Biomedical subjects

J C Morris

Publications and source records attributed to J C Morris.

At least 217 records · Page 12Linked to original sources

PubMed1993

The consortium to establish a registry for Alzheimer's disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease.

Reliable information on rate of progression of cognitive impairment in probable Alzheimer's disease (AD) is important for evaluating possible beneficial effects of therapeutic agents and in planning long-term care for patients with this chronic illness. However, wide variability exists in published rates of change for psychometric measures of the dementing process, and there is need for an accurate analysis of large numbers of persons with the disorder studied over long periods. Utilizing the large, well-characterized sample of the Consortium to Establish a Registry for Alzheimer's Disease and employing a least squares regression method to adjust for different levels of impairment and periods of observation, we report rates of change on the Short Blessed Test, Mini-Mental State Examination, Blessed Dementia Scale, Clinical Dementia Rating, and other cognitive measures in 430 patients with probable AD (mean age at entry = 70.9 +/- 8.0 SD years) studied for up to 4 years. We found that rate-of-change determinations are less reliable when the observation period is 1 year or less, that dementia progression may be nonlinear when described by certain measures, and that simple change scores do not accurately characterize the rate of decline. We also found that rate of progression in AD is determined by the severity of cognitive impairment: the less severe the dementia, the slower the rate of decline.

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PubMed1993

Molecular cloning of murine FLT and FLT4.

A wide range of growth and differentiation processes are regulated by the signalling of receptor tyrosine kinases (RTKs). We have developed a nested polymerase chain reaction (PCR) procedure with degenerate primers, and used it to identify RTKs expressed in murine fetal thymus. A novel RTK, called FLT4, and the murine homologue of FLT were found, and their PCR fragment sequences were used to isolate larger cDNA clones spanning the complete coding regions of these receptors. FLT4 was found to contain an extracellular region similar to the corresponding sequences of FLT and Flk-1, containing seven immunoglobulin domains.

Amino Acid Sequence↗

PubMed1992

Synthetic analogs of the carboxyl-terminus of beta-thyrotropin: the importance of basic amino acids in receptor binding activity.

Previously, using a synthetic peptide strategy, we determined that four distinct regions of human beta-thyrotropin (beta TSH) were responsible for interaction of TSH with the TSH receptor. The most potent of these four regions was the carboxyl-terminus of the subunit, represented by the peptide sequence beta 101-112, which inhibited binding of radiolabeled beta TSH to receptor in radioreceptor assay with an IC50 of approximately 100 microM. In the current studies, we systematically substituted the native amino acids in region beta 101-112 with alanine, and we have determined which residues within this span are important to the binding activity of TSH to its receptor. Substitution of Lys101, Asn103, Tyr104, Cys105, Lys107, and Lys110 with alanine each caused a significant fall in activity as compared to the native sequence, whereas substitution at the remaining positions had little or no effect. Because three of these residues are positively charged at physiologic pH, we hypothesized that this charge may be important to the binding activity of the sequence. We modified the charge characteristics of the region by synthesizing two series of analogs in which the residues identified in the alanine substitution studies were substituted with Arg, D-Lys, and D-Arg at each position. In addition, a series of analogs containing basic residues, either added to or substituted for nonbasic residues in the sequence beta 101-112, was synthesized. Substitution of Arg, D-Lys, and D-Arg for Lys101, Lys107, and Lys110 had little effect on activity; however, inclusion of additional basic residues in the beta 101-112 sequence significantly enhanced the inhibitory activity of the region.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1992

Graves' IgG recognizes linear epitopes in the human thyrotropin receptor.

Twenty-nine peptides covering the full extracellular domain of the human thyrotropin receptor have been synthesized and tested for reactivity with Graves' patients' and normal sera in ELISA. Two peptides, amino acids 331-350 and the second extracellular loop of the transmembrane segment, bound IgG-s from 5 and 4 of 10 Graves' disease patients' sera, respectively. Neither of these two peptides showed enhanced binding to normal IgG. There were no apparent differences between the Graves' disease and normal group with respect to the other 27 peptides. We conclude that peptide 331-350 and the second extracellular loop carry important linear epitopes which may contribute to the disease process in selected Graves' patients.

