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Biomedical subjects

A Hesketh

Publications and source records attributed to A Hesketh.

17 recordsLinked to original sources
PubMed2005

Interventions for apraxia of speech following stroke.

BACKGROUND: Apraxia of speech is a communication disorder that can affect stroke patients. Several different intervention strategies are undertaken by speech and language therapists working with this patient group. OBJECTIVES: To assess whether therapeutic interventions improve functional speech in stroke patients with apraxia of speech and which individual therapeutic interventions are effective. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (searched May 2004). In addition, we searched the following databases: the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2003); MEDLINE (1966 to April 2004); EMBASE (1980 to April 2004); CINAHL (1982 to April 2004); PsycINFO (1974 to April 2004); the National Research Register (searched April 2004); and Current Controlled Trials Register (searched May 2004). We reviewed reference lists of relevant articles and contacted authors and researchers in an effort to identify published and unpublished trials. SELECTION CRITERIA: We sought to include randomised controlled trials of non-drug interventions for adults with apraxia of speech following a stroke where the primary outcome was functional speech at six months follow up. DATA COLLECTION AND ANALYSIS: One author searched the titles, abstracts and keywords. Two authors examined the abstracts that might meet the inclusion criteria. Four authors were available to assess trial quality and to extract data from eligible studies. MAIN RESULTS: No trials were identified. AUTHORS' CONCLUSIONS: There is no evidence from randomised trials to support or refute the effectiveness of therapeutic interventions for apraxia of speech. There is a need for high quality randomised trials to be undertaken in this area.

Apraxias↗
PubMed2002

The GlnD and GlnK homologues of Streptomyces coelicolor A3(2) are functionally dissimilar to their nitrogen regulatory system counterparts from enteric bacteria.

Glutamine synthetase I (GSI) enzyme activity in Streptomyces coelicolor is controlled post-translationally by the adenylyltransferase (GlnE) as in enteric bacteria. Although other homologues of the Escherichia coli Ntr system (glnK, coding for a PII family protein; and glnD, coding for an uridylyltransferase) are found in the S. coelicolor genome, the regulation of the GSI activity was found to be different. The functions of glnK and glnD were analysed by specific mutants. Surprisingly, biochemical assay and two-dimensional PAGE analysis showed that modification of GSI by GlnE occurs normally in all mutant strains, and neither GlnK nor GlnD are required for the regulation of GlnE in response to nitrogen stimuli. Analysis of the post-translational regulation of GlnK in vivo by two-dimensional PAGE and mass spectrometry indicated that it is subject to both a reversible and a non-reversible modification in a direct response to nitrogen availability. The irreversible modification was identified as removal of the first three N-terminal amino acid residues of the protein, and the reversible modification as adenylylation of the conserved tyro-sine 51 residue that is known to be uridylylated in E. coli. The glnD insertion mutant expressing only the N-terminal half of GlnD was capable of adenylylating GlnK, but was unable to perform the reverse deadenylylation reaction in response to excess ammonium. The glnD null mutant completely lacked the ability to adenylylate GlnK. This work provides the first example of a PII protein that is modified by adenylylation, and demonstrates that this reaction is performed by a homologue of GlnD, previously described only as a uridylyltransferase enzyme.

Amino Acid Sequence↗
PubMed2001

Induction of ppGpp synthesis in Streptomyces coelicolor A3(2) grown under conditions of nutritional sufficiency elicits actII-ORF4 transcription and actinorhodin biosynthesis.

Production of ppGpp in Streptomyces coelicolor A3(2) was achieved independently of amino acid limitation by placing N-terminal segments of the ppGpp synthetase gene, relA, under the control of a thiostrepton-inducible promoter (tipAp). S1 nuclease protection experiments indicated that induced ppGpp concentrations of 6-12 pmol mg(-1) dry weight in late-exponential phase cultures caused activation of transcription of actII-ORF4, the pathway-specific activator gene for actinorhodin production. This level of ppGpp had no effect on growth rate, implying a causal role for ppGpp in activating actII-ORF4 transcription. No effect was observed on the transcription of the corresponding and homologous activator gene for undecylprodigiosin production, redD, reflecting a requirement for additional regulatory factors for activation of its transcription. This work provides the most compelling evidence yet for the activation of an antibiotic biosynthetic pathway by the stringent factor ppGpp.

