Biomedical subjects

Steven M Paul

Publications and source records attributed to Steven M Paul.

At least 73 records · Page 4Linked to original sources

PubMed2002

Abeta immunization and anti-Abeta antibodies: potential therapies for the prevention and treatment of Alzheimer's disease.

Amyloid-beta (Abeta) is a normally soluble 39-43 amino peptide. Genetic and biochemical data strongly suggest that the conversion of Abeta from soluble to insoluble forms with high beta-sheet content and its buildup in the brain is a key step in the pathogenesis of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Prevention and/or reversal of this process may serve as a treatment. Methods to prevent or reverse Abeta deposition and its toxic effects would include decreasing its production, preventing its conversion to insoluble forms (e.g. inhibit beta-sheet formation) or in changing the dynamics of extracellular brain Abeta, either locally within the brain or by altering net flux of Abeta between the central nervous system (CNS) and plasma compartment. Transgenic mouse models of AD that develop age-dependent Abeta deposition, damage to the neuropil, and behavioral deficits have enabled researchers to test whether different manipulations can influence these AD-like changes. Recently, active immunization with different forms of the Abeta peptide has been shown to decrease brain Abeta deposition and improve cognitive performance in mouse models of AD. Certain peripherally administered anti-Abeta antibodies have similar effects. The mechanism(s) by which anti-Abeta antibodies result in these effects is just beginning to be elucidated. Abeta-related immune therapies in humans are an exciting new area of AD research. Understanding their detailed mechanism(s) of action and their potential usefulness awaits the results of future animal and human studies.

Alzheimer Disease↗

PubMed2002

Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease.

The epsilon4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-beta (Abeta) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on Abeta.

Alzheimer Disease↗

PubMed2002

Apolipoprotein E alters the processing of the beta-amyloid precursor protein in APP(V717F) transgenic mice.

We have recently reported a critical role for apolipoprotein E (apoE) in the process of amyloid deposition and neuritic plaque formation in APP(V717F) transgenic (Tg) mice, an animal model of Alzheimer's disease (AD). In the present study, we have investigated whether the presence or absence of apoE alters the processing of the amyloid precursor protein (APP) to various fragments, including the beta-amyloid peptides (Abeta). Here we show that, in contrast to APP(V717F) Tg mice expressing apoE, APP(V717F) Tg mice deficient in apoE develop anti-Abeta immunoreactive multifocal aggregates, which contain the beta-cleaved C-terminal fragments (beta-CTFs) of APP. Tg mice deficient in apoE also display altered levels of mature full-length APP, increased amounts of beta-CTFs, as well as elevated levels of Abeta(1-40) and Abeta(1-42) in an age- and region-dependent manner when compared to Tg mice expressing apoE. Taken together, these data support a role for apoE in APP processing in vivo.

Age Factors↗

PubMed2002

NF-kappaB mediates IL-1beta-induced synthesis/release of alpha2-macroglobulin in a human glial cell line.

Increasingly, inflammatory responses in localized areas of brain parenchyma in response to the extracellular deposition of the Abeta peptides are thought to play a causative role in Alzheimer's disease (AD) progression. Anti-inflammatory agents, in particular non-steroid anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been shown to be associated with a delayed onset or slowed rate of disease progression in several epidemiological studies. Activation of glial cells and the subsequent expression of a number of proteins including alpha(2)-macroglobulin (alpha(2)M) are associated with the induction of brain tissue inflammation. Additionally cytokines, such as interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are co-localized to senile plaques, a neuropathological hallmark of AD. Alpha(2)M binds various cytokines, including IL-1beta, as well as Abeta. In this study, we demonstrate that IL-1beta induces alpha(2)M synthesis/release from a human astroglial cell line (U373) via the activation of the nuclear transcription factor NF-kappaB. Our data suggest that attenuation of IL-1beta-induced alpha(2)M synthesis/release by blocking NF-kappaB activation may potentially be 'protective' against the development of late-onset AD.

Alzheimer Disease↗

PubMed2002

Developing novel treatments for mood disorders: accelerating discovery.

This review was generated from discussions by the Pharmacologic and Somatic Treatments Section of the National Institute of Mental Health Strategic Plan for Mood Disorders Committee on advancing novel pharmacologic and somatic treatments for mood disorders. The opening section of the article summarizes in broad strokes, current pharmacologic treatments, and new directions in the field. Thereafter the topics focus on specific research initiatives that could advance the current therapeutics for mood disorders including new basic and clinical research in vivo human imaging procedures, somatic therapeutics, and the vast new area of pharmacogenetics. New scientific and technical opportunities exist today based on advances in basic neuroscience, opportunities in clinical testing, industry interest in advancing central nervous system therapeutics, and on active consumer advocacy groups. The question of how to bring all of these positive forces together to accelerate discovery in mood disorder thera-peutics is the topic of this article.

Animals↗

PubMed2002

Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.

Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-beta (Abeta) in vitro. To determine whether endogenous clusterin plays a role in influencing Abeta deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Abeta deposition as did PDAPP, clusterin(+/+) mice. Although Abeta deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Abeta (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Abeta structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.

Alzheimer Disease↗

PubMed2002

A randomized trial of exercise training after renal transplantation.

BACKGROUND: Significant health benefits result from regular physical activity, many which are important for transplant recipients. Although exercise capacity improves initially after transplant, it is not normalized, and only two studies have reported the effects of exercise training in this population. We report a randomized clinical trial of exercise after renal transplantation (RTX). METHODS: One hundred sixty-seven patients were randomized at 1 month after RTX into two groups: exercise intervention (EX) and usual care (UC), with repeat testing at 6 and 12 months. Ninety-five patients completed the following testing at both testing times: symptom-limited treadmill testing with measurement of peak oxygen uptake (peak Vo2); isokinetic muscle testing for muscle strength; and dual-energy X-ray absorptiometry scans for body composition. The SF-36 Health Status Questionnaire assessed self-reported functioning. The exercise intervention consisted of individually prescribed programs to be conducted at home with regular phone follow-up to enhance adherence. Repeated measures analysis of variance was performed to determine differences between the groups for the three testing times. RESULTS: At 1 year 67% of the EX group were exercising regularly compared with 36% of the UC group (P=0.01). Compared with the UC group, the EX group had significantly greater gains in peak Vo2 (P=0.016), percent age-predicted Vo2 (P=0.03), and muscle strength (P=0.05), and a trend toward higher self-reported physical functioning (P=0.06). There were no differences between the groups in changes in body composition. At 1 year, peak Vo2 was significantly correlated with age, percent fat, muscle strength, hematocrit, and self-reported physical functioning. CONCLUSIONS: Exercise training after RTX results in higher levels of measured and self-reported physical functioning; however, exercise alone does not affect body composition.

Adult↗

PubMed2002

Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease.

The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.

Alzheimer Disease↗

PubMed2002

Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury.

Hypoxic-ischemic brain injury in the perinatal period is a major cause of morbidity and mortality. Presently, there are no proven effective therapies with which to safeguard the human neonatal brain against this type of injury. Minocycline, a semisynthetic tetracycline, has been shown to be neuroprotective in certain adult ischemic injury/stroke and neurodegenerative disease models. However, minocycline's neuroprotective effects have not been assessed after insults to the neonatal brain. We now report that minocycline administered either immediately before or immediately after a hypoxic-ischemic insult substantially blocks tissue damage in a rodent model of neonatal hypoxic-ischemic brain injury. Minocycline treatment prevents the formation of activated caspase-3, a known effector of apoptosis, as well as the appearance of a calpain cleaved substrate, a marker of excitotoxic/necrotic cell death. To our knowledge, this is the first report of a systemic treatment that can be administered after a hypoxic-ischemic insult, which provides robust, nearly complete neuroprotection to the developing brain. Our data suggest that minocycline or a related neuroprotective tetracycline may be a candidate to consider in human clinical trials to protect the developing brain against hypoxic-ischemic-induced damage.

Animals↗

PubMed2002

Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease.

The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), perhaps through effects on amyloid-beta (Abeta) metabolism. Detailed analyses of various Abeta parameters in aging APP(V717F+/-) transgenic mice expressing mouse apoE, no apoE, or human apoE2, apoE3, or apoE4 demonstrate that apoE facilitates, but is not required for, Abeta fibril formation in vivo. Human apoE isoforms markedly delayed Abeta deposition relative to mouse apoE, with apoE2 (and apoE3 to a lesser extent) having a prolonged ability to prevent Abeta from converting into fibrillar forms. Isoform-specific effects of human apoE on Abeta levels and neuritic plaque formation mimicked that observed in AD (E4 > E3 > E2). Importantly, observation of an apoE-dependent decrease in percent soluble Abeta and enrichment of Abeta in membrane microdomains prior to Abeta deposition indicates that apoE influences Abeta metabolism early in the amyloidogenic process and provides a possible novel mechanism by which apoE affects AD pathogenesis.

Alzheimer Disease↗

PubMed2002

The self-reported likelihood of patient delay in breast cancer: new thoughts for early detection.

BACKGROUND: Delayed presentation of self-discovered breast symptoms influences stage of cancer at diagnosis and decreases breast cancer survival. METHODS: A total of 699 asymptomatic women (black, white, and Latino), recruited in community settings and stratified by age, income, and educational level, were surveyed for their likelihood to delay (J-Delay scale) in the event of a breast symptom discovery. Models of likelihood were tested with logistic regression analyses. RESULTS: A total of 166 women (23.7%) reported likelihood to delay. Lower income, lower educational level, self identification as Latino or black, experienced prejudice in care delivery, perceived lack of access to health care, fatalism about breast cancer, poor health care utilization habits, self-care behavior, spouse/partner and employer perceived constraints, problem-solving style, and a lack of knowledge of breast cancer's presenting symptoms were associated with likelihood to delay. A combined sample multiple logistic regression model correctly predicted 40.6% of women reporting a likelihood to delay, 94.9% of those not likely to delay, and 82.4% (551 of 669) of cases overall. CONCLUSIONS: Self-reported likelihood of patient delay is measurable in advance of symptom occurrence, and this measure is consistent with behavioral and knowledge variables previously linked with advanced breast cancer at diagnosis.

Adult↗

PubMed2002

Putting cancer pain management regimens into practice at home.

The purpose of this study was to describe the difficulties with pain management that patients and family caregivers bring to a nurse's attention during a teaching and coaching intervention. Data were obtained from audiotaped and transcribed interactions between intervention nurses and patients (n = 52) and their family caregivers (n = 33) who were participating in a randomized clinical trial of a nursing intervention called the PRO-SELF Copyright Pain Control Program. Using qualitative content analysis, we found that patients had difficulty in seven areas when they attempted to put a pain management regimen into practice, namely: obtaining the prescribed medication(s), accessing information, tailoring prescribed regimens to meet individual needs, managing side effects, cognitively processing information, managing new or unusual pain, and managing multiple symptoms simultaneously. The findings from this study suggest that the provision of information about cancer pain management to patients and their family caregivers is not sufficient to improve pain control in the home care setting. Patients and their family caregivers require ongoing assistance with problem-solving to optimize their pain management regimen.

Aged↗

PubMed2002

Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model.

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.

Alzheimer Disease↗

PubMed2002

Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease.

To better understand amyloid-beta (Abeta) metabolism in vivo, we assessed the concentration of Abeta in the CSF and plasma of APP(V717F) (PDAPP) transgenic mice, a model that develops age-dependent Alzheimer's disease (AD)-like pathology. In 3-month-old mice, prior to the development of Abeta deposition in the brain, there was a highly significant correlation between Abeta levels in CSF and plasma. In 9-month-old-mice, an age at which some but not all mice have developed Abeta deposition, there was also a significant correlation between CSF and plasma Abeta; however, the correlation was not as strong as that present in young mice. In further exploring CSF and plasma Abeta levels in 9-month-old mice, levels of CSF Abeta were found to correlate highly with Abeta burden. Analysis of the CSF: plasma Abeta ratio revealed a selective two-fold increase in plaque versus non-plaque bearing mice, strongly suggesting a plaque-mediated sequestration of soluble Abeta in brain. Interestingly, in 9-month-old mice, a significant correlation between CNS and plasma Abeta was limited to mice lacking Abeta deposition. These findings suggest that there is a dynamic equilibrium between CNS and plasma Abeta, and that plaques create a new equilibrium because soluble CNS Abeta not only enters the plasma but also deposits onto amyloid plaques in the CNS.

Age Factors↗

PubMed2002

Oncology outpatients with pain from bone metastasis require more than around-the-clock dosing of analgesics to achieve adequate pain control.

Around-the-clock (ATC) dosing of opioid analgesics is the established approach for the management of chronic cancer pain. The purposes of this study were to determine whether there were differences in pain intensity scores and pain duration between oncology outpatients who were taking opioid analgesics on an around-the-clock (ATC) compared with an as needed (PRN) basis and to determine differences in opioid prescription and consumption between the 2 groups during a period of 5 weeks. Oncology patients (n = 137) with pain from bone metastasis were recruited from 7 outpatient settings. Patients completed a demographic questionnaire and on a daily basis recorded pain intensity scores and medication intake in a diary. No significant differences in average, least, or worst pain intensity scores or number of hours per day in pain were found between the 2 groups. However, the average total opioid dose, prescribed and taken, was significantly greater for the ATC group than for the PRN group. These findings suggest the need for further investigations in the following areas: the appropriate treatments for pain related to bone metastasis, the use of various pain measures to evaluate the effectiveness of analgesic medications, and the need to evaluate how analgesics are prescribed and titrated for patients with cancer-related pain.

Journal Article↗

PubMed2002

Pain management autobiographies and reluctance to use opioids for cancer pain management.

Although pain management education results in improved pain control for some patients, it does not work for all patients because some patients remain reluctant or unwilling to use prescribed analgesics to their optimal effect. In a randomized clinical trial that tested the effectiveness of the PRO-SELF Pain Control Program, 11 patients declined to increase their analgesic use despite moderate to severe pain. These patients were selected for a qualitative analysis of their audiotaped discussions about pain management with their intervention nurses. This analysis revealed that these patients often spontaneously provided detailed explanations about why they were reluctant or unwilling to take analgesics in general or opioids in particular. We termed these explanatory accounts pain management autobiographies because of their narrative character and multilayered, richly detailed quality. Pain management autobiographies included stories about (1) previous experience with chronic pain management, including stigmatizing interactions with clinicians and family members; (2) bad experiences with cancer pain management, including severe constipation; and 3) strongly held conventions about medication use, including the belief that all medications are "toxins" that should be avoided. The study findings suggest that a small subset of patients with cancer pain may need interventions such as individual or family counseling or alternative pain management strategies to augment education about opioids.

Adult↗

PubMed2002

The usefulness of a daily pain management diary for outpatients with cancer-related pain.

PURPOSE/OBJECTIVES: To describe the usefulness of daily pain management diaries to outpatients with cancer who participated in a randomized clinical trial of the PRO-SELF Pain Control Program. DESIGN: Randomized clinical trial in which a daily pain management diary was used for data collection in the control group and for data collection and nurse coaching regarding the pain management program in the intervention group. SETTING: Seven outpatient oncology settings. SAMPLE: 155 patients with pain from bone metastases and 90 family caregivers. METHODS: Content and statistical analysis of audiotaped answers to a semistructured questionnaire. MAIN RESEARCH VARIABLES: Patients' and family caregivers' perceptions of the usefulness of a daily pain management diary; specific ways in which the diary was used. FINDINGS: Patients in both the intervention (75%) and control groups (73%) found the diary useful. The diary was used to heighten awareness of pain, guide pain management behavior, enhance a sense of control, and facilitate communication. Family caregivers in both groups also reported that the diary was useful. CONCLUSIONS: The completion of a daily pain management diary is useful to patients and family caregivers and may function as an intervention for self-care. IMPLICATIONS FOR NURSING: Research-based evidence supports the importance of using a daily pain management diary in clinical practice.

Adult↗

PubMed1990

Measuring pain quality: validity and reliability of children's and adolescents' pain language.

Although considerable research has been conducted to identify children's and adolescents' language of pain, research is lacking regarding a method to quantify the pain quality described by this language. Three descriptive studies involving 1223 children, aged 8-17 years, were conducted in school and hospital settings. The aims were to develop and examine the validity and reliability of a word list for measuring pain quality that was free of age, gender, and ethnic biases. A word list with 43 words was developed and resulted in sensory, affective, evaluative, and total scores that correlated with pain location and pain intensity scores (r = 0.19-0.44; P less than or equal to 0.01). Pain quality scores decreased over time in a postoperative pain model. Test-retest reliability of the word list scores was high (r = 0.78-0.95; P less than 0.001). This word list was revised and resulted in a word list with 56 words relatively free of gender, ethnic, and developmental biases. Additional research is needed to assess the psychometric properties of this word list in pediatric populations experiencing different pain syndromes.

Adolescent↗