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Biomedical subjects

P Ward

Publications and source records attributed to P Ward.

At least 55 records · Page 3Linked to original sources
PubMed1999

Aberrant antigen expression detected by multiparameter three color flow cytometry in intermediate and high grade B-cell lymphomas.

The aberrant expression of antigens (Ag) in lymphoproliferative disorders may cause a diagnostic problem when single parameter immunohistochemical assays are performed on frozen or paraffin sections because coexpression by relevant cells is not determined. This aberrant expression also raises the question as to whether mixed lineage (biphenotypic) lymphoid proliferations exist. Marrow (6) and extramedullary (20) tissues from 26 patients with diffuse, intermediate and high grade, B-cell lymphomas (IWF E=1, F=1, G=19, H=1 and J=4) were analyzed with 19 markers using 3-color flow cytometry. The percentages (%) of patients with double Ag coexpression in at least 20% of the CD19+ or CD20+ lymphoma cells were: stem cell (SC) Ag: CD10 = 58 and CD34 = 15; T-cell Ag: CD2 = 38, CD5 = 19 and CD7 = 19; myeloid (My) Ag: CD13 = 19 and CD33 = 8. The corresponding % with unusual triple Ag coexpression in at least 10% of the CD19+ B-cells were SC+T+ Ag: CD10CD2 = 50, CD10CD5 = 27, CD10CD7 = 38, CD34CD2 = 31, CD34CD5 = 19 and CD34CD7 = 27; T+T+ Ag: CD2CD5 = 35, CD2CD7 = 42 and CD5CD7 = 31; T+My+ Ag: CD2CD13 = 35 and CD2CD33 = 12; and My+My+ Ag: CD13CD33 = 12. Ten of 12 lymphomas tested showed clonal immunoglobulin (Ig) heavy chain gene rearrangements in the absence of clonal T-cell receptor (TCR) gene rearrangements. None (0%) of the My Ag positive cases showed immunoreactivity for myeloperoxidase. We conclude that the anomalous T and My Ag expression seen in the above B-cell lymphomas is not indicative of mixed lineage proliferation but represents the aberrant expression of these antigens by the malignant cells.

Antigens, CD↗
PubMed1998

Neutropenia associated with T-cell large granular lymphocyte leukemia: long-term response to cyclosporine therapy despite persistence of abnormal cells.

T-cell large granular lymphocyte (T-LGL) leukemia is clinically indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We report reversal of severe neutropenia associated with T-LGL leukemia in five patients treated with cyclosporine (CSA). All five had persistent neutrophil counts below 0.5 x 10(9)/L, two had agranulocytosis, and four had recurrent infections. Increased populations of LGL were present in blood and marrow, with a T-LGL immunophenotype (CD3(+)CD8(+)CD16(+/-)CD56(+/-)CD57(+)) shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels. Four patients attained normal neutrophil counts with CSA alone; one required addition of low-dose granulocyte-macrophage colony-stimulating factor. Time to attainment of 1.5 x 10(9)/L neutrophils ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted in recurrent neutropenia. Three patients have maintained normal neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two patients died 1.7 and 4.6 years after initiation of CSA despite normal neutrophil counts-one of metastatic melanoma and one of complications after aortofemoral bypass surgery. Despite resolution of neutropenia, increased populations of T-LGL cells have persisted in all patients during CSA therapy, as shown by morphology and flow cytometry and by the presence of clonal TCR gene rearrangements in four patients' posttreatment blood samples. We conclude that CSA is an effective therapy for neutropenia associated with T-LGL leukemia, and that resolution of neutropenia despite persistence of abnormal cells implies that CSA may inhibit T-LGL secretion of yet unidentified mediators of neutropenia.

Adult↗
PubMed1998

Characterization of mutations in the cystathionine beta-synthase gene in Irish patients with homocystinuria.

We used single-strand conformational polymorphism and nucleotide sequencing to characterize defective cystathionine beta-synthase gene alleles in 18 independent Irish patients with homocystinuria. Six mutations were detected, three of which have been reported previously and three of which were novel. The novel mutations include T302C (L101P), C684G (N228K), and G1063C (A354P). Of the three, only T302C (L101P) was somewhat prevalent, being found in 3 of 37 independent alleles.

Cystathionine beta-Synthase↗
PubMed1998

Patient participation in decision-making.

We review the research both for and against patient participation in decision-making and conclude that (a) patients want to be informed of treatment alternatives, (b) they, in general, want to be involved in treatment decisions when more than one treatment alternative exists, and (c) the benefits of participation have not yet been clearly demonstrated in research studies. However, studies that have addressed the latter issue suffer from methodological problems such as small sample sizes and lack of control for potential confounding variables. We conclude that patient participation in decision-making is justified on humane grounds alone and that physicians should endeavor to engage patients in decision-making, albeit at varying degrees, when more than one effective treatment option exists. We propose that methods be developed to evaluate a patient's level of "readiness" to participate in decision-making and that interventions that match the patient's level of readiness be applied to increase participation.

Decision Making↗
PubMed1998

Pharmacological profile of a novel cyclic AMP-linked P2 receptor on undifferentiated HL-60 leukemia cells.

1. Extracellular ATP (EC50=146+/-57 microM) and various ATP analogues activated cyclic AMP production in undifferentiated HL-60 cells. 2. The order of agonist potency was: ATPgammaS (adenosine 5'-O-[3-thiotriphosphate]) > or = BzATP (2'&3'O-(4-benzoylbenzoyl)-adenosine-5'-triphosphate) > or = dATP > ATP. The following agonists (in order of effectiveness at 1 mM) were all less effective than ATP at concentrations up to 1 mM: beta,gamma methylene ATP > or = 2-methylthioATP > ADP > or = Ap4A (P1, P4-di(adenosine-5') tetraphosphate) > or = Adenosine > UTP. The poor response to UTP indicates that P2Y2 receptors are not responsible for ATP-dependent activation of adenylyl cyclase. 3. Several thiophosphorylated analogs of ATP were more potent activators of cyclic AMP production than ATP. Of these, ATPgammaS (EC50=30.4+/-6.9 microM) was a full agonist. However, adenosine 5'-O-[1-thiotriphosphate] (ATPalphaS; EC50=45+/-15 microM) and adenosine 5'-O-[2-thiodiphosphate] (ADPbetaS; EC50=33.3+/-5.0 microM) were partial agonists. 4. ADPbetaS (IC50=146+/-32 microM) and adenosine 5'-O-thiomonophosphate (AMPS; IC50=343+/-142 microM) inhibited cyclic AMP production by a submaximal concentration of ATP (100 microM). Consistent with its partial agonist activity, ADPbetaS was estimated to maximally suppress ATP-induced cyclic AMP production by about 65%. AMPS has not been previously reported to inhibit P2 receptors. 5. The broad spectrum P2 receptor antagonist, suramin (500 microM), abolished ATP-stimulated cyclic AMP production by HL-60 cells but the adenosine receptor antagonists xanthine amine congener (XAC; 20 microM) and 8-sulpho-phenyltheophylline (8-SPT; 100 microM) were without effect. 6. Extracellular ATP also activated protein kinase A (PK-A) consistent with previous findings that PK-A activation is involved in ATP-induced differentiation of HL-60 cells (Jiang et al., 1997). 7. Taken together, the data indicate the presence of a novel cyclic AMP-linked P2 receptor on undifferentiated HL-60 cells.

Adenosine Triphosphate↗
PubMed1998

Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist.

The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet. Animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0(-15 min)), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg(-1)), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg(-1)) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n = 8), 0.3 (n = 16) or 1.0 (n = 13) mg kg(-1). In eight additional piglets, GR205171 (1 mg kg(-1)) was administered 15 min before the onset of the delayed phase (T16(-15 min)). A further five piglets received GR205171 (1 mg kg(-1)) every 6 h throughout the experiment. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0(-15 min), and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0(-15 min) with GR205171 1 mg kg(-1), eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg(-1)) at T16(-15 min) exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

Animals↗
PubMed1998

Role of the adenovirus DNA-binding protein in in vitro adeno-associated virus DNA replication.

A basic question in adeno-associated virus (AAV) biology has been whether adenovirus (Ad) infection provided any function which directly promoted replication of AAV DNA. Previously in vitro assays for AAV DNA replication, using linear duplex AAV DNA as the template, uninfected or Ad-infected HeLa cell extracts, and exogenous AAV Rep protein, demonstrated that Ad infection provides a direct helper effect for AAV DNA replication. It was shown that the nature of this helper effect was to increase the processivity of AAV DNA replication. Left unanswered was the question of whether this effect was the result of cellular factors whose activity was enhanced by Ad infection or was the result of direct participation of Ad proteins in AAV DNA replication. In this report, we show that in the in vitro assay, enhancement of processivity occurs with the addition of either the Ad DNA-binding protein (Ad-DBP) or the human single-stranded DNA-binding protein (replication protein A [RPA]). Clearly Ad-DBP is present after Ad infection but not before, whereas the cellular level of RPA is not apparently affected by Ad infection. However, we have not measured possible modifications of RPA which might occur after Ad infection and affect AAV DNA replication. When the substrate for replication was an AAV genome inserted into a plasmid vector, RPA was not an effective substitute for Ad-DBP. Extracts supplemented with Ad-DBP preferentially replicated AAV sequences rather than adjacent vector sequences; in contrast, extracts supplemented with RPA preferentially replicated vector sequences.

