Cell-surface expression of hLDLR was confirmed (Fig. 7A). The presence of hLDLR increased HCV binding

to CHO cells by nearly 1 log10 (Fig. 7B), providing signaling pathway an additional proof for the direct HCV-LDLR interaction. To verify the effect of different factors used in this study on HCV binding to LDLR, we pretreated the virus with LPL, sLDLR, or anti-ApoE antibody for 1 hour at 37°C, and we analyzed the effect of these molecules on HCV binding to CHO-hLDLR. Interestingly, LPL treatment increased HCVcc binding to LDLR to 187% (Fig. 7C). Moreover, both anti-ApoE antibody and sLDLR decreased HCV-hLDLR interaction to 52% and 42%, respectively. The specificity of these effects was verified by analyzing the binding of treated viruses on control CHO cells (Fig. 7C). Together, these results confirm that HCV binds to LDLR and that this interaction can be increased by LPL or reduced by sLDLR and anti-ApoE antibody. The association of HCV particle with VLDL provides the opportunity for this virus to interact with the LDLR, a cell-surface receptor known to internalize lipoproteins. Here, we show that HCVcc is able to interact with the LDLR and that this receptor Epigenetics inhibitor plays a role in the HCV life cycle. However, our data do not fit with a major role for the LDLR in productive HCV entry. Its physiological function

is rather important for optimal replication of HCV genome. A functional LDLR is important

for HCV replication. By internalizing lipoproteins, the LDLR contributes to the hepatocyte content of cholesterol and, potentially, other lipids, which could affect HCV replication, because genomic RNA replication is tightly linked to lipid metabolism.34 Interestingly, Huh-7 cells treated with the anti-LDLR antibody showed some changes in lipid composition. In this context, the increase in the ratio of PE to PC is particularly interesting to note. Both PE and 3-mercaptopyruvate sulfurtransferase PC are indeed major phospholipids in mammalian membranes; in particular, they constitute the main components of the endoplasmic reticulum (ER) membrane. Because HCV replicates its genome in association with ER-derived membranes35 and the ratio of PC to PE has been shown to influence membrane integrity,36 we speculate that this lipid composition change, induced by mAb C7, may affect HCV replication. The state of maturation of the lipoproteins associated with HCV particles needs to be taken into account in virus-entry studies. VLDL is assembled by the liver, and upon entry into the plasma, the triglyceride component of VLDL is rapidly hydrolyzed by LPL and the lipoproteins are converted to cholesterol-rich IDL, which is cleared by the liver.10 The IDL is rich in ApoE, whereas in LDL, the vast majority of ApoE and ApoC have been removed. Though LDL is also cleared by the liver, it is through ApoB-LDLR interaction.

The metastasis of cancers is associated with the recovery and prognosis of cancer patients. However, the mechanisms of how gastric cancer check details cells migrate and invade other organs or lymphnode remain to be explored. Considering cancer stem cells are the origin of cancers and are associated with cancer metastasis, we performed migration and invasion assays on a miRNA cluster that were previously found to regulate

gastric cancer stem cell fates in our department – the miR-17-92 cluster. Methods: Migration and invasion assays were used to detect the metastatic abilities of these miRNAs in vitro. caudal veins injection was used to test the metastasis in vivo. Report gene assay and Western Blotting were performed to test the target genes of this cluster. Results: Using migration and invasion assays performed on both stable miR-17-92 expressing cell lines and transient transfection of miR-17-92 precursors and inhibitors, we found members of miR-17-92 cluster can promote metastasis of gastric cancer cells in vitro. Furthermore, injecting miR-17-92 expressing cells https://www.selleckchem.com/products/epz-6438.html into caudal veins

of node mice proved the pro-metastatic functions of miR-17-92 cluster in vivo. Moreover, using report gene assay and Western Blotting, we also found overexpression of miR-17-92 cluster members reduced expression of MXD1. Previous studies have found MXD1 suppressed c-Myc transcription through Myc/Max/Mad1 network. Giving that c-Myc is a direct transcript of miR-17-92 cluster, we thus speculated Etofibrate that miR-17-92 might work within an intricate gene regulatory

