Enhancing Fault / Intrusion Tolerance through Design and Configuration Diversity

Fault/intrusion tolerance is usually the only viable way of improving the system dependability and security in the presence of continuously evolving threats. Many of the solutions in the literature concern a specific snapshot in the production or deployment of a fault-tolerant system and no immediate considerations are made about how the system should evolve to deal with novel threats. In this paper we outline and evaluate a set of operating systems’ and applications’ reconfiguration rules which can be used to modify the state of a system replica prior to deployment or in between recoveries, and hence increase the replicas chance of a longer intrusion-free operation

Severe anaemia after gastric biopsy in an infant with eosinophilic gastritis

Background: Eosinophilic gastrointestinal disorders (EGID) are characterized by eosinophilic inflammation and are subclassified according to the affected site(s) as eosinophilic esophagitis, eosinophilic gastritis, eosinophilic enteritis and eosinophilic colitis. Clinical presentation includes dyspeptic symptoms, vomiting, abdominal pain, diarrhoea and gastrointestinal bleeding. Peripheral eosinophilia is usually found but is not required for the diagnosis. The treatment is based on dietary elimination therapy, consisting of removal of common food triggers, most frequently cow's milk in infants. Corticosteroids are used as first line drug therapy in EG if dietary therapy fails to achieve an adequate clinical response or is impractical. Case presentation: A four month old infant was admitted for an episode of melena and hematemesis. An esophagogastroduodenoscopy showed haemorrhagic gastritis with ulcerative lesions and fibrin. A significant gastric bleeding was noted after the procedure. The gastric mucosa biopsies showed an eosinophilic infiltration. Conclusions: A clinically relevant anaemia is a quite rare complication in infants with eosinophilic gastritis and a biopsy may worsen bleeding, to a potentially severe level of low haemoglobin. In infants with low haemoglobin levels and suspect eosinophilic gastritis a watchful follow up after the biopsy should be considered, as well as the possibility of postponing the biopsy to reduce the bleeding risk

FOREVER: Fault/intrusiOn REmoVal through Evolution & Recovery

The goal of the FOREVER project is to develop a service for Fault/intrusiOn REmoVal through Evolution & Recovery. In order to achieve this goal, our work addresses three main tasks: the definition of the FOREVER service architecture; the analysis of how diversity techniques can improve resilience; and the evaluation of the FOREVER service. The FOREVER service is an important contribution to intrustion-tolerant replication middleware and significantly enhances the resilience

Acquired von Willebrand syndrome in patients with monoclonal gammopathy of undetermined significance investigated using a mechanistic approach

BACKGROUND: Acquired von Willebrand syndrome (AVWS) has been reported to occur in association with monoclonal gammopathy, usually of undetermined significance (MGUS). It may present as a type 1 or type 2 von Willebrand factor (VWF) defect depending on the patient’s representation of large VWF multimers. MATERIALS AND METHODS: The mathematical model by Galvanin et al., already employed for studying inherited von Willebrand disease (VWD), was used to explore the pathogenic mechanisms behind MGUS-associated AVWS. RESULTS: The patients studied showed significantly reduced VWF levels and function; an increased VWF propeptide to VWF antigen ratio; and all VWF multimers present but in reduced quantities, with the low-molecular-weight VWF forms being significantly more represented than those of higher molecular weight. Our mathematical model revealed a significantly increased VWF elimination rate constant, with values similar to those of type Vicenza VWD. An even more increased VWF proteolysis rate constant was observed, with values one order of magnitude higher than in type 2A VWD but, in contrast, no loss of large multimers. The model predicted the same elimination rate for high- and low-molecular-weight VWF multimers, but proteolysis of the high-molecular-weight forms also contributes to the pool of low-molecular-weight oligomers, which explains why they were relatively over-represented. DISCUSSION: In MGUS-associated AVWS the increase of both clearance and proteolysis contributes to the circulating levels and multimer pattern of VWF, with a phenotype that appears to be a combination of type Vicenza and type 2A VWD. Hence, the mechanisms behind the onset of AVWS seem to differ from those of inherited VWD

Behavior of four main dairy pathogenic bacteria during manufacturing and ripening of pecorino siciliano cheese

