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J Wood

Publications and source records attributed to J Wood.

At least 73 records · Page 4Linked to original sources
PubMed2000

Structure and sequence variation of the trypanosome spliced leader transcript.

We have assessed the potential of using the spliced leader (SL) or mini-exon gene as a marker for molecular phylogenetic analysis of genus Trypanosoma. A total of 27 trypanosome sequences were compared, 18 of these being newly reported. In contrast to genus Leishmania, we found the non-transcribed spacer region of the SL locus in trypanosomes to be far too variable for informative comparison of all but the most closely related species. At the other extreme, the short (39 nt) SL exon was usually completely conserved and hence uninformative. The SL RNA showed variation in both length (97-152 nt) and sequence among different trypanosome species, with most variation occurring in stem-loop II. Consequently, this region could not be aligned with confidence in multiple sequence alignment, severely reducing the number of phylogenetically informative nucleotide positions. In computer simulation, most of the SL RNAs readily folded into the 3 stem-loop secondary structure predicted previously, but again stem-loop II was highly variable. No obvious correlation could be seen between the length of this stem-loop and trypanosome biology. We conclude that the SL repeat is not an informative phylogenetic marker for long range evolutionary studies of genus Trypanosoma.

Animals↗
PubMed2000

Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2.

PTEN is a tumor suppressor gene mutated in human cancers. Although many mutations target the phosphatase domain, others create a truncated protein lacking the C-terminal PDZ-binding motif or a protein that extends beyond the PDZ-binding motif. Using the yeast two-hybrid system, we isolated a membrane-associated guanylate kinase family protein with multiple PDZ domains [AIP-1 (atrophin interacting protein 1), renamed MAGI-2 (membrane associated guanylate kinase inverted-2)]. MAGI-2 contains eight potential protein-protein interaction domains and is localized to tight junctions in the membrane of epithelial cells. PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 enhances the ability of PTEN to suppress Akt activation. Furthermore, certain PTEN mutants have reduced stability, which is restored by adding the minimal PDZ-binding motif back to the truncated protein. We propose that MAGI-2 improves the efficiency of PTEN signaling through assembly of a multiprotein complex at the cell membrane.

Gene Expression Regulation↗
PubMed2000

Rapid desensitization of the nitric oxide receptor, soluble guanylyl cyclase, underlies diversity of cellular cGMP responses.

A major receptor for nitric oxide (NO) is the cGMP-synthesizing enzyme, soluble guanylyl cyclase (sGC), but it is not known how this enzyme behaves in cells. In cerebellar cells, NO (from diethylamine NONOate) increased astrocytic cGMP with a potency (EC(50) </= 20 nM) higher than that reported for purified sGC. Deactivation of NO-stimulated sGC activity, studied by trapping free NO with hemoglobin, took place within seconds (or less) rather than the minute time scale reported for the purified enzyme. Measurement of the rates of accumulation and degradation of cGMP were used to follow the activity of sGC over time. The peak activity, occurring within seconds of adding NO, was swiftly followed by desensitization to a steady-state level 8-fold lower. The same desensitizing profile was observed when the net sGC activity was increased or decreased or when cGMP breakdown was inhibited. Recovery from desensitization was relatively slow (half-time = 1.5 min). When the cells were lysed, sGC desensitization was lost. Analysis of the transient cGMP response to NO in human platelets showed that sGC underwent a similar desensitization. The results indicate that, in its natural environment, sGC behaves much more like a neurotransmitter receptor than had been expected from previous enzymological studies, and that hitherto unknown sGC regulatory factors exist. Rapid sGC desensitization, in concert with variations in the rate of cGMP breakdown, provides a fundamental mechanism for shaping cellular cGMP responses and is likely to be important in decoding NO signals under physiological and pathophysiological conditions.

Animals↗
PubMed2000

Loxapine for schizophrenia.

BACKGROUND: Loxapine is a drug with D2/D3 receptor antagonist activity and a higher affinity for D3 than D2. Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal side-effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1996), PSYNDEX (1977-1995) and PsycLIT (1974-1999) were undertaken. In addition, pharmaceutical databases on the Dialog Corporation Datastar and Dialog services were searched. References of all identified studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted but excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Compared to placebo, loxapine is antipsychotic (Global effect - not improved at 6 weeks, n=66, RR 0.6 CI 0.4-0.9 NNT 4 CI 2-62) with similar adverse effect profile to typical drugs. Is as effective as typical drugs in the short term (4-12 weeks) (Global effect - not improved, n=411, RR 0.89 CI 0.7-1.2). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. REVIEWER'S CONCLUSIONS: Loxapine is antipsychotic but its effects are under researched. It is not clearly different from typical drugs in either its positive or adverse effects.

Antipsychotic Agents↗
PubMed2000

Implementation of a large-scale ENU mutagenesis program: towards increasing the mouse mutant resource.

Systematic approaches to mouse mutagenesis will be vital for future studies of gene function. We have begun a major ENU mutagenesis program incorporating a large genome-wide screen for dominant mutations. Progeny of ENU-mutagenized mice are screened for visible defects at birth and weaning, and at 5 weeks of age by using a systematic and semi-quantitative screening protocol-SHIRPA. Following this, mice are screened for abnormal locomotor activity and for deficits in prepulse inhibition of the acoustic startle response. Moreover, in the primary screen, blood is collected from mice and subjected to a comprehensive clinical biochemical analysis. Subsequently, secondary and tertiary screens of increasing complexity can be used on animals demonstrating deficits in the primary screen. Frozen sperm is archived from all the male mice passing through the screen. In addition, tail tips are stored for DNA. Overall, the program will provide an extensive new resource of mutant and phenotype data to the mouse and human genetics communities at large. The challenge now is to employ the expanding mouse mutant resource to improve the mutant map of the mouse. An improved mutant map of the mouse will be an important asset in exploiting the growing gene map of the mouse and assisting with the identification of genes underlying novel mutations-with consequent benefits for the analysis of gene function and the identification of novel pathways.

Animals↗
PubMed2000

Incorporating patient preferences into randomized trials.

When designing trials, an important ethical and practical concern is ensuring that proper consideration is given to patient preferences. A number of design variants on the traditional randomized trial can take account of such preferences in different ways. The partially randomized patient preference (PRPP) design is often advocated for taking these preferences into account. In studies of this type, all eligible patients are followed up, but the primary comparison is still between effects observed in patients randomly allocated to treatment arms. This design and other variants on conventional trials each have different scientific, ethical, and practical implications. We consider these diverse aspects of several modifications to the conventional method for obtaining consent and then, in more detail, the relative merits of the PRPP design. We conclude that none of these adjustments is ideal. Those designing trials should therefore always think carefully about the consent process, for its implications on participation and on how the results will be interpreted.

Epidemiologic Research Design↗
PubMed2000

A case control study of multiple myeloma at four nuclear facilities.

PURPOSE: Reported elevations of multiple myeloma among nuclear workers exposed to external penetrating ionizing radiation, based on small numbers of cases, prompted this multi-facility study of workers at US Department of Energy facilities. METHODS: Ninety-eight multiple myeloma deaths and 391 age-matched controls were selected from the combined roster of 115,143 workers hired before 1979 at Hanford, Los Alamos National Laboratory, Oak Ridge National Laboratory, and the Savannah River site. These workers were followed for vital status through 1990 (1986 for Hanford). Demographic, work history, and occupational exposure data were derived from personnel, occupational medicine, industrial hygiene, and health physics records. Exposure-disease associations were evaluated using conditional logistic regression. RESULTS: Cases were disproportionately African American, male, and hired prior to 1948. Lifetime cumulative whole body ionizing radiation dose was not associated with multiple myeloma, however, there was a significant effect of age at exposure, with positive associations between multiple myeloma and doses received at older ages. Dose response associations increased in magnitude with exposure age (from 40 to 50) and lag assumption (from 5 to 15 years), while a likelihood ratio goodness of fit test reached the highest value for cumulative doses received at ages above 45 with a 5-year lag (X2=5.43,1 df; relative risk = 6.9% per 10 mSv). Dose response associations persisted with adjustment for potential confounders. CONCLUSIONS: Multiple myeloma was associated with low level whole body penetrating ionizing radiation doses at older ages. The exposure age effect is at odds with interpretations of A-bomb survivor studies but in agreement with several studies of cancer among nuclear workers.

Age Factors↗
PubMed2000

Do coping styles differ across sociocultural groups? The role of measurement equivalence in making this judgment.

Cross-sociocultural group measurement equivalency is an important issue that generally has not been studied in the coping literature. Measurement equivalency of the COPE (Carver, Scheier, & Weintraub, 1989) was assessed across two sociocultural groups, a sample of 100 Anglo middle-class divorced mothers and a sample of 122 low-income Mexican American/Mexican immigrant mothers. A series of restrictive confirmatory factor analyses revealed that seven of the COPE's subscales may be measuring the same underlying construct across populations. However, scores derived from the subscales may not represent the same magnitude of the construct in these two groups. This study makes an important first step in furthering the understanding of coping strategies in low-income Mexican American/Mexican immigrant mothers. This study also illustrates the importance of testing for measurement equivalency before conducting comparative research in disparate populations.

Adaptation, Psychological↗
PubMed2000

Low prevalence of psychoses among the Hutterites, an isolated religious community.

OBJECTIVE: The authors estimated the prevalence of psychoses among the Hutterites in Manitoba, Canada, who lived in 102 communal farms or colonies. The study stemmed from an earlier epidemiological survey of North American Hutterite colonies (1950-1953), in which a low prevalence of psychoses was documented. METHOD: Psychiatrically ill individuals identified during the previous survey were rediagnosed with DSM-IV criteria. A current provincial health insurance claims database was queried anonymously for the period June 1992-May 1997, and the prevalence rate of disease among Hutterites, identified by distinctive surnames and unique postal addresses, was compared with the rate in the entire population of the province of Manitoba and in a comparison group of persons with Hutterite surnames but with addresses outside the Hutterite colonies. RESULTS: The annual prevalence of schizophrenia among the communal Hutterites, estimated from the database search by using ICD-9 criteria, was consistent with the prevalence found in the prior epidemiological survey (annual mean of 1.2/1,000 population, compared with 1.3/1,000 in the prior survey). The database search yielded a significantly lower prevalence for schizophrenia and other functional psychoses among communal Hutterites as well as among the comparison group, compared to the total Manitoba population. There was also lower prevalence for affective psychoses and adjustment reaction disorders among the communal Hutterites, compared to the total Manitoba population. Rates for neurotic disorders were elevated both among the communal Hutterites and the comparison group. CONCLUSIONS: The prevalence of specific psychoses was reduced among the Hutterites, although neurotic disorders were more prevalent. These findings suggest some specificity, although possible artifacts such as ascertainment bias must be considered. Further research is needed to examine genetic and environmental factors that may contribute to reduced prevalence of specific psychoses among the Hutterites.

Age of Onset↗
PubMed2000

Assessment of iron absorption from ferric trimaltol.

Therapeutic iron compounds have limited absorption and often have side-effects, which limits patient compliance. Iron trimaltol is a novel, stable complex, formed between ferric iron (Fe3+) and maltol (3-hydroxy-2-methyl-4-pyrone), and is effective in the treatment of iron deficiency anaemia with few side-effects. However, the kinetics of iron absorption from ferric trimaltol and the reliability of normal colorimetric analysis in detecting iron absorbed from this complex have not been established. We measured increases in serum iron levels in 12 volunteers following oral challenge with four different pharmaceutical formulations of ferric trimaltol in a double-blind, cross-over, randomized study. The conventional colorimetric method for detecting serum iron was compared with thermal analyses after trichloroacetic acid (TCA) treatment of serum. Measurements of serum iron levels by TCA treatment and thermal analysis closely agreed with measurements by colorimetry. For all formulations, serum iron levels peaked at 90 min with a plateau of at least 5 h [mean (standard deviation) peak absorption 8.3% (6.3%) of ingested dose, n=48]. Absorption of iron, based on peak serum values or area under the serum curve, was not different for the four formulations (n=12 each) and correlated with the individual's iron status, as assessed by serum ferritin values (r = -0.6; P < 0.001). Normal colorimetry is suitable for analysis of serum iron levels following ingestion of ferric trimaltol. There is rapid and sustained absorption of iron from ferric trimaltol and, as with ferrous iron, uptake appears to be controlled through normal mechanisms of iron acquisition that depend upon body iron stores.

Adult↗
PubMed2000

Is it really so bad? A comparison of positive and negative experiences in Antarctic winter stations.

This study examined the range of positive and negative themes reported by 104 Australian Antarctic winter personnel at four stations during two austral winters. Reports from the expeditioners were subjected to a content analysis using the TextSmart software from SPSS, Inc. Results indicated that, although the list of negative experiences is lengthy, most events are relatively rare. On the other hand, although the list of positive experiences is short, the frequencies with which they are reported are much greater than for most of the problems. Possible explanations for these themes and for future directions are discussed.

Adaptation, Psychological↗
PubMed2000

Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases.

We determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) inhibits the formation of malignant ascites and the progressive growth of human ovarian carcinoma cells implanted into the peritoneal cavity of nude mice. The novel protein tyrosine inhibitor PTK 787 was evaluated in two models of human ovarian cancer: Hey-A8 cells, which express low levels of VEGF/VPF and grow as solid tumor foci on the surface of peritoneal organs, and SKOV3 i.p.1 cells, which express high levels of VEGF/VPF and grow as solid peritoneal tumors and ascites. Treatment of nude mice by daily oral administration of 50 mg/kg PTK 787 was not effective against Hey-A8 tumors. In sharp contrast, it significantly inhibited growth of SKOV3 i.p.1 cells and formation of ascites, significantly increasing survival of mice with the implants. Tumor-induced vascular hyperpermeability in the peritoneum of tumor-bearing mice was inhibited by PTK 787, which accounted for its inhibition of ascites formation. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinomas.

Administration, Oral↗
PubMed2000

Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation.

Malignant pleural effusion (PE) is associated with advanced human lung cancer. We found recently, using a nude mouse model, that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is responsible for PE induced by non-small cell human lung carcinoma cells. The purpose of this study was to determine the therapeutic potential of a VEGF/VPF receptor tyrosine kinase phosphorylation inhibitor, PTK 787, against PE formed by human lung adenocarcinoma (PC14PE6) cells. PTK 787 did not affect the in vitro proliferation of PC14PE6 cells, whereas it specifically inhibited proliferation of human dermal microvascular endothelial cells stimulated by VEGF/VPF. A specific platelet-derived growth factor receptor tyrosine kinase inhibitor, CGP57148 (used as a control because PTK 787 also inhibits platelet-derived growth factor receptor tyrosine kinases), had no effect on proliferation of PC14PE6 or human dermal microvascular endothelial cells. i.v. injection of PC14PE6 cells into nude mice produced lung lesions and a large volume of PE containing a high level of VEGF/VPF. Oral treatment with CGP57148 had no effect on PE or lung metastasis. In contrast, oral treatment with PTK 787 significantly reduced the formation of PE but not the number of lung lesions. Furthermore, treatment with PTK 787 significantly suppressed vascular hyperpermeability of PE-bearing mice but did not affect the VEGF/VPF level in PE or expression of VEGF/VPF protein and mRNA in the lung tumors of PC14PE6 cells in vivo. These findings indicate that PTK 787 reduced PE formation mainly by inhibiting vascular permeability, suggesting that this VEGF/VPF receptor tyrosine kinase inhibitor could be useful for the control of malignant PE.

Adenocarcinoma↗
PubMed2000

Increasing vegetable and fruit intake: randomized intervention and monitoring in an at-risk population.

High vegetable and fruit (V&F) consumption has been associated with a lower risk of several cancers. However, little is known about the ability of individuals to increase their intakes markedly. In this 1-year randomized, controlled diet intervention study of men and women with a recent history of adenomas, the intervention group (n = 100) was asked to increase V&F intake to at least eight servings per day; the control group (n = 101) continued eating their usual diet. End-point measures included V&F intake assessed by 3-day diet records, plasma carotenoids, serum lipids, urinary sodium and potassium, and body weight. The intervention group increased their daily V&F intake an average of 5.5 servings over 1 year; the control group had an average decrease of 0.5 servings per day (P < 0.001). Plasma total carotenoids, alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin were each statistically significantly elevated over baseline (11-54%) in the intervention group compared with the control group over the duration of follow-up (P < 0.001). Urinary potassium excretion was elevated 14% over baseline in the intervention group compared with no change in the control group (P < 0.001). Modest decreases in the intervention but not the control group were observed for total and low-density lipoprotein cholesterol. Plasma lycopene, triglycerides, high-density lipoprotein cholesterol, body weight, and urinary sodium were not affected by the intervention. V&F intake was significantly increased in this motivated population at higher risk of colon cancer and maintained for at least 12 months, as assessed using diet records and an ensemble of biomarkers.

Adenoma↗
PubMed2000

PKC412--a protein kinase inhibitor with a broad therapeutic potential.

The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.

Angiogenesis Inhibitors↗