Adenoviridae↗
PubMed1997

Effect of single point mutations of the human tachykinin NK1 receptor on antagonist affinity.

Molecular modelling and site-directed mutagenesis were used to identify eleven amino acid residues which may be involved in antagonist binding of the human tachykinin NK1 receptor. Recombinant receptors were expressed in mammalian cells using the Semliki Forest virus system. Wild type and mutant receptors showed similar expression levels in BHK and CHO cells, verified by metabolic labelling. Binding affinities were determined for a variety of tachykinin NK1 receptor antagonists in SFV-infected CHO cells. The binding affinity for GR203040, CP 99,994 and CP 96,345 was significantly reduced by mutant Q165A. The mutant F268A significantly reduced the affinity for GR203040 and CP 99,994 and the mutant H197A had reduced affinity for CP 96,345. All antagonists seemed to bind in a similar region of the receptor, but do not all rely on the same binding site interactions. Functional coupling to G-proteins was assayed by intracellular Ca2+ release in SFV-infected CHO cells. The wild type receptor and all mutants except A162L and F268A responded to substance P stimulation.

Animals↗
PubMed1997

Extracellular ATP triggers cyclic AMP-dependent differentiation of HL-60 cells.

Extracellular ATP and ATPgammaS (1-1000 microM) stimulated cyclic AMP (cAMP) production in undifferentiated HL-60 cells. The potency order for adenine nucleotides and adenosine was ATPgammaS > ATP >> ADP > or = AMP = Adenosine. Indomethacin (50 microM) had no effect on ATP-induced cAMP production. ATP and ATPgammaS also suppressed cell growth and induced differentiation as revealed by fMLP-stimulated beta-glucuronidase release 48 h after exposure. The potency order for the induction of fMLP-stimulated beta-glucuronidase release by adenine nucleotides and adenosine was ATPgammaS > or = ATP > ADP > AMP = Adenosine approximately 0. The protein kinase A inhibitor Rp-8-Br-cAMPS (10-200 microM) suppressed ATP-induced differentiation but had no effect on ATP-dependent growth suppression. UTP which, like ATP, activates P2U receptors on HL-60 cells, had no effect on cAMP production, cell growth, or differentiation. The data suggest the existence of a novel receptor for ATP on undifferentiated HL-60 cells that is coupled to the activation of adenylate cyclase and cAMP-dependent differentiation.

Adenosine Triphosphate↗
PubMed1997

Extracellular ATP triggers cyclic AMP-dependent differentiation of HL-60 cells.

Extracellular ATP and ATP gamma S (1-1000 microM) stimulated cyclic AMP (cAMP) production in undifferentiated HL-60 cells. The potency order for adenine nucleotides and adenosine was ATP gamma S > ATP > > ADP > 3 AMP = Adenosine. Indomethacin (50 microM) had no effect on ATP-induced cAMP production. ATP and ATP gamma S also suppressed cell growth and induced differentiation as revealed by fMLP-stimulated beta-glucuronidase release 48 h after exposure. The potency order for the induction of fMLP-stimulated beta-glucuronidase release by adenine nucleotides and adenosine was ATP gamma S > 3 ATP > ADP > AMP = Adenosine approximately 0. The protein kinase A inhibitor Rp-8-Br-cAMPS (10-200 mM) suppressed ATP-induced differentiation but had no effect on ATP-dependent growth suppression. UTP which, like ATP, activates P2U receptors on HL-60 cells, had no effect on cAMP production, cell growth, or differentiation. The data suggest the existence of a novel receptor for ATP on undifferentiated HL-60 cells that is coupled to the activation of adenylate cyclase and cAMP-dependent differentiation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

The activity of GR205171, a potent non-peptide tachykinin NK1 receptor antagonist, in the trigeminovascular system.

