Arteriography during ex vivo renal perfusion A complication

A case of bilateral renal-cell carcinoma unsuccessfully treated with bench surgery is reported. The reason for failure was apparently the toxicity of the contrast media used during the ex vivo arteriographic studies. © 1973

Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon

Colorectal cancer risk is associated with diets high in red meat. Heme, the pigment of red meat, induces cytotoxicity of colonic contents and elicits epithelial damage and compensatory hyperproliferation, leading to hyperplasia. Here we explore the possible causal role of the gut microbiota in heme-induced hyperproliferation. To this end, mice were fed a purified control or heme diet (0.5 μmol/g heme) with or without broad-spectrum antibiotics for 14 d. Heme-induced hyperproliferation was shown to depend on the presence of the gut microbiota, because hyperproliferation was completely eliminated by antibiotics, although heme-induced luminal cytotoxicity was sustained in these mice. Colon mucosa transcriptomics revealed that antibiotics block heme-induced differential expression of oncogenes, tumor suppressors, and cell turnover genes, implying that antibiotic treatment prevented the heme-dependent cytotoxic micelles to reach the epithelium. Our results indicate that this occurs because antibiotics reinforce the mucus barrier by eliminating sulfide-producing bacteria and mucin-degrading bacteria (e.g., Akkermansia). Sulfide potently reduces disulfide bonds and can drive mucin denaturation and microbial access to the mucus layer. This reduction results in formation of trisulfides that can be detected in vitro and in vivo. Therefore, trisulfides can serve as a novel marker of colonic mucolysis and thus as a proxy for mucus barrier reduction. In feces, antibiotics drastically decreased trisulfides but increased mucin polymers that can be lysed by sulfide. We conclude that the gut microbiota is required for heme-induced epithelial hyperproliferation and hyperplasia because of the capacity to reduce mucus barrier function

Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice

F.B. is supported by Swedish Research Council, Swedish Diabetes Foundation, Swedish Heart Lung Foundation, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg foundation, Göran Gustafsson Foundation, Ingbritt and Arne Lundberg’s foundation, Swedish Heart Lung Foundation, Torsten Söderberg’s Foundation, Ragnar Söderberg’s Foundation, NovoNordisk Foundation, AFA insurances, and LUA-ALF grants from Västra Götalandsregionen and Stockholm County Council. F.B. is a recipient of ERC Consolidator Grant (European Research Council, Consolidator grant 615362—METABASE). W.M.d.V. is supported by the Finland Academy of Sciences (grants 137389, 141140 and 1272870 ), the Netherlands Organization for Scientific Research (Spinoza Award and SIAM Gravity Grant 024.002.002) and the European Research Council (ERC Advanced Grant 250172 MicrobesInside). M.N. is supported by a ZONMW-VIDI grant 2013 (016.146.327).Peer reviewedPublisher PD

Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials

Risk factors for renal allograft loss in patients with systemic lupus erythematosus

Risk factors for renal allograft loss in patients with systemic lupus erythematosus. Controversy exists regarding the risk factors for renal allograft loss in patients with systemic lupus erythematosus (SLE). This study is a retrospective evaluation of each of these independent risk factors in 80 renal transplants for ESRD secondary to SLE done at our institution between 1971 and 1994. Our entire non-diabetic cohort of 1,966 renal transplants is used as a comparison group. Our results showed equivalent graft survival rates between lupus patients and the cohort at 1, 5 and 10 years (P = 0.56). However, an analysis of cyclosporine-era cadaver grafts revealed that the lupus group had poorer 5-year graft survival than the cohort (41% vs. 71%, P = 0.02). Evaluation of cyclosporine-era lupus graft survival showed significantly improved out-come in living-related lupus recipients over cadaver grafts at five years (89% vs. 41%, P = 0.003). The majority of grafts lost in the lupus cadaver recipients were due to chronic rejection. Rejection was increased in lupus recipients: 69% of lupus patients experienced rejection in the first year compared to 58% of controls (P = 0.01). Stratified for age, sex, race and cyclosporine use, this difference remained significant (P = 0.003, relative risk 1.7). Nephrectomy, splenectomy and 3 to 6 months of pretransplant dialysis did not improve graft survival. A dialysis duration of greater than 25 months predicted worse graft survival (P = 0.01). Among lupus patients, PRA did not correlate with graft outcome (P = 0.5), and HLA-identical cadaver grafts had improved outcomes compared to cadaver grafts. We conclude that acute and chronic rejection are the major risk factors for graft loss in lupus patients. The superior outcome of living-related over cadaver grafts in lupus patients suggests an increased role for living-related grafts. Pretransplant dialysis, nephrectomy and splenectomy are not indicated

Deciphering the trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach

Host glycans are paramount in regulating the symbiotic relationship between humans and their gut bacteria. The constant flux of host-secreted mucin at the mucosal layer creates a steady niche for bacterial colonization. Mucin degradation by keystone species subsequently shapes the microbial community. This study investigated the transcriptional response during mucin-driven trophic interaction between the specialised mucin-degrader Akkermansia muciniphila and a butyrogenic gut commensal Anaerostipes caccae. A. muciniphila monocultures and co-cultures with non-mucolytic A. caccae from the Lachnospiraceae family were grown anaerobically in minimal media supplemented with mucin. We analysed for growth, metabolites (HPLC analysis), microbial composition (quantitative reverse transcription PCR), and transcriptional response (RNA-seq). Mucin degradation by A. muciniphila supported the growth of A. caccae and concomitant butyrate production predominantly via the acetyl-CoA pathway. Differential expression analysis (DESeq 2) showed the presence of A. caccae induced changes in the A. muciniphila transcriptional response with increased expression of mucin degradation genes and reduced expression of ribosomal genes. Two putative operons that encode for uncharacterised proteins and an efflux system, and several two-component systems were also differentially regulated. This indicated A. muciniphila changed its transcriptional regulation in response to A. caccae. This study provides insight to understand the mucin-driven microbial ecology using metatranscriptomics. Our findings show that the expression of mucolytic enzymes by A. muciniphila increases upon the presence of a community member. This could indicate its role as a keystone species that supports the microbial community in the mucosal environment by increasing the availability of mucin sugars.Peer reviewe

A new liver perfusion and preservation system for transplantation Research in large animals

A kidney perfusion machine, model MOX-100 (Waters Instruments, Ltd, Rochester, MN) was modified to allow continuous perfusion of the portal vein and pulsatile perfusion of the hepatic artery of the liver. Additional apparatus consists of a cooling system, a membrane oxygenator, a filter for foreign bodies, and bubble traps. This system not only allows hypothermic perfusion preservation of the liver graft, but furthermore enables investigation of ex vivo simulation of various circulatory circumstances in which physiological perfusion of the liver is studied. We have used this system to evaluate the viability of liver allografts preserved by cold storage. The liver was placed on the perfusion system and perfused with blood with a hematocrit of approximately 20% and maintained at 37°C for 3 h. The flows of the hepatic artery and portal vein were adjusted to 0.33 mL and 0.67 mL/g of liver tissue, respectively. Parameters of viability consisted of hourly bile output, oxygen consumption, liver enzymes, electrolytes, vascular resistance, and liver histology. This method of liver assessment in large animals will allow the objective evaluation of organ viability for transplantation and thereby improve the outcome of organ transplantation. Furthermore, this pump enables investigation into the pathophysiology of liver ischemia and preservation. © 1990 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted