bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variants of OCTN1–2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis
Authors: PALMIERI O. , LATIANO A. , VALVANO R. , D'INCÀ R. , VECCHI M. , STURNIOLO G. C. , SAIBENI S. , PEYVANDI F. , BOSSA F. , ZAGARIA C. , ANDRIULLI A. , DEVOTO M. , ANNESE V. 
Published: January 2006

SummaryBackground  Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD).Aim  To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes.Methods  Case–control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G→C and 1672C→T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI‐7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively.Results  The 1672TT and −207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P ≤ 0.01) and UC (36% vs. 45%, P ≤ 0.01). The frequency of the TC haplotype was 43% in CARD15‐positive and 44% in CARD15‐negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno‐fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004).Conclusions  Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.
Upper gastrointestinal mucosal abnormalities and blood loss complicating low‐dose aspirin and antithrombotic therapy
Authors: TAHA A. S. , ANGERSON W. J. , KNILL‐JONES R. P. , BLATCHFORD O. 
Published: January 2006

SummaryBackground  Little is known about the site and nature of bleeding lesions related to low‐dose aspirin and other antithrombotic agents.Aim  To describe the mucosal abnormalities in patients presenting with upper gastrointestinal bleeding while being treated with these drugs.Methods  The endoscopic findings and clinical details were analysed in all patients presenting with haematemesis and/or melaena at a single centre during three calendar years. Associations between endoscopic findings and risk factors, including the intake of non‐steroidal anti‐inflammatory drugs, low‐dose aspirin (75 mg daily) and other antithrombotic drugs including warfarin, clopidogrel, and dipyridamole, were assessed by logistic regression analysis.Results  In 674 upper gastrointestinal bleeders, we found that the odds ratio for the presence of erosive oesophagitis in aspirin users was 2 (95% CI, 1–3; P = 0.03) and 3 (2–5; P = 0.0003) in patients taking other antithrombotic agents. In 41 patients with oesophagitis and taking these drugs, 36 (88%) had cardiovascular disease and only 4 (10%) had peptic symptoms.Conclusions  Erosive oesophagitis is common in patients with upper gastrointestinal bleeding taking low‐dose aspirin or antithrombotic agents, and could potentially be confused with the coexisting heart disease.
Efficacy and safety of rifabutin‐containing ‘rescue therapy’ for resistant Helicobacter pylori infection
Authors: BORODY T. J. , PANG G. , WETTSTEIN A. R. , CLANCY R. , HERDMAN K. , SURACE R. , LLORENTE R. , NG C. 
Published: January 2006

SummaryBackground  Current ‘rescue’ therapies provide inadequate Helicobacter pylori eradication rates because of antibiotic resistance.Aim  To test the efficacy of a modified triple regimen combining rifabutin, pantoprazole and amoxicillin as rescue therapy for patients in whom eradication of H. pylori had failed standard clarithromycin‐based triple therapy.Methods  One hundred and thirty patients (mean age 51.7 ± 14.8 years) who had failed one or more eradication attempts with omeprazole, clarithromycin and amoxicillin were treated for 12 days with rifabutin 150 mg daily, amoxicillin 1 g or 1.5 g t.d.s, and pantoprazole 80 mg t.d.s.Results  The intention‐to‐treat and per‐protocol eradication rates were 90.8/90.8%. Metronidazole or/and clarithromycin resistance had no significant impact on H. pylori eradication rates. A higher overall eradication rate of 96.6% (95% CI: 92.1–101%) was obtained in patients treated with a regimen containing 1.5 g amoxicillin t.d.s compared with 90.7% (95% CI: 82–98.6%) using a regimen with 1 g amoxicillin t.d.s but the difference was not significant. Side‐effects reported in 40% of patients were mild.Conclusion  A 12‐day course of low dose of rifabutin with an increased dose of amoxicillin and pantoprazole is well‐tolerated and highly effective against dual‐resistant H. pylori infection after failure of triple therapy.
Genome‐wide linkage disequilibrium in two Japanese beef cattle breeds
Authors: Odani M. , Narita A. , Watanabe T. , Yokouchi K. , Sugimoto Y. , Fujita T. , Oguni T. , Matsumoto M. , Sasaki Y. 
Published: January 2006