network: firstly, the miR-17-92 cluster reduced MXD1 levels which would fail in suppressing c-Myc transcription; therefore, c-Myc expression levels increased because of the lack of MXD1 restrict; furthermore, the increased c-Myc levels promoted transcription of miR-17-92 cluster, which would result in the increased expression of miR-17-92 and the reduction of MXD1 levels, thus establishing a positive feedback auto-regulatory loop within miR-17-92, MXD1 and c-Myc. Conclusion: In conclusion, miR-17-92 cluster acts as a pro-metastatic regulator and an oncogenic cluster in gastric cancer cells. In addition, by targeting MXD1, miR-17-92 represents a self-regulatory aimed at balancing the opposite effects by increasing the robustness of gene circuitries controlling cell malignancy. These data indicates miR-17-92 as a novel therapeutic target for gastric cancer. Key Word(s): 1. Gastric cancer; 2. miR-17-92; 3. metastasis; 4.

Moreover, our data describe a novel miR-196a/ NFKBIA link and imply a potential therapeutic target of miR-196a for pancreatic carcinoma. Key Word(s): 1. miR-196a; 2. pancreatic carcinoma; Ferroptosis activation 3. NFKBIA; Presenting Author: LINJIE GUO Additional Authors: CHUN HUI

WANG, CHENG WEI TANG Corresponding Author: CHENG WEI TANG Affiliations: West China Hospital Objective: The annual incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is still unclear in China. The objective of this study is to estimate the incidence of GEP-NETs in Chengdu city, the fourth biggest city of China. Methods: This study estimated the incidence of GEP-NETs in Chengdu city with the database of West China Hospital and population-based data from Chengdu Health Bureau during 2006 – 2010. Among the hospitals with the ability to diagnose GEP-NETs in Chengdu

city, the annual patients in West China Hospital were 25.6%∼28% of those in whole of the PD0325901 hospitals during the past five years. GEP-NETs incidence in Chengdu was yielded by the number of annual new patients with GEP-NETs in West China Hospital divided with the 25.6% ∼ 28% population of Chengdu city. Results: GEP-NETs incidence in Chengdu increased 1.89 folds during past 5 years from 1.13/100000 to 2.14/100000, p < 0.05. The average duration of symptom before diagnosis was 15 months. Application of GI-Endoscopy increased during the five years. About 46.4% of GEP-NETs were later stage when diagnosis was made. 77% patients were over 40 years. Proportions of GEP-NETs from most common primary sites were rectum 30.6%, pancreas 23.4%, gastric 13.3%, esophagus 11.3%. Proportions of insulinoma, vipoma and non-functional pancreatic neuroendocrine tumors (P-NETs) were 43.1%, 1.7% and 55.2% separately in the P-NETs. Conclusion: The incidence of GEP-NETs is

increasing in Chengdu area with a population of 14.04 million. There is a distinct epidemiologic profile for each primary site. The delayed diagnosis DCLK1 reflects limited medical education regarding GEP-NETs, inadequate disease awareness and paucity of research funding. Key Word(s): 1. GEP-NETs; 2. Incidence; 3. Chengdu city; 4. China; Presenting Author: YALEI WANG Additional Authors: HUI FENG, WEIYAN YAO, XI CHEN, CHENYU ZHANG Corresponding Author: YALEI WANG Affiliations: The first affiliated hospital of Anhui Medical University; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; School of Life Sciences, Nanjing University Objective: MicroRNAs are endogenous non-coding RNAs, playing an important role in regulating gene expression by blocking the translation or triggering the degradation of the target mRNAs. MicroRNA-148a was described to be down-regulated in several types of solid cancers, while it has not been studied in pancreatic cancer.

HNF1/Tcf1 may represent one point of convergence within this regulatory network as the levels of expression induced by BMP-4 are higher in wild-type cells than in the Hex−/− endoderm and dramatically enhanced by the enforced expression of Hex. In addition to playing a regulatory role at the level of Tcf1 expression, evidence exists that Hex can physically interact with Tcf132 suggesting that these transcription factors may function as coactivators of downstream targets. In conclusion, the findings presented here document a pivotal role for Hex in the establishment of the hepatic lineage in ESC cultures

and in doing so provide further evidence that lineage

commitment Selleck Poziotinib in this model accurately reflects that observed in the early embryo. Stage-specific enforced expression of Hex promoted hepatic development and maturation, indicating that this strategy may provide an efficient method find more for the production of relatively mature cell types for studies on lineage commitment, for transplantation in preclinical model of liver disease and for drug discovery and analyses. We thank Mako Yabunouchi and Fumie Otsuka for their excellent technical assistance. Additional Supporting Information may be found in the online version of this article. “
“Aim:  To evaluate the role of natural killer (NK)T cells in the pathogenesis of non-alcoholic steatohepatitis (NASH), here we investigated the expression and function of hepatic NKT cells in KK-Ay mice, an animal model of metabolic syndrome. Methods:  Male, 8-week-old KK-Ay and C57Bl/6 mice were fed a high-fat (HF) diet for 4 weeks. Some mice were given daily intragastric injections of pioglitazone for 5 days prior to or after dietary treatment. Results:  In untreated KK-Ay mice, the percentages of NKT cells in liver mononucleolar cells were

nearly one-third of those in C57Bl/6 controls. Elevations in interleukin (IL)-4 and interferon (IFN)-γ mRNA in the liver after a single injection of α-galactosylceramide Montelukast Sodium (GalCer) were blunted in KK-Ay mice largely. Percentages of NKT cells, as well as GalCer-induced increases in IL-4 mRNA, were blunted significantly in both strains after HF diet feeding for 4 weeks. Interestingly, KK-Ay mice pretreated with pioglitazone showed significant increases in NKT cell proportion, and GalCer-induced increases in IL-4 and IFN-γ mRNA were also enhanced by pioglitazone. In KK-Ay mice, the percentages of annexin V positive NKT cells were nearly 2.5-fold higher than those in C57Bl/6 controls; however, pioglitazone decreased annexin V positive cells significantly. Moreover, pioglitazone increased NKT cell fraction in KK-Ay mice even after HF diet feeding.

El considerar la obesidad como parte del tratamiento de la migraña resultará en mejor salud y un tratamiento exitoso. Si las medidas usuales de dieta y ejercicio no funcionan, hay nuevas maneras de manejar la obesidad. En ese momento se puede considerar

la cirugía bariátrica. ¿Cómo puede esta cirugía afectar las cefaleas? El bypass gástrico y las bandas gástricas muestran ser prometedoras en la reducción de migrañas. De acuerdo a los estudios limitados hasta ahora disponibles, la mayoría de las personas luego de esos procedimientos tienen una reducción significante en la frecuencia de migrañas. El tratamiento médico de la obesidad es otra estrategia. El FDA aprobó en el 2012 una píldora llamada Qsymia la cual combina fenteramina FK866 y topiramato. En dosis bajas esta píldora aparenta

ser algo protectiva para los que sufren de cefalea, y en dosis mas altas solo 1% de las personas se quejaron de cefalea, así que no se cree que esta medicina cause mas migrañas. Ya que la obesidad parece aumentar la frecuencia de las migrañas, es posible que a la larga, solamente la pérdida de peso ayude a mejorar los dolores de cabeza. Cada persona con migraña quiere tener los menos episodios posibles, como también vivir una vida feliz, saludable y productiva. Añadiendo el control de peso como una Selleck Dabrafenib parte del plan de tratamiento de la migraña va a resultar en mayor probabilidad de éxito. Comience pesándose y conversando con su médico de cefaleas sobre las maneras en que este puede ayudarlo(a) a alcanzar sus metas. Material Educativo de Cefaleas: http://www.headachejournal.org/view/0/spanishtoolboxes.html “
“We report the case of a 60-year-old man suffering from episodic cluster headache treated successfully with sodium oxybate. Sodium oxybate may be a therapeutic option in attacks of episodic cluster headache. “
“(Headache 2011;51:999-1001) Olfactory hallucinations have been reported in association with numerous neurological and psychiatric disorders, in particular as a component of partial

complex seizure and psychiatric disorders, but are rarely described in migraine disease. We report the case of an adolescent who reported TCL complex hallucinations during a migraine attack. “
“Genetics and Headache: The Role of the MTHFR Gene in Migraine Stuart S, Cox H, Lea R, Griffiths L. Migraine is a common neurological disorder and is characterized by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia, and occasionally, visual sensory disturbances. A number of genes have been implicated in the pathogenesis of this disease, including genes involved in regulating the vascular system. Of particular importance are the methylenetetrahydrofolate reductase gene (MTHFR) and the role it plays in migraine with aura. Migraine with aura has previously been shown to have a significant comorbidity with stroke, making the vascular class of genes a priority for migraine studies.

