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Biomedical subjects

M E Percy

Publications and source records attributed to M E Percy.

At least 37 records · Page 2Linked to original sources
PubMed1991

Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: I. Application of a new model for estimation of the risk of disease associated with the marker.

We have identified 2 sisters with probable dementia of the Alzheimer type who have an unusual 22-derived marker chromosome with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. A marker chromosome similar in appearance is uncommon in the general population. Eleven of 24 of their biological relatives were also found to have the marker. The known pedigree of this family encompasses 6 generations in 2 of which there is evidence of 10 cases of dementia of the Alzheimer type. The average age-at-onset of dementia is 65.8 +/- 5.5 years; the average age-at-death among those apparently affected is 74.9 +/- 8.3 years. A new model for the estimation of risk was applied to the family data. Persons in this family with the marker were found to be 4 times more likely to develop dementia than those without the marker, the 95% confidence interval for this risk being 1-50. The probability that the association of dementia and the marker is due to chance alone is .05 (1 in 20).

Aged↗
PubMed1991

Localization and quantitation of 68 kDa neurofilament and superoxide dismutase-1 mRNA in Alzheimer brains.

The technique of in situ hybridization with tritiated RNA probes was used to study the expression of the 68 kDa neurofilament (NF68) gene and the superoxide dismutase-1 (SOD-1) gene in the brains of Alzheimer's disease (AD) patients. Messenger RNA (mRNA) for these proteins was localized and quantified in single cells of formalin-fixed, paraffin-embedded sections of 4 pairs of AD and Huntington's disease (HD) brains from patients matched for age at death and autopsy interval. The cerebellar cortex and hippocampal CA1 and CA2 regions were compared in these two groups of subjects, since in AD the CA2 region of the hippocampus and the cerebellum have been found to be relatively unaffected by the Alzheimer process in comparison to the hippocampal CA1 region. The amount of NF68 mRNA was reduced by approximately 50% in pyramidal cells of both the CA1 and CA2 of AD hippocampus (P less than 0.001), and by 15% in the Purkinje cells of AD cerebellum (P less than 0.05) relative to that of the HD individuals. SOD-1 mRNA was reduced by about 22% in the CA1 of AD brains (P less than 0.001) with no corresponding reduction in the CA2, and by only 5% in the AD cerebellum (P greater than 0.5). The paired design of the study suggests that these results are not simply attributable to the effects of autopsy interval or the agonal process in each patient's death.

Alzheimer Disease↗
PubMed1991

Anomalous gene expression in Alzheimer disease: cause or effect.

Altered chromatin conformation and increased amounts of aluminum have been observed in the brains of patients with Alzheimer disease. These factors have been shown to affect gene regulation. In this report, we describe how these changes may selectively alter the pool size of the human light chain neurofilament gene and play a fundamental role in the expression of this disease.

Alzheimer Disease↗
PubMed1991

A family with multiple instances of definite, probable and possible early-onset Alzheimer's disease.

A family with a multigenerational history of proven or suspected early-onset Alzheimer's disease (AD) consistent with autosomal-dominant inheritance is described. To date, the pedigree comprises five generations in which there are 13 known affected individuals. The mean age of onset of cognitive deficits in those for whom data are available (n = 11) is 47.6 (s.d. 3.0) years and the mean age of death (n = 10) is 58.8 (s.d. 4.0) years. The variability in the extent and quality of available data illustrates the diagnostic difficulties encountered in ascertaining such an extended pedigree, and the need for caution in interpreting the evidence.

Adult↗
PubMed1990

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Alzheimer Disease↗
PubMed1990

Red cell superoxide dismutase, glutathione peroxidase and catalase in Down syndrome patients with and without manifestations of Alzheimer disease.

The activities of red blood cell enzymes that scavenge the superoxide radical and hydrogen peroxide were measured in severely to profoundly retarded adult Down syndrome (DS) patients with and without manifestations of Alzheimer disease (AD), and control individuals matched for sex, age, and time of blood sampling. Cu,Zn superoxide dismutase (SOD-1) and glutathione peroxidase (GSHPx) activities were significantly elevated (1.39-fold and 1.24-fold, respectively) in DS individuals without AD. When an adjustment was made for the SOD gene dosage effect, DS patients with AD manifestations had significantly lower SOD levels than the matched control individuals. In contrast, DS patients with and without AD had a similar elevation in GSHPx (an adaptive phenomenon). The mean catalase (CAT) activity was no different in DS and control individuals; however, in a paired regression analysis, DS patients without AD had marginally lower CAT activity than control individuals, whereas DS patients with AD had slightly but not significantly higher CAT activity. Thus, AD manifestations in this DS population are associated with changes in the red cell oxygen scavenging processes.

