Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate

The Effect of Infections on the Mortality of Cirrhotic Patients with Hepatic Encephalopathy

[[abstract]]Cirrhotic patients are prone to having infections, which may aggravate hepatic encephalopathy (HE). However, the effect of infections on mortality in HE cirrhotic patients is not well described. The National Health Insurance Database, derived from the Taiwan National Health Insurance Programme, was used to identify 4150 adult HE cirrhotic patients hospitalized between 1 January 2004 and 31 December 2004. Nine hundred and eighty-five patients (23.7%) had one or more co-existing infections during their hospitalization. After Cox proportional hazard regression modelling adjusted by the patients' gender, age, and medical comorbidity disorders, the hazard ratios (HRs) in HE patients with infections for 30-day, 30- to 90-day, and 90-day to 1-year mortalities were 1.66 [95% confidence interval (CI) 1.42-1.94], 1.51 (95% CI 1.23-1.85) and 1.34 (95% CI 1.13-1.58), respectively. Compared to the non-infection group, the HRs of pneumonia, spontaneous bacterial peritonitis, urinary tract infection, sepsis without specific focus (SWSF), cellulitis, and biliary tract infection were 2.11, 1.48, 1.06, 2.21, 1.06, and 0.78, respectively, for 30-day mortality; 1.82, 1.22, 0.93, 2.24, 0.31, and 2.82, respectively, for 30- to 90-day mortality; and 2.03, 0.82, 1.24, 1.64, 1.14, and 0.60, respectively, for 90-day to 1-year mortality for HE cirrhotic patients. We conclude that infections increase the mortality of HE cirrhotic patients, especially pneumonia and SWSF.[[notice]]補正完畢[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

A Metabolomics Signature Linked To Liver Fibrosis In The Serum Of Transplanted Hepatitis C Patients

Liver fibrosis must be evaluated in patients with hepatitis C virus (HCV) after liver transplantation because its severity affects their prognosis and the recurrence of HCV. Since invasive biopsy is still the gold standard to identify patients at risk of graft loss from rapid fibrosis progression, it becomes crucial the development of new accurate, non-invasive methods that allow repetitive examination of the patients. Therefore, we have developed a non-invasive, accurate model to distinguish those patients with different liver fibrosis stages. Two hundred and three patients with HCV were histologically classified (METAVIR) into five categories of fibrosis one year after liver transplantation. In this cross-sectional study, patients at fibrosis stages F0-F1 (n = 134) were categorised as "slow fibrosers" and F2-F4 (n = 69) as "rapid fibrosers". Chloroform/methanol serum extracts were analysed by reverse ultra-high performance liquid chromatography coupled to mass spectrometry. A diagnostic model was built through linear discriminant analyses. An algorithm consisting of two sphingomyelins and two phosphatidylcholines accurately classifies rapid and slow fibrosers after transplantation. The proposed model yielded an AUROC of 0.92, 71% sensitivity, 85% specificity, and 84% accuracy. Moreover, specific bile acids and sphingomyelins increased notably along with liver fibrosis severity, differentiating between rapid and slow fibrosers

Capsular profiling of the Cronobacter genus and the association of specific Cronobacter sakazakii and C. malonaticus capsule types with neonatal meningitis and necrotizing enterocolitis

Background: Cronobacter sakazakii and C. malonaticus can cause serious diseases especially in infants where they are associated with rare but fatal neonatal infections such as meningitis and necrotising enterocolitis. Methods: This study used 104 whole genome sequenced strains, covering all seven species in the genus, to analyse capsule associated clusters of genes involved in the biosynthesis of the O-antigen, colanic acid, bacterial cellulose, enterobacterial common antigen (ECA), and a previously uncharacterised K-antigen. Results: Phylogeny of the gnd and galF genes flanking the O-antigen region enabled the defining of 38 subgroups which are potential serotypes. Two variants of the colanic acid synthesis gene cluster (CA1 and CA2) were found which differed with the absence of galE in CA2. Cellulose (bcs genes) were present in all species, but were absent in C. sakazakii sequence type (ST) 13 and clonal complex (CC) 100 strains. The ECA locus was found in all strains. The K-antigen capsular polysaccharide Region 1 (kpsEDCS) and Region 3 (kpsMT) genes were found in all Cronobacter strains. The highly variable Region 2 genes were assigned to 2 homology groups (K1 and K2). C. sakazakii and C. malonaticus isolates with capsular type [K2:CA2:Cell+] were associated with neonatal meningitis and necrotizing enterocolitis. Other capsular types were less associated with clinical infections. Conclusion: This study proposes a new capsular typing scheme which identifies a possible important virulence trait associated with severe neonatal infections. The various capsular polysaccharide structures warrant further investigation as they could be relevant to macrophage survival, desiccation resistance, environmental survival, and biofilm formation in the hospital environment, including neonatal enteral feeding tubes