that vascular findings in AIP improve in most patients who receive corticosteroid treatment is interesting and points towards reversibility of such changes, at least in a subset of patients. These promising results should now be confirmed by future studies. “
“To examine the effect of nucleoside analog (NA) therapy on clinical outcome in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) who underwent curative therapy. A total of 131 patients with HBV-related HCC who underwent curative therapy were analyzed. They were divided into an NA group who received NA therapy (n = 99, see more group A) and a control group (n = 32, group B). Group A was further

classified into two groups of patients who either received NA therapy before HCC therapy (n = 34, group Aa) or who received NA therapy with initial HCC BMN 673 order therapy (n = 65, group Ab). Overall survival (OS) and recurrence-free survival (RFS) were compared in the three groups. The 1- and 3-year cumulative OS rates were both in group Aa, 100% and 88.0%

in group Ab, and 100% and 75.7% in group B (overall significance, P = 0.002), respectively. The corresponding RFS rates were 93.1% and 36.0% in group Aa, 78.3% and 45.7% in group Ab, and 78.0% and 38.0% in group B (overall significance, P = 0.734), respectively. Multivariate analysis revealed that being part of group Aa (P < 0.001) or group Ab (P < 0.001) and having albumin levels of 4.0 g/dL or more (P = 0.040) were significantly associated with Megestrol Acetate OS, while HCC stage (P = 0.001) and hepatitis B e-antigen positivity (P < 0.001) were independent predictors linked to RFS. NA therapy in patients with HBV-related HCC may improve survival after curative therapy. "
“High-quality artifact-free ultrasound images can now be produced by a portable machine. Being relatively cheap and non-invasive, ultrasound is widely accepted as the first-line investigation for patients with abdominal symptoms. A negative ultrasound is often regarded as the absence of major

abdominal conditions. Positive findings on ultrasound can guide further imaging (CT/MRI) for better characterization and delineation of the underlying disease. Specific diagnosis of certain disease entities can sometimes be made based on characteristic ultrasound features. The real-time nature of ultrasound can assist correlation with clinical symptoms and provide imaging guidance to obtain tissue biopsy. New advances in technique (contrast-enhanced ultrasound and ultrasound elastography) not only provide morphological but also functional assessment. “
“We investigated left ventricular diastolic dysfunction (LVDD) and its relationship with circulatory function and prognosis in cirrhosis with portal hypertension and normal creatinine.

Growing evidence implicates portal inflammation as a key predictor of histological progression of NAFLD. We find more hypothesise that the manifestation of portal fibrosis and a pro-fibrogenic DR is driven by cross-talk between diverse infiltrating immune cells. Although numerous cytokines and multiple individual cell types have been implicated in NAFLD pathogenesis, the composition of the portal and peri-ductal inflammatory infiltrate has not been systematically investigated. Methods: Liver biopsy sections from 32 NAFLD

patients were immunostained for keratin-7 to highlight the DR, and co-stained for markers of candidate cellular components of the portal inflammatory infiltrate, including CD3, CD8, CD20, CD68, neutrophil elastase (NE), IL-17 and MMP-9. Fresh-frozen liver biopsy samples were available from 23 NAFLD patients for analysis of Collagen-1A and inflammatory gene expression (TGFβ, IL-1β, TNFα, IL-6, IFN-γ, IL-4 and IL-10). Results: Inflammatory cells within the portal tracts were more numerous than centrilobular regions. The portal inflammatory compartment was comprised of a mix of inflammatory cells, including T cells, B cells, macrophages and neutrophils. Significant portal infiltration was not observed until the presence of progressive NASH (fibrosis

stage 2–4) (all P < 0.05) with the exception of macrophage GSK-3 inhibitor review numbers, which increased with the appearance of simple steatosis (P < 0.01) as well as progressive NASH (P < 0.001) when compared with non-diseased control livers. Portal inflammatory cells were present in the peri-ductular inflammatory niche and cell numbers correlated with increasing grade

of DR (all P < 0.05) and stage of fibrosis (all P < 0.001). Collagen-1A mRNA was elevated in patients with simple steatosis and highest in progressive tuclazepam NASH (P < 0.001). TNFα, IL-1β and IL-6 were highly expressed with progressive NASH (P < 0.05) whereas TGFβ, IFN-γ, IL-4 and IL-10 showed no association with disease state and progression. Elevated levels of pro-inflammatory cytokines TNFα and IL-1β occurred before significant portal inflammatory infiltration (P < 0.05). Functional markers highlighted IL-17 production by a subset of neutrophils and MMP-9 by a subset of portal and lobular macrophages. Conclusion: Cell phenotypes and subsequent signalling are greatly influenced by their microenvironments. A modified hepatic inflammatory environment likely influences resident inflammatory cell phenotypes, and may promote a profibrogenic DR and further infiltration of inflamed portal tracts. "
“We read with interest the review by Martínez et al.

