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Biomedical subjects

J Hardy

Publications and source records attributed to J Hardy.

At least 235 records · Page 13Linked to original sources
PubMed1996

Molecular genetics of Alzheimer's disease.

Four genes have thus far been implicated in the etiology of Alzheimer's disease (AD). A series of mutations in the amyloid precursor protein (APP) gene on chromosome 21, which cause disease with a typical onset of 55 years of age, have been described. These include mutations at APP670/671, APP692, and APP717. The epsilon 4 allele of the apolipoprotein E (ApoE) gene on chromosome 19 is positively associated with disease, whereas the epsilon 2 allele is usually negatively associated with disease. Mutations in the S182 gene on chromosome 14 seem to cause disease with an onset age of < 50 years and mutations in a gene on chromosome 1 (S182 Like Protein: S182LP) cause disease with variable onset. These genetic findings are reviewed within the framework of the amyloid cascade hypothesis of AD etiology and pathogenesis. The occurrence and effects of the mutations in APP and the fact that the epsilon 4 allele of ApoE are genetic risk factors point to the hypothesis that the extracellular deposition of beta-amyloid is the key initiating event in the pathogenesis of AD.

Alzheimer Disease↗
PubMed1996

Joint pressure influences synovial tissue blood flow as determined by colored microspheres.

We measured regional blood flow in synovial tissue of the antebrachiocarpal, midcarpal, and metacarpophalangeal joints of six normal adult anesthetized horses by using 15-microns-diameter polystyrene colored microspheres. The midcarpal fibrous capsule and synovial membrane blood flows (SMBF) were compared, and the effect of increased intra-articular pressure (30 and 60 mmHg) on midcarpal SMBF was investigated. Dorsal, medial palmar, and lateral palmar midcarpal SMBF measured 108 +/- 36, 61 +/- 12, and 50 +/- 11 microliters.min-1.g-1, respectively. Antebrachiocarpal, dorsal, and palmar metacarpophalangeal SMBF measured 103 +/- 8, 17 +/- 3, and 26 +/- 5 microliters.min-1.g-1, respectively. Midcarpal fibrous joint capsule blood flow was significantly lower than that of the synovial membrane. An increase in midcarpal intra-articular pressure to 30 or 60 mmHg resulted in an 84% decrease in SMBF. Colored microspheres provided a useful technique to determine sequential SMBF. Increased intra-articular pressure significantly altered SMBF, suggesting a role of the regional circulation in the pathogenesis of joint disease.

Animals↗
PubMed1996

New insights into the genetics of Alzheimer's disease.

In early 1993, the genetic data implicating the amyloid precursor protein as one of the loci leading to early onset Alzheimer's disease were reviewed (Hardy and Duff, Annals of Medicine, 25: 437-440), together with the evidence implicating abnormal deposition of beta-amyloid as the initiating point of the process leading to the disease. Since that time, three other genetic loci have been directly implicated in the aetiology of the disease: the apolipoprotein E locus on chromosome 19, the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1. In this article, I review the progress over the last three years and attempt to assess whether the evidence for the amyloid cascade hypothesis still stands scrutiny.

Alzheimer Disease↗
PubMed1996

Surgical outcome after repeated transsphenoidal surgery in acromegaly.

Transsphenoidal selective adenomectomy is the most efficient primary treatment for acromegaly. However, management of persistent or recurrent disease remains controversial. The objective of the present study was to evaluate the early and long-term efficacy and safety of a second transsphenoidal surgery performed in those cases. The results of a retrospective study of 16 patients undergoing reoperation by the senior author (J.H.) between 1970 and 1991 are reported. Reoperation was performed for persistent or progressive acromegaly in 11 patients, visual impairment in four, and disease recurrence in one. Normalization of growth hormone (GH) was defined as a basal GH level of less than 5 micrograms/L and suppression to less than 2 micrograms/L during the oral glucose tolerance test. Long-term follow-up data were available in 15 patients. The second transsphenoidal surgery induced a greater than 50% decrease of GH level in 11 patients. Three (19%) of 16 patients were cured according to the authors' criteria and remained so after 2, 7, and 20 years. Two more patients had a postoperative basal GH level of less than 5 micrograms/L but incomplete suppression during the oral glucose tolerance test. Thus, a total of five patients (31%) achieved a basal GH of less than 5 micrograms/L. One other patient who had no initial improvement after the second transphenoidal surgery had spontaneous normalization of his GH level after 13 years. The following complications of the second surgery occurred in three patients: one subarachnoid hemorrhage, two new visual field defects, one cranial nerve palsy, and one meningitis. Moreover, 10 patients (62.5%) developed one or more new pituitary hormone deficiencies. In conclusion, reoperation for persistent or recurrent acromegaly has low success and high complication rates. According to the authors' experience, this procedure should be reserved for patients unresponsive to other forms of therapy or with progressive visual impairment despite medical therapy.