Adult↗
PubMed1990

Autoimmune thyroiditis associated with mild "subclinical" hypothyroidism in adults with Down syndrome: a comparison of patients with and without manifestations of Alzheimer disease.

Serum tests of thyroid function were compared in Down syndrome (DS) patients with and without manifestations of Alzheimer disease (AD). Relative to control individuals, DS patients had, overall, lower mean total T4 (P = 0.070) and T3f (P = 0.015), higher T3U (P = 0.013) and TSH (P = 0.020), no difference in free T4, and higher thyroid antithyroglobulin (ATA) (P = 0.033) and antimicrosomal autoantibody (AMA) titres (P = 0.0097). Similar trends were apparent in DS males and females, and in DS patients off all drugs. In an analysis of case/control pairs with corrections for age and sex, DS patients with AD manifestations (n = 9) had significantly lower T3 (P = 0.029) and higher AMA (P = 0.043) than paired control individuals, whereas DS patients without AD manifestations (n = 20) had significantly lower T3 (P = 0.013) but higher ATA (P = 0.0065). T3 was significantly lower in the DS patients with AD manifestations than in the unaffected (P = 0.0013). These data suggest that autoimmune thyroiditis associated with a mild "subclinical" form of hypothyroidism is common in adult DS patients and more pronounced in patients with AD manifestations than in those without. This "subclinical" hypothyroidism may contribute to cognitive deficits in ageing DS patients.

Adult↗
PubMed1989

Human papillomavirus infection of morphologically normal cervical epithelium adjacent to squamous dysplasia and invasive carcinoma.

We have begun a systematic study of human papillomavirus (HPV) infection in colposcopically and/or morphologically normal epithelium of the uterine cervix. Paired biopsies were taken from the lesions (cervical intraepithelial neoplasia [CIN], condyloma, invasive carcinoma) and from the normal-appearing adjacent epithelium 3 to 5 mm from the edge of the lesion. Myometrium or ectocervical epithelium from patients who had undergone hysterectomy for reasons other than genital dysplasia or malignancy served as controls. One biopsy was examined histologically. DNA from the second biopsy was digested with Pst I, and the presence or absence of HPV was determined by Southern blotting using HPV-16 DNA as a probe. HPV was not detected in any of the 12 control samples. Of 30 patients with CIN and/or condyloma, five of 18 who were HPV-positive had either HPV-16 (three cases) or virus resembling HPV-31 (two cases) in the lesion and adjacent epithelium. Of seven patients with invasive carcinoma, four had HPV in the lesion and adjacent epithelium; two of these four patients had typical HPV-16. Such infection of apparently normal epithelium has major implications for our understanding of the pathogenesis, treatment, and follow-up of patients with cervical neoplasia.

Blotting, Southern↗
PubMed1988

Carrier detection in hemophilia A: ABO blood group, multiple measurements, and application of logistic discrimination.

In healthy 20- to 50-year-old women, the ABO blood group has a significant effect on levels of von Willebrand factor (VWF:Ag, formerly VIIIR:Ag) and on factor VIII activity (F.VIII:C). However, there is no significant effect of ABO group or subject age on the ratio log e(F.VIII:C/VWF:Ag). Multiple measurements of the "ratio" on possible carriers of hemophilia A may be combined with pedigree information using logistic discrimination to yield final risk assessment. To reduce misclassification of carriers as normal women, a lower limit, specified by the logistic model, is set on the logistic carrier probabilities. In this study, the proportion of blood group A for a population of obligate carriers was significantly higher than that expected for the general population (60% vs. 42%); for a population of control women it was lower than expected (22.5 vs. 42%). The effect for the carriers came primarily from daughters of affected fathers, as 81.3% were of blood group A. These observations indicate that a "universal" discriminant should be applied with caution.

ABO Blood-Group System↗
PubMed1988

Localization of the 68,000-Da human neurofilament gene (NF68) using a murine cDNA probe.

A recent investigation, using a human genomic probe, has indicated that the 68,000 dalton neurofilament gene (NF68) is on the short arm of chromosome 8. We have used a murine cDNA probe on 65 metaphase spreads in situ to localize the human NF68 gene to 8p21 (20/370 grains; p less than 0.0001). In addition, we have found secondary hybridization sites at the centromeric region of chromosome 2 and the long arm of chromosome 7, which are putative loci for other intermediate filaments.

Animals↗
PubMed1987

Making the most of multiple measurements in estimating carrier probability in Duchenne muscular dystrophy: the Bayesian incorporation of repeated measurements using logistic discrimination.

In carrier detection studies, females-at-risk are usually tested several times if the results are ambiguous, whereas subjects in the control and obligate carrier reference groups may not be tested as often. The question is how to incorporate the multiple measurements most effectively with information in the family pedigree into combined carrier risks. Sets of measurements on individuals are not independent, but are related with the correlation coefficient 0 less than rho less than 1. We have developed a procedure for incorporating repeated measurements on individuals and their a priori chance of having the disease into logistic models. This procedure utilizes the set of measurements and an estimate of rho. We describe application of this procedure to carrier detection in Duchenne muscular dystrophy (DMD) using serum creatine kinase (CK) measurements as the biochemical indicator of carrier status. Estimates of rho for controls and obligate DMD carriers did not differ significantly from 0.5. Repeated testing with use of rho = 0.5 significantly decreased the median logistic carrier probability for controls and increased it for carriers. In some cases four to six rather than the three CK tests conventionally used in genetic counseling were necessary to obtain a stable logistic carrier probability for a subject.

Creatine Kinase↗
PubMed1986

DUCHEN: an interactive computer program for calculating heterozygosity (carrier) risks in X-linked recessive lethal diseases, and its application in Duchenne muscular dystrophy.

The program DUCHEN calculates the probability that a woman is a carrier of an X-linked, lethal recessive disease on the basis of information in the woman's family and any available biochemical data. It is easily used by persons without computer knowledge or experience. The present version can accommodate families consisting of up to 100 people in seven generations. Risks may be estimated on the basis of pedigree information only, or with the inclusion of one or more types of biochemical test results. Biochemical data are incorporated with pedigree information into final risks using the powerful statistical technique of logistic discrimination, a procedure particularly suited for the separation of non-normal populations on the basis of overlapping quantitative characteristics. Mutation rates are specified separately for males and females. DUCHEN is available in FORTRAN 77, IBM BASIC, and Applesoft BASIC, and may be used on a variety of mainframe or microcomputers. The model was used to calculate risks for 375 girls and women in 46 families with Duchenne muscular dystrophy (DMD); serum creatine kinase tests had been carried out on 167 of these subjects who were of reproductive age. Carrier probabilities equal to or lower than the population risk (0.0004) were obtained for 21% of the aunts and 43% of the cousins of affected boys from families with an isolated case of DMD and for 14% of the cousins of affected boys from families with a known DMD history. DUCHEN should assist counsellors in determining which members of large families should be further examined using either standard biochemical carrier detection methods or DNA marker studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatine Kinase↗
PubMed1984

Serum myoglobin in Duchenne muscular dystrophy carrier detection: a comparison with creatine kinase and hemopexin using logistic discrimination.

Logistic discrimination was used to assess the effectiveness of serum myoglobin (Mb), creatine kinase (CK), and hemopexin (H) measurements in identifying Duchenne muscular dystrophy (DMD) carriers. Subjects included 36 obligate carriers, 46 age-matched control women, 30 mothers of isolated cases, and 14 DMD patients. The percentages of obligate carriers with logistic carrier probabilities exceeding the upper normal 95th centile (or 97.5th centile) were: CK alone, 63% (50%); Mb alone, 65% (62%); CK and Mb, 66% (62%); CK and H, 78% (65%); CK H and Mb, 72% (65%). In this study, Mb identified more carriers than CK at the 97.5% level, but there was no advantage in using Mb measurements with CK. CK provided slightly better overall separation of the control and carrier groups than Mb. CK, Mb, and H in combination provided significantly better separation than CK and H, or CK alone.

Adult↗
PubMed1984

Catalase: an old enzyme with a new role?

