Search PubMed⌕ Search

Biomedical subjects

M Baker

Publications and source records attributed to M Baker.

At least 19 recordsLinked to original sources
PubMed2002

Analysis of tau haplotypes in Pick's disease.

Pick's disease (PiD) is characterized by the deposition of tau protein as three-repeat tau Pick bodies, whereas progressive supranuclear palsy (PSP) involves the deposition of four-repeat tau neurofibrillary tangles. PSP is associated with the tau H1 haplotype. The authors investigated a possible association between PiD and the tau H1 or H2 haplotype. There was no difference between the tau H2 haplotype or H2H2 genotype frequency in PiD cases and control subjects. No tau mutations were identified in pathologically typical cases of PiD, with antibody 12-E8-negative Pick bodies.

Aged↗
PubMed2002

Toxicological evaluation of Catha edulis leaves: a long term feeding experiment in animals.

In this study the long term (6 months) toxicological effect of varying levels of Catha edulis leaves were examined on the plasma concentration of liver enzymes as well as the histopathology of tissue sections of the liver. Both biochemical and histopathological data presented demonstrate signs of C. edulis toxicity. Our results show a significant increase in plasma levels of Alkaline phosphatase (ALP), Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) with all levels of C. edulis leaves tested and throughout the treatment period. The increase of ALP was more prominent than both ALT and AST at the higher level of 30%. Plasma levels of AST though were only moderately increased at the higher level of 30% at the early stage of treatment (3 months) it significantly increased with all levels of C. edulis leaves in the long term (4-6 months). In addition, a time-dependent gradual increase in indirect bilirubin with a concomitant decrease in direct bilirubin levels were observed with the lower level of C. edulis (10%) with no signs of haemolysis. Histopathology of tissue sections of liver display evidences of increasing chronic inflammation with porto-portal fibrosis in the tissue sections obtained from animals treated with both 20 and 30% C. edulis.

Alanine Transaminase↗
PubMed2002

Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene.

Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

Age of Onset↗
PubMed2002

Familial frontotemporal dementia associated with a novel presenilin-1 mutation.

We report a kindred with three cases of dementia. The proband presented with forgetfulness and personality changes at age 56, followed shortly thereafter by behavioral dyscontrol, hyperphagia, hypersexuality, delusions, illusions, disinhibition and double incontinence. Neuroimaging studies were consistent with frontotemporal dementia (FTD). In one allele, an arginine insertion at codon 352 in the presenilin 1 (PSEN1) gene was identified; no mutation was identified in the amyloid precursor protein or tau genes. We conclude that the clinical features of the Kluver-Bucy syndrome and FTD can be associated with PSEN1 mutations. Furthermore, presenilin analyses may be helpful to characterize kindreds with familial dementing illnesses regardless of the phenotype, particularly if no tau mutation is present.

Dementia↗
PubMed2001

The microtubule associated protein Tau gene and Alzheimer's disease--an association study and meta-analysis.

Several studies have suggested an association between polymorphisms and an extended haplotype of the microtubule associated protein tau gene and Alzheimer's disease (AD) in synergy with apolipoprotein E (APOE) epsilon 4 status. However these findings have not been consistently replicated. We investigated the role of the tau haplotype in AD by conducting an association study as well as a meta-analysis of all the studies conducted to date. We examined six polymorphisms known to be in the extended tau haplotypes, one in exon 7 and five in and around exon 9 in 200 late onset AD and 189 control samples. All the polymorphisms examined fell into the recognised tau haplotypes. There was no statistical significant association with any of the polymorphisms and late onset AD. Stratification of data by APOE epsilon 4 status also produced no strongly significant association. The meta-analysis showed no significant differences between AD cases and controls, however stratification of data by APOE epsilon 4 status showed a small significant decrease in the H1 haplotype in AD before correction for multiple testing.

Aged↗
PubMed2001

Weekly docetaxel with either gemcitabine or vinorelbine as second-line treatment in patients with advanced nonsmall cell lung carcinoma: Phase II trials of the Minnie Pearl Cancer Research Network.

