Search

Hemolytic uremic syndrome (HUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia, and renal impairment mostly triggered by strains of Shiga-like toxin-producing Escherichia coli (STEC-HUS). A rarer form of HUS, defined as atypical HUS (aHUS), is associated with genetic or acquired dysregulation of the alternative pathway of the complement system and presents a poorer prognosis than STEC-HUS. Factor H autoantibodies (anti-FHs) have been reported in aHUS in 5–11% of cases and are strongly associated with the homozygous deletion of CFHR3-CFHR1 genes. In the large majority of patients, anti-FH-associated aHUS is commonly preceded by gastrointestinal or respiratory tract infections. Here, we described the clinical case of a 3-year-old boy who was hospitalized for aHUS preceded by Mycoplasma pneumoniae (MP) infection. He resulted positive for anti-FHs and carried the homozygous deletion of CFHR3-CFHR1. Of relevance, he also showed a variant of unknown significance in the C5 gene. The patient was successfully treated with eculizumab and achieved hematological and renal remission. The anti-FH titer decreased, became negative after 6 months of mycophenolate mofetil (MMF) treatment, and remained negative for 21-month follow-up indicating that immunosuppression was effective and could prevent the reappearance of anti-FHs. We hypothesized that MP, likely through an evasion strategy of immunosurveillance based on binding of pathogen to FH, triggers anti-FH antibody generation and aHUS in a subject genetically predisposed. In conclusion, to the best of our knowledge, here, we reported the first case of anti-FH-mediated aHUS after an MP infection who benefited from eculizumab and immunosuppressive therapy based on MMF. Hence, monitoring of anti-FHs in patients with post-MP infection glomerulonephritis could be recommended, especially in those with low C3 plasma levels.

IgA nephropathy (IgAN) has been anecdotally reported in association with atypical hemolytic uremic syndrome (aHUS). The association likely portends poor renal outcome, and the possible relationship with complement overactivation has yet to be elucidated. We evaluated a series of IgAN patients with aHUS and reviewed the available literature. Adult patients who received a diagnosis of IgAN and developed aHUS between January 2009 and December 2019 were included in this retrospective review. We identified six IgAN-aHUS patients, all of whom developed end-stage kidney disease. At aHUS presentation all patients had decreased serum C3 levels. Predisposing pathogenetic variants and risk haplotypes for aHUS in CFH gene heterozygosity were documented in four out of six patients. Anti-CFH antibodies were found to be negative in the five tested patients. In the literature we identified 21 case reports involving aHUS-IgAN and six retrospective studies evaluating the presence of TMA at the time of renal biopsy. Hypertension, severe proteinuria, reduced sC3 and a worse renal prognosis were the common features of most cases. Our case series and literature review show that the onset of either aHUS or renal TMA in the course of IgAN are associated with very poor renal outcome. Activation of the alternative pathway revealed by consumption of serum C3 seems to play a major role. Our hypothesis is that the presence of a predisposing factor (e.g. dysregualtion of complement alternative pathway and/or other intrarenal precipitating factors) might be at the heart of aHUS-IgAN pathophysiology.

Mesenchymal stromal cells (MSC) have emerged as a promising therapy to minimize the immunosuppressive regimen or induce tolerance in solid organ transplantation. In this randomized open-label phase Ib/IIa clinical trial, 20 liver transplant patients were randomly allocated (1:1) to receive a single pre-transplant intravenous infusion of third-party bone marrow-derived MSC or standard of care alone. The primary end-point was the safety profile of MSC administration during the one-year follow-up. Nineteen patients completed the study, and none of those who received MSC experienced infusion-related complications. The incidence of serious and non-serious adverse events was similar in the two groups. Circulating Treg/memory Treg and tolerant NK subset of CD56bright NK cells increased slightly over baseline, albeit not to a statistically significant extent, in MSC-treated patients but not in the control group. Graft function and survival, as well as histologic parameters and intragraft expression of tolerance-associated transcripts in 1-year protocol biopsies were similar in the two groups. In conclusion, pre-transplant MSC infusion in liver transplant recipients was safe and induced mild positive changes in immunoregulatory T and NK cells in the peripheral blood. This study opens the way for a trial on possible tolerogenic efficacy of MSC in liver transplantation. ClinicalTrials.gov identifier: NCT02260375.

