Universality of Entanglement Transitions from Stroboscopic to Continuous Measurements.

Measurement-driven transitions between extensive and subextensive scaling of the entanglement entropy receive interest as they illuminate the intricate physics of thermalization and control in open interacting quantum systems. While this transition is well established for stroboscopic measurements in random quantum circuits, a crucial link to physical settings is its extension to continuous observations, where for an integrable model it has been shown that the transition changes its nature and becomes immediate. Here, we demonstrate that the entanglement transition at finite coupling persists if the continuously measured system is randomly nonintegrable, and show that it is smoothly connected to the transition in the stroboscopic models. This provides a bridge between a wide range of experimental settings and the wealth of knowledge accumulated for the latter systems.

Heat and Work Along Individual Trajectories of a Quantum Bit.

We use a near quantum limited detector to experimentally track individual quantum state trajectories of a driven qubit formed by the hybridization of a waveguide cavity and a transmon circuit. For each measured quantum coherent trajectory, we separately identify energy changes of the qubit as heat and work, and verify the first law of thermodynamics for an open quantum system. We further establish the consistency of these results by comparison with the master equation approach and the two-projective-measurement scheme, both for open and closed dynamics, with the help of a quantum feedback loop that compensates for the exchanged heat and effectively isolates the qubit.

Information Gain and Loss for a Quantum Maxwell's Demon.

We use continuous weak measurements of a driven superconducting qubit to experimentally study the information dynamics of a quantum Maxwell's demon. We show how information gained by a demon who can track single quantum trajectories of the qubit can be converted into work using quantum coherent feedback. We verify the validity of a quantum fluctuation theorem with feedback by utilizing information obtained along single trajectories. We demonstrate, in particular, that quantum backaction can lead to a loss of information in imperfect measurements. We furthermore probe the transition between information gain and loss by varying the initial purity of the qubit.

Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients.

Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV-positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1-42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7-6.1) with 12 patients (11.9%) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p = 0.005), phosphorylated tau (p = 0.008), and 1-42 beta amyloid (p = 0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p = 0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p = 0.035), and 1-42 beta amyloid (1134 vs. 830 pg/mL, p = 0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV-positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations.

Prevalence and predictors of blood-brain barrier damage in the HAART era.

Blood-brain barrier damage (BBBD) is prevalent in HIV-positive patients and may enhance cell trafficking to the central nervous system. A retrospective analysis in adult HIV-positive patients with no central nervous system disease was conducted in order to estimate the prevalence and risk factors of BBBD (according to cerebrospinal fluid to plasma albumin ratios). One hundred fifty-eight HIV-positive adult patients were included. BBBD impairment and intrathecal IgG synthesis were respectively observed in 45 (28.5 %) and 100 patients (63.3 %). Low CD4 nadir and high CSF HIV RNA were independently associated with both abnormalities. BBBD is common in HIV-positive patients, and its main determinants are advanced immune depression and compartmental viral replication.

Anti-cardiolipin and anti-ß2-glycoprotein I antibodies: normal reference ranges in northwestern Italy.

Laboratory tests for anticardiolipin antibodies (aCL) and anti-ß2glycoprotein I antibodies (a-ß2GPI) face problems common to many autoantibody assays: the lack of a reference standard and the need for each laboratory to assess assay-specific cut-off values. The aims of the study were to evaluate the reference range upper limits (99th percentile) used for aCL and a-ß2GPI in the northwest of Italy and to investigate the analytical performances of these assays with the newly obtained reference ranges. We assayed aCL and a-ß2GPI in 104 serum samples from patients without a history of thrombosis, pregnancy morbidity, tumours, infections and/or autoimmune diseases (30 males and 74 non-pregnant females). We tested all the commercial assays available in our regions (i.e. Orgentec Diagnostika, Aesku Diagnostics and Inova Diagnostics ELISA; CliA Zenit-RA and EliA Phadia Laboratory Systems). A further 30 serum samples, including 10 from healthy subjects, 10 from antiphospholipid syndrome (APS) patients and 10 from septic patients were assessed to investigate the analytical performance of the obtained cut-off limits. Reference range upper limits obtained with the commercial kits differ among assays and from the values reported by the manufacturer. Moreover, normal reference ranges calculated for IgG and IgM aCL differed from the arbitrary selected laboratory classification values suggested in the guidelines of 40 GPL and MPL.