BACKGROUND: The current study was conducted to evaluate the feasibility, toxicity, and efficacy of weekly docetaxel when paired with either gemcitabine or vinorelbine as the second-line treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Patients with progressive nonsmall cell lung carcinoma after one previous chemotherapeutic regimen, an Eastern Cooperative Oncology Group performance status of 0-2, and measurable lesions were eligible for treatment in these Phase II trials. Patients who had not received gemcitabine previously were treated with docetaxel, 30 mg/m(2), and gemcitabine, 800 mg/m(2), both of which were administered intravenously (i.v.) on Days 1, 8, and 15 of a 28-day cycle. If the patients had received gemcitabine as part of first-line therapy, they were treated with docetaxel, 30 mg/m(2), and vinorelbine, 20 mg/m(2) i.v., on Days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after two courses of treatment, and responding patients continued treatment for six courses or until disease progression. RESULTS: Forty patients were treated with a combination of docetaxel and gemcitabine, and 23 patients received docetaxel and vinorelbine. The docetaxel/gemcitabine combination was reasonably well tolerated, with moderate myelosuppression and a few nonhematologic toxicities reported. The objective response rate was 10%, with a 1-year survival rate of 20%. The docetaxel/vinorelbine combination was found to be poorly tolerated, with Grade 3/4 leukopenia reported in 71% of patients and neutropenic fever reported in 70% of patients despite frequent dose reductions and omission of the Day 15 doses. Enrollment onto this regimen was stopped prematurely due to toxicity, and after no major responses were observed in the first 20 evaluable patients. CONCLUSIONS: The combination of weekly docetaxel/gemcitabine appears to be feasible and relatively well tolerated as second-line treatment in patients with advanced nonsmall cell lung carcinoma, whereas a weekly combination of docetaxel and vinorelbine did not appear to be tolerable at the doses and schedule used in the current study. Neither regimen showed a level of activity that suggested any advantage compared with the results obtained with single-agent docetaxel in this setting.

Adult↗
PubMed2001

Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.

Aged↗
PubMed2001

Expression of BRI-amyloid beta peptide fusion proteins: a novel method for specific high-level expression of amyloid beta peptides.

In order to develop transgenic animal models that selectively overexpress various Abeta peptides, we have developed a novel expression system that selectively expresses Abeta40 or Abeta42 in the secretory pathway. This system utilizes fusion constructs in which the sequence encoding the 23-amino-acid ABri peptide at the carboxyl terminus of the 266-amino-acid type 2 transmembrane protein BRI is replaced with a sequence encoding either Abeta40 or Abeta42. Constitutive processing of the resultant BRI-Abeta fusion proteins in transfected cells results in high-level expression and secretion of the encoded Abeta peptide. Significantly, expression of Abeta42 from the BRI-Abeta42 construct resulted in no increase in secreted Abeta40, suggesting that the majority of Abeta42 is not trimmed by carboxypeptidase to Abeta40 in the secretory pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Tau genotype: no effect on onset, symptom severity, or survival in progressive supranuclear palsy.

Genetic studies have shown that progressive supranuclear palsy (PSP) is associated with inheritance of a specific genotype (H1/H1) in the tau gene. The authors investigated whether the H1/H1 genotype or A0/A0 genotype independently or in conjunction with selected environmental risk factors influences the age at onset, severity, or survival in patients with PSP. Our findings suggest that tau genotyping does not predict the prognosis of PSP.

Age of Onset↗
PubMed2001

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.

OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Genotype↗
PubMed2001

The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease.

Pick's disease (PiD) is a rare neurodegenerative condition and is a member of a heterogeneous group of disorders known as tauopathies, so-called because of the predominantly neuronal aberrant tau accumulations found in these diseases. The tauopathy, familial frontotemporal dementia (FTD), is caused by mutations in the tau gene. Moreover, progressive supranuclear palsy (PSP) is associated with the tau H1 haplotype. In certain familial forms of FTD and in PSP the microtubule-binding four repeat tau isoform principally accumulates in neuropathological lesions. However, in PiD three repeat tau accumulations are found. We therefore investigated whether either the tau H1 or H2 haplotype was associated with PiD. Our results indicate a slight increase in H2H2 frequency in Pick's cases which is not statistically significant.

Aged↗
PubMed2001

The genetic and pathological classification of familial frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD. OBJECTIVE: To explore the genetic and pathological basis of familial FTD. DESIGN: Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible. SETTING: Specialist dementia research group, particularly recruiting patients with young-onset dementia. PATIENTS: Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained. RESULTS: Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups. CONCLUSIONS: This study illustrates the value of TAU sequencing in FTD and suggests that around one half of individuals with familial FTD have TAU mutations and dementia with tau pathological findings. Furthermore, these data suggest that there are at least 2 additional genes to be identified among families with autosomal dominant FTD.

Adult↗
PubMed2001

Relationship of the extended tau haplotype to tau biochemistry and neuropathology in progressive supranuclear palsy.