Hepatic resection is the gold standard treatment for patients affected by liver-limited colorectal metastases. Reports addressing the impact of multidisciplinary team (MDT) evaluation on survival are controversial. The aim of this study was to evaluate the benefit of MDT management in these patients in our Institution experience. The objective of the analysis was to compare survivals of patients managed within our MDT (MDT cohort) to those of patients referred to surgery from other hospitals without MDT discussion (non-MDT cohort). Of the 523 patients, 229 were included in the MDT cohort and 294 in the non-MDT cohort. No difference between the two groups was found in terms of median overall survival (52.5 vs 53.6 months; HR 1.13; 95% CI, 0.88–1.45; p = 0.344). In the MDT cohort there was a higher number of metastases (4.5 vs 2.7; p p p

Recurrence after curative hepatectomy for colorectal liver metastases (CRLM) is common. We sought to determine if number and sites of resections of recurrence after hepatectomy for CRLM impact survival.The study included patients who underwent resection of recurrence following complete curative-intent resection of CRLM during 1998-2016 at two academic medical centers in Houston, USA, and Rome, Italy. The survival impacts of number and sites of resections of recurrence were evaluated. Patients with synchronous extrahepatic disease at curative CRLM resection were excluded.Among 2163 patients who underwent curative hepatectomy, 1456 (67.3%) developed a recurrence. Four hundred seventy-eight patients underwent one (322/478; 67.4%) or two or more (156/478; 32.6%) resections of recurrence. The 5-year overall survival (OS) rate was higher in patients with resected than unresected recurrence (70.2% vs. 24.0%; p 0.001). In patients who underwent only one resection of recurrence, the 5-year OS rate differed by location (lung, 81.6%; liver, 64.3%; other, 54.1%). In patients who underwent two or more resections of recurrence, the 5-year OS rate was similar for liver-only resection (87.5%) and resection of liver and other sites (66.1%) (p = 0.223) and for liver-only resection and other-sites-only resection (80.7%) (p = 0.258); 5-year OS rate by site of first resection of recurrence did not differ between liver (78.5%) and lung (81.8%) (p = 0.502) but was worse for other sites (61.1%) than for lung (p = 0.045).When recurrence after initial CRLM resection is resectable, the ability to undergo resection was associated with improved survival and can be considered as an option regardless of the number of recurrence and resection. Sites of resection of recurrence impact survival and should be considered.

No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-specific induced pluripotent stem cells (iPSC), we developed an in vitro model to dissect the role of this mutation in the onset of FSGS. Despite the PAX2 mutation, patient iPSC properly differentiated into podocytes that exhibited a normal structure and function when compared to control podocytes. However, when exposed to an environmental trigger, patient podocytes were less viable and more susceptible to cell injury. Fixing the mutation improved their phenotype and functionality. Using a branching morphogenesis assay, we documented developmental defects in patient-derived ureteric bud-like tubules that were totally rescued by fixing the mutation. These data strongly support the hypothesis that the PAX2 mutation has a dual effect, first in renal organogenesis, which could account for a suboptimal nephron number at birth, and second in adult podocytes, which are more susceptible to cell death caused by environmental triggers. These abnormalities might translate into the development of proteinuria in vivo, with a progressive decline in renal function, leading to FSGS.

