bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co‐administration of the JAK inhibitor CP‐690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment
Authors: Cohen Stanley , Zwillich Samuel H. , Chow Vincent , LaBadie Robert R. , Wilkinson Bethanie 
Published: October 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CP‐690,550 is a novel JAK inhibitor in development as a therapy for rheumatoid arthritis.• Methotrexate is the cornerstone of combination treatment for rheumatoid arthritis.• The safety and tolerability of co‐administration of CP‐690,550 with methotrexate have not been addressed to date. WHAT THIS STUDY ADDS • This study in patients with rheumatoid arthritis shows that there are no clinically relevant effects on the pharmacokinetics of either drug following short‐term co‐administration.• Co‐administration of CP‐690,550 and methotrexate was safe and well tolerated.AIMSTo investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP‐690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP‐690,550 on the PK of MTX, and to evaluate the short‐term safety and tolerability of co‐administration of CP‐690,550 and MTX.METHODSThis was a fixed‐dose drug–drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open‐label study of the PK of multiple doses of CP‐690,550 (30 mg b.i.d.) and single doses of MTX (15–25 mg per week).RESULTSAll patients completed the study and were evaluated for PK and safety. CP‐690,550 exposure was not affected by co‐administration with MTX; AUC12 ratio (CP‐690,550 + MTX/CP‐690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP‐690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co‐administration of CP‐690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments.CONCLUSIONSCo‐administration of CP‐690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co‐administering CP‐690,550 and MTX.
Misdiagnosis and mistreatment of a common side‐effect – angiotensin‐converting enzyme inhibitor‐induced cough
Authors: Vegter Stefan , De Jong‐van den Berg Lolkje T. W. 
Published: October 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Dry cough is a common and well‐documented side‐effect of angiotensin‐converting enzyme inhibitor (ACEi) treatment.• The recommended course of action in case of ACE‐induced cough is substitution of the ACEi with other antihypertensive agents.• Misdiagnosis and mistreatment of ACEi‐induced cough has not been studied before. WHAT THIS STUDY ADDS • In the general population, a significant and clinically relevant proportion of patients with ACE‐induced cough are treated with antitussive agents.• These results suggest misdiagnosis and mistreatment of a well‐known side‐effect.• The estimated frequency of antitussive treatment of ACEi‐induced cough is 15%.AIMSAngiotensin‐converting enzyme inhibitors (ACEi) are frequently prescribed for various cardiovascular and renal diseases. A common side‐effect of these drugs is a persistent dry cough. Physicians who fail to recognize a dry cough to be ACEi‐related may attempt to treat it with antitussive agents instead of recommended ACEi substitution. Prescription behaviour in the general population considering treatment of the side‐effect with antitussive agents has not been studied before.METHODSDrug dispensing data between 2000 and 2007 were retrieved from the IADB.nl database. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEi initiation than the other way around. A logistic regression model was fitted to determine predictors.RESULTSWe identified 27 446 incident users of ACEi therapy. One thousand and fifty‐four patients were incident users of both ACEi and antitussives within a half‐year time span. There was an excess of patients being prescribed antitussive agents after ACEi initiation (703 vs. 351), adjusted sequence ratio 2.2 [confidence interval (CI) 1.9, 2.4]. Female patients were more likely to be prescribed antitussive agents following ACEi therapy initiation, odds ratio 1.4 (CI 1.1, 1.9), age and co‐medications were not significant predictors.CONCLUSIONSThere was a significant and clinically relevant excess of patients receiving antitussives after ACEi initiation. The results suggest that cough as a side‐effect of ACEi is not recognized as being ACEi‐related or is symptomatically treated with antitussive agents instead of ACEi substitution. The estimated frequency of antitussive treatment of ACEi‐induced dry cough is 15%.
Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction
Authors: Fang Zhong‐Ze , Zhang Yan‐Yan , Ge Guang‐Bo , Huo Hong , Liang Si‐Cheng , Yang Ling 
Published: October 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug–drug interaction (DDI) existed when warfarin was co‐administered with noscapine.• In vitrotesting with recombinant human enzyme showed that noscapine inhibited CYP3A4 and CYP2C9 with an IC50of around 1 µm.• However, the clinical relevance of thesein vitrodata remains to be explored.WHAT THIS STUDY ADDS• Noscapine was demonstrated to be both a reversible inhibitor and a time‐dependent inhibitor to CYP3A4 and CYP2C9.• DDI magnitude predicted from reversible inhibition and time‐dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical noscapine–warfarin interaction.AIMSTo investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolatein vivonoscapine‐warfarin interaction magnitude fromin vitrodata.METHODSThe activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co‐ or preincubation with noscapine. A two‐step incubation method was used to examinein vitrotime‐dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolatein vivonoscapine–warfarin interaction magnitude fromin vitrodata.RESULTSAmong seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50of 10.8 ± 2.5 µmand 13.3 ± 1.2 µm. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type withKivalue of 8.8 µm, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner withKivalue of 5.2 µm. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KIandkinact) were calculated to be 9.3 µmand 0.06 min−1for CYP3A4 and 8.9 µmand 0.014 min−1for CYP2C9, respectively. The AUC of (S)‐warfarin and (R)‐warfarin was predicted to increase 1.5% and 1.1% usingCmaxor 0.5% and 0.4% using unboundCmaxwith reversible inhibition prediction equation, while the AUC of (S)‐warfarin and (R)‐warfarin was estimated to increase by 110.9% and 48.9% usingCmaxor 41.8% and 32.7% using unboundCmaxwith TDI prediction equation.CONCLUSIONSTDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction.
Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia
Authors: Theurl Igor , Finkenstedt Armin , Schroll Andrea , Nairz Manfred , Sonnweber Thomas , Bellmann‐Weiler Rosa , Theurl Milan , Seifert Markus , Wroblewski Victor J. , Murphy Anthony T. , Witcher Derrick , Zoller Heinz , Weiss Günter 
Published: October 2009

