Protocol Requirements for Self-organizing Artifacts: Towards an Ambient Intelligence

We discuss which properties common-use artifacts should have to collaborate without human intervention. We conceive how devices, such as mobile phones, PDAs, and home appliances, could be seamlessly integrated to provide an "ambient intelligence" that responds to the user's desires without requiring explicit programming or commands. While the hardware and software technology to build such systems already exists, as yet there is no standard protocol that can learn new meanings. We propose the first steps in the development of such a protocol, which would need to be adaptive, extensible, and open to the community, while promoting self-organization. We argue that devices, interacting through "game-like" moves, can learn to agree about how to communicate, with whom to cooperate, and how to delegate and coordinate specialized tasks. Thus, they may evolve a distributed cognition or collective intelligence capable of tackling complex tasks.Comment: To be presented at 5th International Conference on Complex System

EU-wide baseline survey on the prevalence of Salmonella in holdings with breeding pigs, 2008 - prevalence and factors associated with Salmonella positivity

In order to reduce the incidence of human salmonellosis, European Union (EU) legislation foresees the setting of Salmonella reduction targets for food producing-animals including breeding pigs. To set such a target, an EU-wide baseline survey was conducted in 2008 to determine the prevalence and diversity of Salmonella in holldings with breeding pigs across Member States (MSs)

Information dynamics shape the networks of Internet-mediated prostitution

Like many other social phenomena, prostitution is increasingly coordinated over the Internet. The online behavior affects the offline activity; the reverse is also true. We investigated the reported sexual contacts between 6,624 anonymous escorts and 10,106 sex-buyers extracted from an online community from its beginning and six years on. These sexual encounters were also graded and categorized (in terms of the type of sexual activities performed) by the buyers. From the temporal, bipartite network of posts, we found a full feedback loop in which high grades on previous posts affect the future commercial success of the sex-worker, and vice versa. We also found a peculiar growth pattern in which the turnover of community members and sex workers causes a sublinear preferential attachment. There is, moreover, a strong geographic influence on network structure-the network is geographically clustered but still close to connected, the contacts consistent with the inverse-square law observed in trading patterns. We also found that the number of sellers scales sublinearly with city size, so this type of prostitution does not, comparatively speaking, benefit much from an increasing concentration of people

Epigenetics in Canine Mammary Tumors: Upregulation of miR-18a and miR-18b Oncogenes Is Associated with Decreased ERS1 Target mRNA Expression and ERα Immunoexpression in Highly Proliferating Carcinomas

The expression of miRNAs is one of the main epigenetic mechanisms responsible for the regulation of gene expression in mammals, and in cancer, miRNAs participate by regulating the expression of protein-coding cancer-associated genes. In canine mammary tumors (CMTs), the ESR1 gene encