Run-on mutation and three novel nonsense mutations identified in the PAX6 gene in patients with aniridia.
Explore the source record for details and available documents.
Aniridia↗
Biomedical subjects
L Baum
Publications and source records attributed to L Baum.
Apolipoprotein E promoter and alpha2-macroglobulin polymorphisms are not genetically associated with Chinese late onset Alzheimer's disease.
In this study, we investigated two newly reported polymorphisms in association with late onset Alzheimer's disease (AD) in Chinese. They were a -491 A/T polymorphism in the Apolipoprotein E (APOE) promoter region and a five base pair deletion at exon 18 of alpha2-Macroglobin (A2M). There were 196 AD and 180 normal controls (N), which were age- and sex-matched. APOE epsilon4 alleles were significantly increased in AD vs. N (chi2 = 33.3, P < 0.000001). However, neither the -491 A/T (chi2 = 1.13, P = 0.29) nor A2M (chi2 = 0.18, P = 0.67) polymorphism was associated with AD risk, suggesting that these polymorphisms do not represent risk factors for AD in the Chinese population.
Age of Onset↗
Lipoprotein lipase mutations and Alzheimer's disease.
Lipoprotein lipase (LPL) helps transfer lipids from lipoprotein particles to cells. In the brain, LPL is present in Alzheimer's disease (AD) amyloid plaques. LPL binds apolipoprotein E (ApoE) lipoprotein particles and low-density lipoprotein receptor-related protein (LRP), an ApoE receptor. Since polymorphisms in both ApoE and LRP influence AD risk, we sought to determine whether LPL mutations also affect AD risk. In a case-control study, the frequencies of two of the most common known LPL mutations were measured in European-Americans either clinically diagnosed or pathologically confirmed as AD or normal control (N) subjects. In clinically diagnosed subjects, the Ser447Ter mutation comprised 9.8% (62/630) of alleles in N and 3.8% (9/238) in AD, a significant difference (P = 0.0057), while the Asn291Ser mutation comprised 1.1% (5/460) of alleles in N and 5.1% (8/158) in AD, also a significant difference (P = 0.0073), though in pathologically confirmed subjects the allele frequencies for AD did not significantly differ from N for either mutation. In clinically diagnosed subjects, LPL mutations were associated with altered AD risk, suggesting a potential role for LPL in the causation of AD. Further studies in different populations should help clarify the questions raised by these results.
Aged↗
Low-density lipoprotein receptor-related protein (LRP) gene 766T polymorphism and Parkinson's disease.
The C766T polymorphism in exon 3 of the low-density lipoprotein receptor-related protein (LRP) gene is underrepresented in Alzheimer's disease (AD) compared with normal subjects. We examined this polymorphism in 186 patients with Parkinson's disease (PD) and 187 age-matched normal Chinese subjects in addition to 227 newborns representing the general population. The fraction of individuals with 766T was 12.8% in normal subjects and 11.3% in patients with PD, not a significant difference (p = 0.77). The odds ratio was 0.86 with a 95% confidence interval of 0.44-1.69, thus the LRP C766T polymorphism does not play a major role in risk for PD, although the possibility cannot be excluded that it plays a minor role or is a significant risk factor in other ethnic groups.
Aged↗
Apolipoprotein E genotype and its pathological correlation in Chinese Alzheimer's disease with late onset.
In this study, we attempted to find a relationship between apoliprotein E (ApoE) genotypes and Alzheimer's disease (AD) pathology in different areas of the brain in Chinese. We also studied the borderline group of possible AD (Poss). There were 34 definite or probable AD (Ad), 18 Poss, and 123 brains from age-matched normal subjects (N). ApoE genotype was determined by nested polymerase chain reaction on genomic DNA extracted from archival paraffin-embedded materials. Hippocampus (including entorhinal cortex), amygdala, superior temporal lobe, middle frontal gyrus, and inferior parietal lobule of the brains of Ad and Poss were examined with beta amyloid (A beta) immunostaining, and the same regions plus medial occipital lobe were examined with tau immunostaining. The percentage of plaque area stained for A beta in each brain region was obtained by an image analyzer, and the average number of neurofibrillary tangles stained for tau was counted with an eyepiece graticule. ApoE epsilon4 frequency was increased in both Ad (22.1%, chi2, df = 1, P = .00005), and Poss (33.3%, P = .000005) compared with N (5.3%). A beta load was significantly increased in the neocortex in Ad examined with at least 1 copy of epsilon4 compared with subjects without epsilon4 (Mann-Whitney, P = .014). The same trend, though not statistically significant, occurred in Poss (P = .15). Tau expression was associated with ApoE epsilon4 in neither Ad nor Poss. Poss is genetically and histologically similar to Ad, although the overall A beta load is significantly increased in the latter. These findings support the recent Consensus Report's findings that all Alzheimer-type pathology may be significant.
