bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a High‐Fat Meal on the Pharmacokinetics of the Des‐F(6)‐Quinolone BMS‐284756
Authors: Gajjar Diptee A. , Sukoneck Samuel C. , Bello Akintunde , Ge Zhiyu , Christopher Lisa , Grasela Dennis M.
Published: May 2004

Study Objective. To evaluate the effects of a high‐fat meal on the systemic exposure of oral BMS‐284756.

Design. Open‐label, randomized, two‐way crossover study.

Setting. Clinical research facility.

Subjects. Fourteen healthy individuals.

Interventions. Participants received two single 400‐mg doses of BMS‐284756, separated by at least 1 week. One dose was given while participants were fasting, and one dose was given within 5 minutes of consumption of a high‐fat meal.

Measurements and Main Results. Serial blood samples were collected, and plasma samples were analyzed for BMS‐284756 using a validated liquid chromatography with tandem mass spectrometry detection method. Maximum plasma concentration and area under the plasma concentration‐time curve (AUC) after the high‐fat meal were 19% and 11% lower, respectively, than those in the fasted state. The 90% confidence intervals for the ratios of means (0.71‐0.94 and 0.85‐0.93, respectively) satisfied predefined equivalence criteria. Equivalence of the AUC values for BMS‐284756 in fed and fasted individuals indicates that the presence of food should not affect the efficacy of this drug.

Conclusion. Single doses of BMS‐284756 were safe and well tolerated and may be taken without regard to meals.
Hemorrhagic Complications of Enoxaparin and Aspirin in Patients with Kidney Transplants
Authors: Shullo Michael A. , Rose Meredith L. , Vivas Carlos , Jordan Mark L. , Scantlebury Velma P. , Jain Ashok , Corry Robert J. , Fung John J. , McCauley Jerry , Johnston James , Shapiro Ron
Published: May 2004

Study Objective. To evaluate the frequency of early posttransplant hemorrhagic complications in patients with kidney and kidney‐pancreas transplants who received thromboprophylaxis with enoxaparin and aspirin.

Design. Retrospective chart review.

Setting. University‐based tertiary care center.

Patients. Thirteen patients who had received enoxaparin within 10 days of kidney or kidney‐pancreas transplantation.

Intervention. Medical records were reviewed, and data from patients who had received low‐dose aspirin 81 mg once/day and enoxaparin within 10 days of transplantation were collected.

Measurements and Main Results. Major bleeding events were defined as intracranial or retroperitoneal bleeding, or a decrease in hemoglobin of greater than 2 g/dl that was confirmed on repeat evaluation. Nine (69%) of the 13 patients had confirmed major bleeding events and required blood transfusions. Six of the nine patients had elevated serum creatinine levels.

Conclusion. The combination of enoxaparin and low‐dose aspirin early after kidney or kidney‐pancreas transplantation was associated with a high frequency of hemorrhagic events. Further evaluation is needed to determine the safety of enoxaparin in combination with aspirin after transplantation.
Parenteral Nutrition‐Associated Liver Complications in Children
Authors: Btaiche Imad F. , Khalidi Nabil
Published: May 2004

Parenteral nutrition is a life‐saving therapy for patients with intestinal failure. It may be associated with transient elevations of liver enzyme concentrations, which return to normal after parenteral nutrition is discontinued. Prolonged parenteral nutrition is associated with complications affecting the hepatobiliary system, such as cholelithiasis, cholestasis, and steatosis. The most common of these is parenteral nutrition‐associated cholestasis (PNAC), which may occur in children and may progress to liver failure. The pathophysiology of PNAC is poorly understood, and the etiology is multifactorial. Risk factors include prematurity, long duration of parenteral nutrition, sepsis, lack of bowel motility, and short bowel syndrome. Possible etiologies include excessive caloric administration, parenteral nutrition components, and nutritional deficiencies. Several measures can be undertaken to prevent PNAC, such as avoiding overfeeding, providing a balanced source of energy, weaning parenteral nutrition, starting enteral feeding, and avoiding sepsis.
Combination Therapy with Inhaled Long‐Acting β2‐Agonists and Inhaled Corticosteroids: A Paradigm Shift in Asthma Management
Authors: Stoloff Stuart , Poinsett‐Holmes Kim , Dorinsky Paul M.
Published: May 2004

Long‐acting inhaled β2‐Agonists and inhaled corticosteroids are classes of drugs with different mechanisms of action that are commonly used to provide effective long‐term control of persistent asthma. Scientific and clinical data support the complementary mechanisms of action of the inhaled corticosteroids and the long‐acting β2‐Agonists in achieving a superior level of asthma control. In addition, evidence supports significant reductions in exacerbations and effective control of airway inflammation with an inhaled corticosteroid and a long‐acting β2‐Agonist versus higher dosages of inhaled corticosteroids or combinations of other therapeutic agents with an inhaled corticosteroid. Finally, there are distinct economic advantages to combining an inhaled corticosteroid and a long‐acting β2‐Agonist in the treatment of asthma relative to other treatment regimens.
Therapy with Macrolides in Patients with Cystic Fibrosis
Authors: Gaylor Allyson S. , Reilly Joan C.
Published: May 2004

Cystic fibrosis affects 1/2500 individuals and is the most common lethal autosomal recessive disease in people of northern European descent. It is characterized by chronic infections with mucoid Pseudomonas aeruginosa and progressive deterioration of respiratory function. Much research has focused on the inflammatory component of the disease. Macrolide antibiotics are postulated to suppress inflammatory mediators and interfere with biofilm formation produced by P. aeruginosa. In vitro studies show promising results, and a limited number of human studies reported improvements in respiratory function with the drugs. Macrolide antibiotics are generally safe and well tolerated and may prove to be effective in patients with cystic fibrosis.
Management of Opioid‐Induced Gastrointestinal Effects in Patients Receiving Palliative Care
Authors: Herndon Christopher M. , Jackson Kenneth C. , Hallin Pamala A.
Published: May 2004

Opioid‐induced gastrointestinal side effects, namely, nausea and constipation, are bothersome yet often easy to manage. Due to their widespread frequency, it is imperative that prophylactic and treatment modalities be understood. Although many pharmacotherapeutic agents are available with which to prevent or treat these side effects, few randomized, placebo‐controlled studies have been conducted in terminally ill patients, thus limiting most treatment decisions to empiric therapies based on extrapolated data. A strong understanding of the pathophysiology of the sequelae is therefore paramount. Common agents administered for nausea are butyrophenones, phenothiazines, metoclopramide, and serotonin‐receptor antagonists. Those given to manage constipation are stimulant laxatives and stool softeners, individually or in combination.
Warfarin‐Associated Bleeding Complication Saved Life
Authors: McCall Kenneth L. , MacLaughlin Eric J.
Published: May 2004

A 62‐year‐old Caucasian man with atrial fibrillation who was taking warfarin reported an episode of hematochezia; his international normalized ratio (INR) was 1.74. His weekly warfarin dose was increased by approximately 5%, and he was given three fecal occult blood cards. At follow‐up 1 week later, the patient denied any episodes of hematochezia. His INR was 1.69 despite the increased warfarin dosage. One of the occult blood cards showed a positive result, and colonoscopy revealed a 5‐cm lesion, identified as Dukes' A adenocarcinoma. Warfarin‐associated bleeding generally is considered deleterious; however, in our patient it unmasked an early stage of colon cancer and thus may have saved the patient's life. Although minor gastrointestinal bleeding is common among patients taking anticoagulants, all patients should be fully evaluated because the source of hemorrhage may be malignant.
Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients
Authors: Wiehahn G.J. , Bosch G.P. , du Preez R.R. , Pretorius H.W. , Karayiorgou M. , Roos J.L.
Published: June 2004

A hemizygous deletion of the q11 band on chromosome 22 occurs in 1 of every 5,950 live births (0.017%). The deletion is mediated by low copy repeats (LCRs) flanking this locus. Presence of the deletion is associated with variable phenotypic expression, which can include distinctive facial dysmorphologies, congenital heart disease and learning disabilities. An unusually high percentage of individuals with this deletion (25–30%) have been described to develop schizophrenia or schizoaffective disorder. In previous studies, the prevalence of the 22q11 deletion in patients with schizophrenia was found to be approximately 2% in Caucasian adults and 6% in childhood‐onset cases. Both these frequencies represent a dramatic increase from the prevalence of the deletion in the general population. In this study, we investigate the occurrence of the 22q11 deletion in an independent sample of schizophrenic patients of Afrikaner origin. We first ascertained a sample of 85 patients who meet full diagnostic criteria for schizophrenia for presence of two or more of the clinical features associated with presence of the 22q11 deletion. A group of six patients (7%) met these criteria. This group was subjected to fluorescent in situ hybridization (FISH) and presence of the 22q11 deletion was confirmed for two subjects. Our study therefore confirms the previously reported rate of 2% frequency of the 22q11 deletion in adult schizophrenic patients and provides a two‐stage screening protocol to identify these patients. © 2004 Wiley‐Liss, Inc.
Synthesis and structure of polysiloxane liquid crystalline elastomers with a mesogenic crosslinking agent
Authors: Jia Ying‐Gang , Zhang Bao‐Yan , Tian Mei , Pan Wei
Published: June 2004

A new mesogenic crosslinking agent M‐1 was synthesized to minimize the perturbations of a nonmesogenic crosslinking agent for liquid crystalline elastomers. The synthesis of new side‐chain liquid crystalline elastomers containing a rigid mesogenic crosslinking agent M‐1 and a nematic monomer M‐2 is described by a one‐step hydrosilylation reaction. The chemical structures of the obtained monomers and elastomers were confirmed by 1H NMR and FTIR spectroscopy. The mesomorphic properties and phase behavior were investigated by differential scanning calorimetry, polarizing optical microscopy, and X‐ray diffraction measurements. The influence of the crosslinking units on the phase behavior is discussed. The elastomers containing less than 15 mol % of the crosslinking units showed elasticity, reversible phase transition, and nematic‐threaded texture. However, when the crosslinking density reached 21.6 mol %, the mesophase of polymer P‐8 disappears. The adoption of a mesogenic crosslinking agent diminishes the perturbation of a nonmesogenic crosslinking agent on mesophase of liquid crystalline elastomers, and isotropic temperature and a mesomorphic temperature range slightly decreased with increasing content of the crosslinking agent. In addition, X‐ray analysis shows nematic polydomain network polymers can transform into smectic monodomain by stress induction, leading to the orientation formation macroscopically. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1736–1742, 2004
Crosslinking of natural and polybutadiene rubbers with thiuram sulfur donors in the presence of a thiuram monosulfide
Authors: Valentín J. L. , Rodríguez A. , Marcos‐Fernández A. , González L.
Published: June 2004

