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Biomedical subjects

Steven M Paul

Publications and source records attributed to Steven M Paul.

At least 19 recordsLinked to original sources
PubMed2026

The phytosterol 24(S)-saringosterol alters lipid homeostasis and inflammatory pathways in a cell-specific manner.

BACKGROUND: Neuroinflammation and disrupted cholesterol metabolism in microglia are key contributors to Alzheimer's disease (AD) pathogenesis. Liver X receptors (LXRα/β) regulate lipid metabolism and inflammation. Synthetic pan-LXR agonists, such as T0901317 and GW3965, exert neuroprotective effects by modulating lipid metabolism, making them promising therapeutic strategies for neurodegenerative disorders like Alzheimer's Disease (AD). However, their clinical use is limited by hepatic side effects, including hypertriglyceridemia and steatosis. PURPOSE: To overcome these limitations, we investigated 24(S)-saringosterol, a phytosterol from Sargassum fusiforme, and its potential dissociating effect as a LXR agonist on myeloid cells vs hepatocytes. METHOD: Using primary cultures of myeloid cells (microglia, bone marrow-derived macrophages) and hepatocytes, we performed transcriptomic and lipidomic analyses to assess the impact of 24(S)-saringosterol on lipid metabolism and inflammatory pathways. RESULTS: 24(S)-saringosterol strongly activated LXR-regulated genes, upregulating cholesterol efflux transporter Abca1 in a dose-dependent manner. In myeloid cells, it reduced the expression of interferon-β pathway genes and promoted cholesterol efflux, mirroring GW3965's anti-inflammatory effects. Notably, 24(S)-saringosterol downregulated cholesterol biosynthesis (Dhcr24) and influx (Ldlr) via Srebp2 in both cell types, contrasting with GW3965, which increased lipid synthesis genes via Srebp1. CONCLUSION: These findings suggest 24(S)-saringosterol acts as a selective LXR agonist in a cell-specific manner, retaining beneficial effects while minimizing hepatic risks. This compound represents a promising candidate for AD and other metabolic or inflammatory disorders.

Animals↗
PubMed2007

Differences in the prevalence and severity of side effects based on type of analgesic prescription in patients with chronic cancer pain.

An understanding of the relationship between the type of analgesic prescription and the prevalence and severity of side effects is crucial in making appropriate treatment decisions. The purposes of this study were to determine if there were differences in the prevalence of side effects among four different types of analgesic prescriptions (i.e., no opioid, only an as needed (PRN) opioid, only an around-the-clock (ATC) opioid, or an ATC+PRN opioid); to determine if there were differences in the severity of side effects among the four prescription groups; and to determine the relationships between the total dose of opioid analgesic medication prescribed and taken and the severity of side effects. As part of a larger study, 174 cancer patients with bone metastasis reported their analgesic use and the prevalence and severity of 11 side effects. Significant differences (P<0.05) were found in prevalence rates for seven of the side effects among the four prescription groups. The highest prevalence rates were found in the only ATC and ATC+PRN groups. Significant differences were found in the severity scores for five of the side effects, with the highest severity scores reported by patients in the only ATC and ATC+PRN groups. Significant positive correlations were found between the severity of six of the side effects and the total dose of opioid prescribed and taken. Risk factors for analgesic-induced side effects are ATC and ATC+PRN prescription types and higher doses of opioid analgesics.

Adult↗
PubMed2006

Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice.

The low density lipoprotein receptor-related protein (LRP) is highly expressed in the brain and has been shown to alter the metabolism of amyloid precursor protein and amyloid-beta peptide (Abeta) in vitro. Previously we developed mice that overexpress a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer disease. Overexpression of mLRP2 in 22-month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble Abeta in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 overexpression on 3-month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated Abeta42 in the hippocampus of mice that overexpressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal Abeta42 in the hippocampus and frontal cortex of PDAPP mice, which frequently co-localized with the lysosomal marker LAMP-1. Interestingly, PDAPP mice lacking apolipoprotein E (apoE) had much less intraneuronal Abeta42. We also found that PC12 cells overexpressing mLRP2 cleared Abeta42 and Abeta40 more rapidly from media than PC12 cells transfected with the vector only. Preincubation of apoE3 or apoE4 with Abeta42 increased the rate of Abeta clearance, and this effect was partially blocked by receptor-associated protein. Our results support the hypothesis that LRP binds and endocytoses Abeta42 both directly and via apoE but that endocytosed Abeta42 is not completely degraded and accumulates in intraneuronal lysosomes.

Amyloid beta-Peptides↗
PubMed2006

Subgroups of patients with cancer with different symptom experiences and quality-of-life outcomes: a cluster analysis.

