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Biomedical subjects

D Shaw

Publications and source records attributed to D Shaw.

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

Association between Alzheimer's disease and the NOS3 gene.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder of later life. Genetic studies have demonstrated that the apolipoprotein E (ApoE) gene is an important susceptibility locus; however, other environmental and genetic factors operating alone or in combination with ApoE must also be involved. Among candidate genes that may contribute to this residual risk is the endothelial nitric oxide synthase (NOS3) gene. NO release from vascular endothelium accounts in large part for endothelium-derived relaxing factor bioactivity. Abnormalities of cerebral small vessels occur early in AD, and it has been demonstrated recently that beta-amyloid interacts with endothelial cells in blood vessels to produce an excess of superoxide radicals. We have genotyped 122 cases of early-onset AD (EOAD) and 317 cases of late-onset AD (LOAD) as well as 392 controls for a common structural polymorphism Glu/Asp at codon 298 in the NOS3 gene. We find a highly significant enrichment for Glu/Glu homozygotes in LOAD compared with controls. The effect appears to be independent of ApoE status. NOS3 may be a new genetic risk factor for LOAD.

Adult↗
PubMed1999

Accuracy and sensitivity of DNA pooling with microsatellite repeats using capillary electrophoresis.

DNA pooling is a genetic screening method that combines DNA from many individuals in a single polymerase chain reaction (PCR) reaction to generate a representation of allele frequencies. The substantial saving in effort with DNA pooling over individual genotyping facilitates linkage disequilibrium scanning of the human genome using many thousands of genetic markers, and is applicable to mapping of complex diseases such as schizophrenia. However, the literature to date has not addressed several crucial technical aspects of DNA pooling. These include: DNA quantification; the choice of electrophoresis methods; sensitivity (the minimum reliably detectable difference between pools); and methods of dealing with 'plus-A' stutter. We have examined these points and make recommendations as to the best procedures to adopt as well as quantifying reproducibility and sensitivity. We conclude that, although allele frequencies derived from microsatellite pooling are distorted, differences of 5% or greater between pools can be reliably detected.

Alleles↗
PubMed1999

Monitoring of liver enzymes in patients treated with traditional Chinese drugs.

BACKGROUND: Use of traditional Chinese drug treatment is widespread. While cases of hepatotoxic effects have been reported, little is known about the frequency of such effects. OBJECTIVES: To investigate the frequency, magnitude and course of liver enzyme elevations in patients treated with traditional Chinese drugs. DESIGN: Retrospective study. SETTING: Hospital for traditional Chinese medicine in Germany. PATIENTS: All 1507 patients admitted for inpatient treatment between February 1994 and July 1995. MAIN OUTCOME MEASURE: Number of patients who presented at discharge with a more than 2-fold elevation of alanine amino transferase (ALT) levels (over maximum normal values or elevated admission values). RESULTS: A more than 2-fold elevation of ALT values was observed in 14 patients (0.9%). In 13 cases a causal relationship with Chinese drug therapy seemed possible and, for one patient, likely. However, all patients were also on non-Chinese drug treatment. Follow-up values of ALT within 8 weeks after discharge were normal in 11 patients (six of them had continued to take traditional Chinese drugs) and close to normal in the remaining three. In five patients there were indications for previous liver damage. CONCLUSIONS: In the population and setting studied, clinically relevant liver enzyme elevations occurred in about 1/100 patients treated with traditional Chinese drugs.

Adult↗
PubMed1999

Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry.

1 The cerebrovascular receptor(s) that mediates 5-hydroxytryptamine (5-HT)-induced vasoconstriction in human cerebral arteries (HCA)has proven difficult to characterize, yet these are essential in migraine. We have examined 5-HT receptor subtype distribution in cerebral blood vessels by immunocytochemistry with antibodies selective for human 5-HT1B and human 5-HT1D receptors and also studied the contractile effects of a range of 5-HT receptor agonists and antagonists in HCA. 2 Immunocytochemistry of cerebral arteries showed dense 5-HT1B receptor immunoreactivity (but no 5-HT1D receptor immunoreactivity) within the smooth muscle wall of the HCA. The endothelial cell layer was well preserved and weak 5-HT1B receptor immunoreactivity was present. 3 Pharmacological experiments on HCA with intact endothelium showed that 5-carboxamidotryptamine was significantly more potent than alpha-methyl-5-HT, 2-methyl-5-HT and 5-HT in causing vasoconstriction. The 5-HT1B/1D receptor agonists naratriptan, sumatriptan, zolmitriptan and 181C91 (N-desmethyl zolmitriptan), all induced equally strong contractions and with similar potency as 5-HT. The maximum contractile response was significantly less for avitriptan and dihydroergotamine. There was a significant correlation between vasoconstrictor potency and 5-HT1B- and 5-HT1D-receptor affinity, but not with 5-HT1A-, 5-ht1F or 5-HT2- receptor affinity. 4 The 5-HT1B/1D-receptor antagonist GR 55562 (10-7 - 10-6 M) inhibited the contractile responses to sumatriptan and 5-CT in a competitive manner with a pKB value for GR 55562 of 7.4. Furthermore, ketanserin (10-7 M), prazosin (10-7 M), and sulpiride (10-7 M) were devoid of significant antagonistic activity of 5-HT-induced contraction in the HCA. 5 The results are compatible with the hypothesis that the 5-HT1B receptors play a major role in 5-HT-induced vasoconstriction in HCA.

Binding, Competitive↗
PubMed1999

Tissue plasminogen activator (tPA) as therapy for hepatotoxicity following bone marrow transplantation.

The treatment of established veno-occlusive disease (VOD) of the liver with tissue plasminogen activator (tPA) has been disappointing. In attempts to improve upon these results we identified a subgroup of patients with consistently elevated bilirubin levels who did not meet conventional criteria for VOD (Susp VOD) but who had a significant risk of later developing clinical VOD. In January 1994 we began to treat patients who developed Susp VOD with tPA rather than waiting until they developed clinical VOD. We now report on the results of the first 37 patients who ultimately developed clinical VOD and received tPA therapy prior to Susp VOD, or at the time they had established VOD. Significant bleeding complications occurred in 13 (35%) patients but resolved with discontinuation of therapy in all but one. We found that patients treated early in the course of hepatotoxicity prior to the development of overt VOD had a significantly higher response rate and 100 day survival than patients treated at the time of established VOD. Given the poor results seen in treating late VOD, we suggest that early treatment with tPA may improve the outcome in patients who develop signs of hepatotoxicity following marrow transplantation.

Adolescent↗
PubMed1999

A comparison of sampling and analytical methods for assessing occupational exposure to diesel exhaust in a railroad work environment.

Methods of assessing occupational exposure to diesel exhaust were evaluated in a railroad work environment. The American Conference of Governmental Industrial Hygienists (ACGIH)-recommended elemental carbon and respirable combustible dust methods of sampling and analysis for assessing diesel exhaust were included in the study. A total of 215 personal and area samples were collected using both size-selective (nylon cyclone and Marple) and non-size-selective samplers. The results demonstrate that the elemental carbon method is suitable for the railroad environment and the respirable combustible dust method is not. All elemental carbon concentrations measured were below the proposed ACGIH Threshold Limit Value (TLV) of 0.15 mg/m3. The concentrations of oxides of nitrogen (nitric oxide and nitrogen dioxide) were also found to be below their respective TLVs. There is no correlation between elemental carbon or respirable combustible dust and the oxides of nitrogen. The elemental carbon as fraction of total carbon is about 13 percent, except for onboard locomotives where it is about 24 percent. Comparison of elemental carbon and respirable combustible dust measurements showed consistent relationships for most sampling locations, with respirable combustible dust concentrations 12 to 53 times higher than the elemental carbon levels.

Data Interpretation, Statistical↗
PubMed1999

Association study of the CACN1A4 (SCA6) triplet repeat and schizophrenia.

The P/Q type Ca2+ channel alpha 1-subunit (CACN1A4) gene on chromosome 19p13 is a promising candidate susceptibility locus for schizophrenia. Point mutations in CACN1A4 cause familial hemiplegic migraine and episodic ataxia. Expansion in a coding 3' CAG repeat causes spino-cerebellar ataxia type 6 (SCA6). The mouse mutant phenotype totterer has a form of petit-mal epilepsy. These are neurological conditions, all of which exhibit features in common with schizophrenia. The 19p13 area is also paralogous to other genomic regions of interest in schizophrenia genetics. For these reasons, we performed an association study with the CAG repeat and schizophrenia using 225 Scottish schizophrenia and 198 unrelated Scottish controls. The repeat was not associated with the disorder (P = 0.72) and neither did the schizophrenics have significantly longer alleles than the controls (P = 0.45). We conclude that the SCA6 CAG repeat is not associated with schizophrenia susceptibility. However, it remains possible that other variants in the region could be involved.

Alleles↗
PubMed1999

Dyslexic children have abnormal brain lactate response to reading-related language tasks.

BACKGROUND AND PURPOSE: Children with dyslexia have difficulty learning to recognize written words owing to subtle deficits in oral language related to processing sounds and accessing words automatically. The purpose of this study was to compare regional changes in brain lactate between dyslexic children and control subjects during oral language activation. METHODS: Brain lactate metabolism was measured during four different cognitive tasks (three language tasks and one nonlanguage task) in six dyslexic boys and in seven control subjects (age- and IQ-matched right-handed boys who are good readers) using a fast MR spectroscopic imaging technique called proton echo-planar spectroscopic imaging (1-cm3 voxel resolution). The area under the N-acetylaspartate (NAA) and lactate peaks was measured to calculate the lactate/NAA ratio in each voxel. RESULTS: Dyslexic boys showed a greater area of brain lactate elevation (2.33+/-SE 0.843 voxels) as compared with the control group (0.57+/-SE 0.30 voxels) during a phonological task in the left anterior quadrant. No significant differences were observed in the nonlanguage tasks. CONCLUSION: Dyslexic and control children differ in brain lactate metabolism when performing language tasks, but do not differ in nonlanguage auditory tasks.

Aspartic Acid↗
PubMed1998

Development and characterisation of human 5-HT1B- or 5-HT1D-receptor specific antibodies as unique research tools.

The serotonin 5-HT1B/1D-receptor family comprises of two closely related receptors encoded by two distinct genes. There are no pharmacological ligands which can adequately distinguish between these two receptor subtypes in human tissues. Therefore, we have developed human 5-HT1B- and 5-HT1D-receptor subtype specific polyclonal antibodies. Rabbits were immunised with synthetic peptides identical to unique amino acid sequences located in the third intracellular loops of these receptors. Polyclonal antibodies were subjected to immunoaffinity purification and were characterised using ELISA, dot blot analysis and immunostaining of stably-transfected CHO cell lines expressing either human 5-HT1B-receptors or 5-HT1D-receptors and in human trigeminal ganglia. The antibodies were specific for either the 5-HT1B- or 5-HT1D-receptors and did not cross-react. Both 5-HT1B- and 5-HT1D-immunoreactivities were detected on cell bodies in human trigeminal ganglia. In the absence of selective pharmacological agents, these antibodies represent unique and essential research tools to study the anatomical distribution of 5-HT1B/1D-receptor subtypes in human tissue.

Amino Acid Sequence↗
PubMed1998

Retroviral coexpression of thymidylate synthase and dihydrofolate reductase confers fluoropyrimidine and antifolate resistance.

Retroviral gene transfer of dominant selectable markers into hematopoietic cells can be used to select genetically modified cells in vivo or to attenuate the toxic effects of chemotherapeutic agents. We show that retroviral gene transfer of thymidylate synthase (TS) confers resistance to TS directed anticancer agents and that co-expression of TS and dihydrofolate reductase (DHFR) confers resistance to TS and DHFR cytotoxic agents. Retroviral vectors encoding Escherichia coli TS, human TS, and the Tyr-to-His at residue 33 variant of human TS (Y33HhTS) were constructed and fibroblasts transfected with these vectors conferred comparable resistance to the TS-directed agent fluorodeoxyuridine (FdUrd, approximately 4-fold). Retroviral vectors that encode dual expression of Y33HhTS and the human L22Y DHFR (L22YhDHFR) variants conferred resistance to FdUrd (3- to 5-fold) and trimetrexate (30- to 140-fold). A L22YhDHFR-Y33HhTS chimeric retroviral vector was also constructed and transduced cells were resistant to FdUrd (3-fold), AG337 (3-fold), trimetrexate (100-fold) and methotrexate (5-fold). These results show that recombinant retroviruses can be used to transfer the cDNA that encodes both TS and DHFR and dual expression in transduced cells is sufficiently high to confer resistance to TS and DHFR directed anticancer agents.

Animals↗
PubMed1998

Developmentally-regulated expression of a putative protease inhibitor gene in the lactating mammary gland of the tammar wallaby, Macropus eugenii.

A novel milk protein, which is secreted only in the early stage of lactation, has been identified in the whey fraction of milk from the tammar wallaby (Macropus eugenii). The amino acid sequence currently available suggests the protein comprises 71 amino acids. The protein migrates at 18 kDa when analysed by SDS polyacrylamide gel electrophoresis but has a calculated molecular weight of 8 kDa. A partial cDNA clone of 153 bp has been isolated by reverse transcriptase PCR. Northern analysis of mammary gland RNA extracted from various stages throughout the entire lactation period showed a messenger RNA transcript of approximately 500 bp present only in the first third of lactation. The protein shares 74.5% similarity at the amino acid level with early lactation protein (ELP) from the brush-tailed possum (Trichosurus vulpecula) and 37% with bovine colostrum trypsin inhibitor, a member of the Kunitz family of protease inhibitors. We hypothesise that the expression of this gene may be controlled by changes in the sucking patterns of the dependent pouch young.

Amino Acid Sequence↗
PubMed1998

An intelligent control system for ventilators.

This study reports on a ventilator system that consists of several intelligent modules for controlling ventilator operation. These modules are software programs in two controllers. One controller is a personal computer used for diagnoses, determining settings and checking the effects of settings. The other controller is a single-chip microprocessor in a ventilator that controls the ventilator's settings in accordance with the computer settings. After setting up the system, an artificial lung model simulating a patient's lung is used to test the system. The result of test run indicated that it always responds to a patient's lung condition in a stable manner. Thus, the proposed system with its intelligent modules may assist clinicians in caring for patients and managing ventilator operation.

Algorithms↗
PubMed1998

Evidence for the continuity of early problem behaviors: application of a developmental model.

Evidence of the continuity of early problem behaviors in young girls and boys was examined developmentally. Data were gathered on 104 mother-child dyads from low-income families when children were between 1 and 5 years of age. Difficult temperament, aggression, and noncompliance from 12 to 24 months, and externalizing and internalizing problems at 36 and 60 months, were assessed. The results provide evidence for the continuity of early behavioral and emotional problems and support for the early differentiation between internalizing and externalizing problems. Implications of the current findings for prevention efforts are presented.

Aggression↗
PubMed1998

Trying to improve compliance with prophylactic penicillin therapy in children with sickle cell disease.

AIMS: To evaluate compliance with prophylactic penicillin therapy in sickle cell disease (SCD) in children. METHODS: Forty-five children aged 37 +/- 19 (9-84) months [mean +/- s.d; range] with homozygous SCD were recruited. After a baseline period of 2 months the patients were randomized to either the intervention or non-intervention group. The intervention consisted of a slide show explaining the pathogenesis of sickle cell disease and its complications; weekly phone calls by the clinic social worker; and a calendar. Compliance was again evaluated after the 2 month intervention period and after a further 2 month monitoring period without intervention. Compliance was monitored using the Medication Event Monitoring System. At the end of the 6 months, parents in both groups completed a questionnaire the aims of which were to determine knowledge and understanding of sickle cell disease and previous experience with infection. Patient admissions to the hospital during the study were recorded. RESULTS: Compliance during the 2 month baseline assessment was 66.0 +/- 32.5 (1.3-98.2)% and 69.3+25.4 (19.8-96.5)% in the intervention (n = 13) and non-intervention (n = 10) groups respectively (P = 0.79). During the next 2 months, compliance in the intervention group (n = 11) was 79.0 +/- 31.4 (11.0-100.0)% and in the non-intervention group (n = 9) was 66.0 +/- 20.2 (42.2-96.8)% (P = 0.297). In the final 2 month monitoring period compliance was 82.0 +/- 34.7 (3.8-100.0)% and 65.8 +/- 25.3 (25.0-98.2)% in the intervention (n = 7) and the non-intervention (n = 6) groups respectively (P = 0.366). No statistically significant differences were found when comparing compliance between the groups. CONCLUSIONS: Compliance with prophylactic antibiotic therapy in children with sickle cell disease is highly variable and its evaluation is problematic.

Administration, Oral↗
PubMed1998

Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors.

AIMS: We compared the vasoconstrictor effects of 5-HT with those of the selective 5-HT1B/1D-receptor agonists sumatriptan and rizatriptan in human isolated cranial (middle meningeal) arteries. In addition selective 5-HT1B- or 5-HT1D-receptor antibodies were used in combination with semiquantitative immunohistochemical techniques to compare the levels of expression of these receptors in human middle meningeal and coronary arteries. METHODS: Middle meningeal and coronary arteries were obtained (with consent) from either neurosurgical patients or donor hearts, respectively. Segments of middle meningeal artery were mounted in organ baths for isometric recording and cumulative concentration-effect curves to 5-HT, rizatriptan and sumatriptan were obtained. Frozen fresh sections of middle meningeal and coronary arteries were subjected to standard immunohistochemical techniques using specific 5-HT1B- or 5-HT1D-receptor primary antibodies and a radiolabelled secondary antibody. Data were subjected to analysis of variance (ANOVA) and nonlinear regression analysis. RESULTS: 5-HT, rizatriptan and sumatriptan were potent vasoconstrictors in human isolated middle meningeal artery (EC50 values=32, 90 and 71 nM, respectively). A significantly higher level of 5-HT1B-receptor immunoreactivity was detected in middle meningeal artery compared with coronary artery (ANOVA, F=7.95, DF=1,4, P<0.05). CONCLUSIONS: Rizatriptan and sumatriptan act selectively to cause vasoconstriction in human isolated middle meningeal artery and are 10-fold more potent than in human coronary artery. The higher level of expression of 5-HT1B-receptors in middle meningeal compared with coronary artery provides a pharmacological basis for the craniovascular selectively of both rizatriptan and sumatriptan.

Adult↗