A 6-month-old boy presented with acute renal failure, thrombocytopenia, and severe non-immune hemolytic anemia. Infection by Shiga-like toxin-producing Escherichia coli and other causes of microangiopathic hemolysis were ruled out, leading to a diagnosis of atypical hemolytic uremic syndrome (aHUS). Neither pathogenic variants in HUS-associated genes nor anti-factor H antibodies were identified. Copy number variation analysis uncovered 4 copies of complement factor H related genes, CFHR1-CFHR4, conceivably leading to higher than normal levels of the corresponding proteins. However, this abnormality was also found in the healthy relatives, neither explaining the disease nor the excessive complement deposition on endothelial cells detected by an ex-vivo test. Whole-exome sequencing revealed a pathogenic homozygous variant in GRHPR encoding the glyoxylate and hydroxypyruvate reductase. Recessive GRHPR mutations cause primary hyperoxaluria type 2 (PH2). The presence of renal calculi in the patient and elevated oxalate levels in the urine were consistent with the genetic diagnosis of PH2. We hypothesize that, in this patient, hyperoxaluria caused by the GRHPR genetic defect triggered endothelial perturbation and complement activation, which was amplified by impaired factor H regulatory activity due to the increased ­CFHR1-CFHR4 copy numbers, resulting in aHUS.

The liver represents the first metastatic site in 5–12% of metastatic breast cancer (MBC) cases. In absence of reliable evidence, liver metastasectomy (LM) could represent a possible therapeutic option for selected MBC patients (patients) in clinical practice. A retrospective analysis including MBC patients who had undergone an LM after a multidisciplinary Tumor Board discussion at the Hepatobiliary Surgery Unit of Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS in Rome, between January 1994 and December 2019 was conducted. The primary endpoint was overall survival (OS) after a MBC-LM, the secondary endpoint was the disease-free interval (DFI) after surgery. Forty-nine MBC patients underwent LM, but clinical data were only available for 22 patients. After a median follow-up of 71 months, median OS and DFI were 67 months (95% CI 45–103) and 15 months (95% CI 11–46), respectively. At univariate analysis, the presence of a negative resection margin (R0) was the only factor that statistically significantly influenced OS (78 months versus 16 months, HR 0.083, p &lt, 0.0001) and DFI (16 months versus 5 months, HR 0.17, p = 0.0058). A LM for MBC might represent a therapeutic option for selected patients. The radical nature of the surgical procedure performed in a high-flow center and after a multidisciplinary discussion appears essential for this therapeutic option.

The term smart city is often synonymous with a sustainable city. The word smart implies the use of digital technology that serves to make processes and services more efficient and to connect the different actors on the urban scene. However, this is no guarantee of sustainability. A city can become sustainable if it changes its metabolism and from linear to circular as in nature's ecosystems. For this to happen, it is necessary to overcome the paradigm of quantitative economic growth based on the infinite substitutability between natural and economic capital. If smart city governance stakeholders primarily pursue profit according to the logic of the free market, the city may be smarter and efficient in the use of energy and resources, but it is not sustainable, often not even inclusive. The challenge of sustainability implies a paradigm shift and the use of digital technologies at the service of the collective good. In this context, after a general analysis of the characteristics of smart cities, the chapter focuses on an Italian case study, Turin Smart City.

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal impairment and is associated with dysregulation of the alternative complement pathway on the microvascular endothelium. Outcomes have improved greatly with pharmacologic complement C5 blockade. Abnormalities in complement genes (CFH, CD46, CFI, CFB, C3, and THBD), CFH–CFHR genomic rearrangements, and anti-FH antibodies have been reported in 40–60% of cases. The penetrance of aHUS is incomplete in carriers of complement gene abnormalities; and multiple hits, including the CFH–H3 and CD46GGAAC risk haplotypes and the CFHR1*B risk allele, as well as environmental factors, contribute to disease development. Here, we investigated the determinants of penetrance of aHUS associated with CD46 genetic abnormalities. We studied 485 aHUS patients and found CD46 rare variants (RVs) in about 10%. The c.286+2T>G RV was the most prevalent (13/485) and was associated with G RV who experienced a severe form of aHUS and developed end-stage renal failure. The father and paternal uncle with the same variant in homozygosity and six heterozygous relatives are unaffected. Flow cytometry analysis showed about 50% reduction of CD46 expression on blood mononuclear cells from the heterozygous proband and over 90% reduction in cells from the proband's unaffected homozygous father and aunt. Further genetic studies did not reveal RVs in known aHUS-associated genes or common genetic modifiers that segregated with the disease. Importantly, a specific ex vivo test showed excessive complement deposition on endothelial cells exposed to sera from the proband, and also from his mother and maternal uncle, who do not carry the c.286+2T>G RV, indicating that they share a circulating defect that results in complement dysregulation on the endothelium. These results highlight the complexity of the genetics of aHUS and indicate that CD46 deficiency may not be enough to induce aHUS. We hypothesize that the proband inherited from his mother a genetic abnormality in a complement circulating factor that has not been identified yet, which synergized with the CD46 RV in predisposing him to the aHUS phenotype.

