composition and exercise performance of patients with sickle-cell anaemia.

1. As an ancillary study carried out during the recently completed Multicenter Study of Hydroxyurea, we examined the effect of hydroxyurea on the body weight, body composition and exercise capacity of adult patients with sickle-cell anaemia. 2. The subjects received either hydroxyurea (six males and four females) or placebo (eight males and six females). Data for each subject were generated during four separate 24 h admissions to the General Clinical Research Center. These admissions occurred at baseline and then at 6, 12 and 18 months after the start of study drug (hydroxyurea or placebo) administration. During each admission, body composition was measured by using a dual X-ray absorptiometer, and exercise testing was performed by cycle ergometry. Anaerobic performance was assessed according to a 'Wingate' protocol (20 s at maximal intensity against a cycling resistance of 7.5% body weight). Aerobic performance was examined using a steady state submaximal exercise protocol (10 min cycling time). 3. At baseline, no significant difference in any parameter was found between the hydroxyurea- and placebo-treated groups. At 18 months, the hydroxyurea-treated subjects exhibited an average weight gain of 3.16 kg. The mean weight gain in the placebo-treated subjects was 1.82 kg. Body composition analysis showed that the additional weight in both groups involved both lean and fat body mass components. In anaerobic performance, the subjects given hydroxyurea showed an increase in peak muscle power of 104.9 W. The placebo group also showed an increase, but theirs was a more modest gain of 57.7 W. The most marked improvement in anaerobic performance was observed in the hydroxyurea-treated men (P < 0.05). In aerobic performance, the hydroxyurea-treated subjects exhibited a decrease in peak heart rate response to a standardized workload of 15.2 beats/min, as compared with a decrease of only 4.3 beats/min in the placebo-treated patients. 4. Taken together, the overall weight gain, combined with increases in both anaerobic muscular performance and aerobic cardiovascular efficiency, provides objective data to support the subjective impression that hydroxyurea administration produces an improvement in the physical capacity of patients with sickle-cell anaemia.

Adult↗
PubMed1997

Identifying home advantage in international tennis and golf tournaments.

A regression analysis of competitors' tournament results in relation to their world rankings was proposed to identify the effect of home advantage in international 'grand-slam' tennis and 'major' golf tournaments. The results provided little evidence of home advantage in either the grand-slam tennis or the golf tournaments held in 1993. The only possible evidence of home advantage was found in the Wimbledon tennis and the US Open golf championships. Even these findings can be explained, at least partially, by (1) the availability of information concerning the low world rankings of the British tennis players competing at Wimbledon, and (2) selective entry, allowing only the world's top-ranked foreign golfers into the US open golf tournament. In both cases, the lower ranking home competitors have a greater opportunity to perform above their anticipated world rankings. Therefore, provided entry into tennis and golf tournaments is truly 'open' to both the host nation's representatives and foreign competitors alike, home advantage does not appear to be a major factor influencing the competitors' performance in such competitions. These findings may be explained by the relatively objective nature of the scoring systems used in tennis and golf, unlike the subjective influence of refereeing decisions on the results of team-games such as soccer.

Analysis of Variance↗
PubMed1997

The effects of hyperventilation on postural control mechanisms.

The effect of hyperventilation on postural balance was investigated. Voluntary hyperventilation increased body sway in normal subjects, particularly in the sagittal plane. The possibility that this hyperventilation-induced unsteadiness is due to interference with lower limb somatosensory input, vestibular reflexes or cerebellar function was assessed. (i) The effect of hyperventilation on peripheral compound sensory action potentials (SAPs) and somatosensory evoked potentials (SEPs) (recorded centrally, from the scalp) elicited by electrical stimulation of the sural nerve was measured in six normal adults. A reduction in the scalp SEP amplitude and an increase in the peripheral SAP amplitude were observed during hyperventilation, which reversed during the recovery period. These changes indicate increased peripheral neural excitability which could lead to a higher level of ectopic activity; the latter would interfere with central reception of peripheral input. (ii) The click-evoked vestibulo-collic reflex was recorded to study the effect of hyperventilation on vestibulo-spinal activity. EMG recordings from both sternocleidomastoid muscles of six healthy subjects were made in response to loud clicks presented to either ear. Neither the amplitude nor the latency of the response were altered significantly by hyperventilation. (iii) Eye-movement recordings were obtained in the six normal subjects to assess the effect of hyperventilation on the vestibulo-ocular reflex and its visual suppression, the latter being a function largely mediated by the cerebellum; no changes were detected. (iv) Three-dimensional eye-movement recordings and body-sway measurements were obtained in six patients with longstanding unilateral vestibular loss in order to evaluate if hyperventilation disrupts vestibular compensation. In all patients, a horizontal nystagmus either appeared or was significantly enhanced for > or = 60 s after voluntary hyperventilation. Sway was also enhanced by hyperventilation in these patients, particularly in the frontal plane. This study suggests that hyperventilation disrupts mechanisms mediating vestibular compensation. The increase in sway may be, at least partly, mediated by deranged peripheral and central somatosensory signals from the lower limbs. Hyperventilation seems to spare vestibular reflex activity and cerebellar-mediated eye movements.

Acoustic Stimulation↗