Although animal catalase has been studied for decades, its physiological role has remained perplexing. It has two enzymatic functions, not only catalyzing the breakdown of H2O2 into O2 and H2O, but also in the presence of low concentrations of H2O2 catalyzing the oxidation of electron donors such as ethanol or phenols. In this article, I have summarized some well-known properties of the enzyme and have also described several recently discovered features. Of particular interest is the finding that, although catalase has been regarded as an intracellular enzyme, there is published evidence for its association with the plasma membrane of the erythrocyte. Moreover, recent work from my laboratory indicates that in vitro at alkaline pH in the presence of Mg2+, the biologically active diphenols (beta-3,4-dihydroxyphenylalanine and the beta-adrenergic agonists isoproterenol, norepinephrine, and epinephrine) appear to function as electron donor substrates for human erythrocyte catalase and inhibit the production of O2 from H2O2 at micromolar concentrations. The beta-adrenergic antagonist propranolol inhibits O2 production much less effectively and appears to competitively inhibit the reaction of catalase with epinephrine. These observations suggest an analogy between catalase and the beta-adrenergic hormone receptor and raise many questions of interest to basic science, health, and disease.

Animals↗
PubMed1982

Duchenne muscular dystrophy carrier detection using logistic discrimination: serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase in combination.

In the absence of an unambiguous test for identifying Duchenne muscular dystrophy (DMD) heterozygotes, methods are needed for combination of the results of individually equivocal tests as effectively and rationally as possible. Tw used logistic discrimination to assess the effectiveness of measurements of serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase alone and in various combinations in identifying DMD carriers. We analyzed 127 serum samples from 63 normal female controls (20-40 years old) and 67 from 38 obligate DMD carriers. The best two tests to use in combination were creatine kinase and hemopexin, and these two, with lactate dehydrogenase, were the best three. t the 95% level (with 5% of controls misclassified), 54% of the carriers were identified by CK alone, whereas 88% were identified by means of the four tests. Although a small proportion of known carriers still cannot be identified, application of the four tests to a group of 45 possible carrier mothers of isolated cases of DMD resolves the population into fairly discrete "normal" and "abnormal" subgroups. Thus, if bias of selection can be eliminated, application of logistic discrimination may permit a direct estimate of the proportion of mothers of affected boys who are homozygous normal.

Adult↗
PubMed1982

Serum creatine kinase in the detection of Duchenne muscular dystrophy carriers: effects of season and multiple testing.

The usefulness of serum creatine kinase (CK) activity in the detection of Duchenne muscular dystrophy (DMD) carriers is dependent upon a reliable control distribution. In controls there is a small but reproducible seasonal variation in CK activity, with a statistically significant variation in the upper 95th percentile (78 IU/liter in May, 53 IU/liter in November, as compared with 67 IU/liter for the whole calendar year). Because CK values in DMD heterozygotes are higher in November than in May, the carrier detection rate may be highest in November. Failure to consider this seasonal variation in controls may cause misclassification of too many normal subjects. If tests are conducted throughout the year, however, the seasonal influence can be reduced by serial testing at intervals of several months. In this case, use of the highest of the results obtained in 3 tests compared with the normal range of single measurements misclassifies too many normal subjects. Use of the mean of 3 determinations provides more accurate classification.

Adult↗
PubMed1981

Duchenne muscular dystrophy carrier detection using logistic discrimination: serum creatine kinase and hemopexin in combination.

Creatine kinase (CK) activity and hemopexin concentration were measured in 208 serum samples from 104 normal females and 22 obligate carriers of Duchenne muscular dystrophy (DMD) 20-40 years old. Logistic discrimination was used to assess the effectiveness of the parameters alone or in combination in identifying DMD carriers. In this approach, a serum sample with particular CK, hemopexin, or a combination of CK and hemopexin values is given a probability that if drawn at random from a defined mixture of controls and carriers, it comes from a carrier. The carrier probability based on the biochemical tests can be directly combined with the carrier probability determined from a woman's pedigree to yield a final posterior probability that she is a carrier. When CK and hemopexin were considered individually, 65 and 27% of the carriers, respectively, could be distinguished from 95% of the controls. When the two tests were used in combination, 82% of the carriers could be distinguished from 95% of the controls. When the two-test method was applied to 93 possible carriers, 35 women were classified as carriers, whereas only 29 were identified using CK alone. This method can be extended to include other variables in order to further improve the identification of DMD carriers. It can also be applied to carrier detection in other genetic disorders.

Adolescent↗