Age of Onset↗
Low density lipoprotein receptor related protein gene amplification and 766T polymorphism in astrocytomas.
Low density lipoprotein receptor related protein (LRP) is a receptor for protease complexes, and may function in cell growth and repair, and in tumor invasiveness. LRP expression increases in glioblastomas compared to lower grade astrocytomas. Two potential mechanisms for this increased expression were investigated. The LRP C766T polymorphism is protective against Alzheimer's disease, perhaps through alteration of LRP expression. The frequency of the polymorphism was measured in astrocytoma patients and controls, but no significant difference was found. Differential PCR revealed LRP gene amplification in four of 25 high-grade gliomas and 0 of 23 other brain tumors. Co-amplification with epidermal growth factor receptor (EGFR) occurred in all four of the LRP-amplified tumors. Thus, LRP amplification may be partly responsible for increased LRP expression in astrocytomas, and may often occur in conjunction with EGFR amplification.
Astrocytoma↗
Alterations in cell surface carbohydrates on T cells from virally infected mice can distinguish effector/memory CD8+ T cells from naive cells.
Glycosylation changes on surface molecules of T cells affect cell trafficking and function and may be useful in discriminating between naive, effector, and memory T cells. To analyze oligosaccharide structures on T cells activated in vivo, we examined alterations in sialic acid residues on T cells following infection of mice with lymphocytic choriomeningitis (LCMV), vaccinia virus, and vesicular stomatitis virus. We found that the majority of CD8 T cells from mice acutely infected with these viruses showed increased binding to peanut agglutinin (PNA). All of the PNAhighCD8 T cells from infected mice were CD44high, indicating that glycosylation changes were occurring on activated T cells. There was also an increase in the PNAhighCD4 T cell population in virally infected mice. Increased PNA binding to activated CD8 T cells correlated with higher endogenous neuraminidase levels in these cells. This higher neuraminidase activity most likely contributed to the PNAhigh phenotype by cleaving sialic acid residues off the core-1 O-glycans or glycoproteins destined for the cell surface. A PNAhighCD8 T cell population persisted in immune mice that had cleared the LCMV infection. When spleen cells from immune mice were sorted into PNAhigh and PNAlow populations, >95% of the LCMV-specific memory CD8 T cells segregated with the PNAhigh population. This shows that virus-specific memory CD8 T cells remain hyposialylated and can be distinguished from naive CD8 T cells based on PNA binding. Thus, PNA can be used as a marker for Ag-experienced T cells.
Animals↗
Low density lipoprotein receptor related protein gene exon 3 polymorphism association with Alzheimer's disease in Chinese.
Since apolipoprotein E4 (apoE4) is the major genetic risk for late onset Alzheimer's disease (AD), proteins that interact with apoE might be involved in AD pathogenesis. Low density lipoprotein receptor related protein (LRP) is an apoE receptor in the brain. In exon 3 of the LRP gene a polymorphism was found to be underrepresented in AD compared to normal Caucasian subjects (N). We examined this polymorphism in Chinese AD and N subjects. The polymorphism frequency in N was roughly half that reported for Caucasians. Compared to N, the frequency was significantly decreased in pathologically diagnosed, but not in clinically diagnosed AD patients. Thus, the role of the LRP exon 3 polymorphism in AD has now been demonstrated in two ethnic groups, suggesting the importance of LRP in AD pathogenesis.
Aged↗
No association detected between very-low-density lipoprotein receptor (VLDL-R) and late-onset Alzheimer's disease in Hong Kong Chinese.
The epsilon4 allele of apolipoprotein E (ApoE) is a risk factor in late-onset Alzheimer's disease (AD). As a receptor for ApoE, very-low-density lipoprotein receptor (VLDLR) might be involved in AD pathogenesis. A Japanese study [Okuizimi, K., et al., Nature Genet., 11 (1995) 207-209] has shown an increased 5 and decreased 8 CGG-repeat allele frequency in the 5' untranslated region of VLDLR in Japanese AD versus normal controls (N). Subsequent studies in Caucasian Americans failed to duplicate the result. We examined this polymorphism in pathologically- or clinically-diagnosed Chinese late-onset AD. Our data did not show a significant increase in the 5 CGG-repeat in AD, thus suggesting no association to VLDLR. However, our data did show that the allele frequencies for each CGG-repeat were similar in both Chinese and Japanese.
Age of Onset↗
A new kind of Alzheimer's disease plaque.
Explore the source record for details and available documents.
Alzheimer Disease↗
Effect of intravenous immunoglobulin G on natural killer cell cytotoxicity in vitro in women with recurrent spontaneous abortion.
Intravenous immunoglobulin (IVIg) has been used to treat women with recurrent spontaneous abortion (RSA), particularly for women with elevated natural killer (NK) cells. We investigated the effect of IVIg on peripheral blood NK cell activity in vitro in women with RSA. 51Cr-release assays using K562 in the presence of varying concentrations of IVIg were performed using PBL from 16 women with RSA. Antibody dependent cellular cytotoxicity (ADCC) was evaluated using Daudi cells. Effectors and targets were preincubated with IVIg. Binding of IVIg to K562 and Daudi was evaluated by flow cytometry. The effect of K562 absorbed IVIg on NK activity was compared to that of non-absorbed IVIg. NK cytotoxicity and ADCC in the presence of F(ab')2 fragments were compared with those in the presence of intact IVIg. IVIg produced a significant, dose dependent inhibition of NK activity in vitro. Inhibition of NK activity occurred when effectors but not targets were preincubated with IVIg. IVIg binds to K562 and Daudi. IVIg increased ADCC when targets but not effectors were incubated with IVIg. K562 absorbed IVIg produced more inhibition of NK cytotoxicity than non-absorbed IVIg. Suppression of NK cytotoxicity by F(ab')2 was as effective as that of IVIg. However, F(ab')2 did not increase ADCC. IVIg effectively reduces peripheral blood NK cytotoxicity in vitro. Inhibition of NK cytotoxicity is mediated at the effector cell level through the antigen binding portion of the immunoglobulins. Women with RSA and elevated NK cells may benefit from IVIg treatment.
Abortion, Habitual↗
Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortion.
We previously reported elevation of natural killer (NK) cells in women with recurrent spontaneous abortion (RSA) of immune etiology. In this study, we investigated the effect of intravenous immunoglobulin G (IVIg) on peripheral blood NK activity in vivo in women with RSA. Blood was drawn prior to and 7-11 days after IVIg therapy in eight women with RSA. NK activity was measured using K562 as target cells for 51Cr-release assays. Serum IgG concentrations were also measured. All received 400 mg/kg/day of IVIg for 3 consecutive days. 1) Seven of eight women became pregnant. Five delivered a live born infant. Three out of five women (60%) who delivered a live born infant showed a significant inhibition of NK cytotoxicity post IVIg and the rest did not show any changes; 2) NK cytotoxicity was significantly increased in a woman who miscarried again; 3) A woman who miscarried a chromosomally abnormal fetus showed a significant inhibition of NK cytotoxicity after IVIg; and 4) Serum IgG concentration increased significantly from 9.3 +/- 3.0 mg/ml to 23.5 +/- 5.1 mg/ml post IVIg therapy. IVIg effectively inhibits peripheral blood NK activity in vivo. These results are consistent with our previous finding showing that IVIg inhibits NK cell activity in vitro. Women with RSA and elevated NK cells may benefit from IVIg treatment.
Abortion, Habitual↗
Overexpressed tau protein in cultured cells is phosphorylated without formation of PHF: implication of phosphoprotein phosphatase involvement.
Pyramidal neurons in affected regions of Alzheimer's disease (AD) brain contain neurofibrillary tangles (NFT), aggregates of paired helical filaments (PHF) composed mainly of phosphorylated microtubule-associated protein tau. To explore the role of tau phosphorylation in the aggregation of tau into PHF, we constructed mammalian cell culture systems producing high levels of intracellular phosphorylated tau. COS-1 fibroblast-like cells were transiently transfected to simultaneously express tau, MAP kinase (MAPK), and MAP kinase kinase (MAPKK), or alternatively to express tau and glycogen synthase kinase 3 (GSK3). B103 neuron-like cells (which contain MAPK but little tau or GSK3) were stably transfected to express tau or tau and GSK3. In both systems, GSK3-transfected cells contained tau AT8/M (defined by AT8 staining and tau PHF-like mobility), but MAPK-transfected cells required phosphatase inhibitors, such as okadaic acid (OKA) or calyculin (CAL), to produce tau AT8/M. In vitro, the same concentrations of CAL and OKA inhibit phosphatases 1 and 2A (PP1 and PP2A), except that 100-1000 times as much OKA is needed to inhibit PP1. Inducing tau phosphorylation at the AT8 site in MAPK-transfected cells required 2-10 times more OKA than CAL, suggesting both PP1 and PP2A helped block the phosphorylation. Though levels of tau AT8/M reached 2-8% of total cellular proteins in COS-1 cells, the ratio of particulate to supernatant tau levels did not increase, and no tangles were observed; perhaps post-translational modifications or co-aggregating proteins are needed to induce PHF.
Animals↗
O-ring coping attachments for removable partial dentures.
Clinical experiences for the past 9 years have demonstrated the practicability of the O-ring coping attachment, a modification of the telescopic crown-and-sleeve coping retainers, for removable partial dentures. A circumferential groove placed in the primary coping receives an elastomeric O-ring that fits into a corresponding groove made in the internal surface of the telescopic crown. The O-ring not only provides controllable retention but also acts as a shock absorber. Long-term retention of the prostheses can be easily maintained by periodic replacements of the O-rings. Sophisticated procedures and expensive machines are not required to make the prostheses. Excellent patient acceptance and the versatility in clinical applications make this system one of the winning designs for removable partial prosthodontics.
Crowns↗
Analysis of staining methods for different cortical plaques in Alzheimer's disease.
This study evaluated current methods for demonstrating and categorizing cortical plaques, with the aim of establishing objective methodology for future diagnostic evaluation. Analysis of four methods of tissue processing revealed that the highest numbers of plaques were identified in formalin-fixed, paraffin-embedded tissue regardless of the stain used. Analysis of three silver stains and four immunohistochemical dilutions of an antibody to beta A4 protein revealed that the recent silver method published by Garvey et al. [(1990) J Histotechnol 14: 39-42] was equivalent to beta A4 immunohistochemistry in demonstrating the highest number of plaques. Plaque differentiation was easier and more reliable in silver compared to beta A4-stained sections, although the number of identifiable small compact plaques was significantly reduced in silver-stained sections. These studies show that plaque differentiation may be compromised by tissue processing and staining protocols. The establishment of superior methods may provide better diagnostic resolution for patients with Alzheimer's disease.
Aged↗
Chronic health effects among sheep and humans surviving an aldicarb poisoning incident.
Aldicarb is a granular carbamate insecticide, acaricide and nematocide applied to soil. In 1989, a large scale aldicarb poisoning of grazing sheep occurred in south central Washington State. Among 1600 animals in 3 different groups, 288 of 318 sheep in 1 group died within a very short time. An investigation by the Washington State Department of Agriculture concluded that aldicarb poisoning was the cause of the acute sheep deaths. Within 3 w of the incident, all the 30 sheep which survived the initial exposure from the 1 group had died or were near death and euthanized. Among the approximately 1300 sheep nearby but not affected by the acute incident, low fertility and poor health were apparent over the next 3 y. These sheep also suffered more deaths than expected, and lambs born to the sheep had a higher frequency of limb and gastrointestinal malformations than usual. All of the 6 men present in the field the day of the acute sheep deaths complained of acute symptoms. Three men were hospitalized the night of the sheep deaths and 2 were seen by a physician the next day. All men were healthy prior to the sheep deaths. Within a few days 4 of the 6 men developed a productive cough and 1 reported right-sided abdominal pain. Three years after the incident 5 of the men were still seeking medical attention or reporting symptoms they felt associated with the acute exposure. The chronic health effects in the sheep and men are not expected following exposure to aldicarb. No explanation exists for the chronic health effects, nor have such effects been previously reported in aldicarb poisonings.
Agricultural Workers' Diseases↗
Degradation of proteins in the membrane-cytoskeleton complex in Alzheimer's disease. Might amyloidogenic APP processing be just the tip of the iceberg?
Explore the source record for details and available documents.
Alzheimer Disease↗
Casein kinase II is associated with neurofibrillary tangles but is not an intrinsic component of paired helical filaments.
Neurofibrillary tangles (NFT) are pathological cytoskeletal structures composed of paired helical filaments (PHF), and are found in neurons of patients afflicted with many neurodegenerative disorders, including Alzheimer's disease (AD). We previously found that an antiserum against casein kinase II (CK-II) stained NFT intensely in the brain tissue of AD patients. In the current study, we found that the anti-CK-II antiserum stains NFT and neuronal inclusions in many other neurodegenerative diseases as well, including Guam-Parkinson dementia complex, chromosome 18 deletion syndrome, progressive supranuclear palsy, Kufs' disease, and Pick's disease. This antiserum reacted, in crude brain homogenates, with both a doublet of Mr 43,000 and a Mr 27,000 Da protein which could correspond to the alpha, alpha', and beta chains of CK-II. The staining of these bands was adsorbed by preincubating anti-CK-II antiserum with purified CK-II. Preincubation of brain sections with purified CK-II strongly intensified the immunostaining of NFT with anti-CK-II, suggesting that NFT may bind CK-II. In the AD brain homogenates, the particulate CK-II levels are increased whereas the cytosolic levels are decreased without a change in total CK-II levels, consistent with the idea that CK-II binds to the particulate PHF, a major constituent of NFT. In accord with these findings, purified PHF bound CK-II, but purified PHF did not contain CK-II as its component. These results suggest that CK-II might be an extraneously deposited component of NFT. Thus, the altered CK-II compartmentalization might have significant consequences in the pathogenesis of AD.
Brain↗