Acromegaly↗
PubMed1996

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD. For LOAD, the work on ApoE indicates that the epsilon 4 allele is a risk factor for developing AD. However, 35-50% of all AD patients do not have an epsilon 4 allele. Other loci contributing to LOAD remain to be mapped and characterized. As in other complex disorders, these additional loci may involve genetic interactions with the known AD loci. Identification of all susceptibility loci for AD is a major goal in resolving the pathogenesis of AD.

Alternative Splicing↗
PubMed1995

Apolipoprotein E in the genetics and epidemiology of Alzheimer's disease.

The role of apolipoprotein E (ApoE) alleles and isoforms in the etiology and pathogenesis of Alzheimer's disease is discussed. The possibility that ApoE itself is not involved in the disease pathogenesis but is merely in genetic disequilibrium with the real locus is discussed and dismissed. The data showing that the epsilon 4 allele is associated with an increased risk of developing the disease and with an earlier onset age are reviewed. The data showing that, at least in some circumstances, the epsilon 2 allele is associated with a decrease in the risk of developing the disease, and with a later onset age are also reviewed. Data from the genetic analysis of other disorders are reviewed and presented, and it is suggested that the genetic data support the notion that the role of ApoE in the etiology of the disease directly relates to beta-amyloid deposition and plaque formation. This suggestion is in concordance with the most likely mechanism for the role of beta-amyloid precursor protein gene mutations as other risk factors for the disease.

Age of Onset↗
PubMed1995

Human recombinant nerve growth factor replaces deficient neurotrophic support in the diabetic rat.

Manipulation of neurotrophic support is a developing strategy for new therapy aimed at neurodegenerative diseases. This study demonstrates reduced content and retrograde transport of endogenous nerve growth factor (NGF) in sciatic nerve of diabetic rats. There were also reductions in the diabetic rats in NGF protein and mRNA in skin and muscle of the hindlimb. These deficits correlated with reductions in substance P and calcitonin gene-related peptide--both products of NGF-influenced genes in primary afferents. These manifestations of deficient neurotrophic support were corrected by intensive insulin treatment and surmounted by administration of exogenous human recombinant NGF in a dose-related manner. Impaired neurotrophic support may, therefore, participate in the pathogenesis of diabetic and other peripheral neuropathies.

Animals↗
PubMed1995

Treated delinquent boys' substance use: onset, pattern, relationship to conduct and mood disorders.

We describe relationships between substance use, conduct disorder (CD), depression, and history of self-injury or suicide attempts, in referred, delinquent, substance involved, adolescent males. Sixty youths (mean age 16.3 years) completed standardized assessments for substance use and other psychiatric disorders, aggressiveness, and social class. All boys met modified criteria for CD. Most had high aggression ratings. Twenty percent had depressive diagnoses. By age 13, 78% had begun regular substance use. Marijuana was the first substance for 42%. The boys had substance dependence on a mean of 3.2 different drugs (usually including alcohol and marijuana), with abuse of an average of one additional drug. CD symptoms began 3.6 years (mean) before regular use. CD symptom count correlated with number of dependence diagnoses, and both of those (but not depression) related significantly to suicide attempt and self-injury histories. Improved understanding of substance involvement in youths with CD may generate more rational prevention and treatment.

Adolescent↗
PubMed1995

Familial non-specific dementia maps to chromosome 3.

