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Biomedical subjects

P Taylor

Publications and source records attributed to P Taylor.

At least 145 records · Page 8Linked to original sources
PubMed1999

Structural and mechanistic mapping of a unique fumarate reductase.

The 1.8 A resolution crystal structure of the tetraheme flavocytochrome c3, Fcc3, provides the first mechanistic insight into respiratory fumarate reductases or succinate dehydrogenases. The multi-redox center, three-domain protein shows a 40 A long 'molecular wire' allowing rapid conduction of electrons through a new type of cytochrome domain onto the active site flavin, driving the reduction of fumarate to succinate. In this structure a malate-like molecule is trapped in the enzyme active site. The interactions between this molecule and the enzyme suggest a clear mechanism for fumarate reduction in which the substrate is polarized and twisted, facilitating hydride transfer from the reduced flavin and subsequent proton transfer. The enzyme active site in the oxidized form is completely buried at the interface between the flavin-binding and the clamp domains. Movement of the cytochrome and clamp domains is postulated to allow release of the product.

Amino Acid Sequence↗
PubMed1999

Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD)

The aim of our study was to assess the efficacy of extracorporeal photopheresis (ECP) in chronic graft-versus-host disease (GVHD). Eleven patients with chronic cutaneous GVHD were studied. Four had mucosal involvement and five had pulmonary involvement. All had failed to improve on first- and second-line therapy. Three patients received ECP alone; the remainder continued to receive steroids and/or immunosuppressive therapy. Patients received ECP twice monthly for 4 months and then once monthly for 3 months. They were evaluated by serial skin scores, mucosal and skin photography, pulmonary function tests, biochemical and haematological parameters. Nine patients showed objective evidence of cutaneous improvement with a mean reduction in skin score of 48% overall. In the 10th patient, skin scores and oral involvement improved on twice monthly ECP but deteriorated when reduced to once monthly. The final patient died from renal failure secondary to cyclosporin toxicity. Two out of five patients with lung involvement showed a mild improvement in pulmonary function tests. Liver function tests were abnormal in five patients; they improved in one and deteriorated in three. All patients receiving concomitant immunosuppressive/steroid therapy were able to reduce drug dosages by trial completion. Our results indicate that ECP can benefit patients with cutaneous and mucosal chronic GVHD who have failed on first- and second-line therapies. The effect on the systemic manifestations of GVHD is less consistent.

Adolescent↗
PubMed1999

Use of a skin explant model for predicting GVHD in HLA-matched bone marrow transplants - effect of GVHD prophylaxis.

Over the last decade we have successfully evaluated the use of a human skin explant assay for predicting acute GVHD in HLA-matched sibling transplants. In the present study, we modified GVHD prophylaxis on an individual patient basis depending on the GVHD outcome predicted by the skin explant model. We have summarised our previous data describing how the skin explant assay results correctly predict GVHD occurrence and severity in 45/56 patients (80%); P< 0.0001, chi2 19.97, df = 1. In a further cohort of 19 patients, all were predicted to develop grade II or above GVHD. These patients were given increased GVHD prophylaxis with the addition of methotrexate and a significant reduction in the expected incidence of GVHD was observed (P = 0.02; chi2 7.7, df = 1; Fisher exact test P = 0.04). The results from these studies suggest that modifying GVHD prophylaxis, based on skin explant assay results, may reduce the expected incidence and severity of GVHD. We suggest that the technique might be used for selective GVHD prophylaxis in T cell non-depleted HLA matched sibling transplants.

Adolescent↗
PubMed1999

Clinical audit of 5 years provision of the Odstock dropped foot stimulator.

The Odstock dropped foot stimulator (ODFS) is a foot switch controlled single channel neuromuscular stimulator for correction of dropped foot. Following a randomized controlled trial, the ODFS was recommended for use in the United Kingdom's National Health Service and a clinical service established. The patient performance was assessed by measurement of walking speed over 10 m, physiological cost index (PCI), and by questionnaire. After 4.5 months stroke patients (n = 111) showed a mean increase in walking speed of 27% and reduction in PCI of 31% with stimulation and changes of 14% and 19%, respectively, unassisted. Multiple sclerosis patients (n = 21) gained similar orthotic benefit but no carry over. The principal reason cited for using the equipment was that it reduced the effort of walking. The principal reasons identified for discontinuing were an improvement in mobility, electrode positioning difficulties, and deteriorating mobility. A comprehensive clinical follow-up service is essential to achieve the maximum continuing benefit from FES based orthosis.

Cerebrovascular Disorders↗
PubMed1999

A novel syndrome of episodic muscle weakness maps to xp22.3.

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.

Adolescent↗
PubMed1999

Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature.

A sibship is described where the brother and a sister both have Kallmann's syndrome (anosmia and deficiency of gonadotrophin releasing hormone) and the woman also has streak ovaries. Although there are several conditions that may occur with Kallmann's syndrome, there are no known reports of ovarian dysgenesis being associated with this disorder. Cytogenetic analysis showed no rearrangement or major deletions of the chromosomes. Linkage analysis using informative microsatellite markers predicts that a gene other than KAL1 (at Xp22.3) is implicated in the Kallmann's syndrome manifesting concurrently with ovarian dysgenesis found in this family.

Adult↗
PubMed1999

Purification, characterization and crystallization in two crystal forms of bovine cyclophilin 40.

The purification and crystallization of two different crystal forms of the two-domain protein bovine cyclophilin 40 is reported. Tetragonal crystals grown in methyl pentanediol belong to space group P4222 with unit-cell parameters a = 94.5, c = 118.3 A. Long thin needles grown from PEG belong to space group C2 with unit-cell parameters a = 125.71, b = 47.3, c = 74.6 A, beta = 93.90 degrees. The N-terminal 170 amino acids have significant homology with the well characterized human cyclophilin A. The C-terminal domain is largely made up of three copies of the tetratricopeptide repeat motif thought to be involved in mediating protein-protein interactions. Cyclophilins are frequently found as domains in larger multidomain proteins. To date, only X-ray structures of single-domain cyclophilins have been reported, and this work provides the first example of the purification and crystallization of a larger protein containing a cyclophilin domain.

Amino Acid Sequence↗
PubMed1999

Sigmoidoscopy in a nurse-practitioner community clinic using telemedicine.

We evaluated the feasibility of remote endoscopy in a community setting. Realtime teleconsultation and telesigmoidoscopy were carried out by a nurse practitioner at a community clinic while a colorectal specialist was present at the main hospital. Rigid video-sigmoidoscopes were used and the images were transmitted via ISDN lines at 384 kbit/s. Over three months, 32 patients (mean age 35 years; 19 men and 13 women) with bleeding per rectum took part in the study. Evaluation was carried out using satisfaction questionnaires for the patients, the nurse practitioner and the clinicians. The mean grade for clarity of intraluminal views was 3.5 (1 poor, 4 excellent). Only two cases had views graded less than 3, due to the presence of excessive faecal residue. All the patients were satisfied with the teleconsultation and video-endoscopy and would return for a similar visit. User satisfaction was also high on the part of the nurse practitioner and the clinician.

Adult↗
PubMed1999

Psychiatric features of 36 men convicted of sexual offenses.

BACKGROUND: To increase understanding of the relationship between sexual violence and mental illness, the authors assessed the legal histories and psychiatric features of 36 males convicted of sexual offenses. METHOD: Thirty-six consecutive male sex offenders admitted from prison, jail, or probation to a residential treatment facility received structured clinical interviews for DSM-IV Axis I and II disorders. The participants' legal histories, histories of sexual and physical abuse, and family histories of psychiatric disorders were also assessed. RESULTS: The participants' mean +/- SD age was 33+/-8 years. They had been convicted a mean of 1.8+/-1.4 times (range, 1-9 times) for sexual offenses and incarcerated a mean of 8+/-6 years (range, 0-22 years). Participants displayed high rates of lifetime DSM-IV Axis I disorders: 30 (83%) had a substance use disorder; 21 (58%), a paraphilia; 22 (61%), a mood disorder (13 [36%] with a bipolar disorder); 14 (39%), an impulse control disorder; 13 (36%), an anxiety disorder; and 6 (17%), an eating disorder. Participants also displayed high rates of Axis II disorders, with 26 (72%) meeting DSM-IV criteria for antisocial personality disorder. In addition, subjects reported experiencing high rates of sexual (but not physical) abuse and high rates of Axis I disorders, especially substance use and mood disorders, in their first-degree relatives. Compared with subjects without paraphilias, subjects with paraphilias displayed statistically significantly higher rates of mood, anxiety, and eating disorders, as well as significantly higher rates of childhood sexual abuse. CONCLUSION: Recognition and treatment of major psychiatric disorders among sex offenders may increase chances for successful rehabilitation, reduce recidivism and public victimization, and produce significant public health and economic benefits. More studies in this area appear warranted to search for more effective interventions for this severe public health problem.

Adolescent↗
PubMed1999

Calcineurin enhances acetylcholinesterase mRNA stability during C2-C12 muscle cell differentiation.

Treatment of C2-C12 mouse myoblasts with the immunosuppressant drug cyclosporin A (CsA) enhances the increase in acetylcholinesterase (AChE) expression observed during skeletal muscle differentiation. The enhanced AChE expression is due primarily to increased mRNA stability because CsA treatment increases the half-life of AChE mRNA, but not the apparent transcriptional rate of the gene. Neither tacrolimus (FK506), an immunosuppressive agent with a distinct structure, nor cyclosporine H, an inactive congener of CsA, alters AChE expression. The enhanced AChE expression is associated with the muscle differentiation process, but cannot be triggered by CsA exposure before differentiation. Myoblasts and myotubes of C2-C12 cells express similar amounts of cyclophilin A and FKBP12, immunophilins known to be intracellular-binding targets for CsA and tacrolimus, respectively. However, cellular levels of calcineurin, a calcium/calmodulin-dependent phosphatase known to be the cellular target of ligand-immunophilin complexes, increase 3-fold during myogenesis. Overexpression of constitutively active calcineurin in differentiating cells reduces AChE mRNA levels and CsA antagonizes such an inhibition. Conversely, overexpression of a dominant negative calcineurin construct increases AChE mRNA levels, which are further enhanced by CsA. Thus, a CsA sensitive, calcineurin mediated pathway appears linked to differentiation-induced stabilization of AChE mRNA during myogenesis.

Acetylcholinesterase↗
PubMed1998

X-ray structures and analysis of 11 cyclosporin derivatives complexed with cyclophilin A.

Eight new X-ray structures of different cyclophilin A/cyclosporin-derivative complexes are presented. These structures, combined with the existing three published cyclosporin complexes, provide a useful structural database for the analysis of protein-ligand interactions. The effect of small chemical differences on protein-ligand hydrogen-bonding, van der Waals interactions and water structure is presented.

Cyclosporine↗
PubMed1998

Conformational differences of an immunosuppressant peptolide in a single crystal and in a crystal complex with human cyclophilin A.

The crystal structure of (Thr2, Leu5, d-Hiv8, Leu10)-cyclosporin (cyclic peptolide SDZ 214-103) has been determined as the unbound crystal form and as a complex with human cyclophilin A. This pair of structures provides an example of a significant difference in conformation between free and bound ligand in crystals. The conformation of the unbound form is unlike that of both free and bound conformations of cyclosporin A (with the amide bond between residues 3 and 4 in the cis conformation), while the bound conformation is similar to that of CsA bound to cyclophilin. The cyclophilin-bound conformations of both ligands are similar, though this involves a significantly different waterellipsisligand hydrogen-bonding structure, which compensates for the chemical differences between the two ligands.

Cyclosporins↗
PubMed1998

Splicing of 5' introns dictates alternative splice selection of acetylcholinesterase pre-mRNA and specific expression during myogenesis.

Splicing of alternative exon 6 to invariant exons 2, 3, and 4 in acetylcholinesterase (AChE) pre-mRNA results in expression of the prevailing enzyme species in the nervous system and at the neuromuscular junction of skeletal muscle. The structural determinants controlling splice selection are examined in differentiating C2-C12 muscle cells by selective intron deletion from and site-directed mutagenesis in the Ache gene. Transfection of a plasmid lacking two invariant introns (introns II and III) within the open reading frame of the Ache gene, located 5' of the alternative splice region, resulted in alternatively spliced mRNAs encoding enzyme forms not found endogenously in myotubes. Retention of either intron II or III is sufficient to control the tissue-specific pre-mRNA splicing pattern prevalent in situ. Further deletions and branch point mutations revealed that upstream splicing, but not the secondary structure of AChE pre-mRNA, is the determining factor in the splice selection. In addition, deletion of the alternative intron between the splice donor site and alternative acceptor sites resulted in aberrant upstream splicing. Thus, selective splicing of AChE pre-mRNA during myogenesis occurs in an ordered recognition sequence in which the alternative intron influences the fidelity of correct upstream splicing, which, in turn, determines the downstream splice selection of alternative exons.

Acetylcholinesterase↗