PURPOSE/OBJECTIVES: To identify subgroups of outpatients with cancer based on their experiences with the symptoms of fatigue, sleep disturbance, depression, and pain; to explore whether patients in the subgroups differed on selected demographic, disease, and treatment characteristics; and to determine whether patients in the subgroups differed on two important patient outcomes: functional status and quality of life (QOL). DESIGN: Descriptive, correlational study. SETTING: Four outpatient oncology practices in northern California. SAMPLE: 191 outpatients with cancer receiving active treatment. METHODS: Patients completed a demographic questionnaire, Karnofsky Performance Status scale, Lee Fatigue Scale, General Sleep Disturbance Scale, Center for Epidemiological Studies Depression Scale, Multidimensional Quality-of-Life Scale Cancer, and a numeric rating scale of worst pain intensity. Medical records were reviewed for disease and treatment information. Cluster analysis was used to identify patient subgroups based on patients symptom experiences. Differences in demographic, disease, and treatment characteristics as well as in outcomes were evaluated using analysis of variance and chi square analysis. MAIN RESEARCH VARIABLES: Subgroup membership, fatigue, sleep disturbance, depression, pain, functional status, and QOL. FINDINGS: Four relatively distinct patient subgroups were identified based on patients experiences with four highly prevalent and related symptoms. CONCLUSIONS: The subgroup of patients who reported low levels of all four symptoms reported the best functional status and QOL. IMPLICATIONS FOR NURSING: The findings from this study need to be replicated before definitive clinical practice recommendations can be made. Until that time, clinicians need to assess patients for the occurrence of multiple symptoms that may place them at increased risk for poorer outcomes.

Aged↗
PubMed2006

Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms.

Lifelong cognitive stimulation is associated with a lower risk of Alzheimer's disease (AD), but causality is difficult to prove. We therefore sought to investigate the preventative potential of environmental enrichment (EE) using mice expressing both human mutant presenilin-1 and the amyloid precursor protein (PS1/PDAPP). At weaning, mice were placed into either an enriched or standard housing environment. Behavioral testing at 4.5-6 months showed that environmentally enriched PS1/PDAPP mice outperformed mice in standard housing, and were behaviorally indistinguishable from non-transgenic mice across multiple cognitive domains. PS1/PDAPP mice exposed to both environmental enrichment and behavioral testing, but not to EE alone, showed 50% less brain beta-amyloid without improved dendritic morphology. Microarray analysis revealed large enrichment-induced changes in hippocampal expression of genes/proteins related to Abeta sequestration and synaptic plasticity. These results indicate that EE protects against cognitive impairment in AD transgenic mice through a dual mechanism, including both amyloid dependent and independent mechanisms.

Alzheimer Disease↗
PubMed2006

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody.

Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid beta (A beta) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human A beta peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked A beta-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-A beta antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the A beta peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-A beta antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.

Acetylcholine↗
PubMed2006

Neuroleptics antagonize nalbuphine antianalgesia.

UNLABELLED: To evaluate the role of sigma receptors in the sexually dimorphic antianalgesic effect of agonist-antagonist kappa opioids, 2 neuroleptics, haloperidol, a sigma receptor antagonist, and chlorpromazine, which has minimal effect at sigma receptors, were administered with the agonist-antagonist kappa opioid nalbuphine in patients with postoperative pain. Before surgical extraction of bony impacted mandibular third molar teeth, patients received haloperidol (1 mg), chlorpromazine (10 mg), or placebo by oral administration. After surgery, the pain intensity did not differ significantly between the 3 treatment groups, suggesting lack of analgesic effect produced by either haloperidol or chlorpromazine. All patients were then administered nalbuphine (5 mg, intravenous). As previously reported, the group that did not receive a preoperative neuroleptic exhibited sexually dimorphic analgesia, with women experiencing greater analgesia than men. Antianalgesia was also observed, with men experiencing late onset increased pain compared with baseline, starting approximately 1 hour after nalbuphine administration. Both neuroleptics blocked nalbuphine antianalgesia, resulting in enhanced analgesia and elimination of the sex differences. Because chlorpromazine and haloperidol enhanced nalbuphine analgesia and eliminated sexual dimorphism, the receptor at which neuroleptics act to antagonize the "antianalgesia" might be a common site of action to both drugs. PERSPECTIVE: This study demonstrates that neuroleptics can block the antianalgesic effect of agonist-antagonist kappa opioids. These findings could help inform the development of novel analgesics.

Analgesics, Opioid↗
PubMed2006

Using the American Pain Society's patient outcome questionnaire to evaluate the quality of postoperative pain management in a sample of Norwegian patients.

UNLABELLED: In the United States, quality improvement (QI) approaches have been used to evaluate pain management. However, the use of QI approaches to evaluate the quality of patient care is just emerging in many European countries. The purposes of this study, using the American Pain Society's QI Standards, were: to describe changes over time, in pain severity, in pain interference with function, and in the doses of analgesics administered; to describe patients' level of satisfaction with postoperative pain management; and to determine the relationships between pain severity and patient outcomes. Results from a sample of patients who underwent orthopedic surgery suggest that undertreatment of pain persists across the first 5 postoperative days and that pain's level of interference with function decreases significantly between the third and fifth postoperative days. As in other studies, despite high pain intensity scores, patients reported high levels of satisfaction with postoperative pain management. PERSPECTIVE: Findings suggest that the undertreatment of pain results in significant decrements in function over the first 5 postoperative days. Future studies designed to improve the quality of postoperative pain management need to use multimodal approaches and evaluate not only pain intensity, but improvements in function as critical outcome measures.

Aged↗
PubMed2006

The prevalence and occurrence of diabetic foot ulcer pain and its impact on health-related quality of life.

UNLABELLED: This study describes the prevalence and occurrence of diabetic foot ulcer (DFU) pain and the impact of DFU pain on health-related quality of life (HRQL) using generic and disease specific instruments. Data were obtained from 127 patients with DFU who were recruited from 6 hospital-based diabetic outpatient clinics. HRQL was measured using the Medical Outcome Study-Short Form (SF-36) and the Diabetes Foot Ulcer Scale (DFS). Occurrence of pain was assessed using 2 items from the DFS (ie, pain while walking and/or standing and pain during the night related to foot ulcer problems). Seventy-five percent reported some pain related to DFU and 57% reported DFU pain while walking and/or standing and also during the night. Twenty-five percent reported pain none of the time. A higher percentage of patients with pain reported having a prescription for an analgesic medication than those without pain. Patients who reported pain most or all of the time had statistically and clinically significantly poorer HRQL than those who did not report pain. These findings suggest that pain associated with DFU is a significant clinical problem. Additional research is warranted to further characterize the pain associated with DFU and its impact on patient outcomes and HRQL. PERSPECTIVE: Numerous basic and clinical studies have focused on pain associated with diabetic peripheral neuropathy. Findings from this study suggest a new pain problem in patients with diabetes, namely, pain associated with foot ulcers, that warrants further investigation.

Adult↗
PubMed2006

Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors.

Pain from radiation therapy (RT)-induced mucositis is a significant clinical problem for patients with head and neck cancer (HNC). The purpose of this study was to determine the pattern, severity, and time course of RT-induced mucositis pain; self-care behaviors (SCBs) used to manage mucositis pain; and the effectiveness of these behaviors in relieving such pain. Forty-nine patients with HNC were assessed using the MacDibbs Mouth Assessment Tool to determine the severity of RT-induced mucositis pain over their course of RT and at a one-month follow-up visit. All patients developed pain due to RT-induced mucositis. A Self-Care Diary was used weekly by patients to record SCBs and their effectiveness. The most effective SCBs for RT-induced mucositis pain were mouth rinsing and using oral analgesics. However, more severe pain with swallowing was not managed well throughout the study. Future studies need to test more effective strategies to manage RT-induced mucositis pain.

Adult↗
PubMed2006

Hospice care in nursing homes: does it contribute to higher quality pain management?

PURPOSE: The purpose of this study was to investigate pain management among 42 hospice and 65 non-hospice residents in two proprietary nursing homes. DESIGN AND METHODS: In this prospective, anthropological, quantitative, and qualitative study, we used participant observation, event analysis, and chart review to obtain data. The Medication Quantification Scale was used in order to account for the prescription and administration of all analgesic medications. RESULTS: Although 72% of residents experienced pain, we found no statistically significant differences in the proportion of hospice versus non-hospice residents (a) who had been prescribed opioids and co-analgesics, and (b) whose medication was administered around the clock or as needed. Limited physician availability, lack of pharmacologic knowledge, and limitations of nursing staff hindered pain management of both groups of residents. IMPLICATIONS: Although hospice care is of some benefit, pain management and high-quality end-of-life care is dependent upon the context in which it is provided. Given that between 1991 and 2001 Medicare expenditures for nursing home-based hospice care increased from dollar 8.6 million to dollar 21.8 million, the effectiveness of hospice-care programs in nursing homes warrants further study.

Aged↗
PubMed2006

The exploration of the establishment of cutpoints to categorize the severity of acute postoperative pain.

OBJECTIVES: Although several studies have established different cutpoints (CPs) for mild, moderate, and severe pain for a variety of chronic pain conditions, only one study by Mendoza and colleagues reported on CPs for acute postoperative pain that were derived using ratings of worst pain. The purpose of this study was to explore the establishment of the optimal CPs for mild, moderate, and severe postoperative pain using ratings of average and worst pain and to determine if these CPs distinguished among the pain severity groups on several outcomes. METHODS: The study is a reanalysis of data from patients who underwent hip and knee replacement surgery. Using the methodology described by Serlin et al, a series of CP derivations were performed based on both single item scores for pain intensity and mean scores for pain intensity. One-way analyses of variance, chi analyses, or Kruskal-Wallis tests were conducted to determine if the optimal CPs for pain severity distinguished among the 3 pain severity groups on several outcomes. RESULTS: CPs 3,5 were found using a mean score based on patients' ratings of average and worst pain on the third postoperative day. Findings suggest that mean pain scores of >3 have a significant effect on general activity, mood, walking ability, and sleep. DISCUSSION: Possible explanations for the differences in the CPs found in this study compared with the results by Mendoza and colleagues are discussed. The findings warrant replication in other samples of postoperative patients.

Acute Disease↗
PubMed2005

Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo.

Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.

Action Potentials↗
PubMed2005

P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.

Accumulation of amyloid-beta (Abeta) within extracellular spaces of the brain is a hallmark of Alzheimer disease (AD). In sporadic, late-onset AD, there is little evidence for increased Abeta production, suggesting that decreased elimination from the brain may contribute to elevated levels of Abeta and plaque formation. Efflux transport of Abeta across the blood-brain barrier (BBB) contributes to Abeta removal from the brain. P-glycoprotein (Pgp) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In Pgp-null mice, we show that [I]Abeta40 and [I]Abeta42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a Pgp inhibitor, Abeta levels within the brain interstitial fluid significantly increased within hours of treatment. Furthermore, APP-transgenic, Pgp-null mice had increased levels of brain Abeta and enhanced Abeta deposition compared with APP-transgenic, Pgp WT mice. These data establish a direct link between Pgp and Abeta metabolism in vivo and suggest that Pgp activity at the BBB could affect risk for developing AD as well as provide a novel diagnostic and therapeutic target.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.

Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.

ATP Binding Cassette Transporter 1↗
PubMed2005

Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.

sorLA (Sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is reduced in the brain of patients with Alzheimer's disease (AD), we tested involvement of this receptor in intracellular transport and processing of the amyloid precursor protein (APP) to the amyloid beta-peptide (Abeta), the principal component of senile plaques. We demonstrate that sorLA interacts with APP in vitro and in living cells and that both proteins colocalize in endosomal and Golgi compartments. Overexpression of sorLA in neurons causes redistribution of APP to the Golgi and decreased processing to Abeta, whereas ablation of sorLA expression in knockout mice results in increased levels of Abeta in the brain similar to the situation in AD patients. Thus, sorLA acts as a sorting receptor that protects APP from processing into Abeta and thereby reduces the burden of amyloidogenic peptide formation. Consequently, reduced receptor expression in the human brain may increase Abeta production and plaque formation and promote spontaneous AD.

Alzheimer Disease↗
PubMed2005

Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease.

PDAPP transgenic mice overexpress a mutant form of human amyloid precursor protein under control of the platelet-derived growth factor promoter in CNS neurons that causes early onset, familial Alzheimer's disease in humans. These mice, on a mixed genetic background, have been shown to have substantial learning impairments from early ages, as well as an age-dependent decline in learning ability that has been hypothesized to be caused by amyloid-beta (Abeta) accumulation. The goals of this study were to determine: (1) whether PDAPP mice on a pure C57BL/6 background develop more severe age-dependent learning deficits than wild-type mice; (2) if so, whether Abeta accumulation accounts for the excessive decline in learning ability; and (3) whether the learning deficits are reversible, even after significant Abeta deposition. At 4-6, 10-12, or 17-19 months of age, PDAPP and littermate wild-type mice on a C57BL/6 background were tested on a 5 week water maze protocol in which the location of the escape platform changed weekly, requiring the mice to repeatedly learn new information. PDAPP mice exhibited impaired spatial learning as early as 4 months (pre-Abeta deposition), and the performance of both wild-type and PDAPP mice declined with age. However, PDAPP mice exhibited significantly greater deterioration with age. Direct evidence for the role of Abeta accumulation in the age-related worsening in PDAPP mice was provided by the observation that systemic treatment over several weeks with the anti-Abeta antibody 10D5 reduced plaque deposition, increased plasma Abeta, improved hippocampal long-term potentiation, and improved behavioral performance in aged PDAPP mice with substantial Abeta burden.

Amyloid beta-Protein Precursor↗