bluuebunny/crossref_metadata_2025_split huggingface dataset:
rHuEPO and Treatment Outcomes: The Preclinical Experience
Authors: Ludwig Heinz 
Published: December 2004

Abstract

Learning Objectives
After completing this course, the reader will be able to:
Discuss some of the animal model systems that have been used to understand the effects of erythropoietin on cancer treatment. Describe the effects of hypoxia on treatment end points in animal model systems. Discuss our evolving understanding of the effects of erythropoietin on the immune system.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit atCME.TheOncologist.com
The presence of hypoxic areas is a common feature of solid tumors and has been associated with decreased sensitivity of the tumors to radiation therapy and oxygen-dependent chemotherapeutic agents, as well as worsened outcomes, including survival. Anemia is also common in cancer patients and is believed to contribute to tumor hypoxia. Thus, the rationale exists for administering recombinant human erythropoietin (rHuEPO, epoetin alfa) in an effort to increase hemoglobin levels, correct anemia, and thereby possibly increase the sensitivity of tumors to standard cancer treatment and improve patient outcomes. The results of several preclinical studies that examined the impact of anemia prevention by rHuEPO on tumor sensitivity to radiation therapy in rodent models of cancer showed that induction of anemia increased hypoxia in tumor cells and that correction of anemia with rHuEPO could improve tumor oxygenation. Further studies in rodent models showed significantly delayed tumor growth in both irradiated mice and irradiated rats treated with rHuEPO. In those studies, the increased radiosensitivity observed was believed to be due to improved tumor oxygenation following the correction of anemia. Similarly, enhancements in chemosensitivity were found in rHuEPO-treated rodent models. In the chemosensitivity studies, as in the radiosensitivity studies, the therapeutic benefit obtained was believed to reflect improved tumor oxygenation subsequent to an rHuEPO-related increase in oxygen availability. One study evaluated the potential biologic effects of epoetin alfa on tumor progression using murine myeloma models (MOPC-315 and 5T33 MM). Treatment of MOPC-315 tumor-bearing mice with epoetin alfa induced complete tumor regression in 30%–60% of mice. Regression was found to be tumor specific, and the effect of epoetin alfa was shown to be T-cell mediated. Additionally, epoetin alfa administration prolonged survival and reduced morbidity and mortality in the 5T33 MM tumor model. Those investigators suggested that epoetin alfa may have antitumor activity in addition to its hematopoietic effects. Overall, these preclinical findings suggest that correction of anemia by rHuEPO can increase tumor sensitivity to both radiation therapy and chemotherapy and that epoetin alfa may exert an immunomodulatory effect in multiple myeloma.
Microbiological Condition of Urban Groundwater in the Vicinity of Leaky Sewer Systems
Authors: Paul Miriam , Wolf Leif , Fund Katharina , Held Inka , Winter Josef , Eiswirth† Matthias , Gallert Claudia , Hötzl Heinz 
Published: December 2004

AbstractThe possible deterioration of the microbiological quality of groundwater due to leaky sewer systems was investigated in a medium‐sized city (Rastatt) in SW‐Germany. Specially constructed focus observation wells drilled close to leaky sewers have been compared with the background observation wells in urban and rural areas.The sampling was performed in March (shallow depth of groundwater) and in July and October (deep groundwater table). It included the measurement of ammonium ions, temperature, electric conductivity, oxygen, and the depth of the groundwater table. Coliforms, Escherichia coli, and enterococci were enumerated as indicator organisms for wastewater contamination. In addition, the total number of colony forming units was determined.Bacterial counts of coliforms and E. coli generally increased during the course of the investigation (March to October). This may have been caused either by a slightly increased groundwater temperature (higher activity rates) or by a higher proportion of sewage in the urban groundwater system as a result of the dry season (summer). The contamination with faecal indicator bacteria was greater adjacent to leakage locations. In addition, elevated concentrations of ammonium ions were observed at these areas. The results provide evidence that leaky sewer systems elevate faecal indicator concentrations in groundwater with associated potential health risk where such waters are used for potable water supply.
Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti–cyclic citrullinated peptide antibody
Authors: Mikuls T. R. , O'Dell J. R. , Stoner J. A. , Parrish L. A. , Arend W. P. , Norris J. M. , Holers V. M. 
Published: December 2004

AbstractObjectiveTo examine the association of treatment response and disease duration with changes in rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti‐CCP) antibody levels among patients with rheumatoid arthritis (RA).MethodsThe study sample included 66 RA patients who completed double‐blind, randomized clinical protocols and for whom baseline and followup serum samples were available. Anti‐CCP and RF levels were measured using commercially available assay kits. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the association of response and disease duration with declines in antibody levels.ResultsPatients had a mean ± SD age of 49.9 ± 12.0 years and were predominantly female (n = 51; 77%). The mean ± SD duration between the times at which the baseline and followup serum samples were obtained was 13.7 ± 8.6 months. Among the 64 subjects with positive antibody at baseline, 33 (52%) experienced a ≥25% reduction in the anti‐CCP antibody level during the course of treatment, and 35 patients (55%) had a ≥25% reduction in RF. After adjustment for the baseline anti‐CCP antibody level, only a shorter disease duration (≤12 months) was significantly associated with a decline in the level of anti‐CCP antibody (OR 3.0, 95% CI 1.0–8.8), and no association with treatment response was observed. Conversely, treatment response was the only significant determinant of a decrease in RF levels (OR 3.6, 95% CI 1.2–10.4).ConclusionShorter disease duration predicts greater declines in anti‐CCP antibody levels with treatment in RA. Although treatment response is a robust determinant of a decrease in RF, it does not appear to be associated with declines in the anti‐CCP antibody level.
Efficacy and tolerability of a selective α2C‐adrenergic receptor blocker in recovery from cold‐induced vasospasm in scleroderma patients: A single‐center, double‐blind, placebo‐controlled, randomized crossover study
Authors: Wise Robert A. , Wigley Fredrick M. , White Barbara , Leatherman Gwen , Zhong Jianhua , Krasa Holly , Kambayashi Jun‐ichi , Orlandi Cesare , Czerwiec Frank S. 
Published: December 2004

AbstractObjectiveOPC‐28326 is a selective α‐adrenergic antagonist with preferential binding to the α2C‐adrenergic receptor (α2C‐AR) subtype. This study observed the effect of OPC‐28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma.MethodsThe study was designed as a single‐center, double‐blind, placebo‐controlled, randomized, 3‐period crossover study of OPC‐28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature.ResultsTwelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC‐28326 40‐mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P = 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P = 0.01]). These recovery times tended to be shorter in the 10 mg OPC‐28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P = 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P = 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC‐28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug‐related were reported more frequently with 40 mg OPC‐28326 than with 10 mg OPC‐28326 or with placebo, but none were serious or sustained.ConclusionOPC‐28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC‐28326 suggests that selective α2C‐AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.
A shift in the balance of inhibitory and activating Fcγ receptors on monocytes toward the inhibitory Fcγ receptor IIb is associated with prevention of monocyte activation in rheumatoid arthritis
Authors: Wijngaarden Siska , van de Winkel Jan G. J. , Jacobs Kim M. G. , Bijlsma Johannes W. J. , Lafeber Floris P. J. G. , van Roon Joel A. G. 
Published: December 2004

AbstractObjectiveTo assess surface expression of the inhibitory receptor for IgG (Fcγ receptor IIb [FcγRIIb]) in relation to activating FcγR on monocyte/macrophages from patients with rheumatoid arthritis (RA) and healthy controls and to study the influence of proinflammatory and antiinflammatory cytokines on the balance of inhibitory and activating FcγR.MethodsUsing a combination of genotyping and phenotyping, surface expression of FcγRIIb on monocytes from healthy control subjects and RA patients was demonstrated. Expression of FcγR on CD14+ monocytes was assessed by flow cytometry. Regulation of inhibitory and activating FcγR on monocytes by proinflammatory (interferon‐γ [IFNγ], tumor necrosis factor α [TNFα]) and antiinflammatory (interleukin‐4 [IL‐4], IL‐10) cytokines was studied. A functional change in cytokine‐modulated monocytes was assessed in secondary cultures by their ability to produce TNFα upon FcγR crosslinking by IgG.ResultsMonocytes from healthy controls and RA patients expressed FcγRIIb at similar levels, in contrast to the higher levels of activating FcγRI and FcγRIIa in RA patients. The regulation of FcγR expression was comparable for patients and controls. IFNγ selectively up‐regulated FcγRI. TNFα down‐regulated expression of FcγRIIb and the activating FcγR, whereas IL‐10 up‐regulated expression of monocytic FcγRIIb and all activating FcγR. Increased or sustained levels of activating over inhibitory FcγR induced by IFNγ, TNFα, and IL‐10 alone were associated with enhanced IgG‐triggered TNFα production. In contrast, IL‐4 and, more specifically, IL‐4 plus IL‐10 altered the FcγR balance in favor of FcγRIIb and completely prevented IgG‐triggered TNFα production.ConclusionThe altered balance of FcγR in favor of activating receptors in RA may contribute to increased activation of monocyte/macrophages. A change in the FcγR balance toward the inhibitory FcγRIIb may offer a novel treatment strategy for preventing the pleiotropic activity of FcγR‐triggered macrophages.
Assessment of the efficacy of different statins in murine collagen‐induced arthritis
Authors: Palmer Gaby , Chobaz Véronique , Talabot‐Ayer Dominique , Taylor Sophia , So Alexander , Gabay Cem , Busso Nathalie 
Published: December 2004

AbstractObjectiveHydroxymethylglutaryl‐coenzyme A reductase inhibitors (statins) are widely used lipid‐lowering agents. In addition to their well‐known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen‐induced arthritis, a well‐described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model.MethodsDifferent doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols.ResultsAtorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti–type II collagen IgG production), and biochemical (interleukin‐6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels.ConclusionThis work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune‐mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.
Effect of intermittent administration of human parathyroid hormone on bone mineral density and arthritis in rats with collagen‐induced arthritis
Authors: Fukata Satoru , Hagino Hiroshi , Okano Toru , Yamane Itsuro , Kameyama Yasuhiro , Teshima Ryota 
Published: December 2004

AbstractObjectiveTo investigate the effect of intermittent administration of human parathyroid hormone (PTH) on bone mineral density (BMD) and arthritis in rats with collagen‐induced arthritis (CIA).MethodsSeven‐month‐old female Sprague‐Dawley rats were divided into 4 groups: rats without CIA (control), rats with CIA treated with vehicle, rats with CIA treated with PTH for 4 weeks, and rats with CIA treated with PTH for 6 weeks. PTH (20 μg/kg) was injected subcutaneously 3 times per week. BMD in the proximal metaphysis and the diaphysis of the tibia was measured by peripheral quantitative computed tomography every 2 weeks until week 8. Eight weeks after initial sensitization, the animals were killed, and the BMD and mechanical properties of excised limbs were evaluated. Histomorphometric analysis of tibiae and histologic evaluation of arthritis were also performed.ResultsIn the PTH‐treated rats with CIA, the incidence and severity of arthritis were macroscopically and histologically similar to the findings in the vehicle‐treated rats with CIA. The decrease of BMD caused by CIA was suppressed by treatment with human PTH, in a manner that was dependent on the duration of administration. In the histomorphometric analysis, bone formation parameters were higher and bone resorption parameters were lower in the PTH‐treated arthritic rats compared with vehicle‐treated arthritic rats. Mechanical properties were also maintained in the PTH‐treated rats.ConclusionOur findings indicate that, in an animal model of arthritis, intermittent PTH administration activates bone formation, resulting in increased BMD and preventing deterioration of mechanical properties. However, PTH has no effect on the arthritis itself.
Enhanced generation of endothelial cells from CD34+ cells of the bone marrow in rheumatoid arthritis: Possible role in synovial neovascularization
Authors: Hirohata Shunsei , Yanagida Tamiko , Nampei Akihide , Kunugiza Yasuo , Hashimoto Hideo , Tomita Tetsuya , Yoshikawa Hideki , Ochi Takahiro 
Published: December 2004

AbstractObjectiveTo examine the capacity of bone marrow CD34+ cells to generate endothelial cells, in order to assess the role of bone marrow in neovascularization in the synovium of rheumatoid arthritis (RA).MethodsCD34+ cells purified from the bone marrow of 13 patients with active RA and 9 control subjects (7 osteoarthritis [OA] patients and 2 healthy individuals) were cultured in the presence of stem cell factor (10 ng/ml) and granulocyte–macrophage colony‐stimulating factor (1 ng/ml). After 18 days of incubation, the generation of endothelial cells was assessed by flow cytometry. The generation of endothelial cells was compared with the degree of vascularization in the synovial tissues and with the microvessel densities in the synovium, as determined by microscopy. The expression of vascular endothelial growth factor receptor 2/kinase insert domain receptor (KDR) messenger RNA (mRNA) in CD34+ cells was examined by quantitative reverse transcription–polymerase chain reaction.ResultsThe generation of CD14+ cells from bone marrow–derived CD34+ cells from RA patients was comparable to that from control subjects. However, the generation of von Willebrand factor (vWF)–positive cells and CD31+/vWF+ cells from RA bone marrow–derived CD34+ cells was significantly higher than that from control subjects (P = 0.004 and P = 0.030, respectively). The generation of vWF+ cells from bone marrow CD34+ cells correlated significantly with the microvessel densities in the synovial tissues (r = 0.569, P = 0.021). Finally, RA bone marrow CD34+ cells expressed KDR mRNA at higher levels than OA bone marrow CD34+ cells.ConclusionThese results indicate that RA bone marrow CD34+ cells have enhanced capacities to differentiate into endothelial cells in relation to synovial vascularization. The data therefore suggest that bone marrow CD34+ cells might contribute to synovial neovascularization by supplying endothelial precursor cells and, thus, play an important role in the pathogenesis of RA.
Childhood‐onset osteoarthritis, tall stature, and sensorineural hearing loss associated with Arg75‐Cys mutation in procollagen type II gene (COL2A1)
Authors: Löppönen Tuija , Körkkö Jarmo , Lundan Tuija , Seppänen Ulpu , Ignatius Jaakko , Kääriäinen Helena 
Published: December 2004

AbstractObjectiveTo define the clinical, radiologic, and molecular genetic characteristics of a family with early progressive osteoarthritis mimicking childhood rheumatoid arthritis, Scheuermann‐like changes of the spine, tall stature, short 3 and 4 metatarsals, and moderate sensorineural hearing loss.MethodsWe describe a 22‐year‐old woman and her 54‐year‐old mother with early progressive osteoarthritis mimicking childhood rheumatoid arthritis. The index case, her mother, and 3 other family members underwent a physical examination, anthropometric measurements, and radiologic studies. Their DNA was sequenced for the procollagen type II (COL2A1) gene.ResultsMild scoliosis was noticed in the proband at the age of 6 years, and at the age of 7 years large Schmorl's nodes were found in the vertebrae L1‐2. At the age of 11 years, changes resembling Scheuermann's disease were seen, mostly in the thoracic vertebrae. At the same age, she began to have arthralgia in the weight‐bearing joints and osteoarthritis progressed fast, necessitating a hip prosthesis at the age of 18 years. The proband and her mother had bilateral sensorineural hearing loss of moderate degree. Both mother and daughter had an Arg75‐Cys mutation in the COL2A1 gene.ConclusionThis family is the fourth example of the Arg75‐Cys mutation in the COL2A1 gene, which appears to lead to a clearly recognizable phenotype. The finding suggests that sensorineural hearing loss may be a part of this syndrome.
Beer, liquor, and wine consumption and serum uric acid level: The Third National Health and Nutrition Examination Survey
Authors: Choi Hyon K. , Curhan Gary 
Published: December 2004

AbstractObjectiveTo evaluate the relationship between intakes of beer, liquor, and wine and serum uric acid levels in a nationally representative sample of men and women.MethodsUsing data from 14,809 participants (6,932 men and 7,877 women) age ≥20 years in The Third National Health and Nutrition Examination Survey (1988–1994), we examined the relationship between intakes of beer, liquor, and wine and serum uric acid levels. Alcohol intake was assessed by a food frequency questionnaire.ResultsSerum uric acid levels increased with increasing beer or liquor intake but not with increasing wine intake. After adjusting for age, the difference in serum uric acid levels as compared with no intake increased with increasing beer or liquor intake (P values for trend < 0.001), but the association was inverse with increasing wine intake (P for trend < 0.001). After adjusting mutually for these alcoholic beverages and for other risk factors for hyperuricemia, including dietary risk factors, the associations were attenuated but remained significant for beer or liquor (multivariate difference per serving per day 0.46 mg/dl [95% confidence interval {95% CI} 0.32, 0.60] and 0.29 mg/dl [95% CI 0.14, 0.45], respectively; both P values for trend <0.01), but not for wine (0.04 mg/dl [95% CI −0.20, 0.11]; P for trend = 0.6).ConclusionThese data suggest that the effect of individual alcoholic beverages on serum uric acid levels varies substantially: beer confers a larger increase than liquor, whereas moderate wine drinking does not increase serum uric acid levels.
Managing arthritis and employment: Making arthritis‐related work changes as a means of adaptation
Authors: Gignac Monique A. M. , Badley Elizabeth M. , Lacaille Diane , Cott Cheryl C. , Adam Paul , Anis Aslam H. 
Published: December 2004

AbstractObjectiveTo understand arthritis‐related workplace changes, including occasional work loss and changes to the type and hours of work, and the factors associated with them using theories of adaptation and behavior change as a framework.MethodsParticipants were 492 employed individuals with rheumatoid arthritis or osteoarthritis. They completed an interview‐administered, structured questionnaire assessing demographic, workplace, and psychosocial variables, as well as such work transitions as changes to the hours, type, and nature of work. Hypotheses were examined using multiple linear regression.ResultsSeventy percent of respondents made at least 1 work change. Younger participants and those with greater workplace activity limitations reported more changes. Work changes were associated with greater depression. A hypothesized 3‐way interaction among people's perceptions of their capacity, their future job expectations, and whether they had told their employer about their arthritis was significant.ConclusionThis study extends arthritis employment research by examining a range of work changes. It highlights the dynamic interplay among arthritis, workplace, and psychosocial variables to understand adaptation to arthritis disability.
Cardiac risk factor awareness and management in patients with systemic lupus erythematosus
Authors: Costenbader Karen H. , Wright Elizabeth , Liang Matthew H. , Karlson Elizabeth W. 
Published: December 2004

AbstractObjectiveTo assess awareness and management of traditional cardiac risk factors (CRFs) in patients with systemic lupus erythematosus (SLE) and physicians.MethodsSLE patients (n = 110) completed a questionnaire concerning CRFs. Medical records were reviewed blinded to questionnaire results for the presence and management of 6 CRFs: hypertension, hypercholesterolemia, smoking, obesity, diabetes mellitus, and physical inactivity.ResultsSubjects were predominantly female (97%), mean (±SD) age was 43.4 years (±11.8), mean SLE duration was 15.3 years (±7.2), and 51% had ≥2 CRFs by self report. Twenty‐three percent had never had their cholesterol levels checked. Hypercholesterolemia was more frequently documented in the medical records than reported by the patient (33% versus 24%). Physical inactivity was more frequently self reported than documented (59% versus 23%). Rheumatologists and patients had low interrater reliability for the presence of hypercholesterolemia (κ = 0.26) and physical inactivity (κ = –0.02). More than half (58%) of CRFs were treated, and 21% of subjects with elevated cholesterol received a medication.ConclusionRecognition, recording, and management of CRFs falls short given the significance of the problem.