Two extended haplotypes of the tau gene (H1 and H2) have been described. The frequency of H1 haplotype is increased in progressive supranuclear palsy (PSP). PSP is associated with filamentous tau lesions in neurons and glia, which are reportedly composed exclusively of tau isoforms with four repeats in the microtubule-binding domain (4R tau). To determine the influence of the tau haplotype on tau isoform composition and neuropathology, we studied 25 PSP cases and 6 Alzheimer's disease patients matched for age, sex, and postmortem delay. In the basal ganglia, tau and amyloid burdens were determined to see if there was an effect of concurrent Alzheimer-type pathology, and the ratio of 4R to 3R tau was measured in detergent-insoluble tau fractions. Insoluble tau from PSP was not composed exclusively of 4R tau. All brains had a mixture of 4R and 3R tau, but the ratio was different in Alzheimer's disease and PSP. In Alzheimer's disease there was less 4R than 3R tau, whereas the ratio was reversed in PSP. In PSP cases with concurrent Alzheimer-type pathology, the ratio of 4R to 3R was intermediate between Alzheimer's disease and PSP. The H1 haplotype had no effect on the 4R to 3R ratio or on tau and amyloid burdens. In summary, the H1 haplotype does not have a major influence on the pathological or biochemical phenotype of PSP.

Adult↗
PubMed2001

Comparison of the cumulative irritation potential of adapalene gel and cream with that of erythromycin/tretinoin solution and gel and erythromycin/isotretinoin gel.

BACKGROUND: Adapalene is a naphthoic acid derivative with retinoid activity that is effective in the treatment of mild to moderate acne vulgaris. OBJECTIVE: This study assessed the cumulative irritation potential of adapalene gel (0.1%) and adapalene cream (0.1%) compared with that of erythromycin (4%)/tretinoin (0.025%) solution, erythromycin (4%)/tretinoin (0.025%) gel, erythromycin (2%)/isotretinoin (0.05%) gel, and white petrolatum (negative control). METHODS: This was a single-center, randomized, controlled, investigator-blinded, intraindividual comparison study in healthy subjects with normal skin. The cumulative irritation assay (patch test) was used to assess the potential for irritation (including erythema) of the treatments. Each subject received all study treatments, randomly applied under occlusion (patch), to sites on either side of the midline on the mid-thoracic area of the back. All patches were applied to the same sites throughout the study, unless the degree of reaction to the treatment or adhesive necessitated removal. For 3 weeks, each test material was applied daily, Monday through Friday, for approximately 24 hours; the Friday patches were left in place over the weekend for approximately 72 hours. RESULTS: All 36 subjects (26 men, 10 women; age, 18-49 years [mean, 30 years]) completed the study. In the course of the study, all subjects had > or =1 application discontinued prematurely on > or =1 site due to intolerance. There were no discontinuations with white petrolatum. All erythromycin/tretinoin gel patches were discontinued at day 10; 35 of 36 erythromycin/isotretinoin gel patches were discontinued at day 9; and 35 of 36 erythromycin/tretinoin solution patches were discontinued at day 11 or day 17. The adapalene products, although slightly more irritating (mean cumulative irritation index, 0.25-1) than white petrolatum, were significantly less irritating than the erythromycin/tretinoin and erythromycin/isotretinoin products (P < 0.01). CONCLUSIONS: Adapalene gel and cream were well tolerated, with possible benefits for compliance. Their low irritation potential should be considered when prescribing a topical retinoid for the treatment of acne vulgaris.

Adapalene↗
PubMed2001

Voltage-gated sodium channels.

Increased knowledge of the molecular diversity of sodium channel alpha- and beta-subunits, and their distribution of expression have been highlights of the past year. The development of subtype-specific channel blockers remains elusive, but the discovery of selective inhibitors such as mu-conotoxins promises useful antagonists in the near future.

Animals↗
PubMed2001

Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne.

The emergence of oral and topical retinoids was a major advance in the clinical management of acne vulgaris. However, the benefits of these agents were somewhat limited by the degree of side effects caused by these drugs. Over the last 15 years, researchers have sought compounds that can provide the manifold therapeutic benefits obtained with tretinoin and isotretinoin while minimizing the potential for irritation and other unwanted effects. Adapalene, a naphthoic-acid derivative, is one result of this search, and it serves as an example of rational drug development: the formulation of a novel substance with specific pharmacological properties and clinical objectives in mind. These goals included enhancing stability, enhancing anti-inflammatory effects, maintaining effectiveness and minimizing cutaneous irritation. This paper reviews the history of the development of adapalene, its unique physical and biochemical properties, and the pharmacological studies that demonstrate a wide range of retinoid-receptor, genetic and anti-inflammatory effects, all of which contribute to the therapeutic efficacy and improved tolerability of adapalene observed in the clinical use of this agent for the treatment of acne.

Acne Vulgaris↗
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↗