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J C Morris

Publications and source records attributed to J C Morris.

At least 145 records · Page 8Linked to original sources
PubMed1997

Structure and function of the TSH receptor: its suitability as a target for radiotherapy.

Systemic radiotherapy, such as radioimmunotherapy, is an exciting and rapidly growing field of medical therapeutics for a variety of solid and diffuse human malignancies. This therapy involves the systemic administration of a radionuclide, attached to a carrier ligand (such as hormone analogue or monoclonal antibody), which becomes directed at the tumor through a target receptor or antigen that resides within the malignant tissue. The thyrotropin receptor (TSHr) is a membrane-bound glycoprotein through which the pituitary communicates with thyroid follicular cells. Because it is a thyroid-specific protein and is expressed frequently in differentiated thyroid cancers, it is a potential candidate target for systemic radiotherapy of these malignancies. I will examine the general structure of TSHr and its potential utility such as a target. Several obstacles regarding the concentration and distribution of TSHr as well as the availability of a suitable carrier ligand must be overcome before radioimmunotherapy of thyroid cancers using TSHr as target becomes a reality.

Amino Acid Sequence↗
PubMed1997

Binding of immunoglobulin G from patients with autoimmune thyroid disease to rat sodium-iodide symporter peptides: evidence for the iodide transporter as an autoantigen.

The recent cloning of the rat sodium-iodide symporter (rNIS) from FRTL-5 cells makes possible studies of the role of this thyroid-specific protein as an antigen in autoimmune diseases of the thyroid (AITD). We generated 21 synthetic peptides replicating the entire sequence of the extramembranous domains (ExMD) of rNIS. Each was synthesized by automated chemistry, purified by high-pressure liquid chromatography (HPLC), and characterized by mass spectroscopy. Immunoglobulins were purified using protein A from serum of 27 patients with Graves' disease (GD), 27 patients with autoimmune hypothyroidism (HT), and 20 normal controls. Binding of IgG from patients and controls to each of the rNIS peptides was measured by enzyme-linked immunosorbent assay (ELISA). Binding of patient IgG significantly greater than control was observed with six peptides: peptide 262-280 (representing ExMD 8 between transmembrane [TM] domains VII and VIII), peptide 437-444 (ExMD 11), peptides 468-487, 483-602, and 498-517 from ExMD 12, and peptides 560-579 from the proximal portion of the carboxyl terminus (ExMD 13). 63% of GD patients and 26% of HT patients immunoglobulin G (IgG) bound peptide 498-517 compared to zero controls. Similarly, 59% of GD were positive against peptide 468-487 versus zero controls. Peptide 262-280 bound IgG from 44% of GD patients, 15% of HT patients, and none of the controls. The remaining peptides showed little or no binding of patient IgG. These data indicate that patients with GD and HT possess antibodies that recognize rNIS significantly greater than do normal individuals, suggesting that the iodide transporter represents an important autoantigen in AITD. They further suggest that the incidence of the antibodies is higher in GD than HT, and that the antigenic epitopes involve ExMD 8, 11, 12, and 13.

Amino Acid Sequence↗
PubMed1997

Conversion of non-iodine-concentrating differentiated thyroid carcinoma metastases into iodine-concentrating foci after anticancer chemotherapy.

We present the unusual case of a 29-year-old man diagnosed in 1975 with papillary carcinoma of the thyroid metastatic to regional lymph nodes. The patient underwent surgical resection, postoperative iodine-131 (131I) radioablation and levothyroxine suppression. He was subsequently lost to follow-up. In 1991, he presented with extensive metastatic disease that was not demonstrable on whole-body 131I imaging, but was seen on computerized tomography and whole-body thallium chloride scanning. The patient was treated with cisplatin (Platinol) and doxorubicin (Adriamycin). Repeat 131I imaging after three cycles of chemotherapy showed significant 131I uptake in previously non-iodine-concentrating lesions. The patient was subsequently treated with 200 mCi 131I. We postulate this patient's non-iodine-concentrating thyroid cancer may have become functional by either a differentiating effect of chemotherapy on the tumor cells, or perhaps a selective cytotoxicity against nonfunctional, less differentiated papillary thyroid cancer cells, or both. This would allow more functional differentiated cells to overgrow and become the predominant cell type in the lesions. Chemotherapy may be beneficial in patients with advanced non-iodine-concentrating differentiated thyroid carcinoma by inducing radioiodine uptake and allowing subsequent radioiodine therapy. The possible mechanisms of induction of iodine uptake by chemotherapy are discussed.