The influence of tetramethylthiuram monosulfide (TMTM) in the vulcanization process of natural rubber and butadiene rubber with dipentamethylene thiuram tetrasulfide (DPTT) was investigated. Vulcanization parameters as reaction rate and reversion varied when TMTM was added in NR‐DPTT formulations. Crosslinking density and proportion of monosulfidic crosslinks increased with TMTM content increase. However, a drop in physical properties was observed at high TMTM content and at long times of curing well over t97. Formation of densely crosslinked areas due to polymerization reaction was postulated as the origin of these variations. In BR‐DPTT compounds, torque and monosulfidic crosslink proportions increased when TMTM was added. Polymerization reaction takes place in BR systems too. However, in BR vulcanizates, C—C bonds decreased with TMTM proportion, whereas in NR vulcanizates increased. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1756–1761, 2004
Tensile properties, morphology, and thermal behavior of PVC composites containing pine flour and bamboo flour
Authors: Ge X. C. , Li X. H. , Meng Y. Z.
Published: June 2004

Composites of unplasticized poly(vinyl chloride) (PVC) blended with bamboo flour and pine flour, respectively, were prepared in a batch mixer followed by compression molding. The effects of wood flour fillers on the morphology, static mechanical properties, and thermal properties of the composites were investigated. Compared with neat PVC resin, the introduction of both bamboo flour and pine flour significantly improved the stiffness of the composites, while decreasing the tensile strength to some extent. Tensile tests showed that pine flour–filled composites exhibited better mechanical properties than those filled with bamboo flour with the same particle size at the same loading level. Scanning electron microscopic examination revealed good dispersion and alignment tendency of short pine fiber within the composites at a lower loading level. Moreover, experimental results indicated that both bamboo flour and pine flour additions showed no obviously adverse effect on the thermal stabilities of these composites. Based on the comprehensive properties, these composites meet the need of woodlike material for use as wood structures. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1804–1811, 2004
Influence of alkali treatment on the structure of newcell fibers
Authors: Zhu Yawei , Ren Xuehong , Wu Chengyu
Published: June 2004

Alkali treatment can change the structures and properties of cellulosic fibers. The aim of this work was to study the mechanism of structural changes of Newcell fibers treated with different alkali concentrations and two treatment methods. Raman spectra showed that the molecular conformation of Newcell fibers remained unchanged. X‐ray diffraction indicated that the crystal structure of Newcell cellulose II, treated with different alkali concentrations and different methods, did not change. With the increase of alkali concentration the crystallinty and crystallinity orientation index of Newcell fibers in their original length decreased slightly, whereas those of fibers in relaxed condition substantially decreased, and the crystallite size of 101¯ and 002 increased in both methods. The quasi‐crystallite disassociation and recrystallization in the quasi‐crystalline phase, during the process of alkali treatment, led to changes of crystallinity and orientation index of Newcell fibers. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1731–1735, 2004
Lead Identification for Modulators of Multidrug Resistance based on in silico Screening with a Pharmacophoric Feature Model
Authors: Langer Thierry , Eder Monika , Hoffmann Remy D. , Chiba Peter , Ecker Gerhard F.
Published: June 2004

Considerable effort has been devoted to the characterization of P‐glycoprotein — drug interaction in the past. Systematic quantitative structure‐activity relationship (QSAR) studies identified both predictive physicochemical parameters and pharmacophoric substructures within homologous series of compounds. Comparative molecular field analysis (CoMFA) led to distinct 3D‐QSAR models for propafenone and phenothiazine analogs. Recently, several pharmacophore models have been generated for diverse sets of ligands. Starting from a training set of 15 propafenone‐type MDR‐modulators, we established a chemical function‐based pharmacophore model. The pharmacophoric features identified by this model were (i) one hydrogen bond acceptor, (ii) one hydrophobic area, (iii) two aromatic hydrophobic areas, and (iv) one positive ionizable group. In silico screening of the Derwent World Drug Index using the model led to identification of 28 compounds. Substances retrieved by database screening are diverse in structure and include dihydropyridines, chloroquine analogs, phenothiazines, and terfenadine. On the basis of its general applicability, the presented 3DQSAR model allows in silico screening of virtual compound libraries to identify new potential lead compounds.
New Antithrombotics with an Indazole Structure
Authors: Yildiz Ali Kemal , Rehse Klaus , Stasch Johannes‐Peter , Bischoff Erwin
Published: June 2004

Fifteen new indazole derivatives have been synthesized. In the Born test, compounds 4f and 4g were most active. They inhibited the blood platelet aggregation induced by collagen with an IC50 = 85 or 90 μM, respectively. After oral administration to rats (60 mg/kg) three of the compounds significantly inhibited the formation of thrombi in arterioles and venules. The strongest effect was observed with 4j which showed an inhibition of 15% in arterioles and 7% in venules. Further experiments showed that compound 4j does not mediate these effects by activating soluble guanylate cyclase, but likely by inhibiting phosphodiesterase isoform PDE 5.
Phenylpiperazinylmethylheterocycle Derivatives: Synthesis and Dopamine Receptor Binding Profiles
Authors: Abadi Ashraf H.
Published: June 2004