SummaryThere is little knowledge about the degree of linkage disequilibrium (LD) in beef cattle. This study aims to perform a genome‐wide search for LD in Japanese Black and Japanese Brown beef cattle and to compare the level of LD between these two breeds. Parameter D′ (the LD coefficient) was used as a measure of LD, and LD was tested for significance of allelic associations between syntenic and between non‐syntenic marker pairs. Effects of breed, chromosome, genetic map distance and their interactions with D′ were tested based on least squares analyses. Both breeds showed high levels of LD, which ranged over several tens of cM and declined as the marker distance increased for syntenic marker pairs. A rapid decline of the D′ value was observed between markers that were spaced 5 and 20 cM apart. LD was significant in most cases for marker pairs <40 cM apart but was not significant between non‐syntenic loci. The pattern of LD found in these two breeds was similar to that previously published for dairy cattle. The D′ value between breeds was not significantly different (P > 0.05), but the interaction between breed and chromosome was highly significant (P <  0.001). Genetic selection seems to have caused the heterogeneity of the D′ values among chromosomes within breed. These results indicate that LD mapping is a useful tool for fine‐mapping quantitative trait loci of economically important traits in Japanese beef cattle.
Association of the melanocortin 4 receptor with feed intake and daily gain in F2 Mangalitsa × Piétrain pigs
Authors: Meidtner K. , Wermter A‐K. , Hinney A. , Remschmidt H. , Hebebrand J. , Fries R. 
Published: January 2006

SummaryThe melanocortin 4 receptor (MC4R) is a key factor in the regulation of energy balance and body weight. Hence it is a candidate for feed intake and energy homeostasis‐related traits. Studies in humans and swine have revealed several sequence variants in the gene that are associated with some of these traits. In pigs the coding non‐synonymous missense variant Asp298Asn in MC4R has been associated with feed intake, fatness and growth. Here we confirm the association of this Piétrain‐derived polymorphism with feed intake and daily gain in the F2 generation of a Mangalitsa × Piétrain cross. In one Piétrain founder animal, we detected an additional non‐synonymous missense variant Arg236His. Thus, the MC4R gene could be a useful marker for increased growth in the relatively slow‐growing Piétrain breed.
Orphan drug development is progressing too slowly
Authors: Joppi Roberta , Bertele Vittorio , Garattini Silvio 
Published: January 2006

AimsTo assess the methodological quality of OMP dossiers and to discuss possible reasons for the small number of products licensed.MethodsInformation about orphan drug designation and approval was obtained from the website of the European Commission‐Enterprise and Industry DG and from the European Public Assessment Reports.ResultsOut of 255 OMP designations, only 18 were approved (7.1%). Their dossiers often showed methodological limitations such as inappropriate clinical design, lack of active comparator where available and use of surrogate end‐points.ConclusionsThe paucity of European incentives for manufacturers and the poor documentation underpinning the applications may have limited the number of new OMP. The over 5000 rare diseases awaiting therapy are an important public health issue.
Kinetics and dynamics of the peripheral neurokinin‐1 receptor antagonist SLV317 in healthy individuals
Authors: Hesse Christiane , Luntz Steffen P. , Siedler Heike , Unnebrink Kristina , Mikus Gerd , de Bruijn Marianne , Zondag Edu , de Vries Michiel , Seibert‐Grafe Monika , Haefeli Walter E. 
Published: January 2006

AimsTo investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin‐1 receptor antagonist SLV317.MethodsIn a randomized, double‐blind, placebo‐controlled cross‐over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method.ResultsAdministration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (± SEM) of 77 ± 9 ng ml−1 within 47 ± 3 min; the mean half‐life was 9.9 ± 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 ± 8% and 49 ± 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P‐induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 ± 8% and was observed after 1.47 ± 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 ± 67% h−1; 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 ± 12% h−1; 95% CI −24, 122; P < 0.001).ConclusionsThis study demonstrates that the neurokinin‐1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P‐induced effects in humans.
Autotransplantation versus HLA‐matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research
Authors: Lazarus Hillard M. , Pérez Waleska S. , Klein John P. , Kollman Craig , Bate‐Boyle B. , Bredeson Christopher N. , Gale Robert Peter , Geller Robert B. , Keating Armand , Litzow Mark R. , Marks David I. , Miller Carole B. , Douglas Rizzo J. , Spitzer Thomas R. , Weisdorf Daniel J. , Zhang Mei‐Jie , Horowitz Mary M. 
Published: January 2006

SummaryMost acute myeloid leukaemia (AML) patients lack human leucocyte antigen‐identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant‐related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3‐year survival probabilities were: in CR1 57 (53–61)% with autotransplants and 44 (37–51)% URD (P = 0·002), in CR2 46 (39–53)% and 33 (28–38)% respectively (P = 0·006). Adjusted 3‐year leukaemia‐free survival (LFS) probabilities were: CR1 53 (48–57)% with autotransplants and 43 (36–50)% with URD (P = 0·021), CR2 39 (32–46)% and 33 (27–38)% respectively (P = 0·169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3‐year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two‐thirds of patients and treatment bias cannot be eliminated.
Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long‐term secondary prevention of venous thromboembolism
Authors: Wåhlander Karin , Eriksson Henry , Lundström Torbjörn , Clason Solveig Billing , Wall Ulrika , Nyström Per , Wessman Peter , Schulman Sam ,   THRIVE III Investigators
Published: January 2006