SummaryRecently, the iron and erythropoiesis‐controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in β‐thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients. IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity‐driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD‐related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation.
Serum T helper 1 cytokine levels are greater in patients with alopecia areata regardless of severity or atopy
Authors: Barahmani N. , Lopez A. , Babu D. , Hernandez M. , Donley S. E. , Duvic M. 
Published: October 2009

SummaryBackground. Alopecia areata (AA) is an organ-specific autoimmune disease characterized by folliculotropic T-cell infiltrates around anagen-stage hair follicles. The role of T helper (Th)1 and Th2 cytokines in the pathogenesis of AA have not been established.Aim. To determine whether serum cytokine profiles define the severity of the AA phenotype or are affected by co-existent atopy.Methods. In total, 17 serum cytokines were measured and compared in 269 patients with AA of varying severity with and without atopy and 18 unrelated controls.Results. Of the 269 patients with AA, 96% had active disease and 54% were atopic. The disease phenotype was transient patchy AA in 27 patients, persistent patchy AA in 89 and alopecia totalis or alopecia universalis in 153. Levels of Th1, interleukin (IL)-1 receptor antagonist (ra) and IL-8 levels were higher in all patients with AA than in controls. IL-1α, IL-12 and tumour necrosis factor-α levels were higher in patients with AA and atopy than in patients with AA without atopy.Conclusions. Increased Th1 serum cytokines (IL-2, IL-12 and interferon-γ) and IL-1ra levels are associated with AA regardless of disease severity or the presence of atopy.
Pemphigus herpetiformis: analysis of the autoantibody profile during the disease course with changes in the clinical phenotype
Authors: Lebeau S. , Müller R. , Masouyé I. , Hertl M. , Borradori L. 
Published: October 2009

SummaryBackground. Pemphigus herpetiformis (PH) is a rare dapsone-responsive variant of pemphigus, characterized by annular and vesiculopustular cutaneous lesions. Most PH serum samples contain autoantibodies against desmoglein (Dsg)1, but not Dsg3, and the presence of the latter is almost invariably associated with mucosal involvement, as predicted based on the ‘Dsg compensation theory’.Methods. We describe a patient with features characteristic of PH with histologically eosinophilic spongiosis who repeatedly tested positive for anti-Dsg3 but not anti-Dsg1 autoantibodies by ELISA. To investigate whether the peculiar clinical phenotype was due to a distinct immunological profile, the patient’s serum was tested by ELISA and immunoblotting using recombinant forms of Dsg3.Results. Serum samples were found to have low and high reactivity against the EC1 and the EC4 domains of Dsg3, respectively, whereas the autoantibodies belonged predominantly to the IgG1 and IgG4 subclasses. The overall immunological profile was typical of pemphigus vulgaris. The patient finally developed isolated oral erosions 22 months after initial presentation, without significant changes in the autoantibody profile and of the targeted antigenic sites.Conclusions. Our patient presented features characteristic of PH. Although circulating anti-Dsg3 antibodies were present, the patient had only cutaneous involvement for a long period. Our findings indicate that the proposed Dsg compensation theory cannot always explain the clinical phenotype, changes in which may occur without apparent modification of the autoantibody profile and antibody specificity. Hence, additional factors, such as Fcγ-dependent neutrophil activation, may critically affect the clinical presentation of pemphigus.
Mucosal (oral and vulval) lichen planus in women: are angiotensin-converting enzyme inhibitors protective, and beta-blockers and non-steroidal anti-inflammatory drugs associated with the condition?
Authors: Clayton R. , Chaudhry S. , Ali I. , Cooper S. , Hodgson T. , Wojnarowska F. 
Published: October 2009

Summary
Aim. To determine whether there is an association between the use of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and nonsteroidal anti-inflammatory drugs (NSAIDS) in women with mucosal (oral and vulval) lichen planus (LP) compared with a control population.
Methods. This was a retrospective review of medical records in dedicated vulval and oral clinics in hospitals. The study population comprised 141 women with vulval LP and 106 women with oral LP. Medications taken at the time of diagnosis were recorded.
Results. Patients with mucosal LP were more likely to be on NSAIDS and beta-blockers, but less likely to be on ACE inhibitors compared with controls. All three groups were found to have an inverse relationship with ACE inhibitors, but no association was found between patients with oral LP and beta-blockers.
Conclusions. Beta-blockers and NSAIDS are associated with LP, suggesting that withdrawal of these drugs should be considered. Further studies are needed to confirm or refute the inverse relationship between mucosal LP and use of ACE inhibitors.
The profile of dermatological problems in primary care
Authors: Kerr O. A. , Tidman M. J. , Walker J. J. , Aldridge R. D. , Benton E. C. 
Published: October 2009

Summary
Background. Cutaneous disease is thought to account for 10–15% of patient consultations with general practitioners, but relatively little is known about the demography of dermatological conditions in primary care.
Aim. To assess the proportion and diagnostic profile of dermatological conditions seen in primary care in the southeast of Scotland, and to draw comparisons with secondary dermatological care.
Methods. General practitioners in 13 general practices were asked to note all skin-related consultations during a 2-week period. The case notes of these patients were reviewed, and diagnosis and treatment was recorded. Patients who had consulted for the same skin disorder on ≥ 3 occasions during the previous year were invited for assessment by a consultant dermatologist. Where possible, the case notes from 10% of all consultations during the 2-week study period were examined to assess accuracy of recording.
Results. The percentage of consultations relating to cutaneous disorders varied between practices, ranging from 3% to 18.8%, with a mean of 8.4%. Eczema accounted for 22.5%, infections 20.3% and benign tumours for 11.4% of consultations with a dermatological basis. In contrast, in secondary care, benign tumours accounted for 23.8%, malignant tumours for 16.4% and eczema for 16.3% of dermatological consultations.
Conclusions. Dermatological disorders make up a significant proportion of general practitioners’ workload. The diagnostic profile of primary-care dermatology differs markedly from that of hospital practice. General practitioners may benefit from training specifically tailored to the common primary-care dermatological conditions.
Are dark-skinned people really protected from ultraviolet radiation?
Authors: Young A. L. , Levy S. , Nighland M. , Grossman R. , Silvers D. N. , Celebi J. T. 
Published: October 2009