Outcomes in culture positive and culture negative ascitic fluid infection in patients with viral cirrhosis: cohort study

<p>Abstract</p> <p>Background</p> <p>Ascitic fluid infection (AFI) in cirrhotic patients has a high morbidity and mortality. It has two variants namely, spontaneous bacterial peritonitis (SBP) and culture negative neutrocytic ascites (CNNA). The aim of this study was to determine the outcome in cirrhotic patients with culture positive (SBP) and culture negative neutrocytic ascites.</p> <p>Methods</p> <p>We analyzed 675 consecutive hepatitis B and/or C related cirrhosis patients with ascites admitted in our hospital from November 2005 to December 2007. Of these, 187 patients had AFI; clinical and laboratory parameters of these patients including causes of cirrhosis, Child Turcotte Pugh (CTP) score were recorded.</p> <p>Results</p> <p>Out of 187 patients with AFI, 44 (23.5%) had SBP while 143 (76.4%) had CNNA. Hepatitis C virus (HCV) infection was the most common cause of cirrhosis in 139 (74.3%) patients. Patients with SBP had high CTP score as compared to CNNA (12.52 ± 1.45 vs. 11.44 ± 1.66); p < 0.001. Platelets count was low in patients with SBP (101 ± 53 × 10⁹/L) as compared to CNNA (132 ± 91 × 10⁹/L), p = 0.005. We found a high creatinine (mg/dl) (1.95 ± 1.0 vs. 1.44 ± 0.85), (p = 0.003) and high prothrombin time (PT) in seconds (24.8 ± 6.6 vs. 22.4 ± 7.2) (p = 0.04) in SBP as compared to CNNA. More patients with SBP (14/44; 31.8%) had blood culture positivity as compare to CNNA (14/143; 9.8%), p = 0.002. Escherichia. Coli was the commonest organism in blood culture in 15/28 (53.5%) patients. SBP group had a higher mortality (11/44; 25%) as compared to CNNA (12/143; 8.4%), p = 0.003. On multiple logistic regression analysis, creatinine >1.1 mg/dl and positive blood culture were the independent predictors of mortality in patients with SBP.</p> <p>Conclusion</p> <p>Patients with SBP have a higher mortality than CNNA. Independent predictors of mortality in SBP are raised serum creatinine and a positive blood culture.</p

eCLIPs bifurcation remodeling system for treatment of wide neck bifurcation aneurysms with extremely low dome-to-neck and aspect ratios: a multicenter experience

In our case series, 24 patients treated at 12 international centers were taken from a larger prospective voluntary post-marketing registry of 65 patients treated with the eCLIPs device and coiling. Those who had WNBAs at either the carotid or basilar terminus with a DTN ratio Wide necked bifurcation aneurysms (WNBA) are among the most difficult aneurysms to treat. Very low dome-to-neck (DTN) and aspect ratios provide an even greater challenge in the management of WNBAs. We present the safety and efficacy profile for endovascular clip system (eCLIPs) device in the treatment of this subset of WNBAs with very unfavorable morphologies.Our series of patients with aneurysms having adverse DTN and aspect ratios demonstrated that the eCLIPs device has a safety and efficacy profile comparable with currently available devices in the treatment of WNBAs.The eCLIPs device was successfully deployed in 23 cases (96%). One patient (4.2%) died due to guidewire perforation distal to the implant site. No other complications were documented. After a mean follow-up of 15.8 months (range 3-40 months), good radiologic outcomes (modified Raymond-Roy classification (MRRC) scores of 1 or 2) were documented in 20 of 21 patients (95%) with follow-up data. The lone patient with an MRRC score of 3 showed coiled compaction after incomplete neck coverage with the device.</div

Everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study

Background and aim: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. Methods: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels <_ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. Results: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. Conclusion: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation