Biomedical subjects

M E Percy

Publications and source records attributed to M E Percy.

At least 19 recordsLinked to original sources

PubMed2005

The sweet thing about Type 1 diabetes: a cryoprotective evolutionary adaptation.

The reasons for the uneven worldwide distribution of Type 1 diabetes mellitus have yet to be fully explained. Epidemiological studies have shown a higher prevalence of Type 1 diabetes in northern Europe, particularly in Scandinavian countries, and Sardinia. Recent animal research has uncovered the importance of the generation of elevated levels of glucose, glycerol and other sugar derivatives as a physiological means for cold adaptation. High concentrations of these substances depress the freezing point of body fluids and prevent the formation of ice crystals in cells through supercooling, thus acting as a cryoprotectant or antifreeze for vital organs as well as in their muscle tissue. In this paper, we hypothesize that factors predisposing to elevated levels of glucose, glycerol and other sugar derivatives may have been selected for, in part, as adaptive measures in exceedingly cold climates. This cryoprotective adaptation would have protected ancestral northern Europeans from the effects of suddenly increasingly colder climates, such as those believed to have arisen around 14,000 years ago and culminating in the Younger Dryas. When life expectancy was short, factors predisposing to Type 1 diabetes provided a survival advantage. However, deleterious consequences of this condition have become significant only in more modern times, as life expectancy has increased, thus outweighing their protective value. Examples of evolutionary adaptations conferring selection advantages against human pathogens that result in deleterious effects have been previously reported as epidemic pathogenic selection (EPS). Such proposed examples include the cystic fibrosis mutations in the CFTR gene bestowing resistance to Salmonella typhi and hemochromatosis mutations conferring protection against iron-seeking intracellular pathogens. This paper is one of the first accounts of a metabolic disorder providing a selection advantage not against a pathogenic stressor alone, but rather against a climatic change. We thus believe that the concept of EPS should now include environmental factors that may be nonorganismal in nature. In so doing we propose that factors resulting in Type 1 diabetes be considered a result of environmental pathogenic selection (EnPS).

Acclimatization↗

PubMed2000

Are hereditary hemochromatosis mutations involved in Alzheimer disease?

Mutations in the class I-like major histocompatibility complex gene called HFE are associated with hereditary hemochromatosis (HHC), a disorder of excessive iron uptake. We screened DNA samples from patients with familial Alzheimer disease (FAD) (n = 26), adults with Down syndrome (DS) (n = 50), and older (n = 41) and younger (n = 52) healthy normal individuals, for two HHC point mutations-C282Y and H63D. Because the apolipoprotein E (ApoE) E4 allele is a risk factor for AD and possibly also for dementia of the AD type in DS, DNA samples were also ApoE genotyped. Chi-squared analyses were interpreted at the 0.05 level of significance without Bonferroni corrections. In the pooled healthy normal individuals, C282Y was negatively associated with ApoE E4, an effect also apparent in individuals with DS but not with FAD. Relative to older normals, ApoE E4 was overrepresented in both males and females with FAD, consistent with ApoE E4 being a risk factor for AD; HFE mutations were overrepresented in males and underrepresented in females with FAD. Strong gender effects on the distribution of HFE mutations were apparent in comparisons among ApoE E4 negative individuals in the FAD and healthy normal groups (P < 0.002). Our findings are consistent with the proposition that among ApoE E4 negative individuals HFE mutations are predisposing to FAD in males but are somewhat protective in females. Further, ApoE E4 effects in our FAD group are strongest in females lacking HFE mutations. Relative to younger normals there was a tendency for ApoE E4 and H63D to be overrepresented in males and underrepresented in females with DS. The possibility that HFE mutations are important new genetic risk factors for AD should be pursued further.

Adult↗

PubMed1999

Search for a Caenorhabditis elegans FMR1 homologue: identification of a new putative RNA-binding protein (PRP-1) that hybridizes to the mouse FMR1 double K homology domain.

A mixed stage lambdagt10 Caenorhabditis elegans cDNA library was screened with a probe derived by polymerase chain reaction from the double K homology (KH) domain of mouse FMR1 cDNA, a region that is highly conserved in the human, mouse, chicken, and frog FMR1 proteins. Four positively hybridizing cDNAs were cloned and characterized by sequencing. The overlapping sequences map to cosmid R119 from C. elegans linkage group (chromosome) I, and encode a novel proline-, polyglutamine-, and RGG box-rich putative RNA-binding protein. While the cDNA has two regions with similarity to the mouse double KH domain probe at the nucleotide level, there is no significant similarity of the amino acid sequence with human FMR1, FXR1 or FXR2, nor with KH amino acid motifs. The R119 protein, therefore, does not represent an FMR1 homologue.

Amino Acid Sequence↗

PubMed1998

Iron metabolism and human ferritin heavy chain cDNA from adult brain with an elongated untranslated region: new findings and insights.

Ferritin is a ubiquitous protein which plays a major role in iron sequestration, detoxification and storage. In this paper we highlight the role of ferritin in iron homeostasis and describe factors and diseases that affect its expression. We also describe new studies which further characterize the structure and expression of a novel form of ferritin heavy (H) chain mRNA that was identified in brain and discuss possible implications of these findings. Human fetal and adult brain cDNA libraries previously were screened with cDNA for well-characterized liver ferritin H. In addition to 'liver-like' brain ferritin H cDNA, novel ferritin H cDNAs with an additional 279 nucleotide sequence at the 3'untranslated region (UTR) were identified in both libraries (see refs. 1 and 2; Dhar, M., Chauthaiwale, V., and Joshi, J. G., Gene, 1993, 126, 275 and Dhar, M., and Joshi, J. G., J. Neurochem., 1993, 61, 2140). However, relative to liver ferritin H cDNA, these novel cDNAs were incomplete at their 5'ends [see ref. 3; Joshi, J. G., Fleming, J. T., Dhar, M. S., and Chauthaiwale, V., J. Neurol Sci., 1995, 134, (Suppl.), 52]. In the present paper, by sequencing of cDNAs using reverse transcriptase polymerase chain reaction, we show that the 279 nt 3'UTR sequence, a coding sequence identical to that in human liver ferritin H, and a full-length 5'UTR that includes one mRNA regulatory iron-response element sequence, co-exist in at least one species of ferritin H transcript in six normal human adult and six late-onset, sporadic Alzheimer disease (AD) brains. This sequence is the same in the normal and AD brains. Dot-blot analysis of poly A+ RNAs from different human tissues indicates that relative to the coding sequence of ferritin H, expression of the 279 nt 3'UTR sequence varies among different tissues, is highest in the adult brain, and is very low in fetal brain. In normal adult hippocampus, ferritin H RNA with the novel 279 nt sequence localizes strongly to small non-neuronal cells, capillary endothelial cells, and to selected populations of neurons (granule cells of the dentate gyrus). Significant homology was observed between a region in the 279 nt 3'UTR segment of ferritin H RNA and the 3'UTR of cyclooxygenase-2 mRNA (an inducible iron-containing enzyme involved in prostaglandin synthesis). Possible functions for ferritin H protein derived from the novel message and for the elongated 3'UTR and 5'UTR are discussed.

Adult↗

PubMed1996

Accumulation of S100 beta mRNA and protein in cerebellum during infancy in Down syndrome and control subjects.

S100 protein is a 20 kDA calcium-binding protein that accumulates during CNS maturation in mammals. The human gene coding for the beta subunit of S100 protein (S100 beta) is located on chromosome 21, in a subtelomeric position in 21q22.3. In order to investigate the effect of trisomy 21 on S100 beta gene expression, we performed Southern, Northern and Western blot analysis on DNA, RNA and protein, respectively, extracted from the cerebellum of control and Down syndrome (DS) subjects aged 1-18 months. Southern blot analysis revealed a novel EcoRI polymorphism in the S100 beta gene in two of 15 DNA samples examined, and a 1.5 gene dosage for S100 beta in DS. Northern and Western blot analysis showed an approximately 10-fold increase in S100 beta mRNA and protein levels between 1 and 18 months. No differences in the rates of accumulation of S100 beta mRNA and protein were observed between DS and normal subjects. These results demonstrate an increase in S100 beta mRNA and protein levels during infancy indicative of postnatal astrocytic maturation and show that there is no gross deregulation in the expression of the S100 beta gene in DS as a consequence of trisomy 21.

Age Distribution↗

PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗

PubMed1995

The transmission of phoneme-level information by multichannel tactile speech perception aids.

Current research on the effectiveness of tactile aids for speech perception by hearing-impaired persons suggests that substantial training, lasting over months or years, is necessary for users to achieve maximal benefits from a tactile device. A number of studies have demonstrated the usefulness of training programs that include an analytic component, such as phoneme training, together with more synthetic tasks such as sentence identification and speech tracking. However, particularly in programs for children, it is desirable to structure training experiences so that easy distinctions are trained first, and more difficult distinctions are approached only later in training. In the present study, a systematic evaluation of phoneme-level information provided by the Tactaid VII, a multichannel tactile aid, was performed. Adult subjects were tested in minimal pairs and closed set phoneme discrimination and identification tasks under tactile aid alone, speechreading alone, and speechreading plus tactile aid conditions, to provide an inventory of stimulus identifiability and permit ranking of discriminations as easy or more difficult. Because these rankings might differ as a function of coarticulation effects, three different vowel contexts were tested for consonant stimuli. Results indicated that there were indeed considerable differences across vowel contexts, and that the /ae/ vowel context yielded the most identifiable stimuli. These data could be used by teachers and therapists to construct viable stimulus sets for training programs for tactile aid users.

Adult↗

PubMed1995

Localization of a new ferritin heavy chain sequence present in human brain mRNA to chromosome 11.

Two types of ferritin heavy (H) chain clones have been isolated from cDNA libraries of human fetal and adult brain: one corresponds to the ferritin H chain mRNA that is abundant in liver and is called "liver-like" brain cDNA; the other contains an additional 279 nucleotide (nt) sequence in the 3' untranslated region and is called brain ferritin H chain cDNA. To map the 279-nt sequence, polymerase chain reaction (PCR) amplification was carried out using DNA from rodent x human hybrid cell lines containing single human chromosomes as templates, and oligomeric primers homologous to the 3' end of the 279-nt sequence (primer A) and to a coding sequence just 5' to the 279-nt sequence. Significant PCR product of the size expected from analysis of the brain ferritin H chain cDNA clones and a genomic ferritin H chain clone (487 bp) was generated only from hybrid-cell DNA containing human chromosome 11. This PCR product and the "liver-like" brain cDNA (lacking the 279-nt sequence) both hybridized to chromosome 11 fragments that are known to define the well-characterized functional liver ferritin H chain gene and a putative pseudogene. Preliminary data indicate that primer A (and thus the 279-nt sequence) maps to the functional ferritin H chain gene fragments, but binding to the pseudogene has not been ruled out.

Adult↗

PubMed1994

Copper/zinc superoxide dismutase mRNA levels are increased in sporadic amyotrophic lateral sclerosis motorneurons.

Mutations of the Cu/Zn superoxide dismutase (SOD-1) gene were recently implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS). We measured SOD-1 mRNA levels in motorneurons of the more common sporadic form of the disease and found a 42% increase in ALS motorneurons (P = 0.058) as compared with controls. These results suggest that oxidative stress may also play a role in the pathogenesis of sporadic ALS.

Adult↗

PubMed1994

Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis.

Mutations in the Cu, Zn superoxide dismutase (SOD1) gene have been reported in some pedigrees with Familial Amyotrophic Lateral Sclerosis (FALS). We have investigated the functional and structural effects of a Gly-->Ser mutation at codon 41 of SOD1 in a pedigree with FALS and the topography of SOD1 expression in the mammalian CNS. These analyses show that the 41Gly-->Ser mutation causes a 27% reduction in Cu, Zn SOD activity. SOD1 is transcribed at high levels in rat motoneurons and four other types of neurons homologous to upper motoneurons that degenerate in human ALS. However, SOD1 is transcribed at lower levels in other types of neurons, such as cerebellar Purkinje cells, which are not usually involved significantly in human ALS. On the other hand, immunocytochemical studies indicate that most types of rat neurons contain similar levels of Cu, Zn SOD immunoreactive protein. Nevertheless, these results suggest that the essential feature causing this subtype of ALS is either a reduction in Cu, Zn SOD activity in cell types that presumably critically require Cu, Zn SOD for protection against oxidative damage or the fact that the mutation in SOD1 associated with FALS results in a novel gain of function that is particularly deleterious to those cell types expressing SOD1 at high levels.

Amino Acid Sequence↗

PubMed1994

Molecular genetic predictive testing for Alzheimer's disease: deliberations and preliminary recommendations.

Forty-one participants representing diverse professional back-grounds attended a workshop on genetic predictive testing for familial Alzheimer's disease (FAD) on January 23, 1993 at Surrey Place Centre in Toronto, Canada. Rapidly emerging molecular genetic findings in AD indicate that predictive testing is now technologically feasible for selected individuals, although defining eligibility criteria remains problematic. Legal, ethical, biomedical, and psychosocial issues related to establishing predictive testing programs for AD were discussed at the workshop. This article reflects these discussions, provides the current biomedical background for them and examines the Huntington's disease (HD) predictive testing experience. Observations concerning molecular genetic predictive testing for AD in light of its genetic heterogeneity and clinical characteristics, such as usual later age of onset than HD, are presented. It is proposed that predictive testing for AD can now be cautiously offered in a research setting primarily according to the recommendations contained within the Ethical Issues Policy Statement on Huntington's Disease Molecular Genetics Predictive Test. However, in their application to AD, some points in the statement are considered to require emphasis, modification, or currently to be of uncertain applicability. This represents an initial step in an on-going process of debate concerning AD that will be required as new advances occur in genetic and clinical research and in bioethics.

Aged↗

PubMed1994

Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons.

The presence of large neurofilamentous accumulations in the perikaryon and proximal axon of motor neurons in amyotrophic lateral sclerosis (ALS) suggests that the expression of this abundant cytoskeletal protein may be altered. We performed quantitative in situ hybridization for the low molecular weight neurofilament subunit (NF-L) messenger RNA in six cases of sporadic ALS and six controls. We found a 41% decrease (p < 0.02) in the NF-L mRNA levels in anterior horn cells in ALS, with a 60% decrease (p < or = 0.01) in alpha motor neurons. This alteration may represent a non-specific response to axonal or neuronal injury or, alternatively, reflect the regenerative activity of residual normal motor neurons. NF-L mRNA levels were consistently low (in the third and fourth quartiles) in spheroid-bearing motor neurons, indicating that the neurofilamentous accumulations observed in ALS are not likely the result of overexpression of the NF-L gene. Total neuronal polyadenylated mRNA levels were also 50% lower (p = 0.02) in anterior horn cells and 48% lower (p < or = 0.05) in alpha motor neurons in ALS, possibly reflecting a decrease in selected mRNA species in diseased motor neurons.

Adult↗

PubMed1993

Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: II. Further cytogenetic analysis of the marker and characterization of the high-level repeat sequences using fluorescence in situ hybridization.

We have further characterized an unusual 22p+ marker chromosome with a double nucleolus organizer region (dNOR) previously identified in a family with late-onset dementia of the Alzheimer type. G-banding and morphology of the marker's q arm were typically normal. However, the p+ arm had a terminal cytological satellite and a GT-positive region at the midpoint. Standard C-banding documented 2 C-positive regions: one was associated with the primary centromere; the other, which was at the midpoint of the p arm, was not associated with a constriction. With replication-banding, there was a darkly staining region in the middle of the p+ arm that resembled the pericentromeric region of a chromosome 21 or 22. Fluorescence in situ hybridization with pXlr 101, a probe recognizing the full repeating unit of rDNA, indicated that the marker had an unusually larger rDNA region; with pU 1.2, a probe recognizing the human rDNA promoter, the signal was a doublet. The marker had 2 signals with a beta-satellite probe, and a second signal in addition to that present at the primary centromere under low stringency with alpha-satellite probes and a classic satellite probe. Immunostaining of chromosome spreads after R-banding and ultraviolet (UV) denaturation showed that the major portion of the marker's p arm was highly methylated.