Adult↗
PubMed1997

Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study.

This article reports the development and psychometric properties of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). At present, a number of unvalidated CGIC scales are used in clinical trials, with various methods for making ratings. The ADCS-CGIC was designed on the basis of a survey of ADCS clinicians and by adapting existing instruments. It includes an organized but unstructured format, with which a clinician can address clinically relevant change. The instrument's reliability and validity were assessed in a prospective trial of Alzheimer's disease (AD) and healthy subjects over a 12-month period. It showed good short-term reliability at 1 and 2 months, with 90 and 94% of AD subjects, respectively, rated as having changed not at all or only minimally. The ADCS-CGIC's face validity was demonstrated by untreated. AD subjects rated as having worsened over time at both 6 months (56% rated as having worsened) and 12 months (81% rated as having worsened), whereas only 2% of control subjects showed minimal worsening. As a measure of predictive validity, ADCS-CGIC ratings at 12 months were significantly associated with change on four severity scales. As with other measures, change ratings were sensitive to dementia severity. Moderately impaired subjects showed greater worsening than other subjects. ADCS-CGIC ratings of greater worsening were made after the informant interview, regardless of whether informants or subjects were interviewed first. The ADCS-CGIC is a valid and reliable instrument for use in clinical trials.

Aged↗
PubMed1997

Environmental cueing may effect performance on a road test for drivers with dementia of the Alzheimer type.

This paper examines the impact of environmental cueing on a road test for persons with dementia of the Alzheimer type (DAT). In an earlier study, we demonstrated the reliability and stability of the Washington University Road Test in a sample of 58 healthy elderly controls and 65 subjects with DAT. We found that dementia adversely affects driving performance even in its mild stages. Here were elaborate on the results of a follow-up road test conducted 1 month after the baseline test (n = 63) explore possible reasons why the stability of the follow-up road test was lower than expected. We conclude that environmental cueing may affect performance on a road test in DAT.

Aged↗
PubMed1997

The role of selective attention in driving and dementia of the Alzheimer type.

This paper examines the relationship between cognitive processes and driving in aging and dementia of the Alzheimer type. Several studies that have explored the relationship between neuropsychological test performance and various indicators of driving safety are reviewed. It is argued that deficits in selective attention are specific to impaired driving performance in dementia of the Alzheimer type. Results from a recent study supporting this notion are presented. It is suggested that screening measures that emphasize the ability to selectively attend to relevant information and inhibit irrelevant information should be used to identify mildly demented individuals who are at risk for unsafe driving.

Alzheimer Disease↗
PubMed1997

Combined modality therapy for stage II and stage III pancreatic carcinoma.

PURPOSE: To study the outcome achieved with three-drug chemotherapy and split-course external-beam radiotherapy as a treatment for unresectable stage II and III pancreatic carcinoma. PATIENTS AND METHODS: Radiotherapy was given in three cycles of 2 Gy/d on days 1 to 5 and 8 to 12 (total dose, 54 Gy) concurrently with fluorouracil (FU) 1,000 mg/m2/d by continuous infusion for 4.5 days, streptozocin (STZ) 300 mg/m2 on days 1, 2, and 3 and cisplatin (P) 100 mg/m2 on day 3 of each every-28-day cycle. Subsequent treatment consisted of leucovorin (LV) 200 mg/m2 and FU 600 to 1,000 mg/m2 every 14 days. RESULTS: The median survival time for the 35 patients was 15 months and 26% of patients were alive at 24 months. Fifteen patients (42.8%) had objective responses to therapy. Six (17%) had a complete response (CR). Three of nine patients with partial responses (PRs) achieved a radiographic CR within the next 3 months. Nine patients underwent attempts at surgical resection: five were resected (median survival time, 31 months; range, 12.8 to 44.7+), two had no residual disease found at complete resection, and three others also had a complete resection. Of four others who could not be resected, three underwent intraoperative radiotherapy and one had occult metastatic disease. Of primary tumors, 91% did not produce either back pain or local gastrointestinal complications for 2 years. The rates of severe side effects were stomatitis 15%, anemia 14%, granulocytopenia 6%, and thrombocytopenia 6%. CONCLUSION: Palliation and survival compare favorably with other series, including many surgical series. The response findings encourage studies of both unresectable and (as neoadjuvant therapy) resectable tumors.

Adenocarcinoma↗
PubMed1997

Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.

To clarify the neuropathologic criteria for the diagnosis of vascular dementia principally caused by large-vessel cerebral infarction, we solicited autopsy cases of vascular dementia from 10 university neuropathology laboratories. We included only those cases with progressive dementia clinically diagnosed as Alzheimer's disease (AD) or multi-infarct dementia, in whom autopsy revealed only cerebral infarction, without significant neuropathologic features of AD or other neurodegenerative disorders. Only six cases, all men, met these criteria. Each of them had, for a year or longer, gradually increasing cognitive impairment sufficient to interfere with daily activities, without clear evidence of "stepwise" progression. The age of onset of dementia was 66 years or less in five of the six patients. The duration of dementia ranged from 2 to 14 years. Five of the six cases had a history of either cerebral ischemia or acute stroke with residual focal neurologic deficits. Only two were known to have hypertension. At autopsy severe atherosclerosis of the cerebral arteries was present in three cases; two of these had a thrombotic occlusion of one internal carotid artery and one had partial obstruction of other cerebral arteries. In five of six brains, gross infarctions were present involving the thalamus, caudate, putamen, or large portions of the frontal, parietal, and temporal lobes of one or both hemispheres. Vascular amyloid was absent in all but one of these five brains. In four cases, the dementia was clinically indistinguishable from AD except for a history of focal neurologic deficits. The difficulty encountered in finding large numbers of cases of VaD without coexisting neuropathologic evidence of AD suggests that "pure" vascular dementia is very uncommon.

Adult↗
PubMed1997

Clinical dementia rating training and reliability in multicenter studies: the Alzheimer's Disease Cooperative Study experience.

Global ratings of dementia severity are used increasingly in clinical trials of antidementia compounds. Such ratings are clinically relevant, but their reliability in multicenter settings has not been determined. To evaluate the reliability of one global scale, the Clinical Dementia Rating (CDR), 82 investigators of the multicenter Alzheimer's Disease Cooperative Study participated in a training and reliability protocol using videotaped assessments of subjects in various stages of Alzheimer's disease. Following training, overall agreement of the investigators with "gold standard" CDR scores was 83%. These results indicate that the training protocol is useful for establishing good levels of agreement in staging dementia severity and that the CDR can be standardized as a clinical global scale for multicenter studies of Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

The relationship between extrapyramidal signs and cognitive performance in patients with Alzheimer's disease enrolled in the CERAD Study. Consortium to Establish a Registry for Alzheimer's Disease.

The objective of this study was to determine the relationship between the presence of extrapyramidal signs and the severity of cognitive and functional impairment in patients with Alzheimer's disease (AD). Eleven university medical centers in the United States and France participated in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) study of extrapyramidal signs in AD. Forty-seven patients with probable AD who had extrapyramidal signs were matched by sex, race, education, and age with 132 probable AD patients without extrapyramidal signs. The main outcome measures were the Clinical Dementia Rating, Blessed Dementia Scale, and the CERAD Neuropsychology Battery (verbal fluency, naming, Mini-Mental State Examination, word list learning, word list recall, savings ratio, word list recognition, and constructional praxis). AD patients with extrapyramidal signs performed more poorly than AD patients without parkinsonism on various neuropsychological tests, even after controlling for the Clinical Dementia Rating and reported duration of cognitive impairment. The severity of the extrapyramidal manifestations was related to the degree of cognitive and functional impairment. Muscular rigidity and bradykinesia were the most frequent extrapyramidal signs associated with AD. Patients with AD associated with extrapyramidal signs have greater cognitive and functional impairment than AD patients without clinical evidence of parkinsonism.

Aged↗
PubMed1997

Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.

Following is the report of the committee working on clinical global measures for antidementia drug guidelines. The concepts involved in global scales, the distinctions between change and severity scales, advantages and disadvantages of structured interviews, and anchoring of change scores are discussed, and selected existing clinical global scales are described. In addition, the committee assessed the utility of global scales in clinical trials for antidementia drugs. There was a consensus among the members of the working group on the following: (1) Clinical global scales are interview based; in most cases, they include information obtained from caregivers as well as directly from patients, but they can rely on information from the subject only. (2) Clinicians' global ratings are intended to assess clinically meaningful change based on multidimensional clinical assessment and take into account the clinical heterogeneity of dementia by assessing at least cognition, behavior, and functioning. (3) There are two distinct types of clinical global measures: (a) clinicians' interview-based global severity scales, which generally incorporate classification by stage or severity of illness and (b) clinicians' interview-based global change scales, which incorporate global assessment ratings of clinical change. The committee could not reach a consensus on whether global scales should be required in phase II and phase III clinical trials, or whether other specific assessments such as well-designed activities of daily living, cognition, and behavior measures could, when used in appropriate combinations, replace the global as assessments of clinical meaningfulness.

Activities of Daily Living↗
PubMed1997

Alzheimer's disease: a review of clinical assessment and management issues.

As the population of the United States ages, the prevalence of dementia is increasing. Among dementing illnesses, Alzheimer's disease (AD) is by far the most common and increasingly can be diagnosed accurately by informant-based clinical methods alone. Symptomatic therapies are now available for the treatment of the cognitive symptoms of AD, and more drugs are in development. Noncognitive aspects of dementia include behavioral complications, safety and security issues, advance directives, and caregiver burden. These should be addressed and appropriately managed by physicians. An expanded role for primary care physicians is anticipated for the assessment and management of AD.

Alzheimer Disease↗
PubMed1996

Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease.

The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were approximately 650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by approximately 90%, and the number of neurons in layer IV decreased by approximately 70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.

Aged↗
PubMed1996

Phosphatidylinositol phospholipase C is activated allosterically by the aminoglycoside G418. 2-deoxy-2-fluoro-scyllo-inositol-1-O-dodecylphosphonate and its analogs inhibit glycosylphosphatidylinositol phospholipase C.

Phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus is inhibited by myo-inositol-1-O-dodecylphosphonate (Ins-1-O-dodecylphosphonate) (Morris, J. C., Ping-Sheng, L., Shen, T. Y., and Mensa-Wilmot, K.(1995) J. Biol. Chem. 270, 2517-2524). A set of novel fluorinated 2-deoxy-Ins-1-O-dodecylphosphonates were tested against PI-PLC, with potent competitive inhibition by 2-deoxy-2-fluoro-scyllo-Ins-1-O-dodecylphosphonate (VP-616L) (Xi(50) = 0.09). 2-Deoxy-2-fluoro-myo-Ins-1-O-dodecylphosphonate and 2-deoxy-2,2-difluoro-myo-Ins-1-O-dodecylphosphonate were 8.3-fold and 4.8-fold less effective, respectively, than VP-616L. Methyl 2-deoxy-2,2-difluoro-myo-Ins-1-O-dodecylphosphonate was inactive. Also, a hundredfold less PI-PLC is required to cleave a glycosylphosphatidylinositol (GPI) than is needed to cleave PI. Implied in these observations are the following: (i) in powerful inhibitors an active site residue probably interacts with the equatorially oriented fluoro substituent; (ii) substrate recognition requires a negative charge on the phosphoryl at the Ins-1 position, and (iii) a GPI is better substrate than PI, for PI-PLC. Aminoglycoside antibiotics kanamycin A, gentamycin, and G418 stimulated PI-PLC cleavage of the GPI anchor of variant surface glycoprotein (VSG) from Trypanosoma brucei 2- to 4-fold. G418, which appears to act on the enzyme.substrate complex, increased kcat and Km 6.4-fold and 9.9-fold, respectively. PI-PLC was activated by G418 even in the presence of the inhibitor VP-616L. In control experiments, the lectin concanavalin A (ConA), which probably acts by substrate sequestration, inhibited both PI-PLC (Xi(50) = 0.00025) and GPI-specific phospholipase D (Xi(50) = 0.00018). G418 failed to activate PI-PLC when ConA was present. These observations indicate that G418 is an allosteric activator of Bacillus cereus PI-PLC. Since G418 stimulates a purified enzyme that is not involved in aminoglycoside metabolism, we propose that binding of aminoglycosides to cellular proteins could contribute to the development of the nephrotoxicity associated with the use of these aminoglycoside antibiotics.

Allosteric Regulation↗
PubMed1996

Polymorphism in AACT gene may lower age of onset of Alzheimer's disease.

The ApoE-epsilon 4 allele is a predisposing factor for late onset Alzheimer's disease (AD), however it is neither necessary nor sufficient to cause the disease. A candidate for explaining part of the remaining genetic component is alpha 1-antichymotrypsin (AACT). In a case-control study we genotyped a polymorphism within the AACT gene to test for association with the disease. No allele of this gene showed an increased incidence among the population with AD compared with controls, even when taking ApoE genotype into account. This contrasts with the results of a recently published report. The mean age of onset was apparently lowered by the presence of the AACT AA genotype among ApoE-epsilon 4 bearers. If AACT genotype has an effect on risk for AD it may be predominantly amongst individuals with early onset AD.

Age of Onset↗