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J Wood

Publications and source records attributed to J Wood.

At least 37 records · Page 2Linked to original sources
PubMed2003

A novel assay for discovery and characterization of pro-apoptotic drugs and for monitoring apoptosis in patient sera.

We have developed an apoptosis assay based on measurement of a neoepitope of cytokeratin-18 (CK18-Asp396) exposed after caspase-cleavage and detected by the monoclonal antibody M30. The total amount of caspase-cleaved CK18 which has accumulated in cells and tissue culture media during apoptosis is measured by ELISA. The sensitivity is sufficient for use in the 96-well format to allow high-through-put screening of drug libraries. We here describe strategies allowing classification of pro-apoptotic compounds according to their profiles of induction of apoptosis in the presence of pharmacological inhibitors. The time course of induction of CK18 cleavage can furthermore be used to distinguish structurally similar compounds. We propose that compounds that induce rapid CK18 cleavage have mechanisms of actions distinct from conventional genotoxic and microtubuli-targeting agents, and we present one example of an agent that induces almost immediate mitochondrial depolarization and cytochrome c release. Finally, CK18-Asp396 cleavage products are released from cells in tissue culture, and presumably from tumor cells in vivo. These products can be measured in sera from cancer patients. We present evidence suggesting that it will be possible to use the M30-ELISA assay for measuring chemotherapy-induced apoptosis in patient sera, opening possibilities for monitoring therapy.

Antibodies, Monoclonal↗
PubMed2003

Contribution of indirect computed tomography venography to computed tomography angiography of the chest for the diagnosis of thromboembolic disease in two United States emergency departments.

Recent reports suggest that physicians in non-ambulatory settings can use indirect CT venography (CTV) of the lower extremities immediately following spiral CT angiography (CTA) of the chest to identify patients with a negative CTA who have thromboembolic disease identified on CTV. We sought to determine the frequency of isolated deep venous thrombosis (DVT) discovered on CTV in emergency department (ED) patients with complaints suggestive of pulmonary embolism (PE) yet having a negative CTA. This study was conducted in a suburban and urban ED where patients with symptoms suspicious for PE were primarily evaluated with CTA and CTV. A total of 800 patients were studied, including 360 from the suburban ED and 440 from the urban ED. 88 (11%) patients were diagnosed with thromboembolic disease by CTA, or CTV, or both. Seventy-three patients had a CTA of the chest that was positive for PE, 42 (5.2%) of whom had evidence of both PE on CTA and DVT on CTV. Fifteen patients (2%, 95% CI = 1-3%) had a negative CTA and were subsequently found to have isolated DVT on CTV, all of whom received anticoagulation therapy. These data suggest that indirect CT venography of immediately following CT angiography of the chest significantly increased the frequency of diagnosed thromboembolic disease requiring anticoagulation in ED patients with suspected PE.

Adult↗
PubMed2003

Some current ideas on the pathogenesis and the role of neuroprotection in glaucomatous optic neuropathy.

The primary features of glaucomatous optic neuropathy are characteristic changes in the optic nerve head, a decrease in number of surviving ganglion cells and a reduction in vision. It is now generally accepted that a number of factors, including elevated intraocular pressure, could lead to the changes seen in the optic nerve head and to obtain a pharmacological means to treat the causes will vary from patient to patient. In contrast, a cascade of events have been proposed to explain how the changes in the optic nerve head may lead to the slow and differential death of ganglion cells in the disease. It is also proposed that drugs (neuroprotectants) influencing this cascade of events can attenuate ganglion cell death and lead to the treatment of all glaucoma patients.

Animals↗
PubMed2001

Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.

The vascular endothelial growth factor (VEGF) receptor is a major target for anti-angiogenesis-based cancer treatment. Here we report the treatment effect of ionizing radiation in combination with the novel orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 on endothelial cell proliferation in vitro and with tumour xenografts in vivo. Combined treatment of human umbilical vein endothelial cells with increasing doses of PTK787/ZK222584 and ionizing radiation abrogated VEGF-dependent proliferation in a dose-dependent way, but inhibition of endothelial cell proliferation was not due to apoptosis induction. In vivo, a combined treatment regimen of PTK787/ZK222584 (4 x 100 mg/kg) during 4 consecutive days in combination with ionizing radiation (4 x 3 Gy) exerted a substantial tumour growth delay for radiation-resistant p53-dysfunctional tumour xenografts derived from SW480 colon adenocarcinoma cells while each treatment modality alone had only a minimal effect on tumour size and neovascularization. SW480 tumours from animals that received a combined treatment regimen, displayed not only an extended tumour growth delay but also a significant decrease in the number of microvessels in the tumour xenograft. These results support the model of a cooperative anti-tumoral effect of angiogenesis inhibitor and irradiation and show that the orally bioavailable VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 is suitable for combination therapy with irradiation.

Adenocarcinoma↗
PubMed2001

Workforce planning. Of one mind.

The NHS is heavily reliant on locum doctors, many of whom trained overseas. It is important they are appropriately trained so they can be integrated into the workforce. A pilot nine-session course for consultant locum psychiatrists was well received by participants. Medical directors have expressed willingness to pay for locums to attend such courses.

Clinical Competence↗
PubMed2001

Comparison of single-round polymerase chain reaction (PCR) and pepsin-trypsin digest (PTD) methods for detection of Myxobolus cerebralis.

Single-round polymerase chain reaction (PCR) and pepsin-trypsin digest (PTD) methods were compared for the detection of Myxobolus cerebralis. Parallel tests were conducted on a total of 1743 free-ranging and 400 hatchery-reared salmonids. Concurrent results were found in 84.6% of the free-ranging fish samples, and 83.5% of the hatchery samples. PCR identified M. cerebralis more frequently than did PTD, and did so in many geographic locations previously considered free of the parasite. Average myxospore count by PTD among both free-ranging and hatchery fish increased significantly (p < 0.001) with a subjective evaluation of amplicon staining intensity.

Animals↗
PubMed2001

Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza.

BACKGROUND: In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. METHODS: 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7.5, 15, or 30 microg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, microneutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. FINDINGS: The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 microgram doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7.5 microg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight of ten; H5N3 SRH, ten of ten; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. INTERPRETATION: Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7.5-30 microg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.

Adult↗
PubMed2001

Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells.

The major histocompatibility complex (MHC) class II transactivator (CIITA) acts as a master switch to activate expression of the genes required for MHC-II antigen presentation. During B-cell to plasma cell differentiation, MHC-II expression is actively silenced, but the mechanism has been unknown. In plasma cell tumors such as multiple myeloma the repression of MHC-II is associated with the loss of CIITA. We have identified that positive regulatory domain I binding factor 1 (PRDI-BF1), a transcriptional repressor, inhibits CIITA expression in multiple myeloma cell lines. Repression of CIITA depends on the DNA binding activity of PRDI-BF1 and its specific binding site in the CIITA promoter. Deletion of a histone deacetylase recruitment domain in PRDI-BF1 does not inhibit repression of CIITA nor does blocking histone deacetylase activity. This is in contrast to PRDI-BF1 repression of the c-myc promoter. Repression of CIITA requires either the N-terminal acidic and conserved PR motif or the proline-rich domain. PRDI-BF1 has been shown to be a key regulator of B-cell and macrophage differentiation. These findings now indicate that PRDI-BF1 has at least two mechanisms of repression whose function is dependent on the nature of the target promoter. Importantly, PRDI-BF1 is defined as the key molecule in silencing CIITA and thus MHC-II in multiple myeloma cells.

Genes, MHC Class II↗
PubMed2001

Characterization of cytokine interactions by flow cytometry and factorial analysis.

BACKGROUND: Multiple cytokines are required for the growth and development of hematopoietic cells. The effect of many cytokines depends on the activity of other signaling pathways. These interactions are quantified using factorial experimental design and analysis. METHODS: Human umbilical cord blood (HUCB) CD34+ cells were cultured in fully defined media containing various combinations of recombinant cytokines as defined by resolution IV factorial (2(7-3)(IV)) or full factorial (2(4)) design experiments. The cytokines studied were stem cell factor (SCF), interleukin (IL)-3, megakaryocyte growth and development factor (MGDF), granulocyte-colony stimulating factor (G-CSF), Flt-3 ligand, IL-6, IL-11, and erythropoietin (EPO). In vitro cell divisions were tracked by staining CD34+ cells with 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester, followed by flow cytometric analysis at 4 days of culture. In separate experiments, lineage commitment and differentiation were determined at 7 days by immunophenotype. RESULTS: In addition to the main effects of single cytokines, cytokine interactions were identified. There was a negative interaction between IL-3 and MGDF that resulted in a less than additive effect of these factors on erythroid and megakaryocytic development. The effect of Flt-3 ligand and SCF factor on CD34+ cell production was also less than additive, although the response to both cytokines was greater than single cytokines. The only positive interaction that was identified was between EPO and SCF, which resulted in the synergistic production of erythroid cells. CONCLUSIONS: Factorial analysis provides a powerful methodology to study the integration of multiple signals at the cellular and molecular level.

Analysis of Variance↗
PubMed2001

Prophylactic use of oxytocin in the third stage of labour.

BACKGROUND: Many maternal deaths across the world result from complications of the third stage of labour (when the placenta is delivered). OBJECTIVES: To examine the effect of oxytocin given prophylactically in the third stage of labour on maternal and neonatal outcomes. SEARCH STRATEGY: Relevant trials were identified in the Cochrane Collaboration Controlled Trials Register and the Pregnancy and Childbirth Review Group's Specialised Register of Controlled Trials. Date of last search: May 2001. SELECTION CRITERIA: All acceptably randomised or quasi-randomised controlled trials including pregnant women anticipating a vaginal delivery where oxytocin was given prophylactically for the third stage of labour. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for relevance and methodological quality, and extracted data. Analysis was by intention to treat. Subgroup analyses were based on extent of selection bias, oxytocin in the context of active or expectant management of the third stage, and timing of administration. Results are presented as relative risks, and weighted mean difference, both with 95% confidence intervals using a fixed effects model. MAIN RESULTS: In seven trials involving over 3000 women in hospital and/or developed country settings, prophylactic oxytocin showed benefits (reduced blood loss (relative risk (RR) for blood loss > 500 ml 0.50; 95% confidence interval (CI) 0.43, 0.59) and need for therapeutic oxytocics (RR 0.50; 95% CI 0.39, 0.64).) compared to no uterotonics, although there was a non-significant trend towards more manual removal of the placenta (RR 1.17; 95% CI 0.79, 1.73) which was most marked in the expectant management subgroup, and blood transfusions (RR 1.30; 95% CI 0.50, 3.39) in the trials with more manual removals of the placenta). In six trials involving over 2800 women, there was little evidence of differential effects for oxytocin versus ergot alkaloids, except ergot alkaloids are associated with more manual removals of the placenta (RR 0.57; 95% CI 0.41, 0.79), and with the suggestion of more raised blood pressure (RR 0.53; 95% CI 0.19, 1.58) than with oxytocin. In five trials involving over 2800 women, there was little evidence of a synergistic effects of adding oxytocin to ergometrine versus ergometrine alone. For all other outcomes in the comparisons either there are no data or the number of adverse events is very small, and so definite conclusions cannot be drawn. REVIEWER'S CONCLUSIONS: There are strong suggestions of benefit for oxytocin in terms of postpartum haemorrhage, and the need for therapeutic oxytocics, but without sufficient information about other outcomes and side-effects it is difficult to be confident about the trade-offs for these benefits, especially if the risk of manual removal of the placenta may be increased. There seems little evidence in favour of ergot alkaloids alone compared to either oxytocin alone, or to Syntometrine, but the data are sparse. More trials are needed in domiciliary deliveries in developing countries, which shoulder most of the burden of third stage complications.

Ergot Alkaloids↗
PubMed2001

Tyrosine kinase inhibitors: from rational design to clinical trials.

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

Animals↗
PubMed2001

Immune related genetic polymorphisms and schizophrenia among the Chinese.