SummaryThe impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long‐term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention‐to‐treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had ≥2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.
Distinct comparative genomic hybridisation profiles in gastric mucosa‐associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21)
Authors: Zhou Yuanping , Ye Hongtao , Martin‐Subero Jose I. , Hamoudi Rifat , Lu Yong‐Jie , Wang Rubin , Siebert Reiner , Shipley Janet , Isaacson Peter G. , Dogan Ahmet , Du Ming‐Qing 
Published: January 2006

Summaryt(11;18)(q21;q21) occurs specifically in mucosa‐associated lymphoid tissue (MALT) lymphoma and the translocation generates a functional API2‐MALT1 fusion product that activates nuclear factor (NF)κB. t(11;18) positive lymphomas usually lack the chromosomal aberrations and microsatellite alterations frequently seen in the translocation‐negative MALT lymphomas. To further understand their genetic differences, we investigated gastric MALT lymphomas with and without t(11;18) by comparative genomic hybridisation. In general, both chromosomal gains and losses were far more frequent in t(11;18)‐negative (median = 3·4 imbalances) than t(11;18)‐positive cases (median = 1·6 imbalances), with gains being more frequent than losses. Recurrent chromosomal gains involving whole or major parts of a chromosome were seen for chromosomes 3, 12, 18 and 22 (23%, 19%, 19% and 27% respectively). Discrete recurrent chromosomal gains were found at 9q34 (11/26 = 42%). Bioinformatic analysis of genes mapping to 9q34 revealed potential targets. Among them, TRAF2 and CARD9 are known interaction partners of BCL10, playing a role in NFκB activation. Interphase fluorescent in situ hybridisation confirmed genomic gain of the TRAF2, CARD9 and MALT1 loci in 5/6 and 2/2 cases showing chromosomal gains at 9q34 and 18q21 respectively. The results further highlight the genetic difference between MALT lymphomas with and without t(11;18). Moreover, our findings suggest that genomic gain of genes that modulate NFκB activation, such as MALT1, TRAF2 and CARD9, may play a role in the pathogenesis of the translocation‐negative MALT lymphoma.
Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index
Authors: Møller M. B. , Pedersen N. T. , Christensen B. E. 
Published: January 2006

SummaryThe International Prognostic Index (IPI) is the most commonly used prognostic model for mantle cell lymphoma (MCL). However, the prognostic value of the IPI is limited. The recently published Follicular Lymphoma International Prognostic Index (FLIPI) is built on variables, which are pertinent to MCL. This study was conducted to evaluate the prognostic value of FLIPI in a population‐based series of 93 patients with MCL diagnosed in a 7‐year period. End points of the study were response to therapy, overall survival, and disease‐free survival (DFS) according to the IPI and FLIPI. Applied to the whole series, the FLIPI identified three risk groups with markedly different outcome with 5‐year overall survival rates of 65%, 42%, and 8% respectively. Notably, the high‐risk group comprised 53% of patients. In contrast, the IPI only allocated 16% of cases to the high‐risk group and had a lower overall predictive capacity. When both the FLIPI and IPI were included in a multivariate analysis, only the FLIPI was related to survival. Multivariate analysis of DFS also identified the FLIPI, and not the IPI, as independently significant. Thus, in the present study, the FLIPI was superior as a prognostic model compared with the IPI and can therefore be recommended as a clinical prognostic index for MCL.
High‐density mapping and follow‐up studies on chromosomal regions 1, 3, 6, 12, 13 and 17 in 28 families with chronic lymphocytic leukaemia
Authors: Ng David , Marti Gerald E. , Fontaine Laura , Toro Jorge R. , Caporaso Neil , Goldin Lynn R. 
Published: January 2006

SummaryA subset of chronic lymphocytic leukaemia (CLL) shows familial aggregation. Studies show an increased risk for CLL and other lymphoproliferative disease among first‐degree relatives of affected individuals. A genome‐wide scan of 18 CLL families in 2003 detected LOD or non‐parametric linkage scores ≥1·0 on chromosomes 1, 3, 6, 12, 13 and 17. Follow‐up study with 28 families showed no evidence of linkage at 1p22.1–p21.2, 3q22.1, 3q26.2, 6q22.31–q23.2, 12q24.23, 14q32.13, 17p13.3. Chromosome 13q21.33 remains a region of interest with a P‐value of 0·013 (marker D13S1291) and warrants additional molecular investigation as a susceptibility region for CLL.
Signal transducer and activator of transcription 6 down‐regulates toll‐like receptor‐4 expression of a monocytic cell line
Authors: Fiset P. O. , Tulic M. K. , Skrablin P. S. A. , Grover S. M. , Létuvé S. , Mazer B. D. , Hamid Q. 
Published: January 2006

SummaryBackground
Toll‐like receptor 4 (TLR4), part of the bacterial lipopolysaccharide (LPS) receptor, is an important bridge between innate and adaptive immunity. Our previous studies have indicated reduced expression of TLR4 and reduced responsiveness to LPS in nasal mucosa of atopic adults compared with non‐atopic adults. IL‐4 and signal transducer and activator of transcription 6 (STAT6), which are increased in atopic patients, may have a role in modulating TLR4.Objective
To examine direct effects of IL‐4 and STAT6 on TLR4 expression of U‐937 monocytic cells.Methods
LPS responsiveness, under different conditions of U‐937 cells was measured by nuclear factor (NF)‐κB activation of transcription. TLR4 mRNA was quantified by real‐time PCR and TLR4 surface expression was measured by flow cytometry. The promoter and 4.3 kb of the upstream region of TLR4 were cloned into a plasmid vector and transiently transfected into U‐937 cells. Transfected cells were incubated with IL‐4 and transcriptional activity was assayed by the luciferase assay. STAT6 was transfected to evaluate overexpression of this transcription factor. Cells were also incubated with Tyrphostin AG490 to inhibit tyrosine kinases.Results
NF‐κB activation by LPS was inhibited by IL‐4 pre‐incubation but not when IL‐4 was added at the same time as LPS. TLR4 mRNA expression was inhibited by IL‐4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL‐4 at 12 and 24 h, but returned to baseline at 48 h. IL‐4 inhibited activity of the TLR4 promoter as early as 6 h, but, like the mRNA, these effects were transient. STAT6 overexpression enhanced the inhibition of the TLR4 promoter and prolonged it. Inhibition of TLR4 by IL‐4 was abolished by pre‐incubation with the tyrosine kinase inhibitor Tyrphostin AG490.Conclusion
Our findings demonstrate that IL‐4, through STAT6, can modulate TLR4 expression and suggests that Th2 cytokines can impact on the LPS responsiveness of cells.
Genome‐wide linkage analysis of allergic rhinoconjunctivitis in a Swedish population
Authors: Bu L. M. , Bradley M. , Söderhäll C. , Wahlgren C. F. , Kockum I. , Nordenskjöld M. 
Published: January 2006

SummaryBackground
Allergic rhinoconjunctivitis is a common complex disorder characterized by itching and irritation in the nose, bouts of sneezing, watery rhinorrhoea, nasal congestion and itchy eyes with tears and swelling. Like other atopic disorders such as allergic asthma and atopic dermatitis, the development involves complex interactions of genes and environmental factors.Objective
The purpose of this study was to identify susceptibility loci for allergic rhinoconjunctivitis.Methods
We conducted a genome‐wide linkage analysis using a non‐parametric, affected‐relative‐pair method. The 250 families used were collected originally for an atopic dermatitis linkage study.Results
Three regions showed favour in evidence of linkage to allergic rhinoconjunctivitis: 3q13 (D3S1278: logarithm of odds ratio (LOD)=1.64, P<0.003), 4q34–35 (D4S1652: LOD=1.49, P<0.005) and 18q12 (D18S535: LOD=1.94, P<0.002). In addition, four regions showed weaker evidence in favour of linkage: 6p22–24 (D6S1959: LOD=1.39, P<0.006), 9p11–q12 (D9S1118: LOD=1.15, P<0.02), 9q33.2–34.3 (D9S915: LOD=1.29, P<0.01) and 17q11.2 (D17S1294: LOD=1.13, P<0.02). In single‐point analysis, one locus on chromosome 3 close to marker D3S1278 reaches the suggestive level (LOD=2.28, P<6 × 10−4) while one on chromosome 17 close to marker D17S921 almost reaches this level (LOD=2.17, P<8 × 10−4, Table 3).

Single‐point linkage analysis for allergic rhinoconjunctivitis

Marker
Map position (cM)*
LOD
P‐value†

D3S1278
129.73
2.28
<6 × 10−4

D3S1267
139.12
1.63
<0.004

D4S1625
145.98
1.18
<0.01

D4S1652
208.07
1.77
<0.003

D6STNFa
63.41
1.14
<0.05

D9S257
91.87
1.10
<0.05

D17S921
36.12
2.17
<8 × 10−4

D17S1294
50.74
1.78
<0.005

D18S843
28.1
1.23
<0.001

Position in centiMorgan (cM) of markers from p‐ter to q‐ter based on the Marshfield map (http//research.marshfieldclinic.org/genetics).

P‐values estimated using P (LOD)=0.5 × (χ21 > 2 ln 10 × LOD).

Conclusion
Our results support the linkage to allergic rhinoconjunctivitis on 3q13, 6p23–p24 and 9q34.3 shown in previous investigations.