Enzyme-Linked Immunosorbent Assay↗

PubMed1992

Mild senile dementia of the Alzheimer type. 4. Evaluation of intervention.

The design of trials of interventions intended to slow or arrest the progression of senile dementia of the Alzheimer type must be based on analysis of the natural history of the disease. Using a random coefficients statistical model, we analyzed the natural history of senile dementia of the Alzheimer type in carefully defined subjects with mild disease (n = 68) for periods of up to 10 years. Subject performance was assessed longitudinally on batteries of clinical and psychometric measures. The characteristics of these measures were analyzed relevant to their utility as outcome measures for long-term trials in patients with senile dementia of the Alzheimer type. Estimates were made of sample sizes required to show arrest, and 50% or 25% slowing in the progression of mild disease. We suggest that a clinically relevant global measure, such as the Sum of Boxes of the Clinical Dementia Rating scale, and a performance-based clinical scale or psychometric measure would be appropriate in a 12- or 24-month trial enrolling subjects with mild senile dementia of the Alzheimer type.

Actuarial Analysis↗

PubMed1992

Molecular cloning of the cDNA encoding a receptor tyrosine kinase-related molecule with a catalytic region homologous to c-met.

Receptor tyrosine kinases mediate a range of growth and differentiation processes in multiple biological systems. In this work, we report the identification of a novel tyrosine kinase-related molecule, nyk-r, and the molecular cloning of its complete cDNA. Its extra-cellular domain bears no apparent homology with other receptor families, but its intracellular kinase-related region has considerable similarity with members of the insulin-receptor family such as c-met and trk B. Also, the nyk-r gene is expressed in a wide range of tissues and cell lines.

Amino Acid Sequence↗

PubMed1992

Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson's disease and Alzheimer's disease.

We used tyrosine hydroxylase immunoreactivity (TH) to mark dopaminergic fibers in cerebral tissue from adult persons with Parkinson's disease (PD) or Alzheimer's disease (AD). In the PD cases we found a loss of dopaminergic neurons in the ventral tegmental area (VTA), severely reduced TH fibers in dopaminergic terminal fields (particularly in the hippocampal perforant pathway) and neurofibrillary tangles (NFT), that occurred only in the perforant pathway. In contrast, AD cases were characterized by a lack of significant neuron loss in the VTA and by mild loss of TH fibers. A decreased dopaminergic innervation of the perforant pathway in cases of PD appears to be associated with the occurrence of NFT in these structures.

Alzheimer Disease↗

PubMed1992

Thalamic amnesia: Korsakoff syndrome due to left thalamic infarction.

In order to support the concept that a lesion of the thalamus is sufficient to cause a Korsakoff syndrome, we are presenting 5 patients, all of whom developed the syndrome after sustaining a left (dominant) thalamic infarction. Two patients had pure thalamic strokes followed by a permanent Korsakoff syndrome. One of these patients was studied with neuropsychometric testing, as well as with a modern MRI scan. In 2 other patients, clinical and imaging data indicate that infarction was not limited to the thalamus. Another patient had bilateral thalamic infarcts but only a temporary Korsakoff syndrome. Neuropathological data are needed to elucidate the exact anatomical substrate of dominant thalamic Korsakoff syndrome.

Aged↗

PubMed1992

Inhibition of TSH bio-activity by synthetic beta TSH peptides.

