Rapid biolayer interferometry measurements of urinary CXCL9 to detect cellular infiltrates noninvasively after kidney transplantation

Introduction: measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. Methods: we developed a biolayer interferometry (BLI)−based assay to rapidly measure urinary CXCL9 in 200 pg/ml in subjects with ACR and ≤100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. Discussion: together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients

Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3, and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined “supercontrols,” as a reference group. “Supercontrols” are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6–9.9] years) and 83% lacked FHR1 (n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion (n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions (n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon (n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency (“supercontrols”). Rare likely pathogenetic variants in CFH, THBD, and C3 were found in 24% of cases (n = 6) compared to 2.1% of the “supercontrols” (P-value = 0.005). We also found that the CFH H3 and the CD46GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies

The Recent Evolution of a Maternally-Inherited Endosymbiont of Ticks Led to the Emergence of the Q Fever Pathogen, Coxiella burnetii

International audienceQ fever is a highly infectious disease with a worldwide distribution. Its causative agent, the intracellular bacterium Coxiella burnetii, infects a variety of vertebrate species, including humans. Its evolutionary origin remains almost entirely unknown and uncertainty persists regarding the identity and lifestyle of its ancestors. A few tick species were recently found to harbor maternally-inherited Coxiella-like organisms engaged in symbiotic interactions, but their relationships to the Q fever pathogen remain unclear. Here, we extensively sampled ticks, identifying new and atypical Coxiella strains from 40 of 58 examined species, and used this data to infer the evolutionary processes leading to the emergence of C. burnetii. Phylogenetic analyses of multi-locus typing and whole-genome sequencing data revealed that Coxiella-like organisms represent an ancient and monophyletic group allied to ticks. Remarkably, all known C. burnetii strains originate within this group and are the descendants of a Coxiella-like progenitor hosted by ticks. Using both colony-reared and field-collected gravid females, we further establish the presence of highly efficient maternal transmission of these Coxiella-like organisms in four examined tick species, a pattern coherent with an endosymbiotic lifestyle. Our laboratory culture assays also showed that these Coxiella-like organisms were not amenable to culture in the vertebrate cell environment, suggesting different metabolic requirements compared to C. burnetii. Altogether, this corpus of data demonstrates that C. burnetii recently evolved from an inherited symbiont of ticks which succeeded in infecting vertebrate cells, likely by the acquisition of novel virulence factors

Risultati preliminari delle indagini archeologiche ed etnografiche presso il sito di Togolok 1

Modern Turkmenistan is mainly constituted by a desert landscape, yet despite its harsh climate, cultures have been able to construct networks of water channels since the Bronze Age. This has resulted in a man-made landscape that integrates towns and villages. Extensive surveys and recent archaeological excavations have highlighted that between 2400 and 2100 BC (Namazga V period), the region of the Murghab alluvial fan was characterised by the development of complex urban societies. However, starting from the Late Bronze Age, a new group of mobile pastoralists appeared in the Murghab region and settled along the edges of the sedentary sites. Although their presence is well-attested both by survey and excavation data, their degree of interaction with the sedentary farmers is still debated. In modern Turkmenistan, semi-mobile shepherds continue to drive their cattle across the Murghab, using mobile camps for different months. This paper presents the preliminary results of the excavation of the sedentary site of Togolok 1, as well as the first ethnographic study of the mobile communities of the Murghab region

Monitoraggio ambulatoriale del CXCL9 urinario nel ricevente di trapianto di rene per l'identificazione dello status di quiescenza immunologica