Four series of phenylpiperazinylmethylimidazo[1, 2‐a]pyridine, phenylpiperazinylmethylpyrrole, phenylpiperazinylmethylbenzofuran, and phenylpiperazinylmethylbenzothiophene derivatives were synthesized and investigated for their in vitro binding profiles for the dopamine receptor subtypes D1, D2long, D2short, D3 and D4. All tested compounds showed selectivity towards the D4 receptor subtype. Affinity and selectivity for D4 follows the order imidazo[1, 2‐a]pyridine > benzofuran > benzothiophene > pyrrole derivatives. The D4‐related affinity and selectivity pattern seems to be dependent on the presence of a region of negative molecular electrostatic potential below the heterocyclic moiety.
Electrostatic Surface Potential Calculation on Several New Halogenated Benzimidazole‐like Dopaminergic Ligands
Authors: Šukalović V. , Andrić Deana , Roglić G. , Kostić‐Rajacčić Sladjana , Šoškić V.
Published: June 2004

We examined the effects of the electron density distribution (electrostatic surface potential; ESP) of several new benzimidazole‐type ligands on their binding affinity for the D1 and D2 dopamine receptors (DAR). Receptors were prepared from synaptosomal membranes of bovine caudate nuclei. [3H]SCH 23390 and [3H]spiperone were used as specific radiolabels for the D1 and D2 receptors, respectively. The ESP of these compounds was calculated using Gaussian 98 W software. Calculations performed with known dopaminergic ligands showed that the electron density charge in the aromatic ring of these compounds favors a higher binding affinity for the D2 DAR. This was confirmed by the synthesis of halogenated analogues of several known dopaminergic ligands. Halogenation resulted in an increase in the positive charge of the aromatic part of the molecule. None of the newly synthesized compounds was efficient in displacing [3H]SCH 23390 from the D1 DAR. The introduction of chlorine into the molecule led to a higher binding affinity for the D2 DAR of the new ligands in comparison to both parent compounds and brominated ligands. This difference probably originates from the difference in the sizes of chlorine and bromine atoms, which could influence the interaction of a ligand with the receptor binding site. However, among the new ligands with bromine as a substituent, two compounds (8b and 10b) expressed a higher binding affinity and two of them (9b and 11b) a lower binding affinity for the D2 DAR, when compared to unsubstituted parent compounds. These results indicate that the electrostatic surface potential of a ligand is an important factor in its interaction with the D2 DAR and that this should be taken into account during design and synthesis of dopaminergic compounds.
[1, 2‐Bis(2, 6‐difluoro‐3‐hydroxyphenyl)ethylene‐diamine]platinum(II) Complexes, Compounds for the Endocrine Therapy of Breast Cancer ‐ Mode of Action II: Contribution of Drug Inactivation, Cellular Drug Uptake and Sterical Factors in the Drug‐Target Interaction to the Antitumor Activity
Authors: Schertl Sabine , Hartmann Rolf W. , Batzl‐Hartmann Christine , Bernhardt Günther , Spruß Thilo , Beckenlehner Karin , Koch Marion , Krauser Rudolf , Schlemmer Richard , Gust Ronald , Schönenberger Helmut
Published: June 2004

The marked activity of [meso‐1, 2‐bis(2, 6‐difluoro‐3‐hydroxyphenyl)ethylenediamine]platinum(II) (meso‐3‐PtLL′, L, L′ = Cl2 or L = OH2, L′ = OSO3) on the hormone‐sensitive MXT‐M‐3, 2 breast cancer implanted in mice is most probably due to a mechanism based on the reduction of the endogenous estrogen level. Cytotoxic effects which are poorly pronounced in experiments on several breast cancer cell lines (e.g. MCF‐7), do not significantly contribute to the anti‐breast cancer activity of this compound. In contrast to this, the standard cisplatin and the structurally related comparison compound [meso‐1, 2‐bis(4‐fluorophenyl)ethylenediamine]platinum(II) (meso‐4‐PtLL′, L, L′ = Cl2 or L = OH2, L′ = OSO3) are strongly active in vivo as well as in vitro. Both effects entail programmed cell death, which is responsible for the inhibition of the tumor growth. The minor cytotoxicity of meso‐3‐PtLL′ in breast cancer cell cultures is caused neither by an inappropriate rate of reaction with bionucleophiles (e.g. by a too fast inactivation by plasma proteins) nor solely by the observed poor absorption by the tumor cells resulting in an insufficient drug concentration at the DNA. Additionally, an impeded reaction with biologically important, guanine‐rich sequences of DNA (owing to the 2, 6‐standing F atoms which hinder the drug‐target inter action) must be assumed as cause of its marginal cytotoxicity.
Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus
Authors: Ren Yi , Tang Jinling , Mok M. Y. , Chan Albert W. K. , Wu Adrian , Lau C. S.
Published: June 2004

Objective

To evaluate whether patients with systemic lupus erythematosus (SLE) have a higher rate of apoptosis in and secondary necrosis of polymorphonuclear neutrophils (PMNs) and macrophages compared with controls; to compare the rate of macrophage phagocytic clearance of apoptotic PMNs in patients with SLE and healthy controls; to evaluate whether in vitro PMN and macrophage apoptosis and secondary necrosis, and the ability of macrophages to phagocytose apoptotic bodies, are correlated with lupus disease activity; and to determine whether macrophage clearance of apoptotic bodies in patients with SLE and normal controls is related to certain serum factors.

Methods

Thirty‐six patients with SLE and 18 healthy, nonsmoking volunteers were studied. PMNs and monocytes were isolated from fresh blood and cultured in the presence of different sources of serum. Apoptotic PMNs and macrophages were examined by annexin V binding and morphology on May–Giemsa–stained cytopreparations, at different time points. The presence of secondary necrotic PMNs and macrophages was verified by staining with trypan blue. Macrophage phagocytosis of apoptotic PMNs was measured using a coded, observer‐blinded, microscopically quantified phagocytosis assay. Cells were cultured in the presence of serum obtained from healthy subjects or from patients with SLE.

Results

At 5 and 24 hours, the percentage of apoptotic PMNs from patients with SLE was significantly higher than that of PMNs from healthy subjects. At 24 and 48 hours, the percentage of secondary necrotic PMNs from patients with SLE was also significantly higher than the percentage of necrotic PMNs from controls. Serum from patients with SLE accelerated the rate of apoptosis in and secondary necrosis of PMNs from healthy subjects. Macrophages from SLE patients were less capable of phagocytosing apoptotic PMNs compared with macrophages obtained from controls. Macrophages from patients with active SLE were less capable of phagocytosing apoptotic PMNs than were macrophages from patients with inactive SLE, but the difference was not statistically significant. The percentage of phagocytosis of apoptotic PMNs by macrophages from SLE patients correlated negatively with the SLE Disease Activity Index, serum levels of anti–double‐stranded DNA, and the erythrocyte sedimentation rate, and correlated positively with serum levels of C3, C4, and albumin, the hemoglobin level, and the leukocyte count. Serum from SLE patients not only significantly increased macrophage apoptosis in cells from healthy subjects but also remarkably down‐regulated the clearance of apoptotic PMNs by macrophages from healthy subjects. In contrast, serum from healthy subjects significantly increased phagocytosis of apoptotic PMNs by macrophages from SLE patients.

Conclusion
Reduction of atherosclerosis in low‐density lipoprotein receptor–deficient mice by passive administration of antiphospholipid antibody
Authors: Nicolo Danielle , Goldman Bruce I. , Monestier Marc
Published: June 2004

Objective

Patients with antiphospholipid syndrome (APS) are at a high risk of developing atherosclerotic complications. Conversely, individuals with primary atherosclerosis have an increased prevalence of antiphospholipid antibodies (aPL) and antibodies to oxidized low‐density lipoproteins (ox‐LDL). Several studies suggest that these two antibody populations may in fact overlap, although it is unclear how aPL contribute to pathogenesis. In this study, we characterized an IgG monoclonal aPL and assessed its ability to modulate atherosclerosis in low‐density lipoprotein receptor–deficient (LDLR−/−) mice.

Methods

The cardiolipin‐reactive monoclonal antibody FB1 was obtained from an (NZW × BXSB)F1 mouse, a strain with APS features that make it prone to fatal myocardial infarctions. Using an enzyme‐linked immunosorbent assay, we investigated the binding of this antibody to phospholipid and LDL antigens. We also passively administered FB1 to atherosclerosis‐prone mice to determine its effect on atherogenesis.

Results

In contrast to earlier studies of aPL that were specific for oxidized forms of LDL, FB1 cross‐reacted with both native LDL and ox‐LDL. In vivo, passive administration of FB1 significantly reduced plaque formation in atherosclerosis‐prone LDLR−/− mice.

Conclusion

These results indicate that some aPL may play a protective role in atherogenesis and suggest a novel approach to the prevention of atherosclerosis.
Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate
Authors: Kremer Joel M. , Habros Joseph S. , Kolba Karen S. , Kaine Jeffrey L. , Borton Mary Ann , Mengle‐Gaw Laurel J. , Schwartz Benjamin D. , Wisemandle Wayne , Mekki, for the Tacrolimus‐Methotrexate Rheumatoid Arthritis Qais A.
Published: June 2004

Objective

To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX.

Methods

This was a multicenter open‐label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for ≥1 month with a stable, maximally tolerated dosage of oral MTX (≤20 mg/week, median dosage 15 mg/week, range 5–20 mg/week) were enrolled and received 3 mg/day tacrolimus as a single oral dose once per day for 6 months while continuing to receive MTX at the existing stable dosage. All other disease‐modifying antirheumatic drugs were discontinued; stable dosage of nonsteroidal antiinflammatory drugs and oral corticosteroids (≤10 mg/day prednisone or its equivalent) were allowed. All 80 patients received at least one dose of the study drug and were included in the primary safety and efficacy analyses. Seventy‐five patients had at least one postbaseline efficacy assessment, and 63 patients (78.8%) completed the study. The primary clinical response criterion was the American College of Rheumatology definition of 20% improvement (ACR20) at the end of treatment.

Results

Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (±SD) creatinine (Cr) level increased from 0.74 ± 0.16 mg/dl at baseline to 0.81 ± 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty‐three patients (28.8%) had a ≥30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6–63.4%).

Conclusion

In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well‐tolerated and provides clinical benefit.
Feasibility of T and Z scores from magnetic resonance imaging data for quantification of cartilage loss in osteoarthritis
Authors: Burgkart R. , Glaser C. , Hinterwimmer S. , Hudelmaier M. , Englmeier K.‐H. , Reiser M. , Eckstein F.
Published: June 2004

Objective

T scores (an indicator of the difference between patients and young healthy subjects) and Z scores (an indicator of the difference between patients and age‐matched healthy subjects) are used in the diagnosis of osteoporosis and form the current basis for the definition of osteoporosis by the World Health Organization. We tested the feasibility of using T and Z scores derived from quantitative cartilage imaging with magnetic resonance imaging (MRI) for the diagnosis of osteoarthritis (OA).

Methods

High‐resolution MR images of tibial cartilage were acquired from 126 young healthy adults (ages 20–35 years), 24 age‐matched elderly healthy adults (ages 50–75 years), 7 OA patients prior to tibial osteotomy, and 7 OA patients prior to knee arthroplasty. Cartilage volume, thickness, surface area, and original joint surface area (before onset of disease) were determined in the medial and lateral tibia.

Results

The cartilage volume of the medial tibia of osteotomy patients with varus malalignment displayed moderate T scores (−1.0), and more negative T scores (−3.8) were observed in knee arthroplasty patients with varus malalignment. Normalization of the cartilage volume to the original joint surface area substantially enhanced the scores in patients undergoing osteotomy (−2.3) and in patients undergoing knee arthroplasty (−5.5), and this was superior to the normalization ratios of cartilage volume to body height and cartilage volume to body weight, in terms of distinguishing the loss of articular cartilage.

Conclusion

Quantitative analysis of OA by MRI is feasible using T and Z scores. However, cartilage volume should be normalized to the individual joint surface area in order to maximize the discriminatory power of this technique for the diagnosis of OA.
Inhibition of monosodium urate monohydrate crystal–induced acute inflammation by retrovirally transfected prostaglandin D synthase
Authors: Murakami Yousuke , Akahoshi Tohru , Hayashi Izumi , Endo Hirahito , Hashimoto Atsushi , Kono Shizuka , Kondo Hirobumi , Kawai Shinichi , Inoue Matsuhisa , Kitasato Hidero
Published: June 2004

Objective

Hematopoietic prostaglandin D synthase (H‐PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H‐PGDS in order to investigate the role of H‐PGDS in monosodium urate monohydrate (MSU) crystal–induced acute inflammation.

Methods

Expression of endogenous PGDS in a murine air‐pouch model of MSU crystal–induced acute inflammation was determined by real‐time polymerase chain reaction. H‐PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57‐PGDS cells. Production of prostaglandins by C57‐PGDS cells was measured by enzyme immunoassay. The effect of C57‐PGDS cells on crystal‐induced inflammation was investigated.

Results

Injection of the crystals caused a rapid decrease in H‐PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin‐1β (IL‐1β) and macrophage inflammatory protein 2 (MIP‐2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57‐PGDS cells, but not control cells, produced an increased amount of PGD2 in vitro, but suppressed production of PGE2. Injection of C57‐PGDS cells into air pouches inhibited cellular infiltration and MIP‐2 and IL‐1β expression.

Conclusion

In this murine air‐pouch model of MSU crystal–induced inflammation, retrovirally transfected H‐PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP‐2 and IL‐1β. These findings suggest that gene therapy with H‐PGDS may be useful for treating inflammatory diseases.
Induction of arthritis in SCID mice by T cells specific for the “shared epitope” sequence in the G3 domain of human cartilage proteoglycan
Authors: Hanyecz Anita , Bárdos Tamás , Berlo Suzanne E. , Buzás Edit , Nesterovitch Andrew B. , Mikecz Katalin , Glant Tibor T.
Published: June 2004

Objective

To study the immunologic function and determine the fine epitope structure of a synthetic peptide p135H (2373TTYKRRLQKRSSRHP) of the G3 domain of human cartilage proteoglycan (aggrecan), which contains a highly homologous sequence motif of the shared epitope (QKRAA), the most common sequence motif in HLA–DR4 alleles, which predispose humans to the development of rheumatoid arthritis (RA).

Methods

Synthetic p135 peptides with altered sequences were used for (hyper)immunization of arthritis‐susceptible BALB/c mice and then challenged with a single dose of cartilage proteoglycan. Human p135 (p135H) and mouse p135 (p135M) synthetic peptides of the G3 domain of aggrecan were used to prime lymphocytes, which were then used for adoptive transfer of arthritis into “presensitized” SCID mice, determining cross‐reactivity among p135 peptides and their analogous sequences, and generating T cell hybridomas. T cell hybridomas were also used for arthritis transfer into SCID mice and for characterizing the fine epitope structure of T cell receptor (TCR) and major histo‐compatibility complex (MHC) binding sites of the immunogenic/arthritogenic p135H sequence.

Results

While p135H peptide‐(hyper)immunized mice became sensitized, they developed arthritis only after injection of a single dose of cartilage proteoglycan aggrecan. An altered peptide sequence (p135H‐AA) carrying the shared epitope motif (QKRAA) was as effective as the natural peptide p135H sequence for inducing arthritis. Mouse p135M‐specific lymphocytes induced arthritis with a lower incidence, but synthetic peptides to Escherichia coli heat‐shock protein (DnaJ) or HLA–DR4 allele (both having the shared epitope sequence with different flanking regions) were also positive. Fine epitope sequence recognition of an arthritogenic T cell hybridoma derived from p135H‐primed lymphocyte population was determined. Interestingly, in the most central position, a basic amino acid triplet of p135H peptide was found to be the MHC‐binding motif, whereas the flanking amino acids bound to the TCR.

Conclusion

Peptide p135H, corresponding to the peptide sequence in the G3 domain of human cartilage proteoglycan aggrecan, is immunogenic/arthritogenic in BALB/c mice. Peptide p135H includes a highly homologous motif of the shared epitope, a sequence that is overrepresented in bacterial heat‐shock proteins, envelope protein of human JC polyomavirus, and numerous HLA–DR4 alleles. Since the G3 domain of cartilage proteoglycan aggrecan with the p135 sequence is “lost” during the normal metabolic turnover of cartilage proteoglycan or in pathologic conditions, an antigenoriented T cell migration into joints of presensitized (susceptible) individuals may contribute to the organ‐specificity of RA.
Neuronal and astrocytic damage in systemic lupus erythematosus patients with central nervous system involvement
Authors: Trysberg Estelle , Nylen Karin , Rosengren Lars E. , Tarkowski Andrej
Published: June 2004

Objective

Symptoms originating from the central nervous system (CNS) frequently occur in patients with systemic lupus erythematosus (SLE). CNS involvement in lupus is associated with increased morbidity and mortality. Currently, reliable markers for activity in this condition are absent. The goal of this study was to determine the level of the light subunit of the neurofilament triplet protein (NFL) and that of glial fibrillary acidic protein (GFAP) in the cerebrospinal fluid of SLE patients with clinically verified CNS involvement and compare them with the levels in SLE patients without CNS involvement.

Methods

We assessed cerebrospinal fluid obtained from 99 patients with SLE and 99 age‐matched controls for the presence of soluble molecules indicating neuronal destruction and astrogliosis—NFL and GFAP, respectively. Patients were evaluated clinically, with magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid analyses, and neuropsychiatric tests.

Results

In the group of lupus patients with CNS involvement, intrathecal levels of NFL and GFAP were increased an average of 7‐fold (P ≤ 0.0001) and 3‐fold (P ≤ 0.05), respectively, compared with the levels in SLE patients without overt CNS disease. Intrathecal levels of NFL correlated significantly with cerebrospinal fluid levels of interleukin‐6 (IL‐6) (P ≤ 0.005), IL‐8 (P ≤ 0.005), pleocytosis (P ≤ 0.05), the albumin ratio (P ≤ 0.0005), and the presence of oligoclonal IgG bands (P ≤ 0.005). Cerebrospinal fluid levels of both NFL and GFAP also showed a significant correlation with MRI abnormalities (P ≤ 0.001). Successful cyclophosphamide treatment of CNS lupus resulted in significantly decreased levels of both proteins; levels of GFAP reached those observed in healthy subjects.

Conclusion

This study is the first to show biochemical signs of neuronal and astrocytic damage in patients with neuropsychiatric lupus. It is suggested that biochemical markers of brain damage should be used as a followup tool in this patient group.
Stellar kinematics in the centers of globular clusters
Authors: Gerssen J.
Published: June 2004

The high central stellar densities in globular clusters provide a unique environment to study the fundamental dynamical process of two‐body relaxation. This process is the main driver of the dynamical evolution in the center of a globular cluster and has a profound effect on the structure of the cluster and on its stellar environment. We have obtained stellar absorption line spectra with STIS to measure the radial velocities of individual stars in the crowded center of the globular cluster M15. These data increase the number of stars with known radial velocities within the central arcsec by a factor of about three and significantly improve the constraints on the mass distribution in M15. The data provide the most detailed look of the central structure of any globular cluster and show that there is a compact dark central mass component. Similar studies using ground based facilities can be efficiently performed by employing Integral Field Units. We have started a project to better constrain the central mass density in the globular cluster M3 using the GMOS‐IFU on Gemini North. The data will also allow us to better understand the central rotation which is neither explained nor predicted by any globular cluster model. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Morphology and kinematics in thick box‐peanut bulge galaxies
Authors: Vergani D. , Dettmar R.‐J.
Published: June 2004

Both, observational and theoretical results support the close connection between bars and box/peanut‐shaped bulges in spiral galaxies. However, for the sub‐class of thick box/peanut‐shaped bulges, an environmental process instead of an internal mechanism is suggested to account for the prominence of the box/peanut component. In this paper a multiwavelength study of the morphology and the kinematics of a sample of thick box/peanut‐shaped bulges is presented. The results suggest a scenario in which interaction events play a significant role in the history of thick box/peanut‐shaped bulge galaxies. Most likely these sources have experienced a mass infall. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
First results from SPIFFI, II: The luminous infrared galaxy NGC 6240 and the luminous sub‐millimeter galaxy SMMJ 14011+0252
Authors: Eisenhauer F. , Tecza M. , Thatte N. , Genzel R. , Abuter R. , Iserlohe C. , Schreiber J. , Horrobin M. , Schegerer A. , Baker A.J. , Bender R. , Davies R. , Lehnert M. , Lutz D. , Nesvadba N. , Seitz S. , Tacconi L.J.
Published: June 2004

This is the second of two papers (I: Horrobin et al. 2003) on the first scientific results from the SPIFFI integral field spectrometer at the VLT. Here we discuss the observations and properties of the prototypical luminous infrared galaxy NGC 6240 and the luminous sub‐millimeter galaxy SMMJ 14011+0252. Taking full advantage of the excellent seeing conditions of 0.27″, our integral field spectroscopy data allow us for the first time to study in detail the stellar and gas dynamics in NGC 6240 on scales of 125 pc, and to establish a galactic shock as the origin of the strong emission from molecular hydrogen. Our observations of SMMJ 14011+0252 provide us with deep, spatially resolved near infrared spectra of the SCUBA selected luminous submillimeter galaxy at a redshift of z = 2.565, revealing a remarkably old, massive and metal‐rich starburst galaxy for the early epoch at which it is observed. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Crowded field 3D spectroscopy
Authors: Becker T. , Fabrika S. , Roth M.M.
Published: June 2004

The quantitative spectroscopy of stellar objects in complex environments is mainly limited by the ability of separating the object from the background. Standard slit spectroscopy, restricting the field of view to one dimension, is obviously not the proper technique in general. The emerging Integral Field (3D) technique with spatially resolved spectra of a two‐dimensional field of view provides a great potential for applying advanced subtraction methods. In this paper an image reconstruction algorithm to separate point sources and a smooth background is applied to 3D data. Several performance tests demonstrate the photometric quality of the method. The algorithm is applied to real 3D observations of a sample Planetary Nebula in M31, whose spectrum is contaminated by the bright and complex galaxy background. The ability of separating sources is also studied in a crowded field in M33. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The Euro3D data format: A common FITS data format for integral field spectrographs
Authors: Kissler‐Patig M. , Copin Y. , Ferruit P. , Pécontal‐Rousset A. , Roth M.M.
Published: June 2004

As integral field spectrographs have become more common around the world and in Europe in particular, the need for a common data format has been recognized. Here, we present the Euro3D format that is adapted as a post‐instrumentalsignature‐removal format for all instruments within the Euro3D network. It follows the FITS standard, and includes several extensions, all of them being binary FITS tables. This article is intended to give a comprehensive overview, but does not attempt to serve as a full definition document. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The Euro3D LCL I/O library
Authors: PéContal‐Rousset A. , Copin Y. , Ferruit P.
Published: June 2004

The Euro3D Research Training Network, dedicated to promote the use of 3D spectrography in the astronomical community, has setup a new data format, adhering to the FITS standards, to facilitate data exchange and common software developments. This article is intended to present the C library handling this format. It is not intended to be a full description of the possibilities offered by the library, but attempts to enlighten the philosophy and illustrate with some examples how powerful it can be. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
E3D, the Euro3D visualization tool II: Mosaics, VIMOS data and large IFUs of the future
Authors: Sánchez S.F. , Becker T. , Kelz A.
Published: June 2004

In this paper, we describe the capabilities of E3D, the Euro3D visualization tool, to handle and display data created by large Integral Field Units (IFUs) and by mosaics consisting of multiple pointings. The reliability of the software has been tested with real data, originating from the PMAS instrument in mosaic mode and from the VIMOS instrument, which features the largest IFU currently available. The capabilities and limitations of the current software are examined in view of future large IFUs, which will produce extremely large datasets. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Value of positron emission tomography in the diagnosis of recurrent oesophageal carcinoma
Authors: Kato H , Miyazaki T , Nakajima M , Fukuchi M , Manda R , Kuwano H
Published: June 2004

Background

Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) might be useful for staging oesophageal squamous cell carcinoma (SCC). FDG-PET may be more accurate than computed tomography (CT) in diagnosing lymph node metastasis. This retrospective study compared the ability of FDG-PET and CT to diagnose recurrent oesophageal carcinoma.

Methods

Fifty-five patients with thoracic oesophageal SCC who had undergone radical oesophagectomy were studied. The accuracy of FDG-PET and CT in detecting recurrence during follow-up was calculated using data from the first images generated by either modality that suggested the presence of recurrent disease. Lesions deemed to be equivocal on these scans were considered as positive for recurrence.

Results

Twenty-seven of the 55 patients had recurrent disease in a total of 37 organs. Locoregional recurrence was observed in 19 patients (35 per cent). Distant recurrent disease occurred in 15 patients (27 per cent) in 18 organs. Six patients had recurrence in the liver, four in the lung, six in bone and two in distant lymph nodes. FDG-PET showed 96 per cent sensitivity, 68 per cent specificity and 82 per cent accuracy in demonstrating recurrent disease. The corresponding values for CT were 89, 79 and 84 per cent. The sensitivity of FDG-PET was higher than that of CT in detecting locoregional recurrence, but its specificity was lower because of FDG uptake in the gastric tube and thoracic lymph nodes. In distant organs the sensitivity of PET in detecting lung metastasis was lower than that of CT, but its sensitivity for bone metastasis was higher.

Conclusion

FDG-PET has a larger field than CT. Combined PET–CT would appear to be an appropriate modality for the detection of recurrent oesophageal cancer.