Despite recent studies suggest that, among patients operated on for colorectal liver metastases (CLM), the primary tumor location may impact on postoperative survivals, results are still contrasting.evaluating survivals (overall (OS) and (DFS)) following liver resection of CLM from Right colon Cancer (RcC-CLM) versus Left colon Cancer (LcC-CLM), among patients undergoing preoperative chemotherapy (pCHT), identifying survival predictors, and investigating impact of recurrent disease pattern and management on survival.Among 727 patients operated for CLM(1989-2016), after excluding patients with primary transverse colon/rectum tumor and patients not receving pCHT, 297 patients were identified. Among them, 81 with RcC-CLM were matched 1:1 with LcC-CLM, according to CLM number and diameter, disease-free interval between primary tumor and CLM diagnosis, primary tumor N-status, and the presence of extrahepatic disease.Overall, 66.7% of patients had multiple CLM, 21% had CLM5 cm, 82.7% had DFI12 months, 67.9% had N+ primary tumor, and 11.1% had extrahepatic disease at time of hepatectomy. RcC-CLM patients were similar to LcC-CLM in terms of demographic, clinical, perioperative, and pathologic characteristics. Patients operated for RcC-CLM, compared to LcC-CLM, had significantly shorter 5y-DFS(18% versus 39%) and 5y-OS(38% vs 65%). At multivariate analysis, being operated for RcC-CLM, compared to LcC-CLM, was the strongest predictor of recurrence (Hazard Ratio:2.265,p .001) and death (HR:2.234,p = .001). Among 107 patients experiencing recurrent disease, curative recurrence resection was associated with higher 5y-OS(64% vs 17%; p .001). However, recurrence resection was less frequently feasible among RcC-CLM(26%) patients, compared to LcC-CLM(44%,p = .05).resection of RcC-CLM, compared to LcC-CLM, is associated with worse survivals, probably related to a different pattern of recurrence precluding recurrence resection among RcC-CLM patients.

Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, although cellular targets of such an effect are still ill-defined. Here, we show that human umbilical cord (UC)-MSCs transplanted into mice stimulate tubular cells to regain mitochondrial mass and function, associated with enhanced microtubule-rich projections that appear to mediate mitochondrial trafficking to create a reparative dialogue among adjacent tubular cells. Treatment with UC-MSCs in mice with cisplatin-induced acute kidney injury (AKI) regulates mitochondrial biogenesis in proximal tubuli by enhancing PGC1α expression, NAD+ biosynthesis and Sirtuin 3 (SIRT3) activity, thus fostering antioxidant defenses and ATP production. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection. These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply., Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.

We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4+CD25− regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro, without needing cell-to-cell contact, and induced kidney allograft survival prolongation in-vivo. Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administered in-vivo, dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation.

Background Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. Design, setting, participants, & measurements We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome. Results Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). Conclusions Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.

Hepatectomy for initially unresectable colorectal liver metastases (IU-CLM) is considered at high risk due to the extensive preoperative chemotherapy (CHT) and complex surgical procedures required, and its results are questioned due to frequent and early post-operative recurrence. We aim to compare patients with initially resectable CLM (IR-CLM) and IU-CLM and identify prognostic factors among IU-CLM patients.A total of 81 patients with IU-CLM, undergoing hepatectomy following conversion CHT, were compared to 526 IR-CLM patients. Predictors of overall (OS) and disease-free survival (DFS) were identified for IU-CLM patients.Patients resected for IU-CLM, compared to IR-CLM, had more and larger CLM and more frequently underwent prolonged CHT and major/extended hepatectomy (P 0.001 for all comparisons). Such characteristics paralleled higher rates of overall and major (Clavien-Dindo ≥3) complications, longer median post-operative length of stay and lower 5-year survival rates (P 0.001 for all comparisons) among IU-CLM patients compared to IR-CLM, with similar mortality (1.2% and nil for IU-CLM and IR-CLM, respectively). Among IU-CLM patients, 62 with partial response to CHT (versus tumour stability according to the Response Evaluation Criteria in Solid Tumors criteria) had better DFS (hazard ratio 2.76, P = 0.001) and OS (hazard ratio 2.83, P = 0.002), and their 5-year survival rates (DFS 19.8%, OS 46.7%) approached those of IR-CLM patients (DFS 31%, OS 59%, P 0.05 for both comparisons).Resection of IU-CLM has acceptable perioperative results. Tumour responsiveness to conversion CHT improves IU-CLM patient selection for hepatectomy.

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.

Background. To assess the efficacy of intraoperative ultrasound (IOUS) compared with liver-specific magnetic resonance imaging (MRI) in patients with colorectal liver metastases (CRLMs). Methods. From January 2010 to December 2017, 721 patients underwent MRI as a part of preoperative workup within 1 month before hepatectomy and were considered for the study. Early intrahepatic recurrence (relapse at cut surface excluded) was assessed 6 months after the resection and was considered as residual disease undetected by IOUS and/or MRI. IOUS and MRI performance was compared on a patient-by-patient basis. Long-term results were also studied. Results. A total of 2845 CRLMs were detected by MRI, and the median number of CRLMs per patient was 2 (1–31). Preoperative chemotherapy was administered in 489 patients (67.8%). In 177 patients, 379 new nodules were intraoperatively found and resected. Among 379 newly identified nodules, 317 were histologically proven CRLMs (11.1% of entire series). The median size of new CRLMs was 6 ± 2.5 mm. Relationships between intrahepatic vessels and tumors differed between IOUS and MRI in 128 patients (17.7%). The preoperative surgical plan was intraoperatively changed for 171 patients (23.7%). Overall, early intrahepatic recurrence occurred in 8.7% of cases. To assess the diagnostic performance, 24 (3.3%) recurrences at the cut surface were excluded; thus, 5.4% of early relapses were considered for analysis. The sensitivity of IOUS was superior to MRI (94.5% vs 75.1%), while the specificity was similar (95.7% vs 95.9%). Multivariate analysis at the hepatic dome or subglissonian and mucinous histology revealed predictive factors of metastases missing at MRI. The 5-year OS (52.1% vs 37.8%, p=0.006) and DF survival (45.1% vs 33%, p=0.002) were significantly worse among patients with new CRLMs than without. Conclusions. IOUS improves staging in patients undergoing resection for CRLMs even in the era of liver-specific MRI. Intraoperative detection of new CRLMs negatively affects oncologic outcomes.

Background The albumin-indocyanine green evaluation (ALICE) model based on serum albumin and indocyanine retention rate has been shown to be an effective method for predicting postoperative outcomes in hepatocellular carcinoma patients. Aim of the study was to validate the ALICE model in a large Western cohort of patients by comparing the albumin-bilirubin (ALBI) score and Child-Turcotte-Pugh (CTP) score. Methods A total of 400 patients who underwent hepatic resection from January 2005 to June 2016 at three centers were enrolled. The ALICE, ALBI, and CTP scores were computed for all patients. Results The ALICE score correlated better with ALBI (r = 0.428) than with CTP score (r = 0.302). Both the ALICE (grade 1: 49%; grade 2: 51%) and the ALBI (grade 1: 52.5%; grade 2: 47.5%) scores stratified the CTP class A patients into two distinct classes. The incidence of ascites (grades 1-3: ALICE 11%, 20%, 58%; ALBI 11%, 23%, 50%) and severe liver failure (ALICE 8.7%, 10.5%, 41.7%; ALBI 8.6%, 12%, 50%) increased with increasing ALBI and ALICE grade and were similar for the same grade. Conclusions The ALICE model can assess hepatic functional reserve and predict postoperative outcomes with efficacy comparable with the ALBI grade and better than the CTP score.