The in vitro bioactivity of the human beta TSH subunit was investigated utilizing eleven overlapping synthetic peptides representing the entire 112 residue sequence. The peptides were tested for both stimulatory and inhibitory activity in two sensitive bioassay systems: the first based on cAMP production in FRTL-5 rat thyroid cells, and the second based on stimulation of iodine trapping by the same continuous cell line. Peptides from three distinct regions of the beta-subunit showed concentration dependent inhibition of TSH bio-activity, including beta 1-15, beta 11-25, beta 31-45, beta 81-95, and beta 91-105 with IC50 values ranging from 150 to 304 microM. An additional peptide representing the entire sequence of the "intercysteine loop" region of beta TSH, beta 31-52, also inhibited TSH activity with somewhat higher potency than its fragment peptide beta 31-45 (IC50 of 87.5 +/- 14.7 microM for beta 31-52 versus 207 +/- 92.4 microM for beta 31-45). Three of these, beta 1-15, beta 31-45, and beta 31-52, also inhibited binding of TSH to the receptor in a radio-receptor assay, as previously reported (1), supporting their importance in receptor interaction. None of the synthetic peptides stimulated either cAMP production or iodine trapping. Two other overlapping peptides, beta 81-95 and beta 91-105, possessed bio-inhibitory activity but did not inhibit binding of labeled TSH. Computer analysis of this sequence predicted an extended turn structure for this region. This region has been referred to as the "determinant loop" as it is bounded by cysteine residues at positions 88 and 95 that many believe form a disulfide bond in the native subunit. The current data suggests the beta 88-95 region may play a role in receptor activation after initial binding of hormone to receptor.

Amino Acid Sequence↗

PubMed1992

Blinded clinical evaluation of positron emission tomography for diagnosis of probable Alzheimer's disease.

We evaluated the sensitivity and specificity of positron emission tomography for diagnosis of probable Alzheimer's disease under conditions similar to those encountered in the routine clinical practice of nuclear medicine. We obtained tomographic images of regional cerebral blood flow from three groups of subjects: (1) 13 subjects, ages 69 to 84, who had probable Alzheimer's disease diagnosed by validated clinical criteria; (2) 15 subjects, ages 57 to 77, who had Parkinson's disease without dementia; and (3) 11 subjects, ages 65 to 83, who were normal. Three blinded reviewers, who had not previously seen the images, categorized them as normal, bilateral temporoparietal flow defects typical of Alzheimer's disease, or other abnormality. Consensus interpretation demonstrated sensitivity of 0.38 (5/13) and specificity of 0.88 (23/26) for identifying patients with probable Alzheimer's disease. Thus, the criterion of bilateral temporoparietal reduction in cerebral blood flow used in this study did not have sufficient sensitivity to be of clinical value. While other criteria may be developed to improve diagnostic accuracy, clinical utility can be established only by testing for validity in patients with a full spectrum of complicating neurologic and psychiatric conditions for whom diagnosis is uncertain and who are then followed longitudinally to determine clinical outcome or pathologic findings.

Aged↗

PubMed1991

Further characterization of the receptor-binding region of the thyroid-stimulating hormone alpha subunit: a comprehensive synthetic peptide study of the alpha-subunit 26-46 sequence.

Previously, using a synthetic peptide strategy, we determined that the region of the common glycoprotein hormone alpha subunit between residues 26 and 46 is a site of interaction of the hormone with the thyroid membrane-bound receptor for thyroid-stimulating hormone (TSH). We have undertaken to identify further the specific residues within this 21-amino acid span that are critical in hormone receptor binding. We synthesized three nested sets of peptide, two in which we systematically truncated the amino-terminal region of the sequence and another in which we truncated the carboxyl-terminal region, and we synthesized a fourth nested set in which we systematically substituted alanine for the native residues from the region of highest activity. Each peptide was tested in a TSH radioreceptor assay for its ability to inhibit binding of 125I-labeled bovine TSH to porcine thyroid membranes. Removal either by truncation or alanine substitution, of several specific residues resulted in a significant reduction in the ability of the sequence to interact with receptor; these residues included Cys31, Cys32, Phe33, Arg35, Arg42, Lys44, and Lys45, suggesting that they are crucial for binding activity. Loss of activity also occurred with substitution for Gly30 and Ser34, but the reduction was less pronounced. Amino-terminal truncation of the sequence through Arg35 (leaving the alpha-subunit peptide 36-46) resulted in greater than 98% loss of activity of the sequence. We conclude that two distinct receptor binding regions lie within the alpha-subunit 26-46 sequence. The first lies between residues Gly30 and Arg35 and includes Cys31, Cys32, and Phe33 as important constituents, and the second region lies between residues Arg42 and Lys45 and includes Lys44 as an important residue and Ser43 as a less important component.

Amino Acid Sequence↗

PubMed1991

Secondary structure of human interleukin-3.

1. The secondary structure of human interleuken-3 in solution was determined by circular dichroism spectroscopy. 2. The results were then compared with empirical secondary structure predictions based on primary sequence structure of the protein. 3. The two approaches are in extremently close agreement showing the protein to have 40% alpha-helix, 12% total beta-structure and 48% random coil content.

Amino Acid Sequence↗

PubMed1991

Senile dementia and healthy aging: a longitudinal CT study.

Volumetric indexes of cerebral atrophy obtained by using computed tomography (CT) were measured longitudinally in patients with senile dementia of the Alzheimer type (SDAT) and in healthy elderly control subjects. Measurements were made three times over a 51-month period. Of the original 44 patients with SDAT, five were available for CT examination at the last time of assessment (51 months); in contrast, 41 of the original 58 control subjects were still available for study at 51 months. As a group, scans of SDAT subjects showed greater atrophy than those of control subjects in all volumetric indexes at each time of testing and demonstrated greater progression of atrophy during the study period. However, the overlap of indexes between the patients with SDAT and the control subjects indicates that CT data cannot be used alone to predict the presence or progression of dementia in individual cases.

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PubMed1991

The antigenic structure of the human glycoprotein hormone alpha-subunit: III. Solution- and solid-phase mapping using synthetic peptides.

Twenty-seven synthetic peptides, representing the entire structure of the human glycoprotein hormone alpha-subunit were used to map the antigenic structure of the alpha-subunit. Solution phase and solid phase assays were performed with these peptides and a panel of eight monoclonal antibodies (MAb). Two dominant regions were localized between residues 22-37 and 70-87. All eight antibodies recognized these regions, but differed somewhat with respect to whether they saw the more N-terminal, middle, or C-terminal portions of these regions. The sequence of residues 13-22 was recognized by three MAbs. The C-terminal region from residues 84-92 was recognized by three MAbs. All MAbs recognized conformational epitopes in that they reacted with two or more regions. Three MAbs (two against free alpha and one against human CG) have linear amino acid sequences as part of their conformational epitope.

Antibodies, Monoclonal↗

PubMed1991

The heterogeneity of human chorionic gonadotropin (hCG). III. The occurrence and biological and immunological activities of nicked hCG.

Nicks, or missing peptide linkages, have been found in hCG beta-subunit between residues 44 and 45 and between residues 47 and 48. We examined the occurrence and biological and immunological activities of nicked hCG. As shown by sequence analysis, CR127 standard hCG is approximately 20% nicked, half at beta 44-45 and half at beta 47-48. Treatment with human leukocyte elastase increased the extent of nicking of CR127 standard hCG. The longer the incubation of CR127 standard with human leukocyte elastase (0, 2, and 21 h), the greater the extent of nicked hCG (20%, 46%, and 89%). As the extent of nicking increased, the receptor-binding ability diminished, as did the ability to stimulate progesterone production by rat corpus luteal cells in vitro (0.9, 0.74, and 0.29 microgram/microgram hCG, respectively). In a regression analysis, a linear relationship was indicated between the extent of nicking and receptor binding values (97% correlation) and between the extent of nicking and steroidogenic activity in vitro (99% correlation). From the intercepts of the regression lines, it was estimated that nicks reduced receptor binding by 11-fold and reduced the steroidogenic activity of hCG by 5-fold. We examined eight individual hCG preparations, three purified from pregnancy urine, three from urine from patients with hydatidiform mole, and two from urine from women with choriocarcinoma. In descending order, the eight individual hCG preparations were 100%, 100%, 85%, 76%, 42%, 41%, 0%, and 0% intact. Although no correlation was observed between the percent intact and the ability of the eight individual samples to displace 50% [125I]hCG in binding CG/LH receptor (r less than 0.5), a close correlation was noted between the percent intact and the steroidogenic activity in vitro (98% correlation). This separated the effects of nicking on receptor binding and steroidogenic activities and indicated that while multiple factors influence receptor binding, only nicking suppresses the steroidogenic activity of bound hCG. We examined the recognition of nicked hCG molecules by different hCG immunoassays. The Hybritech Tandem assay measured total hCG and did not distinguish nicked and intact hCG molecules (in a regression analysis, immunoactivity vs. percent intact hCG, r less than 0.5). In contrast, the immunometric assay using B109 hCG dimer-specific monoclonal antibody and anti-beta-peroxidase only detected the intact component of hCG (in a regression analysis, immunoreactivity vs. percent intact hCG, 98% correlation). We used these assays together to estimate the percentage of intact hCG and to deduce the extent of nicking.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1991

Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging.

We compare clinicopathologic data from 10 subjects identified in the very mild stage of senile dementia of the Alzheimer type with findings from similar studies in four cognitively normal subjects. We based the diagnosis of very mild dementia in the 10 subjects on informant reports and the judgment of experienced clinicians. Deficits of some psychometric measures of memory, language, and speeded psychomotor performance were observed for these subjects. The histologic markers of Alzheimer's disease, including neurofibrillary tangles and both the "diffuse" and classic subtypes of senile plaques, were present in the neocortex in all 10 subjects but essentially were absent in the four controls. These findings indicate that even "questionable" dementia can be diagnostic for Alzheimer's disease. Furthermore, because truly normal aging may be unaccompanied by neocortical senile plaques and neurofibrillary tangles, the presence of these lesions should suggest the possibility of clinically undetected Alzheimer's disease.

Activities of Daily Living↗

PubMed1991

The neurology of aging: normal versus pathologic change.

Mild changes in neurologic function occur with aging but generally do not substantially interfere with everyday activities unless disease intervenes. Not infrequently, older adults experience minor impairment in memory, speed of cognitive processing, sleep, vision and hearing, vibratory sense in the lower extremities, and gait and posture. In general, these changes correspond with age-associated neuroanatomic changes (eg, diminished brain weight), but there is wide variability in the extent to which these changes occur. Often, "normal" neurologic changes are difficult to distinguish from impairment associated with disease.

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PubMed1991

Rapid activation of astrocyte-specific expression of GFAP-lacZ transgene by focal injury.

Astrocytes form a key cellular component of the central nervous system. They respond vigorously to diverse neurologic insults by undergoing hypertrophy and increasing expression of the glial fibrillary acidic protein (GFAP) gene, but their functions are largely unknown. To analyze astrocytes in vivo we constructed a transgenic vector from GFAP gene sequences and monitored its efficiency by fusing it to lacZ. Injection of the GFAP-lacZ hybrid gene into the germline of mice yielded six different lines of transgenic mice. In all lines the expression of lacZ was astrocyte-specific. In unmanipulated transgenic animals beta-galactosidase activity was much more prominent in astrocytes of the hippocampal formation, selected white matter tracts, and glial limitans than in astrocytes of other areas. This pattern of expression illustrates the physiologic heterogeneity of astrocytes and probably reflects differences in functional demands placed on these cells in different brain regions. Upmodulation of transgene expression was used to determine the time frame within which astroglial activation and increased GFAP gene expression occur following a neurologic insult. Induction of GFAP-lacZ expression was detectable within 1 hour after focal mechanical trauma. This demonstrates that the response of astrocytes to neurologic injury is very rapid and implies that these cells could fulfill important early functions in wound healing within the central nervous system.

Animals↗