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Biomedical subjects

M Baker

Publications and source records attributed to M Baker.

At least 55 records · Page 3Linked to original sources
PubMed2001

Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia.

We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.

Aged↗
PubMed2001

Cortical synapse loss in progressive supranuclear palsy.

Cortical synapse loss, the probable substrate of cognitive impairment in Alzheimer disease (AD), has not previously been evaluated in progressive supranuclear palsy (PSP). Hypothesizing that synapse loss would be greater in demented than non-demented PSP patients, we examined synaptophysin concentrations in 8 cases of PSP (5 demented and 3 nondemented cases). We found a decrease in mean synaptophysin concentration in these 8 cases in frontal, temporal, and parietal lobes, and in cerebellum, compared to the means in corresponding lobes of 16 controls. The decreases were similar to those in 28 cases of AD, but not as great. We determined synaptophysin concentration from motor cortex in only 4 of our PSP cases, 2 demented and 2 non-demented. The average concentrations in these 4 cases were lower than in AD motor cortex; both were lower than controls. When demented and non-demented PSP cases were compared, neocortical synaptophysin concentrations in non-demented PSP cases were lower than in demented cases. There appears to be a link between AD and PSP, in that synapse loss is found in both. However, the basis and significance of the prominent neocortical synapse loss in PSP, especially in non-demented subjects, remain to be explored.

Aged↗
PubMed2001

Antitumor activity of XR5944, a novel and potent topoisomerase poison.

Inhibitors of topoisomerases are widely used in the treatment of cancer, including inhibitors of topoisomerase I (camptothecin analogs such as irinotecan and topotecan) and topoisomerase II (etoposide and doxorubicin). The novel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II as shown by the stabilization of topoisomerase-dependent cleavable complexes. XR5944 demonstrated exceptional activity against human and murine tumor cells in vitro and in vivo. In a range of cell lines XR5944 (IC50 0.04-0.4 nM) was significantly more potent than TAS-103, originally proposed as a joint topoisomerase I and II inhibitor, as well as agents specific for topoisomerase I or II (topotecan, doxorubicin and etoposide). In addition, XR5944 was unaffected by atypical drug resistance and retained significant activity in cells overexpressing P-glycoprotein or multidrug resistance-associated protein. Antitumor efficacy of XR5944 was demonstrated in human carcinoma xenograft models (H69 small cell lung cancer and HT29 colon). In the HT29 model, which is relatively unresponsive to chemotherapy, XR5944 (15 mg/kg i.v., q4dx3) induced tumor regression in the majority of animals (six of eight), whereas TAS-103, dosed at its maximum tolerated dose (45 mg/kg i.v., q7dx3), only induced a delay in tumor growth compared with control animals. In the H69 model, low doses of XR5944 (5 mg/kg i.v., qdx5/week for 2 weeks or 10-15 mg/kg i.v., q4dx3), induced complete tumor regression in the majority of animals. In contrast, topotecan (20 mg/kg i.v., q4dx3) or etoposide (30 mg/kg i.v., q5dx5) only slowed the tumor growth rate. These studies show that XR5944 is a highly active novel anticancer agent that is well tolerated at efficacious doses.

Aminoquinolines↗
PubMed2001

Structural features of a zinc binding site in the superantigen strepococcal pyrogenic exotoxin A (SpeA1): implications for MHC class II recognition.

Streptococcal pyrogenic exotoxin A (SpeA) is produced by Streptococcus pyogenes, and has been associated with severe infections such as scarlet fever and Streptococcal Toxic Shock Syndrome (STSS). In this study, the crystal structure of SpeA1 (the product of speA allele 1) in the presence of 2.5 mM zinc was determined at 2.8 A resolution. The protein crystallizes in the orthorhombic space group P2(1)2(1)2, with four molecules in the crystallographic asymmetric unit. The final structure has a crystallographic R-factor of 21.4% for 7,031 protein atoms, 143 water molecules, and 4 zinc atoms (one zinc atom per molecule). Four protein ligands-Glu 33, Asp 77, His 106, and His 110-form a zinc binding site that is similar to the one observed in a related superantigen, staphylococcoal enterotoxin C2. Mutant toxin forms substituting Ala for each of the zinc binding residues were generated. The affinity of these mutants for zinc ion confirms the composition of this metal binding site. The implications of zinc binding to SpeA1 for MHC class II recognition are explored using a molecular modeling approach. The results indicate that, despite their common overall architecture, superantigens appear to have multiple ways of complex formation with MHC class II molecules.

Alleles↗
PubMed2001

Drink and drug driving: what's the skipper up to?

OBJECTIVE: Since the introduction of random breath testing (RBT) in Australia there has been a significant reduction in drink driving, as measured by alcohol-related crashes. In contrast, the prevalence of drug-related road fatalities is on the increase. One strategy that targets drink- and/or drug-driving is the promotion of a designated driver or 'skipper'. This paper determines to what extent the 'skipper' is driving alcohol or drug-free. METHODS: A convenience sample of university students from The University of Western Australia completed a questionnaire that included questions on drug and alcohol use while driving as the designated 'skipper'. RESULTS: The mean age of the 286 participants was 21 years. Among the students who reported acting as the designated 'skipper' during the past 12 months, 26% of the students drove, as the designated 'skipper,' while feeling the effects of alcohol. Similarly, 18% of students who reported using drugs drove, as the 'skipper', while feeling the effects of the drug. Multivariate analysis identified that the presence of random drug testing would act as a deterrent for drug driving while the designated 'skipper'. CONCLUSION: Although three-quarters of designated 'skippers' do not drink and/or drug drive, a sizeable proportion of young drivers continue to place themselves and, more importantly, their passengers and the entire community at an elevated risk of injury. IMPLICATIONS: Campaigns that target the responsibility of the 'skipper' and that are included as part of drink-driving campaigns would be beneficial. It is premature to be making recommendations on random drug testing for drivers.

Adult↗
PubMed2001

Formal education programmes for senior house officers: comparison of experience in three hospital specialties.

This study was designed to compare the attendance rate of senior house officers (SHOs) in three specialties at formal educational events, examine experiences of protected time, use of educational objectives, and perceived barriers to attendance and evaluate differences found in the context of variations in training practice within each specialty. A quantitative questionnaire survey was completed by Trent region SHOs in obstetrics and gynaecology, general medicine, and accident and emergency posts. An independent researcher visited a selection of educational programme events over a two month span, recorded attendances, and administered the questionnaire. Attendance rates ranged from 40.8% of those in obstetrics and gynaecology jobs to 55.4% of those in accident and emergency jobs. The questionnaire findings found that service commitments were a major obstacle to attendance for the majority of those in obstetrics and gynaecology and general medicine jobs, while relatively few of the accident and emergency SHOs specified any barriers. SHOs in accident and emergency jobs had significantly more protected time for education and found educational objectives to be more widely used by senior staff. The findings suggest that the planned integration of formal education programmes with appropriate working pattern systems--in this case full shifts within accident and emergency departments--will result in SHOs receiving a better deal in terms of provision and structure of education.

Education, Medical↗
PubMed2001

The effects of the ciliate Paramecium cf. caudatum Ehrenberg on toxin producing Cylindrospermopsis isolated from the Fitzroy River, Australia.

The large ciliate Paramecium cf. caudatum Ehrenberg was found to be a successful grazer of toxin producing Cylindrospermopsis in the laboratory. The feeding rate increased with increasing cell concentration to 1367 cell animal hr-1 at 4.1 x 10(5) cells mL-1 but declined slightly at cell concentrations greater than this. Preliminary studies on the effects of this grazing on toxin concentrations in cultures of both straight and coiled forms of Cylindrospermopsis resulted in the production of different amounts of the toxin cylindrospermopsin in the different isolates. Differences in toxin production were also found between cultured and field populations from the lower Fitzroy River indicating that toxin production may be influenced by a suite of genetic and environmental factors. The proven ability of this ciliate to graze toxic Cylindrospermopsis provides some insight into interactions that may be able to control some toxic blooms in semiarid Australian conditions.

Alkaloids↗
PubMed2001

Chromogenic urinary tract infection medium: evaluation and introduction for routine urine culture in a large clinical microbiology laboratory.

Evaluation and introduction of a chromogenic urinary tract infection (UTI) medium for the primary culture of routine urine specimens in a very large clinical microbiology laboratory is described. A modified scheme for the direct identification of the main groups of organisms causing UTI has led to quality improvements, with enhanced discrimination of mixed cultures and in efficiencies in staffing and working time that counterbalance increases in media costs. These improvements, together with the concurrent introduction of boric acid preservative for specimens from general practice, significantly reduced the level of positive results by 4.6% (2383 specimens) over an eight-month period (P <0.001). Chromogenic medium provided a reliable alternative to CLED medium for the routine culture of urine specimens.

Bacteriological Techniques↗
PubMed2001

Randomized controlled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris.

A prior meta-analysis of 5 randomized controlled trials indicates that adapalene gel 0.1% is as effective as tretinoin gel 0.025% against acne and has greater tolerability. To determine the tolerability and efficacy of adapalene gel 0.1% versus tretinoin microsphere gel 0.1% in 168 patients with acne vulgaris, we conducted a 12-week, multicenter, randomized, controlled, investigator-masked, parallel-group design study. Efficacy variables included noninflammatory, inflammatory, and total lesion counts; global grade; and global assessment of improvement in acne severity. Skin tolerability variables included erythema, desquamation (scaling), dryness, pruritus, and stinging/burning. Our results showed that the efficacy of adapalene gel 0.1% was comparable to that of tretinoin microsphere gel, and both treatments had similar onset of action. Cutaneous tolerability was noted in both groups, with scores significantly better with adapalene gel 0.1% than with tretinoin microsphere gel 0.1%, and significantly fewer treatment-related adverse events were reported with adapalene gel 0.1%.

Acne Vulgaris↗
PubMed2001

Adapalene gel 0.1% is effective and well tolerated in acne patients in a dermatology practice setting.

The US Food and Drug Administration has approved adapalene gel 0.1% for use in the treatment of acne vulgaris. The objective of our study was to evaluate the efficacy and tolerability of adapalene gel 0.1% in the treatment of acne vulgaris in a clinical practice. We used a 12-week, multicenter, open-label, noncomparative phase 4 study of adapalene gel 0.1%. The study involved approximately 600 dermatologists in the United States and included 2,545 healthy men and nonpregnant women older than 14 years who had mild or moderate acne vulgaris. Of the patients enrolled, 75% completed the study and most of them (89%) showed an improvement in their acne (clear of acne or marked, definite, or minimal improvement) from baseline. Most patients (69%) were satisfied or very satisfied with adapalene therapy, and most (80%) wished to continue treatment. Only 3.7% of patients enrolled reported treatment-related adverse events (n=94), the most common being skin irritation (2.2%). We conclude from this open-label trial in a dermatology practice setting that adapalene gel 0.1% was effective and well tolerated and had a favorable safety profile. Furthermore, compliance with once-daily application of adapalene was rated as high by 92% of patients who responded to a self-assessment questionnaire.

Acne Vulgaris↗
PubMed2000

Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees.

Plasma Abeta42 (amyloid beta42 peptide) is invariably elevated in early-onset familial Alzheimer's disease (AD), and it is also increased in the first-degree relatives of patients with typical late-onset AD (LOAD). To detect LOAD loci that increase Abeta42, we used plasma Abeta42 as a surrogate trait and performed linkage analysis on extended AD pedigrees identified through a LOAD patient with extremely high plasma Abeta. Here, we report linkage to chromosome 10 with a maximal lod score of 3.93 at 81 centimorgans close to D10S1225. Remarkably, linkage to the same region was obtained independently in a genome-wide screen of LOAD sibling pairs. These results provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta.

Adult↗
PubMed2000

Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice.

The CD45 tyrosine phosphatase lowers T-cell antigen receptor signalling thresholds by its positive actions on p56(lck) tyrosine kinase function. We now show that mice expressing active lck(F505) at non-oncogenic levels develop aggressive thymic lymphomas on a CD45(-/-) background. CD45 suppresses the tumorigenic potential of the kinase by dephosphorylation of the Tyr394 autophosphorylation site. In CD45(-/-) thymocytes the kinase is switched to a hyperactive oncogenic state, resulting in increased resistance to apoptosis. Transformation occurs in early CD4(-)CD8(-) thymocytes during the process of TCR-beta chain rearrangement by a recombinase-independent mechanism. Our findings represent the first example in which a tyrosine phosphatase in situ prevents the oncogenic actions of a SRC: family tyrosine kinase.

Animals↗
PubMed2000

No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.

Age of Onset↗
PubMed2000

Cumulative incidence of hepatitis C seroconversion in a cohort of seronegative injecting drug users.

AIM: To measure the cumulative incidence of hepatitis C virus seroconversion over a two year period in a group of seronegative injecting drug users. METHODS: The study involved follow-up, in 1996, of a cohort (n=85) of injecting drug users identified as hepatitis C virus seronegative in 1994. Participants were interviewed about risk factors for hepatitis C. A blood sample was also taken for anti-hepatitis C virus antibody and hepatitis C virus RNA testing. RESULTS: Forty-four participants were interviewed and 39 gave blood for testing. Most (80%) were aged 29 years or under and two thirds (n=26) were male. Around half reported borrowing (49%) or lending (57%) needles and syringes since 1994 and both of these behaviours were associated with seroconversion. The majority (88%) also reported sharing other injecting equipment. Nine were anti-hepatitis C virus positive giving a seroconversion rate over two years of 23% (13 per 100 person years). Four out of the nine seropositive specimens tested were also hepatitis C virus RNA positive. CONCLUSIONS: This study demonstrates a high rate of recent hepatitis C virus seroconversion amongst a group of New Zealand injecting drug users. Transmission of hepatitis C virus appears to be unabated by current control measures. These findings confirm the need to develop more effective policy and practices to prevent further spread, not just of hepatitis C, but of other blood-borne viruses in injecting drug user populations.

Adolescent↗
PubMed2000

Prospective memory and aging: forgetting intentions over short delays.

Retrieved intentions often cannot be performed immediately and must be maintained until there is an opportunity to perform them. In 3 experiments, on seeing a target event, younger and older participants were to withhold an action until they encountered the appropriate phase of the experiment. When initial retrieval was made facile by the use of a salient retrieval cue, the age-related decrements were often dramatic, even over unfilled delay intervals as brief as 10 s (Experiments 1 and 2). When initial retrieval was difficult, older adults showed no forgetting over the retention interval (Experiment 3). Several theoretical perspectives were offered as explanations for the age differences observed with salient retrieval cues, including those that focus on age differences in metamemory, the degree to which plans are reformulated, and the ability to nonstrategically maintain current concerns in working memory.

Adolescent↗