Myrtus communis L. is an aromatic shrub widely diffused in the Mediterranean area. A growing interest for this species is due to its pharmacological and aromatic properties. This study explored the genetic diversity and population structure of 460 myrtle plants including 46 selections genotypes and 414 wild accessions from Sardinia using 14 SSR markers. Genetic diversity parameters showed that 10 markers were sufficiently polymorphic to move forward in the further analysis. The observed heterozygosity ranged from 0.21 (Porto Ferro) to 0.44 (Olia Speciosa), with an average value of 0.32. This parameter significantly varied considering the genetic origin of the plant (selections and natural), and the localization of the myrtle sampling sites (North, Center and South area) (P

Dentro de las reflexiones críticas que giran en torno a la construcción de viviendas multipiso de la segunda mitad del Novecientos, en gran parte, el reciente período de bloqueo ha puesto de manifiesto las limitaciones en la relación interna/externa y en la socialidad que genera. ¿Adaptar este patrimonio o reemplazarlo? El artículo identifica en la fachada posterior como un espacio favorable para una concreta ocasión propulsora de regeneración resiliente del edificio que orienta la envolvente del edificio posterior hacia una dimensión relacional del espacio exterior. Se analizan casos de Italia y Argentina rescatando en estos espacios posteriores una oportunidad de regenerar la socialidad de proximidad tan necesaria en el contexto actual de pandemia que requiere de espacios exteriores, dentro de los propios predios.

Rationale & Objective Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. Study Design Case series. Setting & Participants 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced ex vivo C5b-9 endothelial deposition test. Results Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate–activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. Limitations The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. Conclusions The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.

En el marco de la Convocatoria del Politécnico de Turín (Italia), para Proyectos Conjuntos para la Internacionalización de la Investigación, se aprobó el proyecto “Tecnologías para la construcción sostenible: el enfoque biomimético. Métodos, materiales y aplicaciones”. Este Proyecto se lleva adelante por el Department of Structural, Geotechnical and Building Engineering (DISEG) del Instituto Politécnico de Turín (Italia) y el Instituto de Investigaciones Tecnológicas para el Diseño Ambiental del Hábitat Humano (ITDAHu) de la Facultad de Arquitectura y Urbanismo de la Universidad Nacional del Nordeste (Argentina). Los objetivos del proyecto son:  Mejorar la exploración del enfoque biomimético en el diseño de edificios mediante el análisis de proyectos complejos, las herramientas de experimentación y los métodos para aplicar las tecnologías biomiméticas en el campo de la construcción sostenible;  Establecer una asociación de investigación y colaboración entre los dos grupos de investigación y potenciar las actividades de investigación mutua;  Organización de diferentes eventos para difundir la temática. En el marco de este último objetivo se llevó a cabo del 2 al 4 de mayo de 2018, en el Politécnico de Turín un Workshop (summer/winter school) sobre “Biomimética y Proyecto Sostenible” que convocó a profesores-investigadores, profesionales comprometidos con el enfoque biomimético sustentable y empresas de materiales y sistemas sustentables que expusieron sus puntos de vistas en relación a la temática. Las clases expositivas fueron complementadas con actividades prácticas de diseño (trabajo en taller) donde aproximadamente ciento diez (110) alumnos de diversos niveles ajustaron sobre sus proyectos en curso o realizaron diseños nuevos aplicando los principios de la biomimética con el asesoramiento y monitoreo permanente del cuerpo docente participante, de carácter internacional. Por su parte del 28 al 30 de junio de 2018, en la Universidad Nacional del Nordeste, se replicó la experiencia, con ciento veintiséis participantes (125) entre los cuales se contó con estudiantes de arquitectura, de ingeniería y profesionales (arquitectos e ingenieros).

Background The majority of patients with stage III–IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). Patients and methods Matched biopsies (33) taken at Ft-S and Sd-S were selected from the ‘Pandora’ tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. Results A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. Conclusions There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.