bluuebunny/crossref_metadata_2025 huggingface dataset:
Physico-chemical properties of Chitosan films
Authors: Balau Luminita , Lisa Gabriela , Popa M. , Tura V. , Melnig V.
Published: August 2006

Chitosan films obtained by dry phase inversion were prepared from an aqueous solution of chitosan in acetic acid. The films, of thickness less than 20 μm, were transparent, very flexible and had smooth surfaces. Increasing the film thickness induced an increase of the internal tensions and the consequent formation of a rough surface. Structural investigations by X-ray diffraction and Fourier transform IR analysis, showed that the chitosan films, as prepared, are amorphous. Further annealing to evaporate acetic acid and water traces, changed the amorphous phase into a more ordered phase, characterized by diffraction peaks at 2θ values of 9, 17, 20 and 23 degrees. Thermal investigations by TG, DTG, and DTA revealed that the decomposition of the chitosan films as prepared proceeds in two stages, starting from 180°C and 540°C.
Kinetic and equilibrium study of the deprotonation of 4-nitrophenyl[bis(ethylsulphonyl)]methane by organic bases in acetonitrile in the presence of common cation BH+ and tetrabutylammonium perchlorate
Authors: Binkowska Iwona , Jarczewski Arnold
Published: August 2006

The results of kinetic and equilibrium experiments with the set of reaction of proton abstraction from 4-nitrophenyl[bis(ethylsulphonyl)]methane in acetonitrile are reported. Two strong organic bases are used: 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD).

The rates of proton transfer reaction have been measured by T-jump method in the presence of perchlorate of the appropriate base as a common cation BH+ and supporting electrolyte-tetrabutylammonium perchlorate (TBAP) in the temperature range between 20–40°C are: kH=1.32×107−2.00×107 and 2.82×107−4.84×107 dm 3mol−1s−1 for MTBD and TBD respectively. The enthalpies of activation ΔHMTBD≠=13.5 and ΔHTBD≠=18.1 kJmol−1. The entropies of activation are negative: ΔSMTBD≠=−62.3 and ΔSTBD≠=−40.3 Jmol−1K−1.

The change of the absorbance of the anion of 4-nitrophenyl[bis9ethylsulphonyl)]methane at the temperature 25°C in the presence of common cation BH+ gives the equilibrium constants K=705 and 906 M−1 for MTBD and TBD respectively.

Kinetic and equilibrium results are discussed. The possible mechanism of proton transfer reaction between 4-nitrophenyl[bis(ethylsulphonyl)]methane and cyclic organic bases: MTBD and TBD in acetonitrile is proposed.
Structural factors influencing the reaction rates of 4-aryloxy-7-nitrobenzofurazans with amino acids
Authors: Bem Marioara , Vasilescu Marilena , Caproiu Miron , Draghici Constantin , Beteringhe Adrian , Constantinescu Titus , Banciu Mircea , Balaban Alexandru
Published: August 2006

An interesting observation was made when studying the SNAr reaction between several 4-aryloxy-7-nitrobenzofurazans (2) and several amino acids leading to the apparition of detectable fluorescence from the substitution products3. Acidic amino acids reacted very slowly=while basic amino acids react fastest with2 having an unsubstituted phenyl or a 4-formyl-phenyl Ar group. Amongst neutral amino acids, proline reacts fastest at room temperature after 100 min. With2 having a methoxy-subtituted Ar group.
Radionuclides in deposition in the Ignalina NPP region in 2005
Authors: Jasiulionis Rimvydas , Rožkov Andrej
Published: August 2006

Results of radionuclide activity concentration measurements in deposition and ground-level air conducted at the station of the Institute of Physics situated 3.5 km from the Ignalina Nuclear Power Plant (Ignalina NPP) in 2005 are analyzed. Atmospheric depositional fluxes of 7Be, 60Co and 137Cs are estimated. Radionuclide particle deposition rates are calculated. The Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model of the global dispersion and deposition is used to explain variations in the 137Cs activity concentration in the ground-level air in the Ignalina NPP region in 2005. An increase in the 137Cs activity concentration of up to 17.4 µBq m−3 on 30 October-5 November is studied. Modelling results show that the Chernobyl NPP Unit 4 Sarcophagus and the radiocaesium resuspension from the Chernobyl NPP accident polluted regions are sources of 137Cs to the environment of the Ignalina NPP. Results on solubility in water of aerosols — carriers of 137Cs — are discussed.
A correlation between radiation sensitivity and initial chromatid breaks in cancer cell lines revealed by Calyculin A-induced premature condensation
Authors: Yang Jianshe , Jing Xigang , Wang Zhuanzi , Li Wenjian
Published: August 2006