The in vivo activity of GR205171, a novel, highly potent non-peptide tachykinin NK1 receptor antagonist, has been investigated in the trigeminovascular system in order to assess its potential as an acute therapy for migraine headache. In anaesthetised rabbits, GR205171 attenuated reductions in carotid arterial vascular resistance evoked by the tachykinin NK1 receptor agonist, substance P methyl ester (SPOMe), injected via the lingual artery (DR30 (i.e., the dose producing a dose-ratio of 30) = 0.4 microgram/kg, i.v.). In anaesthetised rats, GR205171 (0.1 and 1 mg/kg, i.v.) produced a dose-dependent inhibition of plasma protein extravasation (PPE) in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. In anaesthetised guinea-pigs, GR205171 (1.10 and 100 micrograms/kg, i.v.) inhibited, by up to approximately 60%, expression of c-fos in the trigeminal nucleus caudalis in response to electrical stimulation of the trigeminal ganglion. It is concluded that GR205171 is a potent antagonist of NK1 receptor-mediated cranial vasodilatation, dural PPE and expression of c-fos in the trigeminal nucleus caudalis. Such a profile of action suggests that GR205171 may have potential as a novel therapeutic agent in the treatment of migraine headache.

Animals↗
PubMed1997

Improving cardiopulmonary resuscitation skills retention: effect of two checklists designed to prompt correct performance.

Previous research has shown that regardless of an individual's experience, life support skills such as cardiopulmonary resuscitation (CPR) are poorly performed as soon as 1 month following training. The purpose of this study was to compare the effects of two checklists designed to prompt correct CPR performance. We compared the performance of 169 undergraduate students, at the time of course assessment, with retention testing that occurred 2 months following the course assessment. Students were randomly assigned to a control group, a short version of a CPR checklist and a longer more detailed version. Two groups of variables were created: procedural and compression-ventilation variables. In addition, an overall-performance variable was created, summarizing performance on the procedural variables. Binary variables were assessed with chi 2-tests of independence. One-way ANOVAs, using 'group' as the between-subjects factor, were used to assess each continuous variable. Comparisons between groups yielded significant differences of P < 0.05. The long checklist generally led to superior performance on the procedural variables. The results support the hypothesis that remembering the steps of CPR is too complex for some. Though preliminary, the findings of this study indicate that the detailed checklist was an effective strategy to improve the post-course performance of CPR.

Cardiopulmonary Resuscitation↗
PubMed1997

Corporate management and clinical autonomy: the ethical dilemma in mental health.

Funding constraints and management practices are increasing pressure on clinical autonomy within Australian mental health services. The introduction of total quality management, output-based funding and changes to public mental health policy have promoted business-like efficiency and increased control of resources. It is argued that such moves significantly circumscribe the discretionary authority that mental health professionals have previously enjoyed. This paper attempts to highlight the ethical and moral tension inherent with a corporate management approach, and calls for mental health services to acknowledge the value of intellectual capital, creativity and innovation.

Australia↗
PubMed1997

Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha.

BACKGROUND: The aetiology and pathophysiology of ulcerative colitis remains unclear; however, there is increasing recognition of the critical role of inflammatory cytokines in the pathogenesis of this disease. Among these, tumour necrosis factor alpha (TNF alpha) seems to play an important role. AIM: To study the effects of an engineered human monoclonal antibody to TNF alpha (CDP571) in the treatment of idiopathic ulcerative colitis in the cottontop tamarin. METHODS: Six cottontop tamarins with confirmed ulcerative colitis received repeated doses of CDP571. Progression of disease was assessed by measuring both body weight and rectal biopsy pathology. RESULTS: All animals showed a rapid improvement in clinical condition and rectal biopsy pathology that was maintained following completion of the therapy. CONCLUSION: These studies indicate the efficacy of selective antibody therapy to TNF alpha for the treatment of ulcerative colitis in a primate and suggest that similar therapy in human could be of value.

Animals↗
PubMed1997

Molecular biology and the major psychoses.

OBJECTIVE: To highlight the potential role of molecular biological studies in examining the expression of genes of interest in brain tissue to elucidate the pathophysiological basis of the major psychoses. METHOD: To review the principles underlying the available techniques for expression studies. RESULTS: Detection of messenger RNA by in situ hybridisation and quantitation by Northern analysis are powerful tools to detect abnormalities in gene expression in brain tissue. CONCLUSION: The availability of simple techniques to examine the expression of RNA and protein products of individual genes, including examination at the level of individual cells, offers a clear opportunity to define the molecular basis of the major psychoses.

Brain↗