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Biomedical subjects

J C Morris

Publications and source records attributed to J C Morris.

At least 55 records · Page 3Linked to original sources
PubMed2001

Mild cognitive impairment represents early-stage Alzheimer disease.

BACKGROUND: Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). OBJECTIVE: To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. DESIGN: A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. SETTING: An AD research center. PARTICIPANTS: All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. MAIN OUTCOME MEASURE: Progression to the stage of CDR 1, which characterizes mild definite DAT. RESULTS: Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). CONCLUSIONS: Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

Aged↗
PubMed2001

Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease.

OBJECTIVES: To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration. METHODS: Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD--the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1. RESULTS: There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group. CONCLUSIONS: There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.

Aged↗
PubMed2001

Clinically significant depressive symptoms and very mild to mild dementia of the Alzheimer type.

OBJECTIVE: To compare depressive symptoms reported by persons with very mild or mild dementia of the Alzheimer type (DAT) with those reported for the person by a collateral source. DESIGN: Cross-sectional evaluation. SETTING: Washington University Alzheimer's Disease Research Center. PARTICIPANTS: Consecutive series of elderly volunteers (n = 156) enrolled in longitudinal studies with a Clinical Dementia Rating (CDR) of 0.5 (very mild) or 1 (mild). Twenty-one per cent (n = 33) exhibited clinically significant depressive symptoms for which treatment was recommended. MAIN OUTCOME MEASURES: Presence and frequency of DSM-IV depressive symptoms within the last year and last month reported by the participant or collateral source as ascertained by clinical examination and structured interviews. RESULTS: Collateral source information is essential in diagnosing clinically significant depressive symptoms. The Geriatric Depression Scale scores correlate with participant information only and therefore may substantially underestimate depression. Depressive symptoms fluctuate in individuals with DAT. The most consistent depressive symptoms are depressed mood, fatigue and indecision. CONCLUSIONS: Clinically significant depressive symptoms may be common in individuals with very mild or mild DAT, although they may fluctuate. Information from both a knowledgeable collateral source and the participant is important for detection of depressive symptoms.

Aged↗
PubMed2001

Pharmacotherapy of Alzheimer's disease: is there a need to redefine treatment success?

The traditional aim of Alzheimer's disease treatment in clinical trials has been to improve cognitive abilities. It has become increasingly clear, however, that other aspects are important in assessing treatment responses. A group of 10 physicians recently gathered to review the current criteria for assessing treatment success in Alzheimer's disease. While cognition has been previously viewed as the primary measure of efficacy, areas such as functional abilities, behaviour, caregiver burden, quality of life and resource utilization all need to be comprehensively assessed to fully evaluate treatment effects in patients with Alzheimer's disease, as well as their impacts on caregivers and society. Postponing or slowing decline in any of these areas may represent an important benefit and should be considered as an outcome measure in clinical trials, clinical practice and decision-making about healthcare budgets. Accepted instruments are available for assessing outcomes in each aspect of Alzheimer's disease, but they need to be selected carefully to provide valid, meaningful data. Some of the most frequently used outcome measures in Alzheimer's disease are reviewed. Using expanded criteria for treatment success and clinically relevant outcome measures, data from currently available studies show that cholinesterase inhibitors produce clinically meaningful long-term benefits in multiple domains in patients with Alzheimer's disease.

Activities of Daily Living↗
PubMed2001

Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.

Adult↗
PubMed2001

Gene therapy for prostate cancer: current status and future prospects.

PURPOSE: Locally advanced, relapsed and metastatic prostate cancer has a dismal prognosis with conventional therapies offering no more than palliation. In recent years advances achieved in understanding the molecular biology of cancer have afforded clinicians and scientists the opportunity to develop a range of novel genetic therapies for this disease. MATERIALS AND METHODS: We performed a detailed review of published reports of gene therapy for prostate cancer. Particular emphasis was placed on recent developments in the arena of nonviral (plasmid DNA, DNA coated gold particles, liposomes and polymer DNA complexes) and viral (adenovirus, retrovirus, adeno-associated virus, herpes virus and pox virus) vectors. Therapeutic strategies were categorized as corrective, cytoreductive and immunomodulatory gene therapy for the purpose of data analysis and comparison. RESULTS: Locoregional administration of nonviral and viral vectors can yield impressive local gene expression and therapeutic effects but to our knowledge no efficient systemically delivered vector is available to date. Corrective gene therapy to restore normal patterns of tumor suppressor gene (p53, Rb, p21 and p16) expression or negate the effect of mutated tumor promoting oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models but this approach suffers from the fact that each cancer cell must be targeted. A wide variety of cytoreductive strategies are under development, including suicide, anti-angiogenic, radioisotopic and pro-apoptotic gene therapies. Each approach has strengths and weaknesses, and may best be suited for use in combination. Immunomodulatory gene therapy seeks to generate an effective local immune response that translates to systemic antitumor activity. Currently most studies involve immunostimulatory cytokine genes, such as granulocyte-macrophage colony-stimulating factor, or interleukin-2 or 12. CONCLUSIONS: Various therapeutic genes have proved activity against prostate cancer in vitro and in vivo. However, the chief challenge facing clinical gene therapy strategies is the lack of efficient gene delivery by local and systemic routes. For the foreseeable future vector development may remain a major focus of ongoing research. Despite this caveat it is anticipated that gene therapy approaches may significantly contribute to the management of prostate cancer in the future.

Adjuvants, Immunologic↗
PubMed2001

Adrenal hemorrhage: a 25-year experience at the Mayo Clinic.

OBJECTIVE: To characterize the clinical course of adrenal hemorrhage (AH) by using a systematic review of the presentation, associated conditions, and outcomes in patients with AH seen at our institution between 1972 and 1997 (a 25-year period). PATIENTS AND METHODS: A computer search of recorded dismissal diagnoses identified 204 patients with a diagnosis of AH, but only 141 fulfilled our study criteria. Their records were analyzed systematically by presentation, bilateral or unilateral hemorrhage, corticosteroid treatment, and survival. RESULTS: AH is a heterogeneous entity that occurs in the postoperative period, in the antiphospholipid-antibody syndrome, in heparin-associated thrombocytopenia, or in the setting of severe physical stress and multiorgan failure. Standard laboratory evaluation is not helpful in establishing the diagnosis. Of the 141 cases of AH, 78 were bilateral, and 63 were unilateral. Corticosteroid treatment in situations of severe stress or sepsis had little effect on outcome (9% vs. 6% survival with and without corticosteroid treatment, respectively). This is in sharp contrast to AH occurring postoperatively (100% vs. 17% survival with or without treatment, respectively) or in the antiphospholipid-antibody syndrome (73% vs. 0% survival, respectively). CONCLUSIONS: A high index of suspicion is required to make a timely diagnosis of AH. Fever and hypotension in the appropriate clinical setting necessitate further investigation. Although the diagnosis of AH is infrequently made while the patient is alive, appropriate imaging techniques are useful for establishing a timely diagnosis. In severe physical stress or sepsis, AH may be a marker of severe, preterminal physiologic stress and poor outcome.

Adrenal Gland Diseases↗
PubMed2001

In vivo sodium iodide symporter gene therapy of prostate cancer.

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of thyroid-specific expression of the sodium iodide symporter (NIS). Here we explore the efficacy of a novel form of gene therapy using adenovirus-mediated in vivo NIS gene transfer followed by (131)I administration for treatment of prostate cancer. Prostate cancer xenografts in nude mice injected with an adenovirus carrying the NIS gene linked to the cytomegalovirus (CMV) promoter revealed highly active uptake of radioiodine. Following administration of 3 mCi of (131)I, we observed an average tumor volume reduction of 84 +/- 12%. These results show for the first time that in vivo NIS gene delivery into non-thyroidal tumors is capable of inducing accumulation of therapeutically effective radioiodine doses and might therefore represent an effective and potentially curative therapy for prostate cancer.

Adenocarcinoma↗
PubMed2001

Martorell's hypertensive leg ulcer: case report and concise review of the literature.