Background: Consumption of raw cheese may be associated with different diseases. This study aimed to evaluate behavior of four pathogenic bacteria during manufacture and ripening of Protected Designation of Origin (PDO) Pecorino Siciliano cheese. Methods: The experimental cheese groups were inoculated with pathogenic bacteria, including Escherichia coli O157, Listeria monocytogenes, Salmonella Enteritidis, and Staphylococcus aureus. The cheese making processes were monitored from milk curdling until 3 months ripened cheeses and the levels of Lactic Acid Bacteria (LAB) and the four dairy pathogens were evaluated by plate counts. Randomly Amplified Polymorphic DNA (RAPD)-Polymerase Chain Reaction (PCR) analysis was applied to confirm that the colonies isolated during the several steps of production were the same strains added in milk. Statistical analysis was done using XLStat software. Results: The levels of mesophilic and thermophilic coccus and rod LAB in curd were comparable in both trials and reached values between 8-9 log10 Colony Forming Unit (CFU)/g in cheeses at 90 days of ripening. The four pathogenic bacteria were found in experimental curd at levels higher than those inoculated in milk and completely disappeared after 60 days of ripening. The RAPD analysis clearly demonstrated the presence of the added strain during production and confirmed the results of plate counts. Conclusion: This work showed that the production conditions of PDO Pecorino Siciliano cheese decreased growth of E. coli O157, L. monocytogenes, S. Enteritidis, and S. aureus

Synthesis and biological evaluation of new indazole derivatives

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Clusterin: A potential target for improving response to antiestrogens

Antiestrogens represent the first line of therapy in the treatment of estrogen receptor-positive (ER+) breast cancer patients. Unfortunately, up to 40% of patients develop resistance associated with progression and frequently die for metastatic breast cancer. The molecular events leading to pharmacological resistance are not completely understood. We attempted to verify in an experimental model the role of cytoplasmic clusterin (CLU), a cytoprotective protein found to be up-regulated in antiestrogen-resistant patients, following neoadjuvant treatment with toremifene. The role of cytoplasmic clusterin in modulating response to two antiestrogens (toremifene and tamoxifen) was studied in two ER+ anti-estrogen-sensitive cell lines (MCF-7, 734B) and one ER+ antiestrogen-resistant cell line (T47D) using siRNA strategy. Resistant cells were characterised by higher levels of cytoplasmic clusterin than sensitive cells, and antiestrogen treatments up-regulated clusterin levels in both sensitive and resistant cell lines. Treatment with siRNA completely abolished cytoplasmic clusterin expression in all cell lines, but its down-regulation resulted in a significant decrease of cell growth only In the resistant line. We therefore concluded that: i) basal clusterin levels are higher in antiestrogen resistant cells. ii) clusterin is up-regulated following antiestrogen treatment independently of the sensitivity of the cell line, iii) downregulation of cytoplasmic clusterin restores sensitivity to toremifene in the antiestrogen-resistant cell line. Such results support the concept that targeting CLU could represent a promising therapeutic strategy in association with antiestrogen treatment in breast cancer patients

Sodium 4-Carboxymethoxyimino-(4-HPR) a Novel Water-Soluble Derivative of 4-Oxo-4-HPR Endowed with In Vivo Anticancer Activity on Solid Tumors

4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), an active polar metabolite of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR), was shown to exert promising antitumor activity through at least two independent mechanisms of action. Specifically, differently from 4-HPR and other retinoids, 4-oxo-4-HPR targets microtubules and inhibits tubulin polymerization causing mitotic arrest and on the other hand, analogously to the parent drug, it induces apoptosis through the activation of a signaling cascade involving the generation of reactive oxygen species (ROS). However, the potential in vivo use of 4-oxo-4-HPR is impaired by its poor solubility. By chemical modification of 4-oxo-4-HPR, a new class of compounds with improved solubility and in vivo bioavailability was obtained. We demonstrated here that, among them, the most promising molecule, sodium 4-carboxymethoxyimino-(4-HPR), was endowed with in vitro antitumor efficacy and entirely preserved the double mechanism of action of the parent drug in cancer cells of different histotypes. In fact, the retinoid induced the activation of the apoptotic cascade related to the generation of ROS through endoplasmic reticulum stress response and upregulation of phospho c-Jun N-terminal kinases and PLAcental Bone morphogenetic protein, leading to cell death through caspase-3 cleavage. Otherwise, sodium 4-carboxymethoxyimino-(4-HPR) caused a marked mitotic arrest coupled with multipolar spindle formation and tubulin depolymerization. To assess the compound antitumor activity, in vivo experiments were performed in three mouse xenograft models (ovarian and breast cancers and mesothelioma). The in vivo results demonstrated that retinoid administration as single agent significantly increased the survival in ovarian cancer xenografts, induced a statistically significant decrease in tumor growth in breast cancer xenografts, and caused a 30% reduction in tumor growth in a mesothelioma mouse model. Even though further studies investigating sodium 4-carboxymethoxyimino-(4-HPR) toxicity and in vitro and in vivo activities in combination with other drugs are required, the double mechanism of action of the retinoid coupled with its in vivo antitumor efficacy and potential low toxicity suggest a promising therapeutic potential for the compound in different solid tumors

