Meningitis complicating traumatic lumbar herniation.
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Abdominal Injuries↗
Biomedical subjects
D Wang
Publications and source records attributed to D Wang.
Selective transcriptional profiling for trait-based eQTL mapping.
There is currently great interest in identifying genetic loci associated with the expression of one or more genes by combining methods for the mapping of quantitative trait loci (QTL) with microarray technology. Because of the high cost of microarrays, it is useful to develop strategies for selecting a subset of individuals for expression profiling. We describe a method of selective transcriptional profiling that uses available information on individual quantitative traits and marker data to choose an optimal set of individuals for measurement with microarrays. We show how to analyse the resulting data to identify genes whose expression is associated with a QTL for a traditional trait or any other locus. Examples are used to illustrate the method and highlight some challenges associated with the analysis of selected data.
Animals↗
The nocturnal jejunal migrating motor complex: defining normal ranges by study of 51 healthy adult volunteers and meta-analysis.
Interdigestive human small bowel motility is characterized by the migrating motor complex (MMC). The aims of this study were to: (i) establish the normal range of variables of the nocturnal jejunal MMC and (ii) incorporate these data in a subsequent meta-analysis. Eighty-one recordings were performed by prolonged (24 h) ambulatory manometry in 51 subjects in two centres. Quantitative analysis was undertaken of 419 Phase III and 332 Phase II episodes. Adjusted mean values of seven variables were calculated using a mixed-effects model. Meta-analysis of pooled published data to generate a reliable 95% reference range was also performed. Adjusted mean values and confidence intervals are presented for all seven variables. Intrasubject variances were large in comparison with intersubject. Meta-analysis of 19 studies (356 pooled patients) meeting inclusion criteria produced wide reference ranges. At least five such ranges are useful for the detection of abnormality in the individual. This is the largest study of normal volunteers presented to date, with ranges for many variables produced using appropriate statistical methodology. A model for definition of abnormality has been proposed. We recommend that these data may be used by investigators in this field as a complement to other existing indicators of small bowel dysmotility.
Adolescent↗
Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome.
AIM: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.2 mmol/L) or lowered CSF: plasma glucose ratio (<0.4). METHODS: This is a review of eight Queensland patients with GLUT1-DS. The clinical presentation, clinical course, laboratory investigations and treatment outcomes are discussed. RESULTS: The clinical features noted in our patient cohort include combinations of ataxia, developmental delay and a severe seizure disorder that is refractory to anticonvulsant medications. Seizures are the most common clinical manifestation and may be exacerbated by phenobarbitone. The paired CSF: plasma glucose results ranged from 0.2 to 0.39 (normal <0.6) with an average of 0.33. 3-O-Methyl-D-Glucose uptake and GLUT1 Genotyping analysis have been performed on five patients thus far. Rapid and impressive seizure control was observed in 100% of our patients once the ketogenic diet was instituted, with half of the cohort being able to wean completely from anticonvulsants. CONCLUSION: Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.
3-O-Methylglucose↗
Detecting linkage disequilibrium in the presence of locus heterogeneity.
Locus heterogeneity is a common phenomenon in complex diseases and is one of the most important factors that affect the power of either linkage or linkage disequilibrium (LD) analysis. In linkage analysis, the heterogeneity LOD score (HLOD) rather than LOD itself is often used. However, the existing methods for detecting linkage disequilibrium, such as the TDT and many of its variants, do not take into account locus heterogeneity. We propose two novel likelihood-based methods, an LD-Het likelihood and an LD-multinomial likelihood, to test linkage disequilibrium (LD) that explicitly incorporate locus heterogeneity in the analysis. The LD-Het is applicable to general nuclear family data but requires a working penetrance model. The LD-multinomial is only applicable to affected sib-pair data but does not require specification of a trait model. For affected sib-pair data, both methods have similar power to detect LD under the recessive model, but the LD-multinomial model has greater power when the underlying model is dominant or additive.
Chromosome Mapping↗
Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design.
There is variability in the distribution of inflammatory cells in bronchial tissue in chronic obstructive pulmonary disease (COPD). Better strategies for biopsy sampling of the airway mucosa may improve the capacity to show a difference between study populations where variability in distribution exists. The current authors have examined sources of biological variability in the quantification of inflammatory cells in endobronchial biopsies using immunostained samples taken from 51 subjects with COPD, with a mean forced expiratory volume in one second of 1.71 L, 55% predicted. The distribution of variance contributed by different sources was similar for different inflammatory cell types. For CD8+ cells, a key inflammatory cell in COPD, the largest contribution to intra-subject variability (39%) was time (i.e. 10 weeks between biopsies of placebo-treated subjects), followed by airway generation (23%), biopsy (2.5%), zone (within section; 1.4%) and section (0.4%). Power calculations demonstrated that examining one section from one biopsy, from each of two airway generations, would require a sample size of 32 subjects per group to show a difference of one doubling or halving in CD8+ cells, compared with 47 subjects per group if only one airway generation was sampled. Therefore, biopsies from more than one airway generation should be examined in order to maximise statistical power to detect a difference between study groups.
Adult↗
Linewidth reduction in a large-smile laser diode array.
We present theory and simulations for a spectral narrowing scheme for laser diode arrays (LDAs) that employs optical feedback from a diffraction grating. We calculate the effect of the so-called smile of the LDA and show that it is possible to reduce the effect by using a cylindrical lens set at an angle to the beam. The scheme is implemented on a 19-element LDA with smile of 7.6 microm and yields frequency narrowing from a free-running width of 2 to 0.15 nm. The experimental results are in good agreement with the theory.
Journal Article↗
Prostaglandins and cancer.
Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.
Animals↗
Degradation of methyl isothiocyanate and chloropicrin in forest nursery soils.
Recent studies have observed enhanced degradation of methyl isothiocyanate (MITC) from repeated fumigation in agricultural soils. Little is known about fumigant degradation in forest and nursery soils. This study was conducted to determine degradation rates of MITC and chloropicrin (CP) in two forest soils and the impacts of nursery management on degradation of MITC and CP. The half-life values of MITC and CP were evaluated in the laboratory under isothermal conditions (22 +/- 2 degrees C). Three rates representing 0.5x, 1x, and 2x field application rates for each fumigant were used in laboratory incubations. Effect of microbial degradation was determined by conducting incubations with both fresh and sterilized soils. Soil moisture effects were also studied. There was no difference in MITC or CP degradation between fumigated and nonfumigated forest nursery soils. Soil sterilization and high soil moisture content (15% by wt.) reduced MITC and CP degradation. The degradation rates of MITC and CP varied with factors such as nursery history, fumigant application rates, and freshness of tested soils.
Biodegradation, Environmental↗
Characterization of a late expression gene, Open reading frame 128 of Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus.
Helicoverpa armigera single nucleocapsid nucleopolyhedrovirus (HearSNPV) is a single embedded NPV pathogenic to the bollworm, which is a major agricultural pest in many areas around the world. Ha128 homologues have been identified in all completely sequenced lepidopteran NPV's, but no homologue has been found in a granulovirus (GV) and it is thus considered as a lepidopteran NPV-specific gene. In the HearSNPV-C1 genome Ha128 is located between 120,252 and 121,052 bp and encodes a putative protein of 266 amino acid residues with a predicted molecular weight of 30.5 kDa. Ha128 transcripts in HearSNPV-infected HzAM1 cells could be detected from 24 to 120 h post-infection (p.i.) by Northern blot. The Ha128 protein was detected at 24 h p.i. and remained detectable until 120 h p.i. by western blot using an anti-GST-Ha128 antiserum. The expression of Ha128 was inhibited in the presence of Ara-C, an inhibitor of viral DNA synthesis. These results together indicated that Ha128 was a late gene. The product of Ha128 was found to have an Mr of about 31 kDa, in agreement with the predicted molecular weight. Immunoflorescence using anti-GST-Ha128 serum showed that Ha128 was located in cytoplasm. GST pull-down and co-immunoprecipitation showed that at least two potential host proteins interacted with Ha128. In conclusion, Ha128 is a late protein localized in the cytoplasm of infected cells that may interact with host proteins.
Amino Acid Sequence↗
Differences in signaling pathways and expression level of the phosphoinositide phosphatase SHIP1 between two oncogenic mutants of the receptor tyrosine kinase KIT.
Oncogenic mutations of the receptor tyrosine kinase KIT are encountered in myeloid leukemia and various solid tumors, including gastrointestinal stromal tumors. We previously identified the human oncogenic germ line mutant KIT(K642E), a substitution in the tyrosine kinase 1 domain (TK1D) in a familial form of gastrointestinal stromal tumors. The effects of oncogenic KIT mutants on cell signaling and regulation are complex. Cellular models are valuable basic tools to tailor novel strategies on specific cellular and molecular bases for tumors expressing KIT oncogenic mutants. Murine KIT(WT) and the murine homologues of human KIT oncogenic mutants, further referred to as KIT(K641E) and KIT(del559), a point deletion in the juxtamembrane domain (JMD), were stably expressed in IL-3-dependent Ba/F3 cells. Major differences in the constitutively activation of Akt/PKB, MAP kinases and STATs pathways were observed between KIT(K641E) and KIT(del559), whereas KIT ligand elicited responses in both mutants. Noteworthy, the protein level of the phosphoinositide phosphatase SHIP1, but not SHIP2 and PTEN, was reduced in KIT(K641E) only while inhibition of KIT phosphorylation reversibly raised SHIP1 level in both JMD and TK1D oncogenic mutants, unraveling the control of SHIP protein level by KIT phosphorylation.
Animals↗
Rectal sensorimotor dysfunction in patients with urge faecal incontinence: evidence from prolonged manometric studies.
BACKGROUND AND AIMS: Although external anal sphincter dysfunction is the major cause of urge faecal incontinence, approximately 50% of such patients have evidence of rectal hypersensitivity and report exaggerated stool frequency and urgency. The contribution of rectosigmoid contractile activity to the pathophysiology of this condition is unclear, and thus the relations between symptoms, rectal sensation, and rectosigmoid motor function were investigated. METHODS: Fifty two consecutive patients with urge faecal incontinence, referred to a tertiary surgical centre, and 24 volunteers, underwent comprehensive anorectal physiological investigation, including prolonged rectosigmoid manometry. Patients were classified on the basis of balloon distension thresholds into those with rectal hypersensitivity (n = 27) and those with normal rectal sensation (n = 25). Automated quantitative analysis of overall rectosigmoid contractile activities and, specifically, high amplitude contractions and rectal motor complex activity was performed. RESULTS: External anal sphincter dysfunction was similar in both patient groups. Overall, phasic activity and high amplitude contraction frequency were greater, and rectal motor complex variables significantly altered, in those with rectal hypersensitivity. Symptoms, more prevalent in the rectal hypersensitivity group, were also more often associated with rectosigmoid contractile events. For individuals, reduced compliance and increased rectal motor complex frequency were only observed in patients with rectal hypersensitivity. CONCLUSIONS: We have identified a subset of patients with urge faecal incontinence-namely, those with rectal hypersensitivity-who demonstrated increased symptoms, enhanced perception, reduced compliance, and exaggerated rectosigmoid motor activity. Comprehensive assessment of rectosigmoid sensorimotor function, in addition to evaluation of anal function, should be considered in the investigation of patients with urge faecal incontinence.
Adolescent↗
Reversal of warfarin-induced anticoagulation with factor VIIa prior to rt-PA in acute stroke.
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Acute Disease↗
Characterization of Helicoverpa armigera nucleopolyhedrovirus orf33 that encodes a novel budded virion derived protein, BV-e31.
Homologues of Helicoverpa armigera nucleopolyhedrovirus (HearSNPV) orf33 are found in all 22 completely sequenced members of the lepidopteran nucleopolyhedroviruses and granuloviruses, but so far their functions are unknown. In this report, we describe the characterization of HearSNPV orf33 (ha33). Northern blot analysis showed a single transcript of ha33 of approximately 0.7 kb was transcribed beginning at 3 h post-infection in infected Helicoverpa zea cells (HzAM1) and the gene product could be detected as early as 6 h post-infection by western blot analysis using a rabbit derived polyclonal antibody, suggesting it was an early gene. Western blot analysis also demonstrated the ha33 protein in infected cells was a 31 kDa protein, larger than the theoretical size of 28.4 kDa, and located in the envelope fraction of budded virions (BVs). The results suggested that HearSNPV ha33 gene is a functional gene that encodes a novel structural protein of baculovirus BVs, BV-e31.
Amino Acid Sequence↗
Diabetic patients with acute coronary syndromes in the UK: high risk and under treated. Results from the prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK).
OBJECTIVES: Short-term randomised trials suggest that patients with diabetes mellitus (DM), admitted with acute coronary syndromes (ACS) are at increased risk of subsequent adverse events. We tested whether this hypothesis was true for an unselected population of ACS patients with and without DM admitted with non-ST elevation MI or unstable angina, in a non-trial setting over a longer term of follow-up. METHODS: Prospective, centrally, coordinated multicenter registry involving 56 centers throughout the UK (half having angiographic facilities). Consecutive patients admitted with ACS without ST elevation on the presenting ECG were followed up to 6 months. A sub-group of patients were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Data were collected on 1046 ACS patients of whom 170 (16%) had a prior diagnosis of DM. DM patients had higher baseline co-morbidities and unadjusted mortality rates at 6 months (11.8% vs. 6.4%, p=0.01). After correcting for clinical variables such as age, gender, smoking status and chest pain/ischaemic ECG changes on admission, prior history of any of myocardial infarction, heart failure, hypertension, hypercholesterolemia (on treatment), stroke or coronary revascularisation (PTCA or CABG), mortality rates for DM patients were no longer significantly raised (hazard ratio 1.35, 95% CI: 0.79-2.30; p=0.27 at 6 months and 1.15, 95% CI 0.72-1.83 at 4 years). 30% of diabetics were dead after 4 years of follow-up. Patients with DM were more likely to have been revascularised at 6 months and were more likely to receive ACE inhibitors. Based on the rate of recruitment and the population covered in the study, about 21,000 patients with DM will be admitted with non-ST elevation ACS each year in the UK. CONCLUSIONS: DM is common amongst patients admitted with ACS without ST elevation and is associated with significant morbidity and mortality: approximately 1 in 8 will not survive up to 6 months and 1 in 3 to 4 years. DM patients should be managed aggressively to reduce their risk of future complications.
Aged↗
Engineering and characterisation of chimeric monoclonal antibody 806 (ch806) for targeted immunotherapy of tumours expressing de2-7 EGFR or amplified EGFR.
We report the generation of a chimeric monoclonal antibody (ch806) with specificity for an epitope on the epidermal growth factor receptor (EGFR) that is different from that targeted by all other anti-EGFR therapies. Ch806 antibody is reactive to both de2-7 and overexpressed wild-type (wt) EGFR but not native EGFR expressed in normal tissues at physiological levels. Ch806 was stably expressed in CHO (DHFR -/-) cells and purified for subsequent characterisation and validated for use in preliminary immunotherapy investigations. Ch806 retained the antigen binding specificity and affinity of the murine parental antibody. Furthermore, ch806 displayed enhanced antibody-dependent cellular cytotoxicity against target cells expressing the 806 antigen in the presence of human effector cells. Ch806 was successfully radiolabelled with both iodine-125 and indium-111 without loss of antigen binding affinity or specificity. The radioimmunoconjugates were stable in the presence of human serum at 37 degrees C for up to 9 days and displayed a terminal half-life (T(1/2beta)) of approximately 78 h in nude mice. Biodistribution studies undertaken in BALB/c nude mice bearing de2-7 EGFR-expressing or amplified EGFR-expressing xenografts revealed that (125)I-labelled ch806 failed to display any significant tumour retention. However, specific and prolonged tumour localisation of (111)In-labelled ch806 was demonstrated with uptake of 31%ID g(-1) and a tumour to blood ratio of 5 : 1 observed at 7 days postinjection. In vivo therapy studies with ch806 demonstrated significant antitumour effects on established de2-7 EGFR xenografts in BALB/c nude mice compared to control, and both murine 806 and the anti-EGFR 528 antibodies. These results support a potential therapeutic role of ch806 in the treatment of suitable EGFR-expressing tumours, and warrants further investigation of the potential of ch806 as a therapeutic agent.
Animals↗
Excision of a selectable marker in transgenic rice (Oryza sativa L.) using a chemically regulated Cre/loxP system.
Removal of a selectable marker gene from genetically modified (GM) crops alleviates the risk of its release into the environment and hastens the public acceptance of GM crops. Here we report the production of marker-free transgenic rice by using a chemically regulated, Cre/loxP-mediated site-specific DNA recombination in a single transformation. Among 86 independent transgenic lines, ten were found to be marker-free in the T0 generation and an additional 17 lines segregated marker-free transgenic plants in the T1 generation. Molecular and genetic analyses indicated that the DNA recombination and excision in transgenic rice were precise and the marker-free recombinant T-DNA was stable and heritable.
Base Sequence↗
Polychlorinated biphenyls in eggs of spectacled eiders (Somateria fischeri) from the Yukon-Kuskokwim Delta, Alaska.
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Alaska↗