Hypertensive leg ulcers (Martorell's ulcers) are a unique form of lower extremity ischaemic leg ulcer. First described by Martorell, and Hines and Farber in the 1940s, these ulcers are defined by pain disproportionate to the size of the ulcer, specific location on the lower extremity, female-to-male predominance, association with long-standing, often poorly, controlled hypertension, and healing response to specific antihypertensive agents. We present a case of Martorell's hypertensive ischaemic leg ulcer and a concise review of the 104 previous cases in the world's English literature. Hypertensive ischaemic leg ulcers will be more commonly recognised with a renewed appreciation of the existence of this clinical entity.

Aged↗
PubMed2001

Expression of the sodium iodide symporter in human kidney.

BACKGROUND: The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting that iodide transport in these tissues is conferred by the expression of functional NIS protein. METHODS: The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide accumulation studies in kidney cells. RESULTS: Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO) cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium dependent and sensitive to perchlorate. CONCLUSIONS: Functional hNIS expression was demonstrated in the renal tubular system, suggesting that renal iodide transport may be, at least in part, an active process driven by NIS.

Animals↗
PubMed2001

Approaches to gene therapy with sodium/iodide symporter.

Since cloning and characterization of the sodium iodide symporter (NIS) gene, several investigators explored the possibility of a novel cytoreductive gene therapy strategy based on NIS gene transfer into non-thyroidal tumor cells followed by radioiodine therapy. NIS gene transfer has been shown to be capable of inducing radioiodine accumulation in vitro and in vivo in several non-thyroidal cancer cell lines. Following PSA promoter-mediated NIS gene delivery we were able to demonstrate prostate-specific iodide accumulation in prostate cancer cells that was high enough to elicit a therapeutic response of 131-I in vitro and in vivo. This study clearly demonstrates the potential of NIS as a novel therapeutic gene for non-thyroidal cancers, in particular prostate cancer.

Animals↗
PubMed2001

Renal metastases from thyroid papillary carcinoma: study of sodium iodide symporter expression.

Kidney metastases from thyroid cancer are rare. We report two such patients and demonstrate that the in vivo 131I uptake by the kidney metastasis is associated with high levels of sodium iodide (Na+/I-) symporter (NIS) expression in the first case. Case 1: A 61-year-old woman with papillary thyroid carcinoma-follicular variant (PTC-FV) presented with scapular metastasis. After thyroidectomy and scapulectomy, a 131I posttherapy scan showed left upper quadrant uptake. A 3.0-cm metastatic PTC-FV deposit was removed by partial nephrectomy. Case 2: A 53-year-old woman presented with back pain. A computed tomography (CT) scan showed a 3.5-cm renal mass, a multinodular goiter, and lung metastases thought secondary to a renal cell carcinoma. A unilateral nephrectomy revealed metastatic PTC-FV. After thyroidectomy, a 131I posttherapy scan showed lung and skeletal metastases. NIS immunoreactivity in tumoral tissue was strongly positive in the primary tumor, shoulder, and kidney metastasis in case 1, as well as in the primary tumor in case 2. Spotty, low-level NIS expression was observed in the kidney metastasis in case 2. In conclusion, kidney metastases of PTC-FV may occasionally retain adequate levels of NIS expression, enabling their detection during life. Thus, intense uptake in the abdomen during 131I imaging should not be assumed to be physiological gastrointestinal tract residual radionuclide activity.

Carcinoma, Papillary↗
PubMed2001

Cloning of the mouse sodium iodide symporter.

The iodide-concentrating ability of the thyroid gland is essential to the production of thyroid hormone. We report the nucleotide and amino acid sequence of the mouse sodium iodide symporter (mNIS), which mediates this activity within the thyroid gland. An open reading frame of 1,857 nucleotides codes for a protein of 618 amino acids with 95% identity to rat NIS and 84% identity to human NIS. Transient expression of the mNIS cDNA in Chinese hamster ovary (CHO) cells, a nonthyroid cell line, resulted in sodium-dependent, perchlorate-sensitive iodide uptake. Western blot analysis of membrane preparations of CHO cells transiently transfected with mNIS cDNA showed a band of 90 kd when probed with an antibody directed against rat NIS. mNIS will serve as an important reagent in determining the role of NIS in experimental thyroid diseases and for monitoring the immune response to in animal models of NIS-mediated gene therapy.

Amino Acid Sequence↗
PubMed2001

All-trans retinoic acid facilitates oncoretrovirus-mediated transduction of hematopoietic repopulating stem cells.

A major limiting factor in achieving high levels of gene transfer into hematopoietic stem cells is the ability to retain significant repopulating activity of the stem cells during the ex vivo exposure to oncoretroviral vectors. Recently, we reported that pharmacological levels (1 microM) of all-trans retinoic acid (ATRA) enhanced the maintenance of in vivo repopulating hematopoietic stem cells during liquid suspension culture. Therefore, we investigated the use of ATRA to improve transduction of hematopoietic repopulating cells. Hematopoietic precursors cultured and transduced with a GFP-containing oncoretroviral vector with or without ATRA were transplanted immediately post-transduction (day 3 post-culture initiation) or following extended culture without further transduction (day 7 post-culture initiation). Mice transplanted with 3-day ATRA-treated cells had four-fold more donor cells than the untreated cells. In contrast, there were more GFP-expressing donor cells in recipients of cells cultured without ATRA (31.31 +/- 8.47% no ATRA vs. 16.52 +/- 9.35% ATRA). After 7 days of culture, however, the repopulating ability of the hematopoietic precursors was the same for both treatment groups, but the ATRA-treated cells had significantly more green fluorescence protein (GFP)-expressing donor cells (5.57 +/- O.53% no ATRA vs. 13.67 +/- 2.14% ATRA). Secondary recipients of marrow from recipients of the 3 day cultured cells had similar donor cell levels, but the percentage of GFP-expressing cells within the donor cell population was higher in the recipients of ATRA-treated cells (3.25 +/- 0.70% no ATRA vs. 7.97 +/- 2.71% ATRA). Our data show that the addition of ATRA to cultures of hematopoietic precursors resulted in increased gene transfer into murine hematopoietic repopulating cells. These data suggest that ATRA may be useful in clinical gene therapy protocols using oncoretroviral vectors.

Animals↗
PubMed2001

Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake.

The ability of thyroid cancers to concentrate radioiodine (RAI) is dependent, in part, upon the expression and functional integrity of the sodium iodide symporter (NIS). However, some differentiated thyroid carcinomas (DTCs) and most undifferentiated thyroid carcinomas lack the ability to concentrate iodide and are thereby insensitive to 131I therapy. Variation of NIS protein expression may be an important factor in this behavior. We wished to determine whether NIS protein expression in primary DTC tumors correlated with the subsequent RAI uptake by metastatic lesions in the same patients. We obtained paraffin-embedded tissue specimens from 60 patients with metastatic thyroid cancer who had undergone total or near-total thyroidectomy at the Mayo Clinic for DTC and had known presence or absence of RAI uptake in their tumor deposits determined by total body scanning after thyroid hormone withdrawal. Tissue sections from the primary intrathyroidal tumors were subjected to immunostaining (IS) using a monoclonal antibody against human NIS. Slides were subsequently examined for specific IS by two independent reviewers. For each patient, whole body scan (WBS) uptake was recorded, and correlation between results of IS and WBS was analyzed. Of 43 patients with a positive WBS, 37 also had positive IS of their tumors. In six patients with negative IS, a positive WBS was documented, and in three of these cases TSH at the time of surgery was less than 0.3 mIU/liter. Of the 17 patients with negative WBS, 10 were also negative on IS. Positive IS accurately predicted a positive scan in our study in 84% of cases; the ability of the IS to detect all cases with a positive scan was 86%, and it increased to 90% when patients who were receiving thyroid hormone therapy at the time of surgery were excluded from the analysis. Overall, the results of our retrospective study suggest that NIS IS of the thyroidal primary tumor in patients with papillary and follicular thyroid cancers has substantial ability to predict the behavior of subsequent deposits of metastatic and recurrent cancer with respect to iodine trapping and concentration. Our findings require confirmation in prospective studies to more accurately determine the predictive ability of the test and its role in the postoperative management of patients with DTC. If confirmed, NIS IS of DTC primary lesions may prove useful in the management of patients with known or suspected metastatic thyroid cancer.

Antibodies, Monoclonal↗