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Biomedical subjects

Daniel J Pearce

Publications and source records attributed to Daniel J Pearce.

At least 19 recordsLinked to original sources
PubMed2006

Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging.

It is thought that, as we age, damage to our stem cells may lead to diminished stem cell pool function and, consequently, a reduced organ regeneration potential that contributes to somatic senescence. Stem cells have evolved many antitoxicity mechanisms, and certain mechanisms may be utilized to isolate hematopoietic stem cells. One method exploits the activity of the ATP-binding cassette/G2 transporter to efflux Hoechst 33,342 and results in a stem cell population known as the side population (SP). The SP subset represents a remarkable enrichment for hematopoietic stem cells and provides an opportunity to re-evaluate age-based changes in hematopoietic stem cells. We report here that the frequency of SP cells steadily increases with age, as does the proportion of Lin(-)/Sca-1(+)/c-kit(+) cells that is capable of Hoechst efflux. Phenotyping, progenitor, and long-term repopulation assays have indicated that SP cells in older mice are still stem cells, albeit with a lower homing efficiency than SP cells from younger mice. Analysis of apoptosis within SP cells has revealed an apoptosis-resistant population in SP cells from old mice. Gene expression analysis has determined that SP cells from old mice have a reduced expression of apoptosis-promoting genes than SP cells from young mice. This increase in SP cells with age seems to be an intrinsic property that may be independent of the age of the microenvironment (niche), and our data might provide some clues as to how this alteration in the proportion of stem/progenitor cells occurs. A possible selection-based mechanism of stem cell pool aging is discussed.

Aging↗
PubMed2006

Implications of the expression of myeloid markers on normal and leukemic stem cells.

We have recently described the expression of CD33 and other antigens previously thought to be myeloid specific on both acute myeloid leukemia-initiating cells (AML-IC) and normal hematopoietic stem cells (HSC) that are capable of repopulating immuno-deficient mice. Here, we discuss that the presence of myeloid markers on AML-ICs and HSCs makes identification of an antigen for targeted therapy extremely difficult. Xenotransplantation assays should be used wherever possible to test the suitability of candidate antigens for targeted therapy, including the assessment of the effect on normal cells.

Aminoglycosides↗
PubMed2006

Out of the blue: a comparison of Hoechst side population (SP) analysis of murine bone marrow using 325, 363 and 407 nm excitation sources.

BACKGROUND: The discrimination of side population (SP) cells is a useful flow cytometric tool for the study of putative stem cells in many tissue types. Previous studies on murine bone marrow (BM) SP cells and concurrent surface immunophenotyping provide a good model for comparing Hoechst bivariate profiles. Here we compare the results of SP cells from the same specimens generated on three different instruments. METHODS: Concurrent SP analysis and immunophenotyping was performed on murine BM. The data acquisition was performed on a DakoCytomation MoFlo, a Becton Dickinson LSR and a Becton Dickinson FACSAria to compare the ability of each instrument to discriminate putative stem cells. Further experiments examined the effect of apoptotic changes, assessed by Annexin V binding, and the presence of nucleated erythroid precursors on the Hoechst profile. RESULTS: Identifiable and equivalent side populations were generated on all three instruments despite differences in appearance of the Hoechst profiles. Differences in laser type, collection filter combinations and the presence of erythroid precursors and apoptotic cells all contributed to this effect. CONCLUSIONS: In our hands, murine SP cells with the expected surface immunophenotype can be identified on a MoFlo, LSR and a factory standard FACSAria.

Animals↗
PubMed2006

Low-dose acitretin is associated with fewer adverse events than high-dose acitretin in the treatment of psoriasis.

OBJECTIVE: In practice, lower dose acitretin therapy (25 mg/d) seems to be better tolerated and associated with fewer abnormalities found after laboratory testing. Here we revisit the original phase 3 trials for acitretin to evaluate the evidence for low-dose therapy producing fewer adverse effects than the 50 mg/d dosage. DESIGN: We retrospectively analyzed pooled data from 2 large pivotal trials, each including a randomized, placebo-controlled, 8-week double-blind phase followed by a 16-week open-label phase. SETTING: Multicenter pivotal trial of subjects in referral centers and private practice. PARTICIPANTS: Subjects with severe psoriasis requiring systemic therapy were recruited according to inclusion/exclusion criteria. INTERVENTION: During the double-blind phase, subjects received placebo or one of several fixed acitretin doses. Dose adjustment was allowed during the open-label phase, during which high-dose treatment was defined as a mean dosage of 50 mg/d and low-dose treatment was defined as a mean dosage of 25 mg/d. MAIN OUTCOME MEASURES: The frequency of anomalies found after laboratory testing and clinical adverse events were the outcomes of interest. RESULTS: Common adverse effects (dry skin, alopecia, rhinitis, etc) were 2 to 3 times more frequent in subjects receiving 50-mg/d acitretin than in those receiving 25 mg/d. Increases in hepatic enzymes and triglycerides in subjects receiving low-dose therapy were minimal compared with levels in those receiving high-dose therapy. CONCLUSIONS: We have shown low-dose therapy (25 mg/d) to be an effective strategy for substantially reducing acitretin-associated adverse effects. Many adverse effects associated with acitretin therapy are dose dependent and can limit the usefulness of this potentially beneficial therapy.