The efficacy of pantoprazole

magnesium was compared with that of esomeprazole over 4 and 8 weeks’ treatment in patients with erosive gastroesophageal reflux disease (GERD). Methods: In this multicentre (14 Brazilian sites), phase III, double-blind study, patients with erosive GERD (Los Angeles grades A–D) were randomised to pantoprazole magnesium (n = 290) or esomeprazole (n = 288), both administered at 40 mg once daily for 8 weeks. Severity of esophagitis (at endoscopy) and GERD-related symptoms (using ReQuest™-GI) were assessed at baseline and 4 and 8 weeks, and complete remission (a ReQuest™-GI score below 1.73 Wnt inhibitor plus endoscopically confirmed healing) was compared between treatments (significance p < 0.05). Results: Complete remission with pantoprazole magnesium was non-inferior to that with esomeprazole at 4 and 8 weeks (table). Mucosal healing was similar for the two treatments. However, symptom relief with pantoprazole magnesium was significantly greater at 8 weeks (p = 0.0370) than that with esomeprazole. Both PPIs had similarly low rates of adverse events. Conclusion: Pantoprazole magnesium 40 mg was as effective as esomeprazole 40 mg for complete remission and mucosal healing, but provided greater symptom relief at 8 weeks, suggesting an

extended period of treatment effect. Key Word(s): 1. GERD; 2. Symptom relief; 3. Pantoprazole; 4. Esomeprazole; Complete remission, endotcopically confirmed healing and symptom relief rates after 4 and 8 weeks (intent-to-trcat population) Assessment 4 weeks, n (%) 8 weeks, n(%) Pantoprazole magnesium Esomeprazole buy NVP-LDE225 Pantoprazole magnesium Sitaxentan Esomeprazole *P = 0.0370 versus esomeprazole. Presenting Author: RAPAT PITTAYANON Additional Authors: RATHA-KORN VILAICHONE, TANISA PATCHARATRAKUL, CHINNAVAT SUTTHIVANA, WANIT PIYANIRUN, MONTIRA MANEERATANAPORN, SOMCHAI LEELAKUSOLVONG,

UDOM KACHINTORN, SUTEP GONLACHANVIT, VAROCHA MAHACHAI Corresponding Author: RAPAT PITTAYANON Affiliations: Chulalongkorn University; Thammasart University; Bhumipol Adulyadej Hospital; Pramongkulklao Hospital; Siriraj Hospital, Mahidol University Objective: Introduction: The awareness of gastroesophageal reflux disease (GERD) has led to an increased prevalence of GERD across the Asian region. It has a significant impact on quality of life and health care expenditure. Proton pump inhibitor (PPI) is commonly used to relief the symptoms. The aim of this study was to understand the patient perception on GERD, its impact on quality of life and the pattern of PPI use in GERD patients in Thailand. Methods: Methods: The physician-diagnosed GERD patients recruited from hospitals throughout Thailand participated in the 20 minute face-to-face interviews after signing informed consent. Results: Results: A total of 400 patients from 39 hospitals were enrolled.

e., class III phosphatidylinositol-3-kinase). The process of autophagosome formation involves two major steps: nucleation and elongation of the isolation membrane. The Atg1/unc-51-like

kinase (ULK) complex, the autophagy-specific PI3-kinase complex, and PI3P-effectors and their related proteins are important for the nucleation p38 MAPK activity step, whereas the Atg12- and LC3/Atg8-conjugation systems are important for the elongation step. Studies have demonstrated that autophagy plays a wide variety of physiological and pathophysiological roles. Recent evidence has shown that autophagy is associated with cancer pathogenesis and that pharmacologic manipulation of autophagic pathways may represent a new therapeutic strategy for human cancers. However, to date the role of autophagy in cancer is not clearly defined. Although autophagy is a cancer cell survival mechanism against environmental and cellular stresses, it can be associated with cancer cell death under certain situations. Further,