Il trapianto è il trattamento di scelta per i pazienti affetti da insufficienza renale cronica terminale. La prevenzione del rigetto richiede un trattamento immunosoppressivo che deve essere protratto per tutta la durata di vita del trapianto. La personalizzazione della terapia immunosoppressiva si ritiene possa migliorare gli outcome dei trapianti attraverso un impiego più mirato dei farmaci attualmente disponibili. Lo sviluppo di trattamenti individualizzati richiede l’utilizzo di biomarcatori per stratificare il grado di rischio di danno renale che siano affidabili, riproducibili, non invasivi e poco costosi. Tra tutti il dosaggio urinario della chemochina CXCL9 si è dimostrato lo strumento più adeguato, non solo per individuare i pazienti con un rigetto acuto T cellulare in atto o in fase d’insorgenza ma anche per individuare quel sottogruppo di pazienti immunologicamente stabili che si possono definire in quiescenza immunologica33 grazie al suo elevato valore predittivo negativo. Obiettivo primario dello studio è di confermare l’elevato valore predittivo negativo di bassi livelli di CXCL9 nei pazienti clinicamente stabili che si possono definire in quiescenza immunologica. Obiettivo secondario è stato quello di esaminare i livelli urinari di CXCL9 nei pazienti con lesioni da danno mediato da cellule T, che abbia causato una disfunzione acuta o cronica del graft. La chemochina CXCL9 sembra essere un biomarcatore di quiescenza alloimmunitaria, non invasivo, ripetibile e affidabile nel selezionare i pazienti con assenza di segni di rigetto primitiva o secondaria a un’efficace terapia immunosoppressiva anti-rigetto. Il monitoraggio dell’andamento delle concentrazioni seriate di CXCL9 urinario in corso di terapia per rigetto acuto ci permette inoltre di monitorarne precocemente la risposta: la mancata normalizzazione entro la prima settimana depone per un rigetto resistente con necessità di terapie di secondo livello

Once-daily prolonged-release tacrolimus formulations for kidney transplantation: what the nephrologist needs to know

Tacrolimus has long been the cornerstone of the immunosuppressive standard-of-care in kidney transplantation. Until recently, only an immediate-release formulation of tacrolimus was available in the clinic for twice-daily administration, a schedule that is known to hamper prescription adherence and contributes to the already significant tacrolimus interactions with other drugs and meals. In order to improve patient compliance, two once-daily prolonged-release formulations of tacrolimus have recently been developed and approved. Here we will analyze the main characteristics of these two prolonged-release formulations with the aim to provide practical clinical information for a fully aware drug prescription. Finally, the theoretical advantages of the prolonged-release formulations in terms of prescription adherence, blood level steadiness and drug efficacy and tolerability will be critically reviewed, in order to define the profile of renal recipients who may benefit most from the switch to once-daily tacrolimus

[Ultrafiltration in heart failure].

In patients with heart failure fluid overload is clinically evident as systemic and/or pulmonary congestion, and represents a key issue in the therapeutic approach to the syndrome. Ultrafiltration, obtained by dedicated machines or standard dialysis machines (isolated ultrafiltration), or by the use of the peritoneal membrane (peritoneal ultrafiltration), has been recently proposed for fluid overload correction. This review is aimed at illustrating the operative background, safety, efficacy and cost issues of the different ultrafiltration modalities in heart failure. We retrieved all full-text non-duplicated articles documenting clinical studies on ultrafiltration in heart failure and describing patient characteristics, ultrafiltration procedures, renal outcome and adverse effects, by searching MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials up to December 31, 2011, with the terms ''heart failure'' and ''ultrafiltration OR hemofiltration'' and ''heart failure'' and "peritoneal dialysis". Isolated ultrafiltration can be considered potentially safe for the heart and the kidney in heart failure, and is efficacious for fluid overload removal. However, the available evidence does not support its widespread use as a substitute for conventional diuretic therapy. Isolated ultrafiltration should be employed neither as a quicker way to achieve mechanical diuresis nor as a remedy for an apparently inadequate response to conventional diuretic therapy. Peritoneal ultrafiltration is a promising ultrafiltration procedure that can be safely and successfully performed in heart failure; however, also in this case larger-scale randomized controlled trials are needed. The available evidence supports the concept of reserving ultrafiltration modalities for selected patients with advanced heart failure and true diuretic resistance, as part of a more integrated strategy aimed at fluid overload control

Open and minimally invasive pancreatic neoplasms enucleation: a systematic review

Pancreatic enucleation (pEN) as parenchyma-sparing procedure for small pancreatic neoplasms is quickly becoming the most common surgical option in such setting. Nowadays, pEN is frequently carried out through a minimally invasive approach either laparoscopic or robotic. Its impact on overall perioperative complications and pancreatic fistula (POPF) is still under evaluation. The scope of our systematic review is to assess pEN's perioperative outcomes and to evaluate the effect of the minimally invasive techniques over POPF and other surgical complications