Three human malignancy cell lines were irradiated with 60Co γ-rays. Initial chromatid breaks were measured by using the chemically induced premature chromosome condensation technique. Survival curves of cells exposed to gamma rays was linear-quadratic while the efficiency of Calyculin A in inducing PCC of G2 PCC was about five times more than G1 PCC. A dose-dependent increase in radiation-induced chromatid/isochromatid breaks was observed in G1 and G2 phase PCC and a nearly positive linear correlation was found between cell survival and chromatin breaks. This study implies that low LET radiation-induced chromatid/isochromatid breaks can potentially be used to predict the radiosensitivity of tumor cells either in in vitro experimentation or in in vivo clinical radiotherapy.
Effect of Alpinia galanga extract on cartilage degradation and on gene expression in human chondrocyte and synovial fibroblast metabolism
Authors: Pothacharoen Peraphan , Choocheep Kanyamas , Pitak Tanyaluck , Pompimon Wilart , Premanode Bhusana , Hardingham Timothy , Kongtawelert Prachya
Published: August 2006

We investigated the effects of A. galanga extract on metabolism and gene expression involved in the interleukin-1β (IL-1β) response of human chondrocyte and synovial fibroblast. A. galanga extract inhibited IL-1β enhanced matrix breakdown of the cartilage explants in a dose-dependent manner. It suppressed uronic acid loss from the tissue and decreased the release of sulfated GAG and hyaluronan into the medium. MMP-2 and MMP-9 activity in the culture medium of chondrosarcomas and synovial fibroblasts were significantly reduced in the presence of A. galanga extract, which also suppressed the production of MMP-1,-3 and-13. The A. galanga extract also significantly increased type II collagen, SOX9 and aggrecan gene expression, suggesting an ability to enhance anabolic activity. At a high dose of A. galanga extract there was a down-regulation of aggrecan gene expression. Comparison with Diacerein® showed its general anti-inflammatory potential to be similar. The A. galanga extract was shown to inhibit IL-1β-stimulated cartilage matrix degradation in both systems. Additionally, the extract showed the potential to up-regulate certain chondrocyte anabolic genes. It may, therefore, offer some cartilage protective and anti-inflammatory properties as a therapeutic agent in arthritis.
Xenobiotics with estrogen or antiandrogen action — disruptors of the male reproductive system
Authors: Słowikowska-Hilczer Jolanta
Published: August 2006

The environmental and life-style changes associated with developing industry and agriculture, especially the exposure to endocrine disrupting chemicals (xenobiotics), are considered as causes of the increasing incidence of male reproductive system disorders. Most of the xenobiotics, which harmfully influence the male reproductive system, reveal estrogen-like (xenoestrogens) or anti-androgenic activity. Recent data have revealed physiological roles of estrogens in the male, however, there are evidences that estrogen-like substances may lead to many undesirable symptoms in the male i.e. gonadal dysgenesis, genital malformations, cryptorchidism, decreased fertility potential and testicular neoplastic changes. The number of xenoestrogens is still growing in the environment, whereas the mechanisms of their action are still not exactly known. They can be harmful not only to the present but potentially also to the next generations.
Disseminated extramedullary myeloid tumor of the gallbladder without involvement of the bone marrow
Authors: Bartley Angela N. , Nelson Craig L. , Nelson Donald H. , Fuchs Deborah A.
Published: August 2006

Extramedullary myeloid tumors (myeloid sarcomas) are rare neoplasms that are composed of myeloid precursors. They usually arise concurrently with a diagnosis of acute myeloid leukemia, chronic myeloid leukemia, or other myeloproliferative disorders. They may also indicate relapsing disease in a patient with a prior history of leukemia or myeloproliferative disorder. We present our findings of a 63‐year‐old female diagnosed with extramedullary myeloid tumor first presenting in the gallbladder. She subsequently developed respiratory failure; pre‐ and postmortem bone marrow studies were negative for leukemia by morphology, flow cytometry, and karyotypic analysis. However, the myeloid neoplasm was disseminated throughout most of her remaining organs. Immunohistochemical stains of the cells indicated a neoplasm of myelomonocytic derivation (CD4, CD43, CD45, CD68, myeloperoxidase, and lysozyme positive). To our knowledge, this is the first report of an extramedullary myeloid neoplasm of the gallbladder with disseminated disease without involvement of the bone marrow. Am. J. Hematol., 2006. © Wiley‐Liss, Inc.
Preclinical assessment of curcumin as a potential therapy for B‐CLL
Authors: Everett Peter C. , Meyers John A. , Makkinje Anthony , Rabbi Mohammed , Lerner Adam
Published: August 2006

Curcumin, the principle component of the spice turmeric, has been used as an anti‐inflammatory medication in India and China for centuries. Recent studies, predominantly using actively dividing cell lines, have suggested that this compound could be used as a chemopreventative or therapeutic agent for epithelial tumors. As curcumin has been reported to inhibit the NIK/IKK complex, an activity that would be expected to induce apoptosis in B cell malignancies, we sought to determine whether curcumin induces apoptosis in vitro in primary chronic lymphocytic leukemia (B‐CLL) cells. Primary leukemic cells were incubated with varying dosages of curcumin, followed by assessment for apoptosis. The role of PPARγ or NF‐κB signaling in curcumin‐induced apoptosis was examined by cotreatment with a PPARγ antagonist or EMSA of nuclear NFκB complexes. We also examined whether a clinically achievable concentration of curcumin (1 μM) would augment the apoptotic effects of fludarabine, dexamethasone, vincristine or the PDE4 inhibitor rolipram. In B‐CLL cells from 14 patients, curcumin‐induced apoptosis with a mean EC50 of 5.5 μM. In contrast, the EC50 for whole mononuclear cells from a healthy donor was 21.8 μM. In a 48 hr wash‐out time course, curcumin‐induced apoptosis was time‐dependent, with a substantial reduction in apoptosis observed when curcumin was removed after 5 hr. Curcumin treatment reduced basal nuclear NF‐κB levels and 1 μM curcumin augmented both vinca alkaloid and PDE4 inhibitor‐induced apoptosis in B‐CLL cells. Our studies suggest that curcumin may augment the efficacy of established or experimental therapies for B‐CLL. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Acute myeloid leukemia with T‐cell receptor gamma gene rearrangement occurring in a patient with chronic lymphocytic leukemia: A case report
Authors: Hatoum Hassan A. , Mahfouz Rami A.R. , Otrock Zaher K. , Hudaib Abdel‐Rahman , Taher Ali T. , Shamseddine Ali I.
Published: August 2006

The association of chronic lymphocytic leukemia (CLL) and acute leukemia, either lymphoid or myeloid is a rare event. Our review of the medical literature revealed only 6 cases of CLL transformation to acute myeloid leukemia (AML) (M0, M1 and M2) with no other associated malignancy. We report a similar case but with occurrence of AML‐M4 associated with normal cytogenetic analysis and molecular testing but with positive T‐cell receptor gamma gene rearrangement rather than the usual Vbeta rearrangement. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Function of interleukin‐20 as a proinflammatory molecule in rheumatoid and experimental arthritis
Authors: Hsu Yu‐Hsiang , Li Hsing‐Hui , Hsieh Mei‐Yi , Liu Ming‐Fei , Huang Kuo‐Yuan , Chin Lin‐Show , Chen Pei‐Chih , Cheng He‐Hsiung , Chang Ming‐Shi
Published: August 2006

Objective

The pathogenesis of rheumatoid arthritis (RA) reflects an ongoing imbalance between proinflammatory and antiinflammatory cytokines. Interleukin‐20 (IL‐20) has proinflammatory properties for keratinocytes. In this study, we sought to determine whether IL‐20 is involved in RA.

Methods

We analyzed IL‐20 levels in synovial fluid from RA patients. IL‐20 and its receptors were detected in RA synovial fibroblasts (RASFs), using immunohistochemical staining. The effect of IL‐20 on endothelial cells, neutrophils, and RASFs was investigated using MTT and migration assays. The expression of IL‐20 and its receptors in healthy rats and in rats with collagen‐induced arthritis (CIA) was also analyzed. Soluble IL‐20 receptor type I (sIL‐20RI) or sIL‐20RII was administered to rats with CIA by intramuscular electroporation, and the severity of arthritis was monitored.

Results

RA patients expressed significantly higher levels of synovial fluid IL‐20 than did the rheumatic disease controls. IL‐20 and its receptors were expressed in the synovial membranes and RASFs. IL‐20 induced RASFs to secrete monocyte chemoattractant protein 1, IL‐6, and IL‐8, and it promoted neutrophil chemotaxis, RASF migration, and endothelial cell proliferation. Both IL‐20 and IL‐20RI were up‐regulated in the rat CIA model. In vivo, electroporated sIL‐20RI plasmid DNA decreased the severity of arthritis in the rats with CIA.

Conclusion

IL‐20 was up‐regulated in the synovial fluid of RA patients and acted as a chemokine that attracted the migration of neutrophils and RASFs in vitro. The rat CIA model demonstrated that IL‐20 was involved in the pathogenesis of arthritis, because sIL‐20RI significantly reduced arthritis in rats with CIA. Thus, IL‐20 may modulate the incidence and severity of arthritis and play important roles at local sites of inflammation.
Pathogenesis of osteoarthritis‐like changes in the joints of mice deficient in type IX collagen
Authors: Hu K. , Xu L. , Cao L. , Flahiff C. M. , Brussiau J. , Ho K. , Setton L. A. , Youn I. , Guilak F. , Olsen B. R. , Li Y.
Published: August 2006

Objective

To examine the pathogenetic mechanisms of osteoarthritis (OA)–like changes in Col9a1−/− mice, which are deficient in type IX collagen.

Methods

Knee joints and temporomandibular joints (TMJs) from Col9a1−/− mice and their wild‐type (Col9a1+/+) littermates were examined by light microscopy. Immunohistochemical staining was performed to examine the expression of matrix metalloproteinase 3 (MMP‐3) and MMP‐13, degraded type II collagen, and the discoidin domain receptor 2 (DDR‐2) in knee joints. Cartilage mechanics were also evaluated for compressive properties by microindentation testing of the tibial plateau and for tensile properties by osmotic loading of the femoral condyle.

Results

Histologic analysis showed age‐dependent OA‐like changes in the knee and TMJs of Col9a1−/− mice starting at the age of 3 months. At the age of 6 months, enhanced proteoglycan degradation was observed in the articular cartilage of the knee and TMJs of the mutant mice. The expression of MMP‐13 and DDR‐2 protein and the amount of degraded type II collagen were higher in the knee joints of Col9a1−/− mice than in their wild‐type littermates at the age of 6 months. Changes in cartilage mechanics were observed in the femoral and tibial plateaus of Col9a1−/− mice at 6 months, including a decrease in the compressive modulus and uniaxial modulus. At 3 and 6 months of age, tibial cartilage in Col9a1−/− mice was found to be more permeable to fluid flow, with an associated compromise in the fluid pressurization mechanism of load support. All of these changes occurred only at medial sites.

Conclusion

Lack of type IX collagen in Col9a1−/− mice results in age‐dependent OA‐like changes in the knee joints and TMJs.
Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products
Authors: Yammani Raghunatha R. , Carlson Cathy S. , Bresnick Anne R. , Loeser Richard F.
Published: August 2006

Objective

S100 proteins have been implicated in various inflammatory conditions, including arthritis. The aims of this study were to determine whether chondrocytes produce S100A4 and whether S100A4 can stimulate the production of matrix metalloproteinase 13 (MMP‐13) by articular chondrocytes via receptor for advanced glycation end products (RAGE)–mediated signaling.

Methods

The expression of chondrocyte S100A4 was analyzed by immunohistochemistry using normal and osteoarthritic (OA) cartilage and by immunoblotting of chondrocyte cell lysates. RAGE signaling was examined by stimulating chondrocytes with S100A4 and monitoring for the activation of MAP kinases and NF‐κB. Production of MMP‐13 was determined in the conditioned medium. A pulldown assay using biotin‐labeled S100A4 was used to demonstrate binding to RAGE.

Results

S100A4 expression was detected in human articular chondrocytes by immunoblotting and appeared to increase in the cell lysates from OA tissue. Marked positive immunostaining for S100A4 was also noted in sections of human cartilage with changes due to OA. Stimulation of chondrocytes with S100A4 increased the phosphorylation of Pyk‐2, MAP kinases, and activated NF‐κB, followed by increased production of MMP‐13 in the conditioned medium. This signaling was inhibited in cells pretreated with soluble RAGE, advanced glycation end product–bovine serum albumin, or the antioxidant Mn(III)tetrakis (4‐benzoic acid) porphyrin, or by overexpression of a dominant‐negative RAGE construct. A pulldown assay showed that S100A4 binds to RAGE in chondrocytes.

Conclusion

This is the first study to demonstrate that S100A4 binds to RAGE and stimulates a RAGE‐mediated signaling cascade, leading to increased production of MMP‐13. Since both S100A4 and RAGE are up‐regulated in OA cartilage, this signaling pathway could contribute to cartilage degradation in OA.
Differential expression of stromal cell–derived factor 1 and its receptor CXCR4 in the skin and endothelial cells of systemic sclerosis patients: Pathogenetic implications
Authors: Cipriani Paola , Franca Milia Anna , Liakouli Vasiliki , Pacini Alessandra , Manetti Mirko , Marrelli Alessandra , Toscano Annarita , Pingiotti Elisa , Fulminis Antonietta , Guiducci Serena , Perricone Roberto , Kahaleh Bashar , Matucci‐Cerinic Marco , Ibba‐Manneschi Lidia , Giacomelli Roberto
Published: August 2006

Objective

Systemic sclerosis (SSc) is characterized by early endothelial damage evolving to vascular desertification. Stromal cell–derived factor 1 (SDF‐1) and its receptor CXCR4 regulate specific steps in new vessel formation. We undertook this study to determine whether an alteration of the SDF‐1/CXCR4 axis might be involved in the pathogenetic mechanisms following ischemic damage during SSc.

Methods

We enrolled 36 SSc patients and 15 controls. Skin biopsy samples were obtained from each subject, and the expression of SDF‐1 and CXCR4 was assessed by immunohistochemistry, reverse transcription–polymerase chain reaction (RT‐PCR), and Western blot analyses. Furthermore, isolated microvascular endothelial cells (MVECs) from 4 patients with diffuse cutaneous SSc (dcSSc) and 3 controls were analyzed for SDF‐1 and CXCR4 by confocal laser scanning microscopy, RT‐PCR, and Western blotting.

Results

SDF‐1 and CXCR4 were up‐regulated in the skin of patients with early (edematous) SSc, both in the diffuse and limited cutaneous forms, and progressively decreased, with the lowest expression in the latest phases of both SSc subsets. MVECs from patients with dcSSc expressed significantly higher amounts of both isoforms of SDF‐1 in the early stage of disease, with a progressive reduction of SDF‐1 and CXCR4 in later stages. On the surface of cultured MVECs from patients with dcSSc, SDF‐1 and CXCR4 colocalized in polarized areas, suggesting that they are activated in vivo and that they are under strict genetic control to retain capping function.

Conclusion

Due to its transient expression, SDF‐1 could be considered a future therapeutic target to induce new vessel formation in SSc.
A proposal for a pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1,015 patients with juvenile‐onset systemic lupus erythematosus
Authors: Gutiérrez‐Suárez Raul , Ruperto Nicolino , Gastaldi Roberto , Pistorio Angela , Felici Enrico , Burgos‐Vargas Rubén , Martini Alberto , Ravelli Angelo
Published: August 2006

Objective

To devise a modified version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) for use in children and adolescents with systemic lupus erythematosus (SLE), based on the frequency and distribution of damage in patients with juvenile‐onset SLE and the sources of damage that are most suitable for inclusion in a pediatric damage index.

Methods

In this cross‐sectional study, damage was assessed through the SDI. Clinical assessments included evaluation of growth failure and delayed puberty, which were believed to be important sources of damage that are not incorporated in the SDI but should be included in a pediatric version of the instrument.

Results

A total of 1,015 patients with juvenile‐onset SLE in 39 countries were enrolled in the study. Of these, 405 patients (39.9%) had an SDI score of ≥1 (mean ± SD score 0.8 ± 1.4). Renal damage (13%), neuropsychiatric damage (10.7%), and musculoskeletal damage (10.7%) were observed most frequently, followed by ocular damage (8.2%) and skin damage (7.6%). Growth failure and delayed puberty were recorded in 15.3% and 11.3% of patients, respectively. A pediatric version of the SDI was devised, with inclusion of growth failure and delayed puberty as new domains.

Conclusion

We propose a modified version of the SDI for use in patients with juvenile‐onset SLE. This new instrument warrants prospective validation in other populations of patients seen in different clinical or research settings.
Measuring function in rheumatoid arthritis: Identifying reversible and irreversible components
Authors: Aletaha Daniel , Smolen Josef , Ward Michael M.
Published: August 2006

Objective

Measurement of physical function at one point in time cannot distinguish impairment caused by the active disease process from chronic irreversible impairment. We aimed to dissect these two components of functional limitation in rheumatoid arthritis (RA) by using the disability index of the Health Assessment Questionnaire (HAQ) as the measure of function.

Methods

We performed a secondary analysis of data from 6 contemporary clinical trials of RA (2,763 patients). Patients in whom remission was achieved in the trials, based on a simplified disease activity index, were identified. In an individual patient, HAQ scores at trial entry represented both reversible and irreversible impairments, while HAQ scores at the time of RA remission represented the mostly irreversible component, and the difference between these corresponded to the component related to disease activity. We tested the concept that the HAQ has a reversible and an irreversible component by associating the HAQ score during remission with 2 measures associated with the degree of accrued damage: duration of RA and radiographic severity.

Results

Among patients in whom clinical remission was achieved (n = 295), average HAQ scores despite clinical remission increased progressively with the duration of RA, from 0.19 (<2 years of RA) to 0.36 (2–<5 years) to 0.38 (5–<10 years) to 0.55 (≥10 years) (P < 0.001). The reversibility of HAQ scores decreased with the duration of RA (median 100%, 83.3%, 81.9%, and 66.7%, respectively; P < 0.001). Findings were similar in patients subgrouped by quartile of radiographic scores.

Conclusion

Differences in the sources of functional limitations should be considered in the interpretation of functional measures, and in their use for prediction and in cost analyses.
Insulin resistance and impaired beta cell function in rheumatoid arthritis
Authors: Dessein Patrick H. , Joffe Barry I.
Published: August 2006

Objective

To identify factors that regulate glucose metabolism in rheumatoid arthritis (RA).

Methods

We evaluated the homeostatic model assessment of insulin resistance (HOMA‐IR) and beta cell function (HOMA‐B) in 94 RA patients. We investigated the relationship between characteristics known to affect glucose metabolism in the general population (age, abdominal obesity [waist circumference], hypertension, antihypertensive therapy) as well as characteristics of RA (disease activity, glucocorticoid therapy) and insulin resistance and beta cell function.

Results

Patients with high‐grade inflammation (high‐sensitivity C‐reactive protein value >1.92 mg/liter) (n = 81) were more insulin resistant than patients with low‐grade inflammation (n = 13), whereas beta cell function was similar in both groups. Insulin resistance and beta cell function were similar in both groups after adjustment for waist circumference. All recorded characteristics except for age were associated with HOMA‐IR or/and HOMA‐B in univariate analyses. In mixed regression models, abdominal obesity and patient's assessment of disease activity (by visual analog scale) were predictors of insulin resistance. The Disease Activity Score assessed using 28‐joint counts for swelling and tenderness, tender joint count, and patient's assessment of disease activity were associated with reduced beta cell function, and the cumulative dose of glucocorticoids was associated with enhanced beta cell function. The cumulative glucocorticoid dose in all study patients was a mean of only 536 mg (95% confidence interval 239–1,173). In patients with high‐grade inflammation, age was further associated with impaired beta cell function, whereas use of angiotensin‐converting enzyme inhibitors or angiotensin II type 1 receptor blockers was associated with enhanced beta cell function.

Conclusion

The modifiable factors of abdominal obesity, antihypertensive therapy, disease activity, and use of glucocorticoids appear to affect glucose metabolism in RA.
Tumor necrosis factor α antagonist use and cancer in patients with rheumatoid arthritis
Authors: Setoguchi Soko , Solomon Daniel H. , Weinblatt Michael E. , Katz Jeffrey N. , Avorn Jerry , Glynn Robert J. , Cook E. Francis , Carney Greg , Schneeweiss Sebastian
Published: August 2006

Objective

Concerns persist about a possible association between tumor necrosis factor α (TNFα) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease‐modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA.

Methods

We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on ≥1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time‐varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma).

Results

The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person‐years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person‐years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score–adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71–2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65–1.26) for solid tumors.

Conclusion

Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge.
Association of HLA–C3 and smoking with vasculitis in patients with rheumatoid arthritis
Authors: Turesson Carl , Schaid Daniel J. , Weyand Cornelia M. , Jacobsson Lennart T. , Goronzy Jörg J. , Petersson Ingemar F. , Dechant Sonja A. , Nyähll‐Wåhlin Britt‐Marie , Truedsson Lennart , Sturfelt Gunnar , Matteson Eric L.
Published: August 2006

Objective

To compare HLA–C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease.

Methods

Patients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non‐ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction–based HLA–C genotyping was performed using a sequence‐specific primer kit.

Results

The distribution of HLA–C alleles was significantly different between patients with RA‐associated vasculitis and non‐ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA–C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non‐ExRA controls; P < 0.001) and a decreased frequency of HLA–C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA–C3 and vasculitis was not due to linkage disequilibrium with HLA–DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA–C3 and smoking were both significant predictors of vasculitis in a multivariate model.

Conclusion

Vasculitis in RA is associated with HLA–C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.
Increased collagen degradation around loosened total hip replacement implants
Authors: Ma Guo‐Feng , Ali Ahmed , Verzijl Nicole , Hanemaaijer Roeland , TeKoppele Johan , T. Konttinen Yrjö , Salo Jari
Published: August 2006

Objective

To assess collagen degradation and its relationship to some of the key collagenolytic proteinases in the aggressive synovial membrane–like interface tissue around aseptically loosened hip replacement implants.

Methods

The medical indication for the primary total hip replacement was osteoarthritis in all study patients. Samples from the study patients were compared with control synovial membranes obtained from trauma (hip fracture) patients. Proteoglycans were extracted with 4M guanidinium chloride. Denatured collagen in the remaining matrix was solubilized with α‐chymotrypsin. Nonsoluble matrix and supernatant fractions were acid hydrolyzed before measurement of hydroxyproline. The proportion of soluble (in vivo–degraded) collagen of the total sample collagen content was calculated. Proteinases were stained using the avidin–biotin–peroxidase complex method.

Results

Collagen in the interface membrane from the implants was highly degraded (mean ± SEM 20 ± 3%) compared with that in the control synovial membranes (12 ± 1%; P = 0.007). In controls, the degree of collagen degradation did not correlate with levels of matrix metalloproteinase 1 (MMP‐1), MMP‐13, or cathepsin K, although MMP‐1 approached statistical significance. In interface membranes, the correlations were r = 0.88 (P = 0.002), r = 0.92 (P = 0.001), and r = 0.98 (P < 0.0001) for MMP‐1, MMP‐13, and cathepsin K, respectively.

Conclusion

In normal synovial membrane, collagen matrix remodeling may be mainly an intracellular process. In contrast, pathologic tissue destruction in the interface membrane from prosthetic hip joints is associated with a shift toward MMP‐13 and cathepsin K, which become activated and overcome their endogenous inhibitors (tissue inhibitors of metalloproteinases and cystatin C). The highly significant correlation between collagen degradation and cathepsin K indicates an extracellular role of this acidic endoproteinase, consistent with previous observations concerning the acidity of the interface membrane.
Clinical differences between idiopathic and scleroderma‐related pulmonary hypertension
Authors: Fisher Micah R. , Mathai Stephen C. , Champion Hunter C. , Girgis Reda E. , Housten‐Harris Traci , Hummers Laura , Krishnan Jerry A. , Wigley Fredrick , Hassoun Paul M.
Published: August 2006

Objective

Pulmonary arterial hypertension related to scleroderma (PAH‐Scl) is associated with high morbidity and mortality as well as poorer response to therapy and worse outcomes compared with the idiopathic form of PAH (IPAH). Scleroderma is an autoimmune disease that can affect left and right heart function directly through inflammation and fibrosis and indirectly through systemic and pulmonary hypertension. This study tested the hypothesis that an increased prevalence of left heart disease might explain the higher mortality in patients with PAH‐Scl compared with patients with IPAH.

Methods

The study was designed as a retrospective cohort study comparing the baseline clinical data from 91 consecutive patients (41 with IPAH and 50 with PAH‐Scl). Cox proportional hazards models were used to predict the effect of clinical covariates on patient survival.

Results

Patients with PAH‐Scl had a lower mean pulmonary artery pressure (46.6 mm Hg versus 54.4 mm Hg in patients with IPAH; P = 0.002) despite similar levels of cardiac dysfunction (cardiac index 2.2 and 2.1 liters/minute/m2, respectively; P = 0.19). Echocardiography revealed similar degrees of right ventricular dysfunction in the 2 groups, whereas a predominance of left heart dysfunction was observed in patients with PAH‐Scl. One‐ and three‐year survival estimates were 87.8% and 48.9%, respectively, in patients with PAH‐Scl and 95.1% and 83.6%, respectively, in those with IPAH. Patients with PAH‐Scl were 3.06 times more likely to die than were patients with IPAH, after controlling for the presence of pericardial effusion; there was no significant change in increased risk of death in PAH‐Scl after controlling for left heart disease.

Conclusion

The results confirm that there are significant clinical and survival differences between IPAH and PAH‐Scl. The presence of left heart disease, although more common in PAH‐Scl, was not predictive of the higher mortality in these patients.
Up‐regulated transforming growth factor β–inducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through αvβ3 integrin: Regulation by cytokines
Authors: Nam Eon Jeong , Sa Keum Hee , You Dong Wan , Cho Jang Hee , Seo Jae Seok , Han Seung Woo , Park Jae Yong , Kim Sung Il , Kyung Hee Soo , Kim In San , Kang Young Mo
Published: August 2006

Objective

To delineate the expression of transforming growth factor β–inducible gene h3 (βIG‐H3) in rheumatoid synovitis and to determine the regulatory role of βIG‐H3 in the adhesion and migration of fibroblast‐like synoviocytes (FLS).

Methods

Synovial tissue was obtained from patients with rheumatoid arthritis (RA) during joint replacement surgery, and FLS were isolated using enzymatic treatment. Immunohistochemical staining was performed to show the expression of βIG‐H3 within rheumatoid synovium. Synthesis of βIG‐H3 from FLS was determined by semiquantitative reverse transcription–polymerase chain reaction, Western blot analysis, and enzyme‐linked immunosorbent assay. Cell adhesion and migration assays were performed using the YH18 peptide in the fourth fas‐1 domain of βIG‐H3 and function‐blocking antibodies to integrins.

Results

Expression of βIG‐H3 was up‐regulated in RA synovial tissue compared with synovial tissue from patients with osteoarthritis. FLS isolated from RA synovial tissue constitutively produced βIG‐H3, which was up‐regulated by transforming growth factor β1, interleukin‐1β, and tumor necrosis factor α. Although FLS expressed a variety of integrins, βIG‐H3 mediated adhesion and migration of FLS through interaction with αvβ3 integrin. Cytokines failed to affect the βIG‐H3–mediated adhesion. However, migration of FLS guided by βIG‐H3 was enhanced by interferon‐γ and platelet‐derived growth factor type BB. The YH18 peptide in the fourth fas‐1 domain of βIG‐H3 inhibited adhesion and migration in a dose‐dependent manner.

Conclusion

The results suggest that βIG‐H3, which is abundantly expressed in RA synovial tissue, plays a regulatory role in chronic destructive inflammation through the modulation of the adhesion and migration of FLS. This finding indicates the relevance of βIG‐H3 and αvβ3 integrin–interacting motifs as potential therapeutic targets in this disease.
Differential tissue expression and activation of p38 MAPK α, β, γ, and δ isoforms in rheumatoid arthritis
Authors: Korb Adelheid , Tohidast‐Akrad Makiyeh , Cetin Erdal , Axmann Roland , Smolen Josef , Schett Georg
Published: August 2006

Objective

Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (α, β, γ, and δ), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease.

Methods

Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the α, β, γ, and δ isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry.

Results

Immunoblot analysis revealed that α and γ were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cell‐specific markers revealed that macrophages expressed the α and γ isoforms, synovial fibroblasts the β and γ isoforms, and granulocytes the δ isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double‐labeling with isoform‐specific antibody and pan‐p38 antibody against the phosphorylated form of p38 MAPK showed activation of the α and γ isoforms. Occasional activation of the β isoform was also noted in the synovial lining and the endothelium, whereas the δ isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPKα and ‐γ but not p38 MAPKβ or ‐δ.

Conclusion

These data show that the α and γ isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.
Rapamycin reduces disease activity and normalizes T cell activation–induced calcium fluxing in patients with systemic lupus erythematosus
Authors: Fernandez David , Bonilla Eduardo , Mirza Naureen , Niland Brian , Perl Andras
Published: August 2006

Objective

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Current treatment options are often ineffective or poorly tolerated. Recent observations have revealed mitochondrial hyperpolarization and enhanced Ca2+ fluxing in T cells from SLE patients. Rapamycin, a lipophilic macrolide antibiotic that regulates mitochondrial transmembrane potential and Ca2+ fluxing, has been used safely and effectively to treat renal transplant rejection since 1999. In addition, rapamycin has been shown to ameliorate T cell function and to prolong survival in lupus‐prone MRL/lpr mice. We therefore undertook the present study to investigate whether rapamycin is beneficial in patients with SLE.

Methods

Nine patients with clinically active SLE that had been treated unsuccessfully with other immunosuppressive medications began therapy with rapamycin, 2 mg/day orally. Disease activity was assessed with the British Isles Lupus Assessment Group (BILAG) score, SLE Disease Activity Index (SLEDAI), and requirement for prednisone therapy. Mitochondrial transmembrane potential and Ca2+ fluxing were assessed by flow cytometry.

Results

In patients treated with rapamycin, the BILAG score was reduced by a mean ± SEM of 1.93 ± 0.9 (P = 0.0218), the SLEDAI by 5.3 ± 0.8 (P = 0.00002), and concurrent prednisone use by 26.4 ± 6.7 mg/day (P = 0.0062) compared with pre–rapamycin treatment. While mitochondrial hyperpolarization persisted, pretreatment cytosolic and mitochondrial Ca2+ levels and T cell activation–induced rapid Ca2+ fluxing were normalized in rapamycin‐treated patients.

Conclusion

Rapamycin appears to be a safe and effective therapy for SLE that has been refractory to traditional medications. Mitochondrial dysfunction and Ca2+ fluxing could serve as biomarkers to guide decisions regarding future therapeutic interventions in SLE.
Successful use of a humanized anti–interleukin‐6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis
Authors: Okuda Yasuaki , Takasugi Kiyoshi
Published: August 2006

We report an excellent clinical response to treatment with a humanized anti–interleukin‐6 receptor antibody, tocilizumab, in a patient with progressive amyloid A (AA) amyloidosis complicating very active juvenile idiopathic arthritis. Treatment with tocilizumab immediately normalized the serum AA (SAA) level, and subsequently all of the clinical symptoms of AA amyloidosis disappeared. Serial gastrointestinal biopsy specimens showed marked lasting regression of AA protein deposits. The patient's functional ability score improved dramatically, she maintains her mobility, and she has regained her previous quality of life. Tocilizumab appears to have an excellent ability to suppress SAA levels and could therefore be an important therapeutic strategy in AA amyloidosis secondary to rheumatic diseases.
“Gedankenaustausch über Probleme und Methoden der Forschung”. Transatlantische Gastprofessoren aus Emigrantenkreisen in Westdeutschland nach 1945
Authors: Krauss Marita
Published: August 2006

The history of the sciences and humanities follows cycles in some of which there is greater emphasis on the continuity of developments, in others on the breaks in continuity. In recent years the main focus of research for the 20th century has been on the continuities extending beyond the boundaries of 1933 and 1945. The main aim of this study, however, is to examine the impulses for the internationalization of German universities provided by a transnational group of academic migrants. These migrants, whose origins were in the German academic community, represented an alternative continuity beyond the boundaries of this period: they were visiting academics who were the conveyors and interpreters of ideas from Germany into the USA and Britain and vice versa. The study of this group therefore combines remigration history and the history of universities as institutions, focussing on actors, networks and innovations in teaching, with the history of individual subjects and disciplines.
Wissenstransfer durch Zentrenbildung. Physikalische Methoden in der Chemie und den Biowissenschaften
Authors: Reinhardt Carsten
Published: August 2006

From the 1950s to 1970s, physical techniques replaced many classical methods in the chemical and biological sciences. In this development, a novel type of method‐oriented scientists emerged, relying on cooperation with instrument manufacturers and forging close links with science‐funding agencies. Their main engagement was the development of methods and the improvement of instruments, responding to the needs of the chemical and biomedical communities. In the United States, an important institutional locus of such method‐oriented scientists were instrument centers, providing service to regional and national groups of scientific users. This article analyzes the knowledge transfer involved in investigating the Biotechnology Resources Program of the National Institutes of Health, and presenting the example of one of these centers, the Stanford Magnetic Resonance Laboratory.
Globaler Pflanzentransfer und seine Transferinstanzen als Kultur‐, Wissens‐ und Wissenschaftstransfer der frühen Neuzeit
Authors: Klemun Marianne
Published: August 2006

In three steps, the polyvalent phenomenon of global plant transfer will be analysed. Starting from the model of cultural transfer, the latter one will be discussed in combination with network research. Finally, the connection of various instances of transfer such as botanical gardens, ships and islands will be established. The fact that botanists take part in the process of transfer increasingly and from the middle of the 18th century onwards control the plant transfers in all phases emphasises the entwinement of science and colonialism.
Optimal Spending Functions for Asymmetric Group Sequential Designs
Authors: Anderson Keaven M.
Published: August 2006

We present optimized group sequential designs where testing of a single parameter θ is of interest. We require specification of a loss function and of a prior distribution for θ. For the examples presented, we pre‐specify Type I and II error rates and minimize the expected sample size over the prior distribution for θ. Minimizing the square of sample size rather than the sample size is found to produce designs with slightly less aggressive interim stopping rules and smaller maximum sample sizes with essentially identical expected sample size. We compare optimal designs using Hwang‐Shih‐DeCani and Kim‐DeMets spending functions to fully optimized designs not restricted by a spending function family. In the examples selected, we also examine when there might be substantial benefit gained by adding an interim analysis. Finally, we provide specific optimal asymmetric spending function designs that should be generally useful and simply applied when a design with minimal expected sample size is desired. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)