Alcohol Oxidoreductases↗
PubMed2001

Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2).

Deletion of the (p)ppGpp synthetase gene, relA, of Streptomyces coelicolor A3(2) results in loss of production of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red) and delayed morphological differentiation when the mutant is grown under conditions of nitrogen limitation. To analyze the role of (p)ppGpp as an intracellular signaling molecule for the initiation of antibiotic production, several C-terminally deleted derivatives of S. coelicolor relA that could potentially function in the absence of ribosome activation were placed under the control of the thiostrepton-inducible tipA promoter. While 0.82- and 1.28-kb N-terminal segments failed to restore (p)ppGpp and antibiotic production upon induction in a relA null mutant, 1.46- and 2.07-kb segments did. Under conditions of phosphate limitation, deletion of relA had little or no effect on Act or Red synthesis, potentially reflecting an alternative mechanism for ppGpp synthesis. A second S. coelicolor RelA homologue (RshA, with 42% identity to S. coelicolor RelA) was identified in the genome sequence. However, deletion of rshA had no effect on the ability of the relA mutant to make Act and Red when grown under conditions of phosphate limitation. While high-level induction of tipAp::rshA in the relA mutant resulted in growth inhibition, low-level induction restored antibiotic production and sporulation. In neither case, nor in the relA mutant that was grown under phosphate limitation and producing Act and Red, could (p)ppGpp synthesis be detected. Thus, a ppGpp-independent mechanism exists to activate antibiotic production under conditions of phosphate limitation that can be mimicked by overexpression of rshA.

Adenosine↗
PubMed2001

Molecular and functional analyses of the gene (eshA) encoding the 52-kilodalton protein of Streptomyces coelicolor A3(2) required for antibiotic production.

Analysis of proteins recovered in the S100 precipitate fraction of Streptomyces griseus after ultracentrifugation led to the identification of a 52-kDa protein which is produced during the late growth phase. The gene (eshA) which codes for this protein was cloned from S. griseus, and then its homologue was cloned from Streptomyces coelicolor A3(2). The protein was deduced to be 471 amino acids in length. The protein EshA is characterized by a central region that shows homology to the eukaryotic-type cyclic nucleotide-binding domains. Significant homology was also found to MMPI in Mycobacterium leprae, a major antigenic protein to humans. The eshA gene mapped near the chromosome end and was not essential for viability, as demonstrated by gene disruption experiments, but its disruption resulted in the abolishment of an antibiotic (actinorhodin but not undecylprodigiosin) production. Aerial mycelium was produced as abundantly as by the parent strain. Expression analysis of the EshA protein by Western blotting revealed that EshA is present only in late-growth-phase cells. The eshA gene was transcribed just preceding intracellular accumulation of the EshA protein, as determined by S1 nuclease protection, indicating that EshA expression is regulated at the transcription level. The expression of EshA was unaffected by introduction of the relA mutation, which blocks ppGpp synthesis.

Amino Acid Sequence↗
PubMed2001

The Hanen Parent Programme: a parent's perspective.

In 1997 Salford Community Healthcare Trust embarked on a research project (funded by NHS Executive North West Region) to investigate how viable the Hanen Parent Programme (HPP) (Manolson 1992) was in terms of its effectiveness and suitability for an inner-city UK population in comparison with clinic-based, direct intervention. An important component of that research project involved exploring the parents' perceptions of the therapy they had undertaken. In this paper are summarised the areas in which there were marked differences between parents' experiences and perceptions of therapy as a result of the type of intervention they received. Clinical implications are discussed.

Attitude↗
PubMed2000

Reliability of a measure of post-stroke shoulder pain in patients with and without aphasia and/or unilateral spatial neglect.

