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Biomedical subjects

Y Davidson

Publications and source records attributed to Y Davidson.

17 recordsLinked to original sources
PubMed2006

Comparison of extent of tau pathology in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration with Pick bodies and early onset Alzheimer's disease.

In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Adult↗
PubMed2006

Influence and interactions of cathepsin D, HLA-DRB1 and APOE on cognitive abilities in an older non-demented population.

Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEepsilon4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) (P = 0.016) and an additional test of fluid intelligence (P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability (P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities (P = 0.014 and P = 0.003, respectively). When analysed independently, APOEepsilon4 did not influence any cognitive domains. In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities (P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD.

Aged↗
PubMed2006

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype.

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.

Aged↗
PubMed2006

The apolipoprotein E epsilon4 allele selectively increases the risk of frontotemporal lobar degeneration in males.

OBJECTIVE: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent. METHODS: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE epsilon4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex. RESULTS: The APOE epsilon4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE epsilon2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE epsilon4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE epsilon2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE epsilon2 nor APOE epsilon4 allele frequency varied significantly between any of the clinical subtypes. CONCLUSIONS: In FTLD not associated with mutations in tau gene, possession of APOE epsilon4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.

Adult↗
PubMed2005

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population.

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.

Aged↗
PubMed2003

Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population.

General intelligence is a heritable trait that is a risk factor for both the onset of dementia and the rate of cognitive decline in community-dwelling older persons. Previous studies screening for quantitative trait loci (QTLs) that influence general intelligence in healthy individuals have identified four loci, two of which are located within the genes insulin-like growth factor 2 receptor (IGF2R) and the Msx1 homeobox. Here, we report the finding of another QTL associated with general intelligence that is located within exon 2 of the cathepsin D (CTSD) gene. A group of 767 healthy adults with a follow-up period of over 15 years have been analyzed for cross-sectional and longitudinal trends in cognitive change using the Heim intelligence test score (AH4-1). We observed a significant association (P = 0.01) between a functional C > T (Ala > Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study. Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome.

Aged↗
PubMed2000

Prevalence of asthma in 13-14 yr-old schoolchildren across Israel.

There is evidence that the incidence and severity of asthma are increasing worldwide, but there are limited data on asthma in Israel. The aim of this study was to investigate the prevalence and severity of asthma and asthma symptoms in 13-14 yr-old schoolchildren in Israel. The self-completed questionnaire used was a modified version of that developed by the International Study of Asthma and Allergies in Childhood (ISAAC), and was administered to a national sample of 12,918 children. The prevalence of asthma ever, wheezing ever and wheezing in the last 12 months were 13.7, 23.8 and 17.9% respectively. Significantly higher rates of a history of asthma and asthma symptoms were observed in Jews compared with Arabs. Although asthma ever was more prevalent in males than in females, asthma symptoms were significantly more common in females. The type of area of residence had no effect on the prevalence of wheezing. The ethnic differences in the prevalence of asthma persisted after controlling for sex, district of residence and level of urbanization. The prevalence of both asthma and asthma symptoms in Israel are slightly above the mean reported from 10 other countries in Europe and the Far-East.

Adolescent↗
PubMed1999

The susceptibility of Streptococcus pneumoniae to levofloxacin and other antibiotics.

The aim of this study was to determine the in-vitro susceptibility of Streptococcus pneumoniae to levofloxacin, ciprofloxacin, sparfloxacin, ofloxacin, amoxycillin, cefepime and cefuroxime. In total, 105 isolates (clinical blood and sputum isolates from 1995-96) were selected from the collection of the Department of Clinical Microbiology of the Chaim Sheba Medical Centre. MICs were determined with an agar dilution method according to NCCLS guidelines. The MIC ranges with the test antibiotics against the pneumococcal isolates were: 0.5 mg/L, levofloxacin; 0.12-0.5 mg/L, sparfloxacin; 0.5-2 mg/L, ciprofloxacin; 0.5-1 mg/L, ofloxacin; < 0.03-2 mg/L, amoxycillin; < 0.03-2 mg/L, cefepime; < 0.03-2 mg/L, cefuroxime. The results indicated that although all isolates were susceptible to all the fluoroquinolone agents except ciprofloxacin, some isolates had reduced susceptibility to amoxycillin, cefepime and cefuroxime. We conclude that all S. pneumoniae isolates tested were susceptible to levofloxacin, ofloxacin and sparfloxacin. However, about 85% were susceptible to amoxycillin and the other beta-lactam antibiotics tested.

Anti-Bacterial Agents↗
PubMed1998

Unreliability of disc diffusion test for screening for reduced penicillin susceptibility in Neisseria meningitidis.

The 2-U penicillin and microgram oxacillin discs proposed for screening meningococci for susceptibility to penicillin were evaluated by using MICs measured by the E test. The discs yielded unacceptably high frequencies of misclassification of susceptibility category and should be abandoned in favor of MIC estimations. An agreed breakpoint for reduced penicillin susceptibility in meningococci is needed for the E test.

Humans↗
PubMed1987

The effect of vitamin E deficiency on the induction of age pigment in various tissues of the mouse.

The effect of a dietary deficiency of vitamin E on the concentrations of lipofuscin in the hippocampus and the supraoptic nucleus (SON) of the hypothalamus, and in adrenal cortical cells was assessed in male mice. The animals were fed either a control diet or the vitamin E deficient diet after 2 months of age for a period of 6 months. There was no significant difference in the growth curves of the 2 groups of animals over the period studied. Fluorescence microscopy and transmission electron microscopy were used to assess the effect of the diet on lipofuscin in the different tissues. Quantitative morphological techniques were used to determine the relative volumes of lipofuscin in the neurons from the SON and in the adrenal cortical cells. There was no significant difference in the concentration of lipofuscin in the SON neurons after vitamin E deficiency but there was a significant increase in the adrenal cortical cells. There was a clear difference in the effect of the deficiency on mitotic and fixed post-mitotic cells over the period investigated but further studies would be necessary to determine whether or not there was a critical period in the life span where vitamin E deficiency may induce changes in all cell types.

Adrenal Cortex↗