Effects of intravenous furosemide plus small-volume hypertonic saline solutions on markers of heart failure

Aims: We sought to compare the effects of furosemide + hypertonic saline solution (HSS) treatment in patients with acute decompensated heart failure in comparison with furosemide alone and the response in a compensated state after an acute saline load with regard to serum levels of heart failure biomarkers. Methods and results: We enrolled 141 patients with acute decompensated heart failure with reduced ejection fraction admitted to our Internal Medicine ward from March 2017 to November 2019. A total of 73 patients were randomized to treatment with i.v. high-dose furosemide plus HSS, whereas 68 patients were randomized to i.v. high-dose furosemide alone. Patients treated with furosemide plus HSS compared with controls treated with furosemide alone showed a comparable degree of reduction in the serum levels of interleukin (IL)-6, soluble suppression of tumorigenicity 2 (sST2), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the ‘between-group’ analysis. Nevertheless, patients treated with high-dose furosemide + HSS showed significantly higher absolute delta values of IL-6 (2.3 ± 1.2 vs. 1.7 ± 0.9, P < 0.0005, and 2.0 ± 0.8 vs. 1.85 ± 1.1, P = 0.034), sST2 (41.2 ± 8.6 vs. 27.9 ± 7.6, P < 0.0005, and 37.1 ± 6.6 vs. 28.4 ± 6.7, P < 0.0005), high-sensitivity troponin T (0.03 ± 0.02 vs. 0.02 ± 0.01, P = 0.001, and 0.03 ± 0.02 vs. 0.02 ± 0.01, P = 0.009), NT-proBNP (7237 ± 7931 vs. 3244 ± 4159, P < 0.005, and 5381 ± 4829 vs. 4466 ± 4332, P = 0.004), and galectin-3 (15.7 ± 3.2 ng/mL vs. 11.68 ± 1.9 ng/mL, P < 0.0005, and 16.7 ± 3.9 ng/mL vs. 11.8 ± 2.4 ng/mL, P < 0.0005) than patients treated with furosemide alone. After acute saline load, patients treated with i.v. furosemide + HSS in comparison with subjects treated with furosemide alone showed a significantly lower increase in the serum concentrations of IL-6 (−0.26 ± 0.42 pg/mL vs. −1.43 ± 0.86 pg/mL, P < 0.0005), high-sensitivity troponin T (0 vs. −0.02 ± 0.02 ng/mL, P < 0.0005), sST2 (−8.5 ± 5.9 ng/mL vs. −14.6 ± 6.2 ng/mL, P < 0.0005), galectin-3 (−2.1 ± 1.5 ng/mL vs. −7.1 ± 3.6 ng/mL, P < 0.0005), and NT-proBNP (77 ± 1373 vs. −1706 ± 2259 pg/mL, P < 0.0005). Conclusions: Our findings concerning a comparable degree of reduction in the serum levels of three cardinal biomarkers indicate that a reduction in serum heart failure markers is not linked to the higher degree of congestion relief with a more rapid achievement of a clinical compensation state. This issue may have possible benefits on clinical practice concerning its therapeutic effects over and beyond the simple amelioration of clinical congestion signs and symptoms. Nevertheless, our findings of higher delta values after treatment with i.v. furosemide plus HSS indicate a possible higher efficacy by means of modulation of the stretching and fibrosis mechanisms