Acitretin↗
PubMed2006

The negative impact of psoriasis on the workplace.

BACKGROUND: The health-related quality of life and economic impact of psoriasis has been documented. However, the negative impact of psoriasis on the workplace is poorly understood. AIM/METHODS: Through anonymous surveys from 30 subjects of each of three psoriasis severity groups we aim to quantify the workplace impact experienced by psoriasis patients and factors that may contribute to this impact. Data were collected using several previously validated measures including the Work Productivity Assessment Index (WPAI), SF-8, Hospital Anxiety and Depression (HADS) and past medical/psoriasis history. RESULTS: Psoriasis patients experienced negative impact at work as measured by the WPAI; this impact is directly associated with disease severity. The other instruments confirmed the negative impact of psoriasis though the degree of impact did not always correlate with disease severity or work impact. Owing to the relatively small numbers, the significance of these findings is not certain. CONCLUSIONS: This preliminary study finds that psoriasis is associated with a reduction in work productivity and social functioning; this may explain the relatively high cost of this disease on both a macro- and microeconomic level. As there was a lack of significant trends in this study, formal inferences are limited and further investigation is warranted.

Adult↗
PubMed2006

Novel combination regimens: biologics and acitretin for the treatment of psoriasis-- a case series.

Combination therapy has long been a mainstay of psoriasis treatment, particularly for those that suffer from moderate-to-severe disease. The biologics represent a new and exciting approach to psoriasis treatment though their use in combination regimens has not been adequately examined. This brief series reports on the combination of biologics with acitretin in the treatment of psoriasis.

Acitretin↗
PubMed2006

The cost-effectiveness and cost of treatment failures associated with systemic psoriasis therapies.

BACKGROUND: Psoriasis is difficult at times to treat and treatment failures are not uncommon regardless of approach. With the advent of expensive biologic therapies for psoriasis there is increasing discussion on the cost efficacy of a given systemic or biologic agent. An alternative and overlooked aspect of cost efficacy is the cost that accrues from treatment failures. METHODS: We review the literature and develop a model to analyze the cost-effectiveness and the cost of treatment failures per success for various systemic psoriasis agents using a 12-week treatment period. RESULTS: For continuous-dose agents, the cost-effectiveness results are: methotrexate $623, acitretin $2729, cyclosporine $2969, nUVB $3692, PUVA $4668, etanercept $16 312, and efalizumab $17 196. The cost of expected treatment failures to achieve one success for the same agents were: methotrexate $187, cyclosporine $505, PUVA $767, nUVB $1034, acitretin $1310, etanercept $8319, and efalizumab $12 897. CONCLUSIONS: Methotrexate appears to be the most cost-effective agent for the treatment of severe psoriasis. However, greater efficacy can be achieved with cyclosporine and PUVA, albeit at a greater cost. Because of the high cost of treatment failures, access to a wide array of therapies and combination regimens should not be discouraged by physicians or insurers.

Cost-Benefit Analysis↗
PubMed2006

New treatments for psoriasis: which biologic is best?

Psoriasis is a chronic, debilitating disease affecting not only the skin, but also having a significant impact on a patient's quality of life. The treatment of severe psoriasis is quite challenging due to the chronic, relapsing nature of the disease and the difficulties inherent in treatment planning. Though the biologics are perhaps the most promising of available psoriasis treatments, the decision to institute a given therapy may be fraught with complexity for the clinician. Patients now hear of these promising new treatments for psoriasis via print, television and radio advertising; they frequently come to their physician asking if they are eligible for any of these agents and, if so, 'which biologic is best?'. This paper attempts to determine the ideal biologic agent based upon several parameters: FDA- and EU-approved indications, therapeutic efficacy, impact on quality of life, cost-effectiveness, and safety profile. Certainly the physician is central to medical decision-making, though ultimately patient preference may play the largest role in determining the 'best' biologic agent. There is no single ideal biologic for all patients and a physician's job is to educate patients on the relative advantages and disadvantages of each agent. Through informed discussion, the clinician can help each individual patient decide which biologic agent is ideal for them.

Adalimumab↗
PubMed2006

Trends in on and off-label calcipotriene use.

Following its introduction in 1994, calcipotriene quickly became the single most prescribed medication for psoriasis according to National Ambulatory Medical Care Survey (NAMCS) data. Primarily through regulation of cellular differentiation, calcipotriene may be effective in dermatoses other than psoriasis. We characterize the clinical trends in the utilization of calcipotriene by analyzing a representative sample of visits to US physicians. Demographic characteristics, specialty of the provider, and off-label uses are reported. Calcipotriene was mentioned at 5.8 million of all NAMCS visits during the study period. Nearly 57% of mentions of calcipotriene were not linked to a diagnosis of psoriasis. Adjusted use for gender and race were relatively stable; there was a rise in non-psoriasis uses and use among non-dermatologists in 1997. Our findings support previous reports of the utility of calcipotriene in treating other dermatoses as witnessed by the numerous conditions for which its use was observed. Physicians and policy-makers should be aware of the role that this medication plays in the delivery of dermatologic care.

Calcitriol↗
PubMed2006

Death from psoriasis: representative US data.

OBJECTIVES: Psoriasis can be associated with severe, life-threatening exacerbations. We sought to approximate the mortality associated with hospitalizations for psoriasis. MATERIALS AND METHODS: We analyzed data from two sources to estimate a death rate associated with psoriasis. RESULTS: There were 471 hospital admissions for psoriasis from 1988 to 2001 with a corresponding mortality rate of 1.5%. Documented on nationwide death certificates, there were a total of 29, 33, and 25 deaths attributable to psoriasis in 2001, 2000, and 1999, respectively. CONCLUSIONS: Though effective therapies for severe psoriasis are available, access to them is not guaranteed. It is disturbing to think that the deaths observed here could, at least in part, be prevented with the appropriate use of treatments.

Adult↗
PubMed2006

Critical factors determining the potency of topical corticosteroids.

The vasoconstrictor assay is a highly reliable method used to determine the bioequivalence of topical corticosteroid preparations. By assessing skin blanching, the assay describes the delivery of the active agent through the skin barrier, intrinsic activity at the receptor, and the rate of clearance from the site of application. Vasoconstrictor rankings are generally good predictors of efficacy in clinical trials. Vasoconstrictor assays are not as predictive of outcomes in clinical practice because these assays do not account for a critical factor: how well patients use the medication. Patient compliance plays a vital role in corticosteroid potency.

Administration, Cutaneous↗
PubMed2006

Adverse events from systemic therapies for psoriasis are common in clinical practice.

BACKGROUND: Patients with moderate-to-severe psoriasis frequently require systemic treatment and these medications may be associated with adverse effects. Little is known about the frequency of these events when systemic agents are used in true clinical practice. OBJECTIVE: To determine the frequency of adverse events associated with various systemic psoriasis therapies. METHODS: A retrospective chart review of 753 patients treated in an academic dermatology practice was performed to identify the frequency of adverse events. Poisson regression was used to estimate the odds of significant events for each systemic therapy; UVB-treated patients served as a control population. RESULTS: Methotrexate seemed to be the most prescribed medication. Adverse events were noted with all forms of systemic psoriasis therapy. The highest event rate was seen with oral retinoids, though most of these were considered minor (64%). Cyclosporine had the highest significant adverse event rate (0.9 events/patient). For 'significant' adverse events, oral agents had an adjusted odds ratio>6 compared to standard UVB therapy. The highest risk was for cyclosporine (OR = 20.3); however, the estimate was imprecise (95% confidence interval [4.3, 96.6]). CONCLUSIONS: Traditional psoriasis therapies are associated with significant adverse events in some patients despite toxicity-sparing approaches such as combination therapy. Clinicians need to be aware of screening for adverse events in order to best ensure the safety of their patients and to maximize the efficacy of a given agent. There is still a need for the development of safe and effective treatments for patients with moderate-to-severe psoriasis.

Adult↗
PubMed2006

Psoriasis treatment in the United States at the end of the 20th century.

BACKGROUND: Psoriasis presents many management complexities. A cornerstone of therapy has been topical corticosteroids, although over the past 10 years there have been many additions to the medication armamentarium. Furthermore, various combination regimens and approaches have been advocated. OBJECTIVE: We sought to characterize various patterns of psoriasis health care delivery and the changes associated with these patterns from 1990 to 2001. METHODS: Visits for psoriasis were identified using National Ambulatory Medical Care survey data, a representative survey of visits to physician offices in the United States. We determined basic demographic characteristics, specialty of the physician provider and medications listed at these visits over the 1990-2001 interval. RESULTS: There were more than 13.5 million visits for psoriasis during the 12-year study period. Dermatologists were responsible for the majority of the visits over the study interval (82%) although there was an overall decline in the proportion of psoriasis visits to dermatologists. As a category, the most common medications used for psoriasis were topical steroids. Topical calcipotriene was the single-most listed medication. There was no observed use of non-corticosteroid topical agents at visits to non-dermatologists. Non-dermatologists were as likely as dermatologists to list a systemic medication at a visit as well as use a systemic as monotherapy. DISCUSSION: In conclusion, the primary topical therapies for psoriasis remain clobetasol and calcipotriene. The decreasing role of dermatologists in the treatment of psoriasis is probably a complex issue, but may relate in part to the difficulty of obtaining access to dermatology care.

Administration, Topical↗
PubMed2005

AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and nonengrafters. FLT3 internal tandem duplication (ITD) and nucleophosmin mutations occurred at a similar frequency in engrafters and nonengrafters. The only variable that was related to engraftment ability was the karyotypically defined risk stratification of individual AML cases. Of interest, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID engrafting and nonengrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning, or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and nonengrafting AML cases that correlates with treatment response.

Age Factors↗
PubMed2005

Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia.

Human hematopoietic stem cells (HSCs) are generally regarded as being devoid of the markers expressed by differentiated blood cells, the lineage-specific antigens. However, recent work suggests that genes associated with the myeloid lineage are transcribed in mouse HSCs. Here, we explore whether myeloid genes are actually translated in human HSCs. We show that CD33, CD13, and CD123, well-established myeloid markers, are expressed on human long-term repopulating cells from cord blood and bone marrow. In addition, we demonstrate that nonobese diabetic/severe combined immunodeficiency (NOD/SCID) leukemia-initiating cells (SL-ICs) are restricted to the CD33+ fraction in 11 of 12 acute myeloid leukemia (AML) samples studied, indicating that leukemic stem cells (LSCs) express this antigen. This study changes our view of HSCs and the process of differentiation. Furthermore, based on the phenotypic similarity of HSCs and LSCs, our data provide support for the hypothesis that AML derives from an HSC. Our findings also provide a challenge to contemporary attempts to improve the outcome of AML using myeloid antigen-targeted therapies, given the potential for HSC killing.

Animals↗
PubMed2005

Medication-related factors affecting health care outcomes and costs for patients with psoriasis in the United States.

BACKGROUND: The impact of psoriasis medication therapy on costs and patient outcomes in large nationally representative samples needs further examination. OBJECTIVE: This study examined the association between factors related to medication use, health status, and health care costs associated with psoriasis in the United States. METHODS: A cross-sectional cohort study was performed using the 2000 Medical Expenditure Panel Survey database. Information on health care service use, health status (EuroQol-5D instrument), and patient demographics were obtained from the database representing approximately 1.1 million patients with psoriasis. EuroQol was used in the Medical Expenditure Panel Survey. RESULTS: Weighted multiple linear regression analysis indicated that use of topical corticosteroid therapy was associated with a decrease in psoriasis-specific health care costs (53.2% lower than average costs vs patients using no medications, P = .022) and better health status (34.0% higher than average scores vs patients using no medications, P = .006). CONCLUSIONS: We observed an association with topical corticosteroids for treatment of psoriasis on health care outcomes and costs.

Administration, Topical↗
PubMed2005

The impact of biologics on the quality of life of psoriasis patients and the economics of psoriasis care.

Psoriasis has a tremendous impact on patients' lives, affecting them physically, psychologically, and socially. Thus, it is not merely a cosmetic concern and often warrants appropriately aggressive treatment. Traditional treatments for moderate-to-severe psoriasis include phototherapy, oral retinoids, methotrexate, and cyclosporine. Newer biologics combat the immunologic mechanism responsible for psoriasis and, to date, carry a more favorable side effect profile. We examined the impact on quality of life of biologics and assessed their total direct costs to psoriasis patients. Biologic treatments significantly improve the quality of life of psoriasis patients; however, they cost significantly more than traditional therapies. This difference calls for physicians to weigh the costs and benefits of biologic therapies and compare them to those of traditional treatments when considering care for psoriasis patients.

Biological Products↗