A significant minority of degenerative dementias lack distinctive inclusion bodies, plagues or tangles on pathological examination. Half of these cases have a positive family history of dementia. We have studied the largest published family with such a dementia and mapped the disease locus to a 12 cM region of chromosome 3 spanning the centromere. Haplotype analysis demonstrates a common region shared between all affected individuals between the markers D3S1284 and D3S1603. Like a number of other late onset neurodegenerative diseases, the disease presents at an earlier age when paternally inherited.

Chromosome Mapping↗
PubMed1995

Microsatellite D21S210 (GT-12) allele frequencies in sporadic Alzheimer's disease.

Four disease-causing mutations have so far been described in the amyloid precursor protein gene on chromosome 21 in familial early-onset Alzheimer's disease. Linkage analysis with a fourteen-allele microsatellite at D21S210 named GT-12 has proven useful in the elucidation of amyloid precursor protein gene involvement in Alzheimer's disease families, as it is closely linked to the gene. Most cases of Alzheimer's disease are thought to be sporadic and not familial. However, evidence from earlier studies suggests an important genetic contribution also in sporadic cases, where gene-environment interaction may contribute to the disease. We have determined frequencies of the GT-12 alleles in 78 Swedish and 49 British sporadic Alzheimer's disease cases and 104 healthy elderly control subjects, to investigate if the disease associates with a particular genotype in GT-12. However, no differences in allele frequencies were observed between any of the groups.

Aged↗
PubMed1995

Pressure-volume relationships in equine midcarpal joint.

The effects of joint angle, fluid infusion, history-dependence, and time dependence on the pressure-volume (PV) relationships of normal equine midcarpal joints were determined. Horses (n = 24 and 48 midcarpal joints) were anesthetized and placed in dorsal recumbency, and the four midcarpal joint pouches were cannulated for intra-articular pressure (IAP) measurements and recording. Fluid (synovial fluid or saline) was infused or withdrawn through the dorsal joint capsule. The PV curves were sigmoid and best described by IAP = A x e(B x volume) - C, where B is the fractional change in pressure per unit change of volume, and A and C are constants. Compartmentation was not observed. Elastance was greater at sub- than supra-atmospheric pressures, at 90 degrees than 135 degrees angles, and with saline than synovial fluid. Hysteresis was greater at 90 degrees than 135 degrees angle, and with synovial fluid than saline. Elastance progressively increased with sequential distention at high IAPs. IAP relaxation was a positive logarithmic relationship of IAP. These findings suggest an important role of synovial fluid in articular PV relationships and emphasize the role of joint angle, prior distention cycles, and decay of IAP with time in future studies investigating these phenomena.

Anesthesia↗
PubMed1995

Apolipoprotein E genotype and Lewy body disease.

To determine whether apolipoprotein E (APOE) genotype affects neuropathology in Lewy body disease (LBD), we examined 18 cases of LBD that did not have concurrent Alzheimer's disease by the CERAD criteria. We obtained APOE genotypes, determined diffuse beta-amyloid plaque (A beta P) and Lewy body densities in multiple brain regions, and graded the intensity of CA2-3 ubiquitin-positive neurites, vacuolar change, nigral pathology, amyloid angiopathy, and subpial amyloid deposition. The APOE allele frequencies were as follows: epsilon 2, 0.14 +/- 0.07; epsilon 3, 0.64 +/- 0.08; and epsilon 4, 0.22 +/- 0.03. The mean A beta P density was lower in APOE epsilon 3/3 cases (14.5 A beta Ps per mm2) than in the groups with the APOE epsilon 2 (67.0) or APOE epsilon 4 (46.6) alleles. This difference was due largely to the difference between A beta P density in the APOE epsilon 2 group and the APOE epsilon 3/3 group (F = 5.525, p < 0.02). CA2-3 neuritic degeneration was greater in those with the APOE epsilon 4 allele than in those with the APOE epsilon 3/3 genotype (grade = 1.9 +/- 1.3 versus 0.938 +/- 0.9; Kruskal-Wallis test statistic = 6.962, p < 0.05). These data are consistent with the hypothesis that APOE genotype may affect neuropathology in LBD.

Aged↗