autophagy and apoptosis might be linked to each other and occur simultaneously or sequentially in a cell type-, death stimulus-, and context-dependent manner.[9] Although Hh signaling is known to inhibit cell apoptosis, it remains unknown whether Hh signaling is able to regulate autophagy. The current study describes a novel role of the Hh signaling pathway for regulation of autophagy in human HCC cells. We show that inhibition of the Hh pathway markedly enhanced autophagy http://www.selleckchem.com/products/CP-673451.html through up-regulation of Bnip3 (a member of BH3-only subset of the Bcl-2 family) that displaces Bcl-2 from its binding partner, Beclin-1, and that this process preludes apoptosis. Our findings suggest that the status of autophagy (autophagic flux) is a key factor that may influence cell response to Hh-targeted therapy. Human HCC cells (Huh7, Hep3B, and HepG2) were treated with the Hh signaling ligand, agonists, or inhibitors as indicated and the cells were analyzed for autophagy by immunoblotting

for microtubule-associated Selleckchem Rucaparib protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy (TEM). Western blotting analysis was performed to determine the alteration of key signaling molecules including Shh, Patched, Smo, and Gli1, Bnip3, Bcl-2 family proteins, and MEK/ERK1/2. The interaction between Bcl-2 and Beclin-1 was analyzed by immunoprecipitation and immunoblotting assays. For quantitative reverse-transcription polymerase chain reaction (qRT-PCR), total RNA was extracted with the TRIzol plus RNA purification kit and reverse-transcribed to complementary DNA (cDNA) using Superscript II reverse transcriptase; the cDNA samples were used for real-time PCR analysis in triplicate using the QuantiFast SYBR Green PCR kit (Qiagen) on a Bio-Rad C1000 Thermal Cycler.

“
“This chapter contains sections titled: Introduction Principles of biologic standardization Standardization of factor VIII assays Standardization of factor IX assays Standardization of inhibitor assays Standardization of von Willebrand factor assays Standardization of bypassing agents

Standardization of assays of other coagulation factors Standardization of global assays References “
” Twenty years ago I conceived an idea for a journal about haemophilia. I approached Peter Saugman of Blackwell Publishing – a company that was particularly strong in Haematology: their first scientific publication, the British Journal of Haematology, was published in 1955. Fortunately, they were prepared to take the risk, and wanted the journal to be international and have a strong North American presence. Doreen Brettler, director of the New England Hemophilia Centre, agreed to become the first North American editor. We met to formulate our ideas and develop MLN0128 molecular weight an editorial board at the World AIDS Meeting in Berlin in June 1993. It was important from the outset to have the support of key haemophilia leaders – Shelby Dietrich, then the head of the World Federation of Hemophilia (WFH) publications committee, and Pier Mannucci provided helpful support and advice. Peter Jones, the director of the Newcastle Haemophilia Centre in the

UK, encouraged us to present the idea at a WFH meeting of the ‘Decade Plan’ held in Estoril, Portugal in October 1993. With BGB324 cost some trepidation, at the end of a long meeting,

I presented a mock-up of the first cover with the title Haemophilia – there was no discussion, even about the anglicized Greek spelling! The launch issue appeared in October 1994 with a publication date January 1995. Our mission statement that ‘Haemophilia is an international journal dedicated to the exchange of information regarding the comprehensive care of haemophilia’ Cyclic nucleotide phosphodiesterase continues today. The journal soon became the official journal of WFH and proudly published, for the first time, the abstracts of the WFH meeting held in Dublin 1996. More recently Haemophilia has become affiliated to the European Association for Haemophilia and Allied Disorders (EAHAD) and the Hemostasis and Thrombosis Research Society of North America (HTRS). We publish in translation a Japanese edition and a Chinese edition. Haemophilia is now published by Wiley-Blackwell and is one of their 1500 scientific publications. We continue to publish predominantly in print, but an increasing number of our readers prefer on-line; the authors are also fast moving in this direction as this issue of Haemophilia attests. Haemophilia remains grateful to all the Authors who have submitted, and continue to submit, their research, writing and thinking – together we have created a substantial record of haemophilia, and the many challenges concerning the management of this intriguing condition.