Search PubMed⌕ Search

Biomedical subjects

R F Itzhaki

Publications and source records attributed to R F Itzhaki.

At least 19 recordsLinked to original sources
PubMed2003

Does apolipoprotein E polymorphism influence susceptibility to malaria?

Outcome of infection varies greatly among people, and in the case of three very different viruses, it is determined by apolipoprotein E (APOE) genotype. APOE might affect outcome of malaria infection also, since apoE protein and the protozoon (like the viruses) share cell entry mediators (heparan sulphate proteoglycans and/or specific apoE receptors). APOE polymorphisms give rise to protein variants that differ in binding strength to these mediators; thus, the extent of competition between apoE and protozoon for cell entry, and hence magnitude of protozoan damage, might depend on apoE isoform. Genotypes of infants infected with malaria were examined. It was found that APOE epsilon 2 homozygotes became infected at an earlier age than those carrying the other genotypes, the difference being statistically significant. Parasite densities, all of which were low, did not differ significantly. This effect, although based on small numbers, suggests that APOE epsilon 2 may be a risk factor for early infection.

Animals↗
PubMed2001

Herpes simplex encephalitis: involvement of apolipoprotein E genotype.

It was previously found that herpes simplex type 1 virus (HSV1) when present in the brain, is a risk factor for Alzheimer's disease in carriers of the type 4 allele of the gene for apolipoprotein E (apoE epsilon4), and apoE epsilon4 is a risk factor for herpes labialis. Whether a specific allele of the gene is involved in susceptibility to another disorder caused by HSV1-herpes simplex encephalitis (HSE)-has now been investigated. DNA was prepared from formalin-fixed, paraffin-embedded blocks of specimens from the brain or spleen of 14 United Kingdom patients with HSE, confirmed by necropsy, and from the CSF of seven United Kingdom clinical patients with HSV1 in their CSF detected by polymerase chain reaction (PCR). ApoE genotype of the DNA from blocks was determined by seminested PCR, and of the DNA from CSF by one step PCR, followed by restriction endonuclease digestion. The apoE allele frequencies were compared with values previously obtained for 238 normal people from the United Kingdom. The apoE epsilon2 allele frequency of the patients with HSE was 26%, significantly higher than the value of 7% for the normal subjects (OR=4.6, 95% confidence interval (95% CI) 2. 0-10.8). The apoE epsilon3 and epsilon4 allele frequencies did not differ significantly between the two groups. Thus, it seems that apoE epsilon2 is a risk factor for HSE.

Adolescent↗
PubMed1999

Apolipoprotein E and herpes virus diseases: herpes simplex keratitis.

Our previous studies showed that herpes simplex type 1 virus (HSV1) is present in a high proportion of the brain of elderly normal people and Alzheimer's disease (AD) patients. We subsequently discovered that the combination of HSV1 in brain and carriage of the type 4 allele of the gene for apolipoprotein E (apoE-epsilon 4) is a strong risk factor for AD, and also that apoE-epsilon 4 is a strong risk factor for herpes labialis. In this study we have examined apoE genotypes of sufferers from another disorder caused by HSV1, namely, herpes simplex keratitis (HSK), to find if an apoE allele is involved in the disorder. In 46 HSK patients the apoE-epsilon 4 allele frequency was 15%-the same as that found in 238 unaffected controls. The apoE-epsilon 2 allele frequency was 13%-higher than the value of 7% for unaffected people, but the difference is not statistically significant.

Adolescent↗
PubMed1998

Mechanisms of uptake of gallium by human neuroblastoma cells and effects of gallium and aluminum on cell growth, lysosomal protease, and choline acetyl transferase activity.

We have studied the uptake and removal of gallium, used as an analogue of aluminum, and the effects of aluminum itself on cultured human neuroblastoma cells treated with soluble metal complexes. The prohibitively high cost of measurement of the only available radioisotope of aluminum (26Al) precluded its usage, and so we considered that gallium, which is chemically extremely similar, would be the most suitable model. Gallium has been used thus in a number of previous biological studies and has been found to behave like aluminum in many respects. We have previously shown that Al-EDTA treatment results in uptake of aluminum and expression of hyperphosphorylated tau, a key component of Alzheimer's disease paired helical filaments. Here we demonstrate that gallium uptake can occur by two separate methods, both leading to physiologically relevant intracellular metal concentrations. Uptake from medium containing bovine transferrin occurred mainly by pinocytosis, but in the presence of human transferrin (hTf), uptake by transferrin-mediated endocytosis occurred also, despite a very low level of hTf saturation, indicating that Tf-mediated uptake is a very effective method of Ga internalization. The intracellular gallium is relatively stable, though partially removable by (1 mM) EDTA, desferrioxamine, or 1,2-dimethyl-3-hydroxypyrid-4-one. Aluminum and gallium treatment were found to increase the overall activity of lysosomal proteases, enzymes implicated in amyloid precursor protein cleavage. No effects were detected on choline acetyl transferase activity, cell growth, or tritiated thymidine incorporation or on the structure of the cells, as judged by light or electron microscopy.

Aluminum↗
PubMed1998

Location of aluminium and gallium in human neuroblastoma cells treated with metal-chelating agent complexes.

The subcellular location of aluminium is unknown, probably because of difficulties in investigating aluminium biochemistry and the use of varied experimental approaches of uncertain sensitivity. We have studied levels of uptake and the localization of gallium and of aluminium in cultured human neuroblastoma cells treated with soluble metal complexes (mainly Al- or Ga-EDTA), radiolabeled with 26Al or 67Ga, respectively. Crude nuclei and cytoplasm were obtained by two separate methods, and DNA, RNA, and proteins were prepared from the nuclei by centrifugation in high salt; also, cytosol and noncytosol were separated using a nondissociating method. Levels of uptake were of similar order for the two metals-on average about 50 pmol/10(6) cells for aluminium and 120 pmol/10(6) cells for gallium, after 4 to 8 days treatment at 250 microM, and approximately 50 to 70% of the metal was found in the cytosol. About 20% of the aluminium and 10 to 25% of the gallium was associated with nuclear protein. A lower proportion was bound to DNA and to nuclear RNA. In cells treated with gallium-citrate/transferrin mixtures, 30 to 35% of the gallium in the cytosol was bound to protein, at least 35 being loosely bound; the main gallium-associated protein was probably intracellular transferrin. The remaining 65 to 70% of the metal in the cytosol was in low-molecular-weight form, and we suggest that the latter metal could affect structures such as the cytoskeleton and also metabolic processes in the cytoplasm. The similarity in distribution of the two metals supports the use of gallium as a "surrogate" for aluminium, at least in cell culture studies.

Aluminum↗
PubMed1997

Herpes simplex virus type 1 in brain and risk of Alzheimer's disease.

BACKGROUND: The apolipoprotein E epsilon 4 (APOE-epsilon 4) allele is a risk factor for Alzheimer's disease (AD), but it is neither essential nor sufficient for development of the disease. Other factors-genetic or environmental-must therefore have a role. By means of a PCR we have detected herpes simplex virus type 1 (HSV1) in latent form in brains of elderly people with and without AD. We have postulated that limited reactivation of the virus causes more damage in AD patients than in elderly people without AD because of a difference in the hosts. We now report the APOE genotypes of AD patients and non-AD sufferers with and without HSV1 in brain. METHODS: DNA was extracted from 84 samples of brain from 46 AD patients (39 temporal lobe, 39 frontal lobe, three hippocampus) and from 75 samples of brain from 44 non-AD elderly people (33 temporal lobe, 36 frontal lobe, six hippocampus). PCR amplification was used to detect HSV1 thymidine kinase gene and the host APOE gene. FINDINGS: By multiple logistic regression, the APOE-epsilon 4 allele frequency was significantly higher in the patients positive for HSV1 in brain than in the HSV1-negative AD group, the HSV1-positive non-AD group, or the HSV1-negative non-AD group (52.8% vs 10.0%, 3.6%, and 6.3%, respectively). The odds ratio for APOE-epsilon 4 in the HSV1-positive AD group compared with HSV1-negative non-AD group was 16.8 (95% CI 3.61-77.8) and in the HSV1-negative AD group, 1.67 (0.21-13.4). We also compared APOE genotypes of 40 people who had recurrent cold sores and 33 non-sufferers; the APOE-epsilon 4 allele frequencies were 36% and 9%, respectively (p < 0.0001). INTERPRETATION: These findings suggest that the combination of HSV1 in brain and carriage of an APOE-epsilon 4 allele is a strong risk factor for AD, whereas either of these features alone does not increase the risk of AD. The findings in people with cold sores support our hypothesis that APOE-epsilon 4 and HSV1 together are damaging in the nervous system.

Aged↗
PubMed1997

Neurotropic viruses and Alzheimer's disease: a search for varicella zoster virus DNA by the polymerase chain reaction.

BACKGROUND: In studies on the possible role of viruses in the aetiopathogenesis of Alzheimer's disease, herpes simplex virus type 1 (HSV1) DNA was detected by the polymerase chain reaction (PCR) in a high proportion of normal elderly people and of patients with Alzheimer's disease. The combination of HSV1 and a host factor, the type 4 allele of the gene for apolipoprotein E, is a strong risk factor for the disease. METHODS: Brain specimens were examined for another herpes virus, varicella zoster (VZV), which, like HSV1, is neurotropic, has a predilection for residing latently in the peripheral nervous system, and can reactivate. RESULTS: Using primers for sequences in the VZV origin of replication gene or thymidine kinase gene, VZV DNA was not found in any of 24 samples (18 HSV1 positive), from 17 patients with Alzheimer's disease, nor in 20 samples (12 HSV1 positive from 12 aged normal people. Hybridisation of the PCR products with a radiolabelled oligonucleotide probe capable of detecting less than 10 copies of the target sequence, confirmed the absence of VZV DNA. CONCLUSION: The presence of one neurotropic virus--HSV1--and the absence of another--VZV--in aged human brains is consistent with a role for HSV1 in the aetiology of Alzheimer's disease.

Aged↗
PubMed1994

Chromosome studies in Alzheimer's disease patients: distribution of dicentric breakpoints in lymphocytes irradiated in vitro.

A previous study showed a significant increase in dicentric frequency in lymphocytes irradiated in vitro from non-familial Alzheimer's disease patients compared to normal age-matched controls. This study examined the distribution of the chromosome breakpoints involved in the dicentric formation and found a non-specific increase in all chromosomes.

Alzheimer Disease↗