SF Levels Research Articles

Deferasirox for the Treatment of Transfusional Iron Overload In Sickle Cell Anemia: a 2-Yr Prospective Study

AbstractAbstract 5148 Background:Majority of patients with sickle cell disease receive repeated blood transfusions by adulthood. Because the body has no physiological mechanism to actively excrete excess iron, chelation therapy is important for the management of iron overload and its complications, including iron deposition into the liver, heart and endocrine organs, eventual death. Deferasirox (DFX) is a once-daily, oral iron chelator that is approved as first-line treatment of chronic transfusional iron overload. Its safety, tolerability and efficacy in reducing body iron burden have been demonstrated in patients with β-thalassaemia major and in other chronic transfusion-dependent anaemias, including SCD. Aims and Methods:Objectives of this prospective, non-randomised, phase IV trial were to evaluate the iron overload status, before and after two year-treatment with DFX, using liver iron concentration [LIC, mg/d dry weight (dw)] by magnetic resonance imaging (MRI) hepatic, MRI cardiac (Cardiac T2*, ms), serum ferritin (SF, μ g/L), and to evaluate the safety and tolerability of DFX. Results:A total of 31 patients with SCD and iron overload, defined as the use of ≥ 20 units of RBC units and/or two SF levels ≥ 1000 μ g/L during the 6 months preceding enrollment, received starting dose of 20mg/kg/day of DFX. Efficacy was assessed monthly by measuring change from baseline in SF levels. Safety was evaluated on a monthly basis according to the incidence and type of adverse events and measurement of laboratory parameters, including serum creatinine and liver enzyme levels. Two patients discontinued treatment at 8 and 9 months, due to pregnancy and moving to other city, respectively. One patient died at 18 months due to pulmonary infection and hemorrhagic stroke. DFX was interrupted in 3 patients due to confirmed SF levels <500 μ g/L at 18-month period of treatment and DFX was not reinstated in none of them during the final 6 months of study. Twenty-five patients completed 2-year treatment. Mean ± SD age 26.9 ± 12.5y; 84% female, 90% afrodescendent, 61.3% on regular blood transfusion; median (range) DFX dose over 24 months and DFX exposure were 20 mg/kg/day (15-25) and 90.5 weeks (35.6-98.0), respectively. Mean SF level (μ g/L) did not significantly reduced at 12 months (p=0.052) but significantly dropped at 24 months compared to baseline [from 2344.6 to 1986.3 (p=0.040)]. Mean ± SD LIC significantly dropped at 12 months and at 24 months compared to baseline [from 13.0 ± 5.4 to 10.4 ± 6.3 (p=0.001) and to 9.3 ± 5.7 (p<0.001), respectively]. The proportion of patients with LIC levels (mg/g dw) ≤7.0, >7.0- ≤14.0 and >14.0 from baseline to 24 months by percentage of patients changed from 13.6% to 44.0%, 40.9% to 44.0% and 45.5% to 12.0%, respectively. In all patients, Cardiac T2* was normal (> 20 ms) at baseline, 12 and 24 months of treatment. There was no significant difference between left ventricular ejection fraction values at baseline and after 12 months but this parameter significantly increased at 24 months of treatment compared to baseline [from 62.2 ± 6.0 to 64.6 ± 6.2 (p=0.02)]. The most common drug-related AEs were mild, transient diarrhea (7 pts), headache (7), nausea (5), vomiting (3), skin rash (2), increases in ALT (2), serum creatinine increases that exceeded the ULN (2). No patient experienced progressive increases in serum creatinine or renal failure. Conclusions:Our data confirms that deferasirox is effective in reducing body iron burden in transfused patients with SCD, well tolerated in pediatric and adult patients and with a clinically manageable safety profile. The availability of deferasirox as a once-daily, oral iron chelator would potentially facilitate improved compliance, and thereby reduce morbidity and mortality from iron overload. Disclosures:No relevant conflicts of interest to declare.

Abstract 881: Clinical usefulness of soluble fibrin monomer-fibrinogen complex (SFMC) for the metastasis of malignant neoplasm

Abstract Objective: SF is a complex coupling fibrin monomer and fibrinogen molecules to be formed in the early-activated state of blood coagulation. The level of SF reflects the thrombin generation activity in plasma. There is increasing evidence that SFMC is expected to serve as a parameter for thrombus formation and DIC, in particular its early stage. Thrombin generation is activated in the metastasis of malignant neoplasm, The aim of this study is to determine whether the SF could be a new marker for the metastasis of malignant neoplasm. Material and Methods: From 2007 to 2008, a total of 86 patients who underwent radical surgery for treatment to the cancer of digestive organs (including cancer of esophagus, stomach, colon, rectum, liver, biliary tract, and pancreas) were enrolled in this study. We measured SF together with established tumor markers before the surgery and every three months after the surgery. Each of them was compared with imaging tests such as CT scan, ultrasounds, MRI, PET-CT, GIF, and CF. Results: There were not admitted the rise of SF neither before nor after surgery in the case of stage1 and 2. No metastasis was admitted with the imaging tests in the cases of stage1 and 2, either. In the cases of stage3 and 4, there were some cases with the rise of SF before the surgery. The decrease of SF and tumor markers were admitted in the cases of excising the radical cure. SF was not high in the some cases with relapse or metastasis which condition was considered to be suppressed by chemotherapy and radiotherapy. Moreover, the rise of SF was admitted in all samples in the case of multiple liver metastasis and multiple peritoneal dissemination. Conclusions: Though this study suggests that SF could be a parameter for the condition of metastatic malignant neoplasm, it has not been systematically studied whether SF is useful for early detection of metastasis and relapse or not. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 881.

Functional significance of nerve growth factor and its receptor (TrkA) in inflammatory arthritis

We read the article by Barthel and colleagues [1] in this is sue of Arthritis Research & Th erapy with great interest. Th ey reported that neurotrophin receptors/ligands and specifi cally nerve growth factor (NGF) and NGF receptor (NGF-R) (TrkA and p75) are expressed in synovial fl uid (SF) cells and synovial tissue (ST) of patients with rheuma toid arthritis (RA) or spondyloarthritis (SpA). Th e authors also looked for the cellular source of NGF and demonstrated that the T cells and monocytes/macrophages derived from SF of patients with RA/SpA are enriched with NGF. Furthermore, they reported that STderived fi broblast-like synoviocytes (FLSs) did not produce NGF in vitro. In a recent publication, we observed similarly that NGF levels in SF were signifi cantly higher in patients with psoriatic arthritis (PsA) (365.5 ± 85.2 pg/ mL) or RA (120 ± 35 pg/mL) than in patients with osteoarthritis (OA) (30 ± 6 pg/mL) [2]. However, in regard to the source of NGF, we observed that FLSs produced a signifi cant amount of NGF. Here, we would like to share our observations about the NGF/TrkA system in human FLSs and its function. Synovial biopsies from patients with meniscal injury without any other joint diseases or PsA, OA, or RA were collected. FLSs were isolated and examined for NGF/ NGF-R expression in accordance with our standardized protocols [2]. Using a highly sensitive enzyme-linked immuno sorbent assay (ELISA) for human NGF (NGFEmax assay; Promega Corporation, Madison, WI, USA) and Hi-D fl uorescence-activated cell sorting analyses, we observed that under basal conditions FLSs from healthy individuals express low levels of NGF/TrkA. However, there was a marked upregulation of NGF and TrkA in these FLSs following stimulation with tumor necrosis factor-alpha and interleukin-1-beta (Table 1). A critical observation was that FLSs from patients with PsA or RA produced spontaneously higher levels of NGF and had increased expression of TrkA compared with FLSs of patients with OA (Table 1). Furthermore, we observed that NGF signifi cantly stimulated the proliferation of FLSs derived from PsA synovial tissue (Figure 1). Barthel and colleagues [1] cultured FLSs from only one patient with RA and one patient with SpA and noticed that FLSs did not produce NGF, but the authors do mention that they can’t rule out the production of NGF by FLS. We cultured FLSs from 15 subjects (Table 1), and it is also possible that the NGF ELISA kit that we used is more sensitive. A fully formed pannus is characterized by proliferation of FLSs, infl ammatory infi ltrates, and a marked angiogenesis. NGF and its receptor system are known to

Deferasirox (Exjade®) Treatment of Chelation-Naive and Pre-Chelated MDS Patients with Transfusional Iron-Overload in the Medical Practice:Results From the Observational Studies Extend and Exjange.

Abstract 3805Poster Board III-741 BackgroundRed blood cell (RBC) transfusions on a regular basis are unavoidable in a variety of chronic anemias. Unfortunately, chronic transfusion therapy leads to iron overload (IOL) since the body cannot actively remove excess iron. Transfusional IOL can cause severe organ damage, as exemplified by thalassemia major patients in the past. Many patients (pts) with myelodysplastic syndromes (MDS) also need regular RBC transfusions and are thus threatened by secondary hemochromatosis. Deferasirox (Exjade®), an oral iron chelator taken once-daily, has been shown in several clinical trials to maintain or reduce body iron (assessed by liver iron concentration [LIC] or serum ferritin [SF]) in pts with transfusion-dependent IOL. Here we summarize the results of two post-marketing surveillance studies of previously unchelated (Extend; n=123) and pre-chelated (Exjange; n=44) MDS pts with IOL. Pts were analyzed in the daily-routine setting of office-based physicians. MethodsThe Extend and Exjange observation studies cover 1 year of chelation treatment of iron overloaded, transfusion-dependent MDS pts. Deferasirox was prescribed in accordance with the terms of Exjade marketing authorization in Germany (Fachinformation). No inclusion or exclusion criteria or additional diagnostic or monitoring procedures were applied. Hematological parameters, including SF, and adverse events (AEs) were collected in 2-monthly intervals. Results123 MDS pts (65 M, 58 F; mean age 70.4, range 17.6-90.3 yrs) with a median baseline SF of 2679 (range 184-16500) ng/mL without prior chelation and 44 MDS pts (24 M, 20 F; mean age 69.6, range 42.5-88.5 yrs) with a median baseline SF of 2442 (range 521-8565) ng/mL, mainly pre-chelated with Desferal, were observed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. During treatment, median SF levels clearly decreased from first to final visit [-662.3 ng/ml; p<0.0002 (explorative analysis)] in the chelation-naïve and also in the pre-chelated MDS population [-716.0 ng/ml; p<0.0634 (explorative analysis)]. 64.2% of the Extend MDS pts and 47.7% of the Exjange MDS pts completed the 12 months observation period. Reasons for discontinuation included AEs in 19.5% (n=24) and 25% (n=11), respectively. The most common investigator-assessed drug-related AEs were diarrhea (n=13, 10.6% and n=4, 9.1%), nausea (n=11, 8.9% and n=1, 2.3%), and skin reactions (n=8, 6.5 % and n=2, 4.6%), mainly of mild-to-moderate severity. As in previous clinical trials, serum creatinine values showed a minor increase over the study period (median increase until final visit: 0.2 mg/dL in the Extend and 0.1 mg/dL in the Exjange study). ConclusionsWith deferasirox treatment, SF levels declined significantly over the 1-yr observation period in chelation-naïve MDS pts. A similar reduction was also observed in pre-chelated MDS pts. The safety profile of deferasirox was comparable to that previously reported in clinical trials, with mild-to-moderate diarrhea being the most common drug-related AE. Thus, deferasirox is an effective and safe iron chelator for the treatment of IOL in transfusion-dependent MDS pts in the daily-routine situation. The fact that median baseline levels of SF were around 2500 ng/ml in both the Extend and Exjange studies indicates that in everyday clinical practice MDS patients are started relatively late on iron chelation therapy and tend to be inadequately treated with Desferal. Disclosures:Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Leismann:Novartis: Employment. Nass:Novartis: Employment. Germing:Novartis: Honoraria, Research Funding.

