On the "spin-freezing" mechanism in underdoped superconducting cuprates

The letter deals with the spin-freezing process observed by means of NMR-NQR relaxation or by muon spin rotation in underdoped cuprate superconductors. This phenomenon, sometimes referred as coexistence of antiferromagnetic and superconducting order parameters, is generally thought to result from randomly distributed magnetic moments related to charge inhomogeneities (possibly stripes) which exhibit slowing down of their fluctuations on cooling below T$_c$ . Instead, we describe the experimental findings as due to fluctuating, vortex-antivortex, orbital currents state coexisting with d-wave superconducting state. A direct explanation of the experimental results, in underdoped Y$_{1-x}$Ca$_x$Ba$_2$Cu$_3$O$_{6.1}$ and La$_{2-x}$Sr$$CuO$_4$, is thus given in terms of freezing of orbital current fluctuations

17β-Oestradiol Protects from Hepatitis C Virus Infection through Induction of Type I Interferon

Background and Aims: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17β-oestradiol controls HCV’s life cycle. We investigated the mechanism(s) behind oestrogen’s antiviral effect. Methods: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17β-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. Results: Stimulation of 17β-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. Conclusion: Resulting in viral control and suppression, 17β-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling

HSD17B13 and other liver fat-modulating genes predict development of hepatocellular carcinoma among HCV-positive cirrhotics with and without viral clearance after DAA treatment

Background: Genetic predisposition to accumulate liver fat (expressed by a polygenic risk score, GRS, based on the number of at-risk alleles of PNPLA3, TM6SF2, MBOAT7 and GCKR) may influence the probability of developing hepatocellular carcinoma (HCC) after hepatitis C treatment. Whether this holds true taking into account carriage of the HSD17B13:TA splice variant, also affecting lipogenesis, and achievement of viral clearance (SVR), is unknown. Methods: PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 variants were determined in a cohort of 328 cirrhotic patients free of HCC before starting treatment with direct acting antivirals (DAA). Results: SVR in the study cohort was 96%. At the end of follow-up, N = 21 patients had been diagnosed an HCC; none of the genes included in the GRS was individually associated with HCC development. However, in a Cox proportional hazards model, a GRS > 0.457 predicted HCC independently of sex, diabetes, albumin, INR and FIB4. The fit of the model improved adding treatment outcome and carriage of the HSD17B13:TA splice variant, with sex, GRS > 0.457, HSD17B13:TA splice variant and failure to achieve an SVR (hazard ratio = 6.75, 4.24, 0.24 and 7.7, respectively) being independent predictors of HCC. Conclusion: Our findings confirm that genes modulating liver fat and lipogenesis are important risk factors for HCC development among cirrhotics C treated with DAA

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p\u2009<\u20090.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p\u2009<\u20090.01), with a linear regression between these two variables (r2\u2009=\u20090.64, p\u2009<\u20090.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p\u2009<\u20090.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain

Immune infiltrating cells in duodenal cancers

Duodenal adenocarcinoma (DA) is a rare yet aggressive malignancy, with increasing incidence in the last decades. Its low frequency has hampered a thorough understanding of the pathogenesis of the disease and of its biology, limiting the identification of tailored therapeutic options. A large body of evidence has clearly shown the clinical relevance of immune cells in solid tumors, correlating immune features with post-surgical prognosis. The aim of this study was to analyze the immune contexture in a cohort of duodenal adenocarcinomas surgically resected at our Institution and define its correlation with clinical variables. Methods Tissue slides from paraffin-embedded tumor specimens of 15 consecutive DA and 3 adenomas that underwent a pancreaticoduodenectomy in our center between 2010 to 2018 were immunohistochemically stained. The density (percentage of immune reactive area, IRA%) of immune markers CD45RO, CD8, CD20, IL-17, PD-1, CD68 was quantified by computer-assisted image analysis. Demographic, clinical, histopathological data were collected. Results In our population, median IRA % (IQR) of immune subsets was respectively CD45RO-TILs 2.19 (2.14), CD8-TIL 0.42 (0.81), CD20-TILs 0.22 (0.51), CD20-TLT 2.84 (4.64), CD68-TAM 2.19 (1.56), IL17+ cells 0.39 (0.39), PD1-TILs 0.19 (0.41). The median follow-up was 47.5 (22.4\u201363.3) months. At statistical analysis, the density of CD8-TILs inversely correlated with lymph node ratio (p\u2009=\u20090.013), number of metastatic lymph nodes (p\u2009=\u20090.019), and was lower in N+\u2009adenocarcinomas compared to N0 (1.07 vs 0.29; p\u2009=\u20090.093), albeit not significantly. Stratifying patients for the N status, the density of CD8-TILs decreased with the increasing of the N stage (p\u2009=\u20090.065) and was lower in patients who experienced recurrence and died for the disease (0.276 vs 0.641; p\u2009=\u20090.044). Notably, also CD68-TAM distribution was different in patients who had recurrence versus patients who did not (1.028 vs 2.276; p\u2009=\u20090.036). Conclusions Immune cells showed variable expression in correlation with common prognostic factors, suggesting T cell infiltration may play a protective role towards lymphatic spread of disease and nodal metastatization. Furthermore, T cell density and macrophage infiltration were associated to a lower risk of recurrence and disease related death. A multicentric approach may be indicated to allow analysis of larger cohorts of patients, potentially increasing the power of our observations

Dynamics of the Local Moment Induced by Nonmagnetic Defects in Cuprates

We present a study of the spin dynamics of magnetic defects induced by Li substitution of the plane Cu in the normal state of YBa$_2$Cu$_3$O$_{6+x}$. The fluctuations of the coupled Cu magnetic moments in the vicinity of Li are probed by near-neighbour $^{89}$Y {\it and} $^7$Li NMR spin lattice relaxation. The data indicates that the magnetic perturbation fluctuates as a single entity with a correlation time $\tau$ which scales with the local static susceptibility. This behaviour is reminiscent of the low $T$ Kondo state of magnetic impurities in conventional metals. Surprisingly it extends well above the ``Kondo'' temperature for the underdoped pseudogapped case.Comment: 4 pages, 5 figures (same), major modifications to text, accepted in PR

First-Principles Calculations of Hyperfine Interactions in La_2CuO_4

We present the results of first-principles cluster calculations of the electronic structure of La_2CuO_4. Several clusters containing up to nine copper atoms embedded in a background potential were investigated. Spin-polarized calculations were performed both at the Hartree-Fock level and with density functional methods with generalized gradient corrections to the local density approximation. The distinct results for the electronic structure obtained with these two methods are discussed. The dependence of the electric-field gradients at the Cu and the O sites on the cluster size is studied and the results are compared to experiments. The magnetic hyperfine coupling parameters are carefully examined. Special attention is given to a quantitative determination of on-site and transferred hyperfine fields. We provide a detailed analysis that compares the hyperfine fields obtained for various cluster sizes with results from additional calculations of spin states with different multiplicities. From this we conclude that hyperfine couplings are mainly transferred from nearest neighbor Cu^{2+} ions and that contributions from further distant neighbors are marginal. The mechanisms giving rise to transfer of spin density are worked out. Assuming conventional values for the spin-orbit coupling, the total calculated hyperfine interaction parameters are compared to informations from experiments.Comment: 23 pages, 9 figure

The critical view of safety during laparoscopic cholecystectomy: Strasberg Yes or No? An Italian Multicentre study

Background: Laparoscopic cholecystectomy is considered the gold standard for the treatment of gallbladder lithiasis; nevertheless, the incidence of bile duct injuries (BDI) is still high (0.3–0.8%) compared to open cholecystectomy (0.2%). In 1995, Strasberg introduced the "Critical View of Safety" (CVS) to reduce the risk of BDI. Despite its widespread use, the scientific evidence supporting this technique to prevent BDI is controversial. Methods: Between March 2017 and March 2019, the data of patients submitted to laparoscopic cholecystectomy in 30 Italian surgical departments were collected on a national database. A survey was submitted to all members of Italian Digestive Pathology Society to obtain data on the preoperative workup, the surgical and postoperative management of patients and to judge, at the end of the procedure, if the isolation of the elements was performed according to the CVS. In the case of a declared critical view, iconographic documentation was obtained, finally reviewed by an external auditor. Results: Data from 604 patients were analysed. The study population was divided into two groups according to the evidence (Group A; n = 11) or absence (Group B; N = 593) of BDI and perioperative bleeding. The non-use of CVS was found in 54.6% of procedures in the Group A, and 25.8% in the Group B, and evaluating the operator-related variables the execution of CVS was associated with a significantly lower incidence of BDI and intraoperative bleeding. Conclusions: The CVS confirmed to be the safest technique to recognize the elements of the Calot triangle and, if correctly performed, it significantly impacted on preventing intraoperative complications. Additional educational programs on the correct application of CVS in clinical practice would be desirable to avoid extreme conditions that may require additional procedures