Identification of possible pathogenic pathways in Beh?et's disease using genome-wide association study data from two different populations

Behçet''s disease (BD) is a multi-system inflammatory disorder of unknown etiology. Two recent genome-wide association studies (GWASs) of BD confirmed a strong association with the MHC class I region and identified two non-HLA common genetic variations. In complex diseases, multiple factors may target different sets of genes in the same pathway and thus may cause the same disease phenotype. We therefore hypothesized that identification of disease-associated pathways is critical to elucidate mechanisms underlying BD, and those pathways may be conserved within and across populations. To identify the disease-associated pathways, we developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein–protein interaction networks, and functional information of selected SNPs. Using this methodology, we searched for the disease-related pathways in two BD GWASs in Turkish and Japanese case–control groups. We found that 6 of the top 10 identified pathways in both populations were overlapping, even though there were few significantly conserved SNPs/genes within and between populations. The probability of random occurrence of such an event was 2.24E−39. These shared pathways were focal adhesion, MAPK signaling, TGF-β signaling, ECM–receptor interaction, complement and coagulation cascades, and proteasome pathways. Even though each individual has a unique combination of factors involved in their disease development, the targeted pathways are expected to be mostly the same. Hence, the identification of shared pathways between the Turkish and the Japanese patients using GWAS data may help further elucidate the inflammatory mechanisms in BD pathogenesis.     

Enterovirus infections following T-cell depleted allogeneic transplants in adults

Anecdotally, enteroviruses have been reported to cause serious complications post BMT, but the exact impact of these viruses in the post transplant period has not been reported. We prospectively evaluated stool, urine and throat samples for enteroviruses by viral culture together with relevant body fluids by RT-PCR in 64 allograft recipients receiving grafts T-cell depleted by Campath-1H, following both conventional and reduced-intensity conditioning. Seven patients (10.4%) developed nine episodes of enterovirus infections at a median of 146 days post transplant. Four episodes were associated with symptomatic illnesses, which could be attributable to enteroviruses. There was no mortality directly related to enteroviruses. There was no correlation between dose and mode of Campath-1H use, lymphocyte recovery, IgG and IgA levels and enterovirus isolation. Although enteroviruses tended to be more frequent in TBI-based conventional conditioning recipients, the only significant risk factor for enterovirus infection was unrelated donor graft. The low incidence of the severe enterovirus infections could have been related to a low lymphocyte count in this cohort in the absence of GVHD, particularly CD4+ count, which has been implicated in tissue damage in experimental animals. Further studies are needed to define its impact in different allograft settings.     

Re-evaluation of the value of ascitic fluid pH lactate dehydrogenase and total proteins in the diagnosis of spontaneous bacterial peritonitis (SBP)

In view of high mortality, variable clinical presentation, and late results of bacterial culture, early diagnosis of SBP and treatment are based on indirect parameters of infection. Forty-two patients with ascites and liver cirrhosis were studied. Ascitic fluid (AF) was examined for total protein content, pH, lactate dehydrogenase, amylase, absolute polymorphonuclear cell count (PMN) and for presence of bacteria by examining a fresh smear of the deposit and culture of the fluid under aerobic and anaerobic conditions. AF/serum gradient of total proteins and LDH was calculated. One patient proved to have a malignant ascites and was excluded. The remaining 41 patients fell into two groups: Group I PMN less than 250 cell mm-3, culture negative, sterile ascites, 36 patients. Group II PMN greater than 250 cell mm-3. (a) Culture positive neutrophilic ascites (SBP), three patients. (b) Culture negative neutrophilic ascites (CNNA), two patients. In both CNNA and SBP:AF/serum total LDH gradient greater than 0.75 In the sterile group: AF/serum total LDH gradient less than 0.58 There was no correlation between presence of infection and ascitic fluid pH, protein content and AF/serum total protein gradient. Therefore AF PMN greater than 250 mm and AF/serum total LDH gradient greater than 0.6 should be considered reliable, indirect parameters of infection, and CNNA a variant of SBP with a small bacterial inoculum size.     

Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association

The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease‐associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL‐like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease‐causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL.     

JACIE: A 20 year-old voluntary body functioning worldwide

Hematopoietic Stem Cell Transplantation (HSCT) is a well estabished treatment modality for patients with severe disorders of the hematopoietic system. HSCT is the pioneer of not the adoptive immunotherapy but also cellular therapies. It was first performed in 1957; since then the transplantation numbers have increased every year in almost all parts of the World. However, the increase in the quality of this procedure was not as fast as the numbers. The first Standards for hematopoeietic cell collection, processing and transplantation in Europe was established in 1998 by the European Group for Bone Marrow Transplantation (EBMT) and The International Society for Hematotherapy and Graft Engineering Europe I (SHAGE Europe) and the Joint Accreditation Committee of ISCT EBMT (JACIE) was founded. JACIE is a non-profit voluntary organization that helps all the stakeholders of HSCT, the teams, goverments, regulators, payers and, mostly, the patients. In this review the aims and the twenty years history of JACIE in the World and in Turkey is explained.