Blood Brain Barrier Impairment in HIV-Positive Naïve and Effectively Treated Patients: Immune Activation Versus Astrocytosis.

Blood brain barrier (BBB) damage is a common feature in central nervous system infections by HIV and it may persist despite effective antiretroviral therapy. Astrocyte involvement has not been studied in this setting. Patients were enrolled in an ongoing prospective study and subjects with central nervous system-affecting disorders were excluded. Patients were divided into two groups: treated subjects with cerebrospinal fluid (CSF) HIV RNA <50 copies/mL (CSF-controllers) and in late-presenters CD4+ T lymphocytes <100/uL. CSF biomarkers of neuronal or astrocyte damage were measured and compared to CSF serum-to-albumin ratio. 134 patients were included; 67 subjects in each group (50 %) with similar demographic characteristics (with the exception of older age in CSF controllers). CD4 (cells/uL), plasma and CSF HIV RNA (Log10 copies/mL) were 43 (20-96), 5.6 (5.2-6) and 3.9 (3.2-4.7) in LPs and 439 (245-615), <1.69 (9 patients <2.6) and <1.69 in CSFc. BBB impairment was observed in 17 late-presenters (25.4 %) and in 9 CSF-controllers (13.4 %). CSF biomarkers were similar but for higher CSF neopterin values in late-presenters (2.3 vs. 0.6 ng/mL, p < 0.001). CSARs were associated with CSF neopterin (rho = 0.31, p = 0.03) and HIV RNA (rho = 0.24, p = 0.05) in late-presenters and with CSF tau (rho = 0.51, p < 0.001), p-tau (rho = 0.47, p < 0.001) and S100beta (rho = 0.33, p = 0.009) in CSF-controllers. In HAART-treated subjects with suppressed CSF HIV RNA, BBB altered permeability was associated with markers of neuronal damage and astrocytosis. Additional treatment targeting astrocytosis and/or viral protein production might be needed in order to reduce HIV effects in the central nervous system.

Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutated patients: An evidence-based approach on what women should know.

This review is focused on the ovarian cancer risk reduction management in BRCA mutation carriers and is intended to assist with clinical decision-making. Obviously, treatment decisions must be based on the available evidence. Despite risk-reducing salpingo-oophorectomy is firmly recommended, several separate questions can be raised to address the variety of intense controversy of this approach. A special emphasis lies in the effective preventive surgical measure against ovarian cancer risk, in an attempt to detect the optimal timing and mitigate the impact on patients. The long term implications of risk-reducing salpingo-oophorectomy as well as hormone replacement therapy are also actively debated. This is expected to represent an opportunity for improved management modelling of BRCA mutated patients.

Tyrosine-kinases inhibitors in recurrent platinum-resistant ovarian cancer patients.

For many decades, ovarian cancer (OC) has been one of the most common gynecological cancer. Despite advances in OC diagnosis and treatment, the risk of recurrence is ever present and approximately 85% of patients will experience relapse. Recurrent OC after first-line therapy is almost always incurable. Multiple novel therapies, including tyrosine-kinases inhibitors (TKI), have shown promising results, but their role needs to be clarified. In this review we describe the rationale and the clinical evidence regarding the use of TKI for the treatment of recurrent platinum-resistant OC patients.

Analytical and clinical comparison of different immunoassay systems for the detection of antiphospholipid antibodies.

INTRODUCTION: We evaluated analytical and clinical performances of IgG and IgM anticardiolipin (aCL) antibodies and anti-ß2-glycoprotein I (a-ß2GpI) antibodies and upper limit reference ranges (99th percentiles) in comparison with manufacturer's cutoff values with different commercial methods. METHODS: We assayed aCL and a-ß2GpI in serum samples from 30 healthy individuals, 77 patients with antiphospholipid syndrome (APS) diagnosed according to the Sydney criteria, 51 patients with autoimmune diseases, eight patients with previous thrombotic events, six patients with other diseases, and 18 patients with infectious diseases, using ELISA Inova Diagnostics; EliA Phadia Laboratory Systems; CliA Zenit-RA; and CliA Bio-Flash. RESULTS: Anticardiolipin and a-ß2GpI IgG and IgM immunoassays showed good analytic performances with both 99th percentile and manufacturer's cutoff reference values. Our results showed fair to moderate agreement among assays. In-house cutoff values gave significantly better performances only for a-ß2GpI IgG with all the immunoassays analyzed with the exception of Inova CliA Bio-Flash where we obtained the same performances with in-house and manufacturer's cutoffs. CONCLUSIONS: By guidelines, all laboratories are strongly advised to validate/verify the manufacturer's cutoff values. We recommend establishing low-positive, medium-/high-positive, and high-positive CliA IgG aCL and a-ß2GpI ranges in order to help clinicians in the diagnosis and treatment of APS.

Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis.

OBJECTIVES: To investigate Fas in peripheral lymphocytes from HIV-1-positive patients at different disease stages with respect to the extent of apoptosis. DESIGN: The study included analysis of Fas involvement in T-cell apoptosis observed during HIV-1 infection. Because ligation of Fas can result in costimulation of proliferation or the induction of apoptosis in uninfected cells, we evaluated the effect on T cells of Fas activation by monoclonal antibodies (MAb) of different specificity from both UB2 and CH11 clones and activation by the Fas ligand (Fas-L). METHODS: Fas was measured by FACS in peripheral blood and in phytohaemagglutinin (PHA)-driven cultures derived from 59 HIV-1-positive individuals with different Centers for Disease Control and Prevention stages. The percentage of apoptotic cells was detected by propidium iodide cell staining. The effect of Fas ligation was assessed in peripheral T cells from patients and healthy controls by a proliferative test measuring the 3H-thymidine uptake. RESULTS: FACS analysis revealed that Fas was predominantly expressed in advanced disease, although it was promptly exposed in PHA cultures from asymptomatic individuals. In several instances, Fas overexpression was associated with substantial subdiploid DNA content in cells from severely lymphopenic patients. The proliferative assay showed a significant inhibition of 3H-thymidine uptake in T cells from all patients following Fas ligation by the immunoglobulin (Ig) G1 MAb from the UB2 clone. This was in contrast to the apparent cell activation detected in controls and the weak suppression observed in Fas-positive cell lines. In addition, the IgM anti-Fas and recombinant Fas-L concentrations inducing a moderate inhibition of fresh T cells from controls strongly depressed the proliferative rate of cells from patients. CONCLUSIONS: Our data suggest that Fas overexpression parallels the progression of the disease and that the increased susceptibility of T cells from HIV-1-infected individuals to undergo apoptosis may include a Fas pathway. Functionally exhausted T cells in advanced HIV-1 infection are primed to apoptosis because of their high sensitivity to Fas stimulation even using the IgG1 MAb, which is unreactive to the death domain of Fas. This suggests that the increased sensitivity of Fas is apparently unrelated to its trimeric ligation and supports the hypothesis that Fas pathway plays a role in increasing the lymphocyte apoptosis during the disease.

The influence of titania/hydroxyapatite composite coatings on in vitro osteoblasts behaviour.

The biocompatibility of titania/hydroxyapatite (TiO2 /HA) composite coatings, at different ratio obtained by sol-gel process, were investigated studying the behaviour of human MG63 osteoblast-like cells. The biocompatibility was evaluated by means of cytotoxicity and cytocompatibility tests. Cytotoxicity tests, i.e., neutral red (NR), MTT and kenacid blue (KB) assays, were performed to assess the influence of the material extracts on lysosomes, mitochondria and cell proliferation, respectively. Cell proliferation, some preliminary indications of cell morphology, alkaline phosphatase activity, collagen and osteocalcin production of MG63 cells, cultured directly onto TiO2/HA substrates, were evaluated. The results showed that these materials have no toxic effects. Cell growth and morphology were similar on all the materials tested: on the contrary, alkaline-phosphatase-specific activity and collagen production of osteoblasts cultured on TiO2/HA coatings were significantly higher than uncoated titanium and polystyrene of culture plate and were influenced by chemical composition of the coatings. In particular, TiO2/HA coating at 1:1 ratio (w/w) seems to stimulate more than others the expression of some differentiation markers of osteoblastic phenotype. TiO2/HA coatings resulted to be bioactive owing to the presence of hydroxyl groups detected on their surface that promote the calcium and phosphate precipitation and improve the interactions with osteoblastic cells.

Anti-endothelial autoantibodies in patients with sudden hearing loss.

OBJECTIVES/HYPOTHESIS: Sudden hearing loss (HL) can be caused by autoimmune disorders localized to the inner ear or secondary to systemic immune diseases. Studies in autoimmune animal strains showing HL have reported changes in the cochlear stria vascularis. The authors investigated the presence of antiendothelial cell antibodies (AECA) to see if immune-mediated vasculitis may play a role in human sudden HL. STUDY DESIGN: A prospective study in patients with sudden HL. METHODS: Fifteen consecutive patients (mean age, 32 y) affected by sudden HL and 14 normal subjects were included. Patients with familial deafness and metabolic diseases were excluded. Extensive audiovestibular, imaging, microbiological, immunological, and routine examinations were performed. AECA were detected on rat kidney tissue sections on the sera collected at -20 degrees C. RESULTS: AECA were positive in 8 of 15 patients (53%) (2 of 5 men and 6 of 10 women), thus differing significantly from the normal control population, in which only 2 of 14 tested AECA positive (P = .023). CONCLUSIONS: In patients with sudden HL, immune-mediated vascular damage can have a pathogenetic role and AECA might represent a serological marker of vasculitis.

Sudden hearing loss in a patient hepatitis C virus (HCV) positive on therapy with alpha-interferon: a possible autoimmune-microvascular pathogenesis.

Alpha interferon (alpha-IFN) is used for the treatment of various systemic disorders. Side-effects of alpha-IFN therapy can involve numerous organ systems, but sudden hearing loss has only once been recorded. We report a case of sudden hearing loss occurring in a patient with chronic hepatitis C treated with alpha-IFN and recovered five days after the discontinuation of this agent. This is the first record of anti-endothelial cell antibodies detection in a patient with sudden hearing loss. The finding of anti-endothelial cell antibodies suggests an association between sudden hearing loss and microvascular damage during interferon therapy.

[Apoptosis or programmed cell death: regulatory and pathophysiological mechanisms]. / Apoptosi, o morte cellulare programmata: meccanismi regolatori e fisiopatologia.

Apoptosis is an active death process genetically encoded to eliminate abnormal or unwanted cells. The phenomenon is induced by a cascade of molecular events leading to nucleolysis by endonucleases and involves a number of membrane receptors and cytoplasmic proteins. These structures (including Fas, müllerian inhibiting substance, p53 and the c-myc oncogene) contribute, by interactive regulatory mechanisms, to the promotion or inhibition of apoptosis, on the basis of both external stimulus and cell activation state. Since apoptosis is a selective process to suppress defective cells, deregulation of genes encoding for such apoptosis-related proteins could be relevant in the growth of several tumors. Remarkably, overexpression of the bcl-2 gene in a few experimental lymphomas has been associated with neoplastic proliferation because of its inhibitory effect on apoptosis. Conversely, early activation of Fas, an apoptosis-inducing gene on HIV-infected CD4+ lymphocytes, is thought to aggravate T cell lymphopenia in HIV infection by increasing the level of normal apoptosis. Genetic deregulation of apoptosis has also been postulated in the pathogenesis of several diseases. Indeed, while preliminary studies suggest that apoptosis plays a role in autoimmune disorders including systemic lupus erythematosus, the pathogenesis of a few degenerative neuropathies, such as Alzheimer's disease, could depend on a similar altered mechanism in apoptosis of neuronal cells. However, no studies are presently available to suggest that exploitation of molecular events of apoptosis would imply therapeutic progress.

[Malignant neoplasms and AIDS. Review of the literature and critical considerations on a case of epidermoid carcinoma of the anus]. / Neoplasie maligne e AIDS. Rassegna della letteratura e considerazioni critiche su un caso di carcinoma epidermoide dell'ano.

During the past few years the neoplasms defining the diagnosis of AIDS are in apparent evolution and a new distribution of specific tumors is currently reported in the literature. Besides the Kaposi's sarcoma, non-Hodgkin's lymphomas, and uterine cervical carcinoma, other malignancies are frequently diagnosed in HIV+ population, particularly during the advanced stages of the infection. The pathogenesis of such an increase of tumor diffusion is apparently related to the persistence of several herpes viruses including HHV8 and HPV whose molecular interaction with HIV may contribute to the genetic variations suitable for tumor development. The epidermoid anal carcinoma is a tumor whose appearance is increasingly recurrent in HIV+ patients, although it is not considered as an AIDS-defining neoplasia. This tumor is prevalent in HIV+ homosexual men, in particular during the full-blown immunodeficiency disease. Here we report the case of a patient whose diagnosis of AIDS was emphasized by the concurrent presence of the anal tumor.

[Methods for assessing programmed cell death]. / Metodiche di valutazione della morte cellulare programmata.

Apoptosis, namely programmed cell death, is a fundamental mechanism involved in both organogenesis and tissue homeostasis. Since this process is genetically controlled, its defective regulation plays a role in the pathogenesis of several diseases including inflammatory and degenerative disorders, autoimmunity and neoplasia. Several methods have been suggested to identify the cellular events including the modification of cell size, cytoplasmic condensation and nuclear degradation occurring during this phenomenon. The cell morphologic changes can be observed in detail by electronic microscopy, while the chromatin cleavage is well detected by both electrophoretic and flow cytometry techniques, using various fluorochromes able to bind specifically the double-stranded DNA. Here we review the different techniques to evaluate apoptosis with respect to their sensitivity in both qualitative and quantitative analyses.

Molecular specificities of CD4+ T cell-reactive IgM in human immunodeficiency virus (HIV-1) infection.

The molecular targets and biological properties of lymphocytotoxic sera in 11 human immunodeficiency virus (HIV)+ subjects in CDC stages II to IVC were investigated. A purified soluble CEM membrane used as the CD4+ T cell clonotypic model in immunoblotting techniques revealed a homogeneous pattern of IgM-mediated reactivity to a 43.5-kDa membrane component in 10 sera. Conversely, CEM membrane-reactive IgG from these sera were weakly reactive to various antigens with no prevalent specificity. ELISA assay against purified 25.5-, 43.5-, and 60.8-kDa CEM membrane antigens revealed a significant affinity of IgM from sera 3, 8, 9, and 10 for the 43.5-kDa receptor, thus confirming the high specificity of these cytotoxic antibodies for their substrate. Additional experiments included the idiotypic saturation of purified IgM molecules with increasing amounts of the 43.5-kDa antigen. Functional inhibition of CEM-reactive IgM by their antigen was dose-dependent. The maximum inhibition of the ELISA reactivity was detected at 1/7 antigen/antibody concentration. By contrast, a significant decline of cytotoxic properties of sera 8, 9, and 10 to CEM lymphoblasts was noted only when equivalent concentrations of the 43.5-kDa receptor and purified IgM were incubated. In addition, the 43.5-kDa antigen appeared to be the preferential target of cytotoxic IgM in HIV-1 infection, since purified cytotoxic IgM from two SLE patients were not inhibited by this molecule. Our data provide specific molecular support for earlier evidence of exacerbation by T cell-reactive antibodies of the lymphopenia associated with HIV-1 infection.

Distribution and antigenic analysis of circulating F(ab')2-reactive IgG in patients with HIV-1 infection.

Serum titers and molecular specificity of anti-F(ab')2 antibodies were investigated in human immunodeficiency virus type 1 (HIV-1) infection with respect to their supposed cytopenic role on CD4+ cells. The levels of antibodies to F(ab')2 fragment and to HIV-1 glycoprotein epitopes were measured by immunoenzymatic methods in an HIV-1+ population, including 86 drug addicts, 12 sexually infected patients, and 1 hemophiliac, grouped into Walter Reed (WR) clinical stages 2 to 6 of HIV-1 infection. Monoclonal F(ab')2-reactive IgM and IgG from cloned Epstein-Barr B cell transformants of selected patients were also investigated in regards to their HIV-1 glycoprotein specificities and cytotoxicity to the CD4+ cell membrane antigens (CEM) lymphoblasts by a Terasaki assay. Group A (51 sera from WR2 patients) showed the highest titers of IgG anti-F(ab')2 with no correlation to positivities to gp120, whereas sera with undetectable anti-F(ab')2 levels from group B (37 WR5 and WR6 patients) and from group C (11 WR3-WR6 patients with lymphocytotoxin-associated lymphopenia) were reactive to the virus envelope. Both anti-F(ab')2 monoclonal IgM and IgG failed to cross-react with the HIV-1 glycoproteins and the CD4+ CEM. Based on our data, anti-F(ab')2 antibodies are apparently unrelated to the CD4+ lymphopenia occurring in HIV-1-infection. In addition, their inability to bind the HIV-1 gp120 as sequence homologue of the CH1 domain of IgG suggests that their molecular target could include a few epitopes located within the VH and VL regions, thus supporting their potential role of antiidiotype molecules as described in autoimmunity.