Sandwich ELISA system for cartilage oligomeric matrix protein in equine synovial fluid and serum

Measurement of cartilage oligomeric matrix protein (COMP) in serum has potential for diagnosis of equine osteoarthritis (OA), but clinical use is currently limited by the lack of specificity of an inhibition ELISA as well as by baseline increases due to exercise. Improved methods for ELISA with increased antigen specificity and sensitivity are therefore required for reliable measurement. Measurement of the serum level of COMP by sandwich ELISA allows identification of horses with OA. New monoclonal antibodies (mAbs) were elicited against equine cartilage COMP, their epitopes were determined and a sandwich ELISA was developed. The concentrations of COMP in synovial fluid (SF; n=100) and sera (n=100) from OA cases were measured by sandwich ELISA as well as by inhibition ELISA and compared with concentrations in normal joints (n=95) and horses (n=50). Immunoblots of enzymatically cleaved COMP showed that the new mAbs recognised different epitopes located on a 20 kDa fragment between K63 and K238 of the EGF-like repeats. Inhibition ELISA with any mAb detected significantly increased levels of COMP in OA SF compared with normal SF, whereas no significant difference was detected between serum levels of COMP in OA and normal horses. Conversely, sandwich ELISA with the combination of unlabelled 2A11 x biotinylated 11F10 mAbs detected a significant increase in COMP levels in both serum and SF from OA cases compared with levels in normal animals. Measurement of serum COMP with sandwich ELISA may be useful in identifying horses with OA.

Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluid

Objectives. Lactoferrin is an iron-binding protein that is released from activated neutrophils at sites of inflammation and has anti-microbial as well as anti-inflammatory properties. This study set out to determine whether lactoferrin can delay neutrophil apoptosis and could act as a survival factor for neutrophils in SF.Methods. Human peripheral blood and SF neutrophils were incubated with iron-free lactoferrin and apoptosis determined after 9 h. SF from patients with RA was added to isolated neutrophils, with or without immunodepletion of lactoferrin, and effects on neutrophil apoptosis determined. Levels of lactoferrin in SF were assessed and related to disease duration and markers of disease activity.Results. Iron-free lactoferrin significantly delayed apoptosis of peripheral blood neutrophils, in a concentration-dependent manner after 9 h in culture (P < 0.04). Lactoferrin could also delay apoptosis of neutrophils isolated from SF of patients with RA. SF from patients with established RA delayed apoptosis of peripheral blood neutrophils and this effect was significantly reduced by depletion of lactoferrin (P < 0.03). Lactoferrin levels in SF from patients with established RA did not correlate with disease severity, but did correlate with markers of inflammation (CRP) and with the presence of RF. SF from patients with arthritis of <12 weeks duration did not contain significant levels of lactoferrin.Conclusion. Lactoferrin contributes to extended neutrophil survival in the rheumatoid joint in the established phase of RA but not in very early arthritis.

Deferasirox (Exjade®) in Pediatric Patients with β-Thalassemia: Update of 4.7-Year Efficacy and Safety from Extension Studies

Background: As pediatric patients with β-thalassemia will require lifelong iron chelation therapy, it is important to evaluate the long-term efficacy, safety and growth during treatment with any iron chelator. This analysis presents cumulative efficacy and safety data from a cohort of pediatric patients treated with the once-daily, oral chelator deferasirox during two 1-year core and 4-year extension trials.Methods: β-thalassemia patients aged 2–<16 years with transfusional iron overload were enrolled in two extension studies (107E and 108E) evaluating the long-term safety, tolerability and efficacy (by serum ferritin [SF] levels) of deferasirox; only patients who received deferasirox from the beginning of the core trial are included in this analysis. Deferasirox doses in the extension trials were initially based on end-of-core liver iron concentration, and were adjusted according to trends in SF levels. Efficacy was monitored by monthly SF levels; safety was assessed by the incidence and type of adverse events (AEs) and laboratory parameters.Results: 168 patients (153 patients from study 107 and 15 from study 108) aged 2–<6 (n=30), 6–<12 (n=74) and ≥12–<16 (n=64) years entered the extensions. To date, patients have received deferasirox for a median of 56.1 months (4.7 years) at an average daily dose of 22.5 ± 6.6 mg/kg/day. Mean iron intake during treatment was 0.4 ± 0.1 mg/kg/day. Mean actual dose at month 3 was 19.8 ± 8.8 mg/kg/day, which increased to 28.3 ± 7.3 mg/kg/day by month 54. Median SF levels at baseline were 2419 ng/mL and were maintained to around month 18, reflecting the mean dose of ~20 mg/kg/day (Figure 1). Following dose titration, SF levels began to decrease with an overall median decrease in SF by month 54 of −947 ng/mL.At the time of analysis 137 patients (81.5%) continue to receive deferasirox. Of 31 discontinuations, 13 (7.7%) were due to AEs (drug-related AEs leading to discontinuation included glycosuria [n=3] and proteinuria [n=2]), eight (4.8%) to unsatisfactory therapeutic effect, five (3.0%) to consent withdrawal and four (2.4%) to other reasons. One death (septicemia in a splenectomized patient) occurred, considered by the Program Safety Board unrelated to treatment. Over the study period, the most common drug-related (investigator-assessed) AEs were abdominal pain and vomiting (n=12, 7.1% for both), nausea (n=10, 6.0%) and rash (n=9, 5.4%). The annual frequency of drug-related AEs decreased from year to year. In total, 13 patients (7.7%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; however, there were no progressive increases. Six patients (3.6%) with a normal baseline alanine aminotransferase (ALT), and five (3.0%) with a baseline ALT >ULN had an ALT increase >10×ULN on at least one visit. Growth, as assessed by height, proceeded normally in this population.Conclusions: Over a median period of 4.7 years, deferasirox treatment provided a dose-dependent overall reduction in iron burden in transfusion-dependent children with β-thalassemia, as measured by SF levels. Deferasirox was generally well tolerated with the frequency of investigator-reported AEs decreasing over long-term treatment. [Display omitted]

Efficacy and Safety of Deferasirox (Exjade®) during 1 Year of Treatment in Transfusion-Dependent Patients with Myelodysplastic Syndromes: Results from EPIC Trial

Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here.Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF <1000 ng/mL but requiring >20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters.Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, <1%), death (n=26, 8%, none treatment-related as per investigators' assessments) and other (n=21, 6%). Most common investigator-assessed drug-related AEs were diarrhea (n=110, 32%), nausea (n=45, 13%), vomiting (n=26, 8%), abdominal pain (n=26, 8%), upper abdominal pain (n=25, 7%), rash (n=23, 7%), and constipation (n=21, 6%). Only 25 pts discontinued study drug for drug-related GI AEs. Most AEs were mild-to-moderate (95%) in severity. In total, 14.7% had two consecutive serum creatinine values >33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (<1%) with normal baseline alanine aminotransferase had an increase that exceeded >10xULN on two consecutive visits.Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Change in Liver Iron Concentration (LIC), Serum Ferritin (SF) and Labile Plasma Iron (LPI) Over 1 Year of Deferasirox (DFX/Exjade®) Therapy in a Cohort of Myelodysplastic Patients

Background: Chronic red cell transfusions in patients with MDS result in iron overload, potentially causing hepatic, cardiac and endocrine dysfunction if untreated. DFX, a once-daily, oral iron chelator, has demonstrated dose-dependent reductions in SF and LIC in a variety of iron-overloaded patients. This study, CICL670AUS02, is the first prospective study evaluating the effects of DFX on LIC, SF and LPI in lower-risk patients with MDS.Methods: The study evaluated efficacy and safety of DFX in patients with IPSS Low- and Int-1-risk MDS at three US centers. Initial DFX dose was 20 mg/kg/day with adjustments to 10 or 30 mg/kg/day based on safety and efficacy. LIC was assessed by R2 MRI at baseline (BL), 6 and 12 months (mos). SF, safety analyses and trough LPI levels were also assessed.Baseline characteristics (n=24): Male/female ratio: 16/8; all Caucasian; mean age: 68 years (range 55–81); IPSS Low: 10; Int-1: 14. Time from initial diagnosis: <1 year (n=3; 13%); ≥1–<3 years (n=7; 29%); ≥3 years (n=14; 58%); range (<1–12) years. Mean number of lifetime transfusions was 79 (30–352). Mean (±SEM) SF value was 3848±583 μg/L, mean LIC was 20.64±1.99 mg Fe/g dry weight (dw), and mean LPI was 0.70±0.13 μmol/L; 50% of patients entered the trial with abnormal LPI (>0.5 μmol/L).6-month values: 15/24 patients completed 6 mos. Mean SF (±SEM): 3650±384 μg/L at BL, 3638±870 μg/L at 6 mos (n=13); mean decrease of 12.2 μg/L (P=0.685). Mean LIC (±SEM): 23.10±2.40 mg Fe/g dw at BL, 16.87±1.88 mg Fe/g dw at 6 mos (n=14); mean decrease of 6.2 mg Fe/g dw (P=0.013). Mean LPI (±SEM): 0.82±0.16 μmol/L at BL, 0.12 ± 0.05 μmol/L at 6 mos (n=15); mean decrease of 0.70 μmol/L (P=0.170).12-month values (n=9): Nine patients completed 12 mos of treatment. Mean dose in the nine completers was 20.1 mg/kg/day; three patients increased to 30 mg/kg/day and two decreased to 10 mg/kg/day. Mean SF (±SEM): 4416±1269 μg/L at BL, 2685±316 μg/L at 12 mos; mean decrease of 1730 μg/L (P=0.301; Figure). Mean LIC (±SEM): 23.72±3.82 mg Fe/g dw at BL, 16.79±3.80 mg Fe/g dw at 12 mos; mean decrease of 6.93 mg Fe/g dw (P=0.203). 78% of the nine completers achieved decreases in SF of ≥500 μg/L and >20% from BL. Mean LPI (±SEM; n=8): 0.82±0.19 μmol/L at BL, 0.13±0.10 μmol/L at 12 mos; mean decrease of 0.76 μmol/L (P=0.023)Safety Analysis (n=24): Increases in serum creatinine (SCr) to >33% above BL on ≥2 occasions (highest value 1.7 mg/dL) were seen in seven patients (29%) while on study. New cases of thrombocytopenia (worst value 39×109/L) and neutropenia (worst value 0.50×109/L) developed in one patient each during the study; these were assessed as unrelated to study drug. There were 15 discontinuations (63%): three due to unrelated deaths (two congestive cardiac failure, one subdural hemorrhage); four patients withdrew consent for unknown reasons; two from MDS progression; five because of adverse events (AEs), four of which were related to study drug (one diarrhea, two increased SCr, one increased liver enzymes) and one unrelated (splenic infarct); and one from unsatisfactory therapeutic effect. There were 14 serious AEs reported in 11 patients; 13/14 were considered unrelated to study drug; 1/14 (severe diarrhea/lower abdominal cramping) was related to study drug and the patient completely recovered within 1 day.Conclusions: Sequential LIC measurements in this MDS cohort demonstrated a significant decrease by month 6 and further decreases by month 12 in patients who completed 1 year of treatment. LPI normalized in 80% of the patients. Two thirds of this heavily transfused population discontinued the trial mainly due to disease-related complications; four patients discontinued due to drug-related AEs. Larger studies are continuing to evaluate the clinical benefit of DFX in patients with MDS. [Display omitted]

Diagnosis of pulmonary carcinoma by chest ct and detection of serum CEA,SF levels

目的 探讨胸部CT和血清铁蛋白、癌胚抗原检测及联合应用诊断肺癌的价值.方法 选择肺肿瘤患者73例,均在治疗前行胸部CT检查和检测血清铁蛋白(SF)、癌胚抗原(CEA)两种肿瘤标志物浓度.分别计算两种方法单独及联合诊断肺癌的灵敏度,特异度、诊断正确率、阳性似然比和阴性似然比,并加以比较分析.结果 二法联合检测与二法单独检测相比灵敏度、诊断正确率最高,阴性似然比最低.结论 胸部CT和SF、CEA检测在肺癌诊断中具有较高价值,二者联合应用诊断肺癌具有互补作用。

Effect of soluble and insoluble dietary fiber on embryo survival and sow performance1

Two experiments were conducted to evaluate the effects of soluble (SF) and insoluble (ISF) dietary fiber during gestation on embryo survival and sow performance. In Exp. 1, 43 gilts were assigned randomly to 1 of 4 experimental diets: a corn-soybean meal control (C; 1.16% SF, 9.98% ISF); a 30% oat bran high in SF (HS; 3.02% SF, 10.06% ISF); a 12% wheat straw diet high in ISF (HIS; 1.08% SF, 18.09% ISF); and a 21% soybean hull diet (HS + HIS; 2.46% SF, 24.55% ISF). Gilts were fed the experimental diets based on their initial BW to meet their daily nutrient requirements. At estrus, gilts were inseminated artificially 3 times using pooled semen. Reproductive tracts were harvested 32 d postmating (range = 28 to 35 d). Statistical analysis of data included the effects of diet with days of gestation as a covariate. There were no differences in ovulation rate among gilts fed the experimental diets (avg. = 14.1). Number of live embryos was less for HIS and HS + HIS gilts compared with C and HS (9.9 and 9.1 vs. 11.9 and 10.6, respectively; P < 0.05). Total embryo survival rate (P < 0.05) was less for gilts fed HS + HIS compared with those fed the C and HS diets. These results suggest that high dietary ISF might decrease the total embryo survival rate without affecting ovulation rate. In Exp. 2, 716 sows were used in 3 concurrent trials. In trial 1, diets included a corn-soybean meal control (C; 0.43% SF, 10.50% ISF; n = 122) or a 31% oat bran diet (HS; 1.93% SF, 8.87% ISF; n = 124). In trial 2, diets included a C (n = 97) or a 13% wheat straw diet (HIS; 1.10% SF, 17.67% ISF; n = 119), and in trial 3 sows were fed a C (n = 123) or a 21% soybean hull diet (HS + HIS; 1.50% SF, 17.77% ISF; n = 131). All diets were offered to sows beginning 2 d postmating. All sows had ad libitum access to a standard lactation diet. Statistical analysis included the effects of diet, parity group, genetic line, and season as well as their interactions. The inclusion of SF and ISF in gestation diets did not affect litter size. Sows fed the HS + HIS diet had a greater ADFI and lost less BW during lactation (P < 0.01) than sows fed C. Under the conditions of this study, feeding gestating sows increased levels of SF and ISF from d 2 after breeding to d 109 of gestation did not increase litter size.

Oral Deferasirox (Exjade®, ICL670) Is Effective, with a Clinically Manageable Safety Profile, in Pediatric β-Thalassemia Patients with High Iron Burden.

Background: The ESCALATOR study evaluated once-daily deferasirox in β-thal pts unsuccessfully chelated with DFO and/or deferiprone (L1). Phase II/III studies have shown that deferasirox 20–30 mg/kg/d maintains/reduces iron burden, depending on transfusional iron intake. However, PK evaluation indicated that exposure to deferasirox was lower in children than adults. To examine the relationship between dose and efficacy in heavily transfused children, a subanalysis of ESCALATOR pts (2–<16 years) was performed.Methods: ESCALATOR was a prospective, open-label, 1-year study. Enrolled pts had β-thal and transfusional iron overload (LIC ≥2 mg/g dw, serum ferritin [SF] ≥500 ng/mL), and had been unsuccessfully treated with prior mono- or combination therapy with DFO and/or L1. Pts began treatment with deferasirox 20 mg/kg/d, except 3 who started on 10 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as LIC reduction of ≥3 mg/g if baseline LIC was ≥10 mg/g, or final LIC of 1–7 mg/g if baseline LIC was 2–<10 mg/g. Secondary endpoints included absolute reduction in LIC and safety; SF was assessed as a surrogate marker for LIC.Results: Of 252 pts, 167 were children. In the year before study start, 150 received DFO, 1 L1 and 16 DFO + L1. Median (range) deferasirox dose was 22.6 (12–30) mg/kg/d. Overall, 130 children received dose adjustments to ≥25 mg/kg/d. Median (range) time to dose increase was 31 (8–48) wks. Treatment success rate was 56.9% (95% CI 49.5, 64.4). Mean (SD) baseline LIC and SF levels were 17.1 (8.5) mg/g and 3938 (2262) ng/mL, respectively.The most common drug-related AEs were mild/moderate skin rash (n=16) and vomiting (n=15). No deaths were reported. 46 pts with normal baseline creatinine values experienced increases >33% on ≥2 consecutive visits; values also exceeded ULN in 4 pts. Increases in ALT to >5 × ULN on ≥2 consecutive visits were noted in 21 children; baseline values were high in 16/21 pts. Mean (SD) LVEF increased by 2.5% (8.2). Physical and sexual development progressed normally. At EOS, most pts reported greater satisfaction, convenience and less time lost compared with prior therapy. In total, 94.6% of pts preferred deferasirox.Conclusions: These data suggest that with appropriate dosing, deferasirox can effectively control iron burden with a clinically manageable safety profile in heavily iron-overloaded children who were previously unsuccessfully chelated. Dose increases to ≥25 mg/kg/d were required to reach target reductions in iron burden, with no safety concerns. This highlights the importance of timely dose adjustments to achieve therapeutic goals. Pts preferred deferasirox to previous chelation therapy, which may improve long-term compliance.Mean (SD) change from baseline95% CILIC, mg/g (n=163)−3.0 (6.1)–Baseline LIC ≥7 mg/g (n=143)−3.5 (6.2)−4.5, −2.5Baseline LIC <7 mg/g (n=20)+1.0 (3.9)–SF, ng/mL (n=165)−236 (1237)–BaselineEOSSatisfaction with chelator, %17.492.8Convenience of therapy, %12.695.8Hrs lost in past mo, mean (SD)33.8 (47.8)3.8 (9.6)

Serum ferritin and erythrocyte indices in iron overload.

Raised levels of serum transferrin saturation (TS) and ferritin (SF) are frequently associated with increased values of haemoglobin and erythrocyte indices. In hereditary haemochromatosis this phenomenon has been considered to be a beneficial effect of the C282Y mutation, protecting women from iron deficiency. The elevated values of mean corpuscular volume (MCV) in hereditary haemochromatosis may reflect increased iron uptake and haemoglobin synthesis by immature erythroid cells1–3. In a large screening study of a European population, a higher haemoglobin concentration was found in C282Y homozygous women with either normal or increased TS or SF4. However, when the effect of the C282Y mutation was analysed separately in subjects from different parts of Europe, the mean haemoglobin concentration and MCV were higher in C282Y carriers from northern Europe than in those from southern Europe. This could be due to the higher prevalence of thalassaemia trait in southern Europe5. The variability in TS and SF may depend not only on mutations in HFE or other genes involved in haemochromatosis, but also on other genetic and environmental factors. A recent large screening study (the HEIRS study) conducted in the USA and in Canada found higher mean TS and SF levels among Asians and Pacific Islanders, who do not have an HFE mutation or H63D allele, than in white subjects. There is no consistent evidence supporting the hypothesis that the increased SF in Asians is attributable to liver disease or diabetes. A reduced MCV in Asian men with increased SF could be explained by a high prevalence of thalassaemia trait in this population, although further studies are required to clarify this issue6. In anaemia of chronic diseases (ACD), normal or increased SF and reduced TS levels are usually associated with low haemoglobin levels and normocytic or microcytic erythrocytes. An increased uptake of iron and retention in active macrophages, which is the pathophysiological mechanism of ACD, is linked to increased pro-inflammatory and anti-inflammatory cytokines and is responsible for reduced availability of iron for erythroid progenitors. Recently, it was speculated that a small peptide hormone, hepcidin, might be involved in the pathogenesis of ACD. Hepcidin has antimicrobial activity and its expression increases in response to inflammatory stimuli. In mice, hepcidin mRNA expression is increased in response to lipopolysaccharides and infection. It has been suggested that hepcidin may be one cytokine-regulated gene that impairs erythrocyte iron acquisition by modifying the release of iron from macrophages7. In alcoholic steatosis, the serum TS and SF levels are unrelated to iron deposits. In alcoholic cirrhosis, low haemoglobin concentrations and increased MCV are often detected in association with increased levels of ferritin. These haematological findings are dependent on several factors, including direct and indirect effects of alcohol on the bone marrow, an impaired nutritional state, and the different stages of the liver disease. Hyperferritinaemia is also frequently observed in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. The increased SF values are associated with insulin resistance and mild hepatic iron accumulation. So far, no significant modifications of haematological indices have been reported in NAFLD8.

Widespread elevated atmospheric SF 6 mixing ratios in the Northeastern United States: Implications for groundwater dating

SF 6 is a promising transient tracer for groundwater dating, but elevated levels of atmospheric SF 6 may limit application of this dating method in urban areas. To determine the magnitude of this limitation within the United States (US), this study derives average atmospheric SF 6 mixing ratios from soil air measurements from five major urban areas. All surveyed sites showed SF 6 elevated above Northern Hemisphere clean air levels. In many cases, SF 6 mixing ratios were highest within large cities, but significantly elevated levels persisted hundreds of kilometers beyond the urban centers. Estimated SF 6 emissions from New York city were anomalously large, resulting in average levels over 200% above remote atmosphere values. Emissions from other urban areas included in this study appear to be typical for large cities in the US and maximum observed elevations of SF 6, in these areas, were in the range of 50–100%. These findings imply that caution is needed in choosing an atmospheric input function when using SF 6 as a transient tracer within or near urbanized regions. Within the Northeast US, the assumption of remote atmospheric SF 6 may lead to significant errors in estimation of groundwater ages, especially in the case of an expected future flattening of the atmospheric mixing ratio curve.

Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA).

The expression of immunoregulatory cytokines was investigated in freshly isolated synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) from patients with RA, using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. IFN-gamma, TGF-beta, IL-10 and IL-12 (p40) transcripts were detected in SFMC of patients with early disease (<1 year duration) as well as in patients with long standing arthritis (>1 year). The expression of IFN-gamma, IL-10 and IL-12 mRNA was increased in SFMC compared with RA PBMC. In addition, the expression was higher in RA SFMC than in PBMC from health control individuals. Immunoassay analysis of the secreted IL-12 heterodimer demonstrated increased levels in RA SF compared with levels found in serum from RA patients and control individuals. High levels of TGF-beta mRNA were found in SFMC, but a significantly decreased TGF-beta/beta2-microglobulin (beta2-M) ratio was found compared with PBMC from both patients and control individuals. IL-4mRNA could not be detected, either in SFMC or in PBMC. Cytokine expression in RA PBMC did not differ from control PBMC, with the exception of a decreased TGF-beta/beta2-M ratio in RA patients with early disease. Our findings of IFN-gamma mRNA and IL-12, but undetectable levels of IL-4 mRNA, suggest that the synovitis is characterized by a type 1 immune response. The presence of TGF-beta and IL-10 mRNA indicates that immunosuppressive cytokines may also operate in the inflamed joint, although their level of expression may not be sufficient for down-modulation of immune activation.

The Clinical Relevance of Compound Heterozygosity for the C282Y and H63D Substitutions in Hemochromatosis

Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y substitution have been well characterized, the clinical significance of the C282Y/H63D state remains unclear. This study assessed the phenotypic expression in C282Y/H63D subjects as compared with C282Y homozygotes. Data were obtained from 91 C282Y/H63D probands, 158 C282Y/H63D subjects identified through family screening, and 483 C282Y homozygotes. Subjects underwent clinical evaluation, genotyping, biochemical assessment, and liver biopsy examination where clinically indicated. C282Y/H63D probands had significantly less clinical and biochemical expression than C282Y homozygotes. Biochemical expression was higher in C282Y/H63D probands than in C282Y/H63D subjects identified through family screening (P < .001). Of the C282Y/H63D subjects with serum ferritin levels greater than 1000 mug/L, all had known comorbid factors that could have contributed to the increased ferritin level. Of the 51 C282Y/H63D subjects who underwent liver biopsy examination, significantly increased iron stores were present in 9 subjects and hepatic fibrosis was present in 13. Twelve of the 13 had evidence of hepatic steatosis, excess alcohol consumption, or diabetes. The mobilizable iron level was significantly higher in C282Y homozygous males than in compound heterozygous males (P < .001). Genetic screening of C282Y/H63D first-degree relatives detected 5 C282Y homozygotes. C282Y/H63D subjects referred for assessment had a high prevalence of increased iron indices but did not develop progressive clinical disease without comorbid factors such as steatosis, diabetes, or excess alcohol consumption. When fibrosis was seen, 1 or more comorbid factors almost always were present. Thus, phlebotomy therapy is warranted and cascade screening of relatives should be performed because expressing C282Y homozygotes may be detected.

Cytogenetic damage in buccal epithelia and peripheral lymphocytes of young healthy individuals exposed to ozone

Ozone (O(3)) is an important component of air pollution and a potent oxidant of biomolecules. To address the hypothesis that elevated ambient O(3) can induce cytogenetic damage in healthy people, we collected buccal cells from two groups of students (N = 126) from University of California, Berkeley, in the spring and again in the fall. One group spent their summer in the Los Angeles (LA) area where summer O(3) concentrations are significantly higher than in the San Francisco Bay (SF) area, and another remained in SF. During the school year, all students were exposed to low O(3) levels in SF. The micronucleus assay in a total of 611,000 buccal cells demonstrated that, in the fall, micronuclei (MN) in normal cells for the LA group had increased 39% relative to levels in the spring (1.52 and 0.87 MN/1,000 cells, respectively, P = 0.001). Students who spent the summer in SF had a 12.7% increase (P = 0.48). A similar effect of season was seen in degenerated buccal cells for the LA group (3.23 versus 1.88 MN/1,000 cells, P = 0.003). LA but not SF subjects also had more degenerated cells in the fall sample (P = 0.003). These findings were paralleled by an increase in MN and nucleoplasmic bridges in lymphocytes and MN in buccal cells in a sub-group of 15 students who underwent a 4-h controlled exposure to 200 p.p.b. O(3). This cytogenetic evidence, along with recent studies linking O(3) exposure to elevated lung cancer risk and mortality, suggest potential public health implications from exposures to high oxidant environments.

High levels of ozone and related gases over the Bay of Bengal during winter and early spring of 2001

Measurements of surface ozone and related trace gases were made over a broader region of the Bay of Bengal along with measurements over the Indian Ocean and the Arabian Sea during a Bay of Bengal Experiment (BOBEX) conducted from 18 February to 23 March, 2001. Higher levels of ozone (60–64 ppbv) were observed over the central Bay of Bengal (10–15N, 84–86E) and not near the coastal regions due to different types of wind patterns. Ozone levels in the south of 12N are observed to be higher over the Bay of Bengal than the average levels measured over the Arabian Sea during all the four INDOEX cruises conducted in each winter from 1996 to 1999. The elevated O 3 level is consistent with simultaneously measured higher levels of CO, CH 4 and SF 6 over the Bay of Bengal. These observations together with general wind patterns, 7 days back trajectories and results from a three-dimensional model simulations suggest that higher levels of these trace gases over the Bay of Bengal are due to transport from the continent. These results also suggest that the air over the Bay of Bengal was found to be more polluted than the Arabian Sea during this season.

Relationships of Serum Ferritin, Transferrin Saturation, and HFE Mutations and Self-Reported Diabetes Mellitus in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.

Mean serum ferritin concentration (SF) has been positively associated with diabetes mellitus in some racial/ethnic groups. We evaluated the associations of self-reported diabetes mellitus with SF, serum transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five Field Centers in the multi-center, primary care-based HEIRS Study. Analyses were conducted on the 97,470 participants for whom pertinent data were available. Participants who reported that they had been previously diagnosed with diabetes mellitus and/or hemochromatosis or iron overload were compared to participants who did not report a previous diagnosis. The overall prevalence of diabetes mellitus was 13.8%; the highest prevalence was observed in Native Hawaiian/Pacific Islanders (20.1%). 2.0% of all participants with diabetes mellitus and 2.2% of whites with diabetes mellitus reported that they also had hemochromatosis or iron overload. Mean SF was elevated in women with diabetes mellitus in all racial/ethnic groups and in American Indian/Alaska Native men with diabetes mellitus. Mean SF was significantly lower in Asian men with diabetes mellitus. Mean TfSat was lower (or not increased) in participants with diabetes mellitus than in those without diabetes mellitus. There was no significant association of diabetes mellitus with HFE genotype. Mean SF was greater (p <0.0001) in women with diabetes mellitus than in those without diabetes mellitus for HFE genotypes except C282Y/C282Y and C282Y/H63D. There was a significant positive association of log SF and diabetes mellitus in a logistic regression analysis after adjusting for age, gender, racial/ethnic group, HFE genotype, and Field Center. We conclude that SF is significantly associated with diabetes mellitus, even at levels of SF below those typically associated with hemochromatosis or iron overload.

Relationship between synovial fluid levels of glycosaminoglycans, hydroxyproline and general MMP activity and the presence and severity of articular cartilage change on the proximal articular surface of P1

Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting horses and leads to degeneration of articular cartilage. Diagnosis is based on clinical signs in combination with radiography, which is relatively insensitive and provides only an indication of accumulated damage. Alternative methods, such as molecular markers, are therefore needed that can quantitatively, reliably and sensitively detect osteoarthritic changes in the joints at an early stage of the disease. If such markers are to be used reliably, it is important to know the relationship between marker concentration and cartilage composition. To study the relationship between cartilage composition, synovial fluid levels of glycosaminoglycans (GAGs), hydroxyproline (Hyp) and general matrix metalloproteinase (MMP) activity, and the presence and severity of articular cartilage damage on the articular surface of P1. Synovial fluid (SF) was collected from the metacarpophalangeal joints of 60 mature horses, and levels of GAGs, Hyp and general MMP activity were determined. Further, GAG and denatured collagen content of the articular cartilage were determined at the dorsal articular margin of P1 (site 1) and central cavity (site 2). The presence and severity of cartilage change was quantified using the cartilage degeneration index (CDI), measured at the same 2 sites. Correlations between SF parameters, cartilage composition and degree of cartilage degeneration were sought using correlation analysis. There was no correlation between GAG or Hyp content of SF and the amount of GAGs or denatured collagen, respectively, in cartilage. In joints with moderate to severe cartilage damage, the GAG content of site 1 was significantly lower than in joints with no to minimal cartilage change (P = 0.005) and there was a negative correlation between the amount of denatured collagen and GAG content at site 1 in all joints (r = -039, P = 0.002). Further, in joints with moderate to severe cartilage damage, there was a significant positive correlation between MMP activity in SF and Hyp levels in SF (r = 0.72, P < 0.001) and CDI at sites 1 (r = 0.46, P = 0.03) and 2 (r = 0.43, P = 0.04). General MMP activity in joints with moderate to severe cartilage damage is related to the severity of those cartilage changes and to Hyp levels in SF. Glycosaminoglycan levels in SF are not directly related to MMP activity, GAG content of articular cartilage or severity of cartilage change. Glycosaminoglycan levels in SF are not helpful for the early detection of cartilage lesions. In damaged joints, Hyp levels may give an indication of the severity of cartilage change as they are strongly related to MMP activity, but do not qualify as markers for the presence or absence of cartilage lesions.