Genetic association studies were conducted among two independent cohorts of Chinese ethnicity. The samples consisted of cases and unrelated controls, ascertained from Guangzhou, China, and Singapore. The studies were prompted by our earlier report of an association between schizophrenia and HLA DQB1 alleles (HLA DQB1*0602 and HLA DQB1*0303) in the Singapore sample. Polymorphisms of HLA DQB1 and flanking markers on chromosome 6p21.3 were investigated in the first part of the study. A significant negative association with HLA DQB1*0402 was detected in the Guangzhou sample (Odds ratio, OR 0.26, 95% confidence intervals, CI 0.1, 0.6; p < 0.02, corrected for multiple comparisons). Additional analysis of the Guangzhou and Singapore samples revealed associations at three other anonymous markers flanking HLA DQB1. In the second part of the study, three polymorphisms at the Interleukin-1 gene cluster (IL-1, chromosome 2q13-q21) were investigated in both cohorts, since associations with schizophrenia have been reported in another sample. Persuasive evidence for an association at IL-1 was not detected in either sample. Our results suggest a susceptibility locus for schizophrenia in the HLA region among the Chinese, but further clarification is necessary.

Adult↗
PubMed2001

Anxiety and cognitive inhibition.

In 3 experiments, the authors investigated whether anxiety proneness is associated with impaired inhibitory processing. Participants made speeded decisions requiring inhibition of threatening or neutral meanings of ambiguous words, which were inappropriate in their current context. In Experiment 1 there were no differences found in inhibitory processing associated with anxiety. However, in Experiment 2, when the capacity for controlled processing was reduced by imposition of a mental load, anxious individuals showed a response pattern consistent with a general impairment of inhibitory processing. In Experiment 3, a group who had experienced a traumatic event also showed evidence of impaired inhibition, despite the absence of additional load. Thus anxiety proneness is associated with a general deficit of inhibitory processing, but this may be revealed only under conditions that limit the availability of controlled processing resources.

Adult↗
PubMed2001

Family-based association studies of monoaminergic gene polymorphisms among North Indians with schizophrenia.

Associations between schizophrenia and four candidate genes were tested among Indian patients with schizophrenia and their parents (DSM-IV criteria, n = 179 families). Polymorphisms within the genes encoding the serotonin 2A receptor (HT2A), tryptophan hydroxylase (TPH), catechol-O-methyl transferase (COMT) and dopamine transporter (DAT) were thus investigated. Two polymorphisms each were analyzed at HT2A and TPH, enabling haplotype-based analyses using the transmission disequilibrium test (TDT) for these genes. No significant associations were detected. Pooled analysis of samples like ours may be necessary to definitively exclude putative allelic associations at these loci.

Adult↗
PubMed2001

Reduced memory B-cell populations in boys with B-cell dysfunction after bone marrow transplantation for X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency (XSCID) is a lethal disease resulting in death in infancy. In many instances, haploidentical bone marrow transplantation (BMT) offers reconstitution of T-cell immunity alone, with residual hypogammaglobulinaemia. The exact nature of B-cell dysfunction in these patients is unclear, although differentiation arrest of the B cells is a potential explanation. To ascertain the differentiation status of peripheral blood B lymphocytes from XSCID patients after BMT, the surface expression of CD19, CD10, CD34, CD5, serum immunoglogulin (sIg)M, sIgD, sIgG and CD27 on these B cells was investigated using three-colour flow cytometry. CD27 is a marker of memory B cells. Populations of CD19+IgM-D- B cells, CD19+IgM-only, CD19+IgG+CD27+ and CD19+IgM+ CD27+ B cells were found to be diminished in the XSCID patients after BMT with persistent hypogammaglobulinaemia, compared with both post-BMT patients with B-cell function and age-matched normal controls. This indicated the lack of CD19+IgM-D- B cells, which represent Ig isotype-switched B cells, as well as CD19+IgM-only and CD19+IgG+CD27+ or CD19+IgM+CD27+ memory B-cell populations. Interaction between CD27 and its ligand CD70 has been shown to induce IgG and IgM production by CD27+ B cells. Therefore, the lack of CD27/70 interaction is a probable explanation for the hypogammaglobulinaemia in these patients after BMT.

Agammaglobulinemia↗