OBJECTIVE: To determine the inter/intra-rater reliability of expert physiotherapists (PTs) measuring post-stroke shoulder pain with 100 mm vertical visual analogue scales (VAS; intensity, frequency and affective response) and a categorical site-of-pain scale. DESIGN: Three PTs independently rated subjects (normal clinical procedure but with a standardized starting position) on three days, at the same time of day, during one week in a randomized order determined by a nested latin square. Reliability for VAS scores was determined with the intraclass correlation coefficient (ICC) and for site-of-pain with the kappa statistic (kappa). Acceptable reliability was set at 0.75. The limits of agreement were also calculated. SETTING: Community. SUBJECTS: Thirty-three patients, mean time post stroke 42 months (range 7-360). RESULTS: Mean inter-rater reliability was 0.79 for intensity, 0.75 for frequency and 0.62 for affective response (ICC). The limits of agreement were wide and rater bias was significant for 6/27 ratings. Mean intra-rater reliability was 0.70 for intensity, 0.77 for frequency and 0.69 for affective response (ICC). For site-of-pain inter-rater reliability ranged from 0.156 (kappa) to 0.385 (kappa) and intrarater reliability ranged from 0.300 (kappa) to 0.559 (kappa). CONCLUSIONS: Although inter-rater reliability was acceptable for intensity and frequency there was a consistently large systematic bias between pairs of raters. Agreement might be improved if a standardized assessment procedure was used and/or if training in pain behaviour interpretation was provided.

Aged↗
PubMed1998

The measurement of intervention effects in developmental phonological disorders.

The effectiveness of speech and language therapy for developmental phonological disorders has typically been measured in terms of the diminution of the application of phonological processes. Often substantial amounts of intervention and time may be needed to show up such changes. Shorter and more clinically realistic intervention regimes can result in small but significant changes in speech production which represent positive developments in the phonological system. In order to measure progress in this sort of therapy a sensitive instrument of measurement is required. In this paper we describe a research measurement tool, the probe scoring system, which was designed to detect small changes in the child's phonological system following therapy and contrast it to some of the instruments selected for use in other efficacy studies. The potential for wider clinical application is also considered.

Child↗
PubMed1997

Molecular and functional analysis of the ribosomal L11 and S12 protein genes (rplK and rpsL) of Streptomyces coelicolor A3(2).

A RelC deletion mutant, KO-100, of Streptomyces coelicolor A3(2) has been isolated from a collection of spontaneous thiostrepton-resistant mutants. KO-100 grows as vigorously as the parent strain and possesses a 6-bp deletion within the rplK, previously termed relC. When the wild-type rplK gene was propagated on a low-copy-number vector in mutant KO-100, the ability to produce ppGpp, actinorhodin and undecylprodigiosin, which had been lost in the RelC mutant, was completely restored. Allele replacement by gene homogenotization demonstrated that the RelC mutation is responsible for the resistance to thiostrepton and the inactivation of ppGpp, actinorhodin and undecylprodigiosin production. Western blotting showed that ribosomes from the RelC mutant KO-100 contain only one-eighth the amount of L11 protein found in ribosomes of the parent strain. The impairment of antibiotic production in KO-100 could be rescued by the introduction of mutations that confer resistance to streptomycin (str), which result in alteration of Lys-88 in ribosomal protein S12 to Glu or Arg. No accompanying restoration of ppGpp synthesis was detected in these RelC str double mutants.

Alleles↗
PubMed1997

Outcome measures for aphasia therapy: it's not what you do, it's the way that you measure it.

The development of outcome measures is now seen as crucial within the National Health Service (NHS), and the outcome of aphasia therapy is an area which has for some years been under particular scrutiny. Many districts have developed their own measures and others have taken part in cross-district pilot schemes, but it is not clear how widely used measures are, nor what form they take. This paper presents the results of a questionnaire survey of speech and language therapy services in England and Wales regarding their use of outcome measures for aphasia therapy. The questionnaire requested factual information about the use of measures, and therapists' opinions of their benefits and drawbacks, and also asked for examples of outcome measures currently in use. We summarise the results of the questionnaire and discuss the therapists' and our own perceptions of the merits of the different approaches reported.

Aphasia↗
PubMed1996

Induction of actinorhodin production by rpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3(2).

A strain of Streptomyces lividans, TK24, was found to produce a pigmented antibiotic, actinorhodin, although S. lividans normally does not produce this antibiotic. Genetic analyses revealed that a streptomycin-resistant mutation str-6 in strain TK24 is responsible for induction of antibiotic synthesis. DNA sequencing showed that str-6 is a point mutation in the rpsL gene encoding ribosomal protein S12, changing Lys-88 to Glu. Gene replacement experiments with the Lys88-->Glu str allele demonstrated unambiguously that the str mutation is alone responsible for the activation of actinorhodin production observed. In contrast, the strA1 mutation, a genetic marker frequently used for crosses, did not restore actinorhodin production and was found to result in an amino acid alteration of Lys-43 to Asn. Induction of actinorhodin production was also detected in strain TK21, which does not harbor the str-6 mutation, when cells were incubated with sufficient streptomycin or tetracycline to reduce the cell's growth rate, and 40 and 3% of streptomycin- or tetracycline-resistant mutants, respectively, derived from strain TK21 produced actinorhodin. Streptomycin-resistant mutations also blocked the inhibitory effects of relA and brgA mutations on antibiotic production, aerial mycelium formation or both. These str mutations changed Lys-88 to Glu or Arg and Arg-86 to His in ribosomal protein S12. The decrease in streptomycin production in relC mutants in Streptomyces griseus could also be abolished completely by introducing streptomycin-resistant mutations, although the impairment in antibiotic production due to bldA (in Streptomyces coelicolor) or afs mutations (in S. griseus) was not eliminated. These results indicate that the onset and extent of secondary metabolism in Streptomyces spp. is significantly controlled by the translational machinery.

Alleles↗
PubMed1993

Treatment of advanced non-small cell lung cancer with very high-dose cisplatin combined with etoposide and mitomycin C.

BACKGROUND: Treatment options for advanced non-small-cell lung cancer are inadequate. There remains a critical need for more effective systemic therapies. METHODS: Forty-one patients with advanced non-small-cell lung cancer were treated on a 28-day cycle with a very high-dose, cisplatin-based three-drug regimen. A treatment cycle consisted of an intravenous (IV) injection of cisplatin 100 mg/m2 on days 1 and 8; etoposide 60 mg/m2 IV over 30 minutes on days 1, 2, 8, and 9 (cycles 1 and 3 only); and mitomycin C 8 mg/m2 IV bolus on day 1 (cycles 2 and 4 only) (PEM regimen). RESULTS: The median dose intensity of cisplatin delivered was 49 mg/m2/wk, or 98% of the planned dose. One patient achieved a complete response and 16 patients a partial response or regression, yielding an overall objective response rate of 41%. The median duration of response was 21 weeks. Median survival of all patients was 38 weeks. Neurologic toxicity was dose limiting. The frequency of peripheral neuropathy and ototoxicity was directly related to cumulative cisplatin dose. In five patients, a progressive peripheral neuropathy developed after discontinuation of cisplatin. Hematologic toxicity also was significant. CONCLUSIONS: This very high-dose, cisplatin-based chemotherapy regimen has appreciable activity in advanced non-small-cell lung cancer. In comparison with previous reports on the use of very high-dose cisplatin alone, however, this combination appears at best to be only marginally more active, to confer no additional survival advantage, and to be considerably more toxic.

Adult↗
PubMedDate not supplied

Phonological awareness therapy and articulatory training approaches for children with phonological disorders: a comparative outcome study.

Sixty-one children, aged 3.6-5.0, with developmental phonological disorders (PD) participated in a study comparing the effects of metaphonologically (MET) or articulation-based (ART) therapy. Maturational effects were controlled for by the inclusion of 59 normally speaking control children of the same age range. Measures of phonological (speech) output and phonological awareness were taken before and after therapy for all subjects and at 3 months post-therapy for PD children. Results showed that PD children improved significantly in both phonological output and awareness skills across the intervention period compared with control children, but that there was no significant difference on the awareness measure between ART and MET groups. ART and MET groups differed from each other on one measure of speech improvement only, with the ART group making more change than the MET group on individual probe scores. Follow-up measures for both therapy groups indicated that there was little difference between the groups on phonological awareness change or speech development 3 months after intervention, though there was a trend for MET children to continue to make more long-term change than the ART group on one output measure. Additional analysis showed that there were generally few significant implications for outcome between PD children with good initial phonological awareness skills and those who initially had poor phonological awareness skills.

Articulation Disorders↗