Aged↗

PubMed1993

Age-associated chromosome 21 loss in Down syndrome: possible relevance to mosaicism and Alzheimer disease.

We previously observed low level mosaicism (2-4% normal cells) in phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) in 29% of a small group of elderly persons with Down syndrome (DS). An analysis of cytogenetic data on 154 trisomy 21 cases (age 1 day to 68 years) showed that the proportion of diploid cells in such cultures significantly increased (P < 0.005) with advancing age. Thus, the "occult" mosaicism in PBL of the elderly persons with DS is likely due to the accumulation of cells that have lost a chromosome 21. A consequence of chromosome 21 loss could be uniparental disomy of the 2n cells, a factor that might have significant biological consequences if some chromosome 21 genes are imprinted. Loss of a chromosome 21 from trisomic cells might result in tissue-specific mosaicism and "classical" mosaicism in different age groups. Chromosome 21 loss might also be relevant to the development of Alzheimer-type dementia in DS and in the general population.

Adolescent↗

PubMed1993

Immunoglobulin G subclasses in older persons with Down syndrome.

IgG subclasses were measured in sera from 33 persons with Down syndrome (DS) (mean age 55 +/- 7 years) and 33 age- and sex-matched control individuals using a mouse monoclonal antibody based sandwich enzyme linked immunosorbent assay. Significantly higher levels of IgG1 and IgG3 and lower levels of IgG2 and IgG4 subclasses were found in the DS group compared to the control individuals. The higher levels of IgG1 and IgG3 subclasses found in DS persons were consistent with those seen in patients with autoimmune diseases and chronic viral infections; the lower levels of IgG2 and IgG4 subclasses were consistent with those seen in patients with recurrent infections. Our findings are similar to those reported in children with DS. We speculate that the subclass levels may have little or no relationship to the development of brain lesions typical of Alzheimer disease in older persons with DS. There were no significant differences between the levels of IgG subclasses of persons with DS showing signs of dementia of the Alzheimer type compared to those without such manifestations.

Adult↗

PubMed1992

Monozygotic twins concordant for late-onset probable Alzheimer disease with suspected Alzheimer disease in four sibs.

Probable Alzheimer disease (AD) is described in 79-year-old male twins with monozygosity confirmed by DNA examination. The first twin to be affected began to show signs of intellectual deterioration at age 70. In the other, onset was at age 72. Four of their living sibs (current age range = 75-92) are also suspected to have AD. The possible roles of genetic and environmental factors in the development of AD in this sibship are discussed.

Aged↗

PubMed1992

Methylation of the 5' flanking sequences of the ribosomal DNA in human cell lines and in a human-hamster hybrid cell line.

In a human lymphoblastoid cell line (Z83) in which rDNA genes on chromosome 22 are amplified but transcribed at a low level, immunocytological studies with antibodies to 5 methylcytidine provided evidence for hypermethylation of the rDNA. The extent of methylation of the 5' flanking sequences of the ribosomal DNA was examined by comparing the size of restriction fragments obtained by digestion of genomic DNA with EcoRI and HpaII or EcoRI and MspI. Southern blots indicated hypermethylation of the 5' flanking sequences of many copies of rRNA genes in these cells, but not in a control lymphoblastoid cell line without rDNA amplification. Results obtained with a somatic hybrid human-hamster cell line, in which the rRNA genes on the single human chromosome 22 are inactive, showed that only a small fraction of the CCGG sites in the 5' flanking sequences of the transcriptionally silent rRNA genes in this hybrid were methylated. Since inactive rRNA genes can show such a minimal level of methylation, it is likely that the extreme hypermethylation of the amplified rRNA genes in Z83 occurred in association with their inactivation rather than following it.

Animals↗

PubMed1992

Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimer's disease (FAD) associated with a mutation (G----A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at theta = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.

Adult↗