Summary
Background. Premature ageing of the skin (photoageing) results from the action of ultraviolet radiation (UVR) on skin. One of the histopathological findings of photoageing is the presence of solar elastosis in the dermis. Skin pigmentation is protective against UVR.
Aim. To evaluate the presence of solar elastosis in dark-skinned people.
Methods. Normal facial skin biopsies of 147 dark-skinned and 140 light-skinned people were examined histopathologically for solar elastosis. The degree of solar elastosis was graded on a five-point scale by a panel of dermatopathologists blinded to patient demographics.
Results. There were 112 of 140 (80%) light-skinned and 50 of 147 (34%) dark-skinned patients with high-grade solar elastosis. In the dark-skinned patient group, high-grade solar elastosis was seen in 29 of 61 (47.5%) Hispanic and 5 of 49 (10.2%) African American subjects.
Conclusions. Dark-skinned people are not completely protected from the effects of UVR.
c-Ski promotes skin fibroblast proliferation but decreases type I collagen: implications for wound healing and scar formation
Authors: Liu X. , Li P. , Chen X.-Y. , Zhou Y.-G. 
Published: October 2009

Summary
Background. Accelerating wound healing is always accompanied by excessive scar formation. The focus in chronic wounds has been promoting the proliferation of tissue repair cells while decreasing collagen deposition. Smad3 null mice display more rapid wound closure and reduced scar formation. We hypothesized that c-Ski, acting as a co-repressor of transforming growth factor-β1/Smad3 in epithelial cells and as a complicated regulator of embryo fibroblast proliferation, may play such a role through modulation of skin fibroblast function.
Aim. To investigate the effect of c-Ski on skin fibroblast proliferation, cell-cycle progression, type I collagen secretion and myofibroblast differentiation. The potential involvement of Smad3 was also investigated.
Methods. Cultured rat skin fibroblasts were used. Immunocytochemistry and reverse transcription (RT)-PCR was used to examine the localization and expression of c-Ski. Plasmid transfection technology was used to produce c-Ski or/and Smad3 overexpression. Cell proliferation was analysed by 5-bromo-2-deoxyuridine incorporation; cell cycle by fluorescence-activated cell sorting; type I collagen expression by immunocytochemistry, RT-PCR and western blotting; and myofibroblast differentiation by western blotting.
Results. c-Ski was expressed in cultured skin fibroblasts. Overexpression of c-Ski was able to promote skin fibroblast proliferation and accelerate cell-cycle progression through inhibiting Smad3 activity. It also decreased type I collagen protein and mRNA expression through inhibiting Smad3 activity. It did not affect fibroblast–myofibroblast differentiation.
Conclusions. Because of the important role of fibroblast proliferation and collagen secretion in tissue repair and scar formation, we speculate that c-Ski may be a new candidate molecule for accelerating wound healing and decreasing scar formation.
Topical tazarotene vs. coal tar in stable plaque psoriasis
Authors: Kumar U. , Kaur I. , Dogra S. , De D. , Kumar B. 
Published: October 2009

Summary
Background. The efficacy of topical tazarotene has not previously been compared with the conventional topical treatment of crude coal tar (CCT) in stable plaque psoriasis.
Aim. To assess the comparative efficacy and tolerability of topical tazarotene 0.1% gel and CCT 5% ointment in stable plaque psoriasis.
Methods. In this nonblinded side-to-side comparison study, patients with chronic stable plaque psoriasis, who had bilaterally symmetrical plaques on the limbs, applied 0.1% tazarotene gel on the right side and 5% CCT ointment on the left side once daily for 12 weeks followed by an 8-week treatment-free follow up period. Severity of psoriatic lesions and response to treatment was evaluated by scoring erythema, scaling and induration (ESI).
Results. Of 30 patients recruited, 27 could be assessed. In the per-protocol analysis, the mean percentage reduction in ESI score at the end of the treatment period was 74.15% ± 9.43 and 77.37% ± 10.93 with tazarotene and CCT, respectively (P &gt; 0.05). A reduction in ESI score of &gt; 75% was seen in 11 (40.74%) and 16 (59.26%) patients with tazarotene and CCT, respectively, at the end of 12 weeks. Side-effects were seen in 48.14% of patients treated with tazarotene, but in no patient treated with CCT.
Conclusions. Tazarotene 0.1% gel has comparable clinical efficacy to CCT 5% ointment. CCT ointment remains a cost-effective therapy for plaque psoriasis.
Demethylation of promoter regulatory elements contributes to CD70 overexpression in CD4+ T cells from patients with subacute cutaneous lupus erythematosus
Authors: Luo Y. , Zhao M. , Lu Q. 
Published: October 2009

Summary
Background. Impaired methylation of T-cell DNA is thought to contribute to the development of systemic lupus erythematosus (SLE). CD70 (TNFSF7) is a B-cell costimulatory molecule that contributes to excessive B-cell stimulation in vitro and in vivo. CD70 is overexpressed in CD4+ T cells of patients with SLE, and DNA demethylation occurs in promoter sequences that regulate CD70 expression in SLE CD4+ T cells. However, it is unknown whether the expression and methylation of CD70 in CD4+ T cells are affected in patients with subacute cutaneous lupus erythematosus (SCLE).
Objective. To compare CD70 expression levels and the methylation status of the CD70 promoter region in CD4+ T cells from patients with SCLE and healthy controls.
Methods. We used real-time RT-PCR to compare messenger RNA levels of CD70 and flow cytometry to compare CD70 protein levels in CD4+ T cells from patients with SCLE and healthy controls. Bisulphite sequencing was used to determine the methylation status of the CD70 promoter region.
Results. CD70 is overexpressed at the surface of SCLE CD4+ T cells. Demethylation of the CD70 promoter region was seen in CD4+ T cells from patients with SCLE.
Conclusions. Demethylation of regulatory elements contributes to CD70 overexpression in CD4+ T cells of patients with SCLE.
Elastic interferometry for ocean bottom cable data: Theory and examples‡
Authors: Gaiser J.E. , Vasconcelos I. 
Published: October 2009

ABSTRACTElastic imaging from ocean bottom cable (OBC) data can be challenging because it requires the prior estimation of both compressional‐wave (P‐wave) and shear‐wave (S‐wave) velocity fields. Seismic interferometry is an attractive technique for processing OBC data because it performs model‐independent redatuming; retrieving ‘pseudo‐sources’ at positions of the receivers. The purpose of this study is to investigate multicomponent applications of interferometry for processing OBC data. This translates into using interferometry to retrieve pseudo‐source data on the sea‐bed not only for multiple suppression but for obtaining P‐, converted P to S‐wave (PS‐wave) and possibly pure mode S‐waves. We discuss scattering‐based, elastic interferometry with synthetic and field OBC datasets.Conventional and scattering‐based interferometry integrands computed from a synthetic are compared to show that the latter yields little anti‐causal response. A four‐component (4C) pseudo‐source response retrieves pure‐mode S‐reflections as well at P‐ and PS‐reflections. Pseudo‐source responses observed in OBC data are related to P‐wave conversions at the seabed rather than to true horizontal or vertical point forces. From a Gulf of Mexico OBC data set, diagonal components from a nine‐component pseudo‐source response demonstrate that the P‐wave to S‐wave velocity ratio (VP/VS) at the sea‐bed is an important factor in the conversion of P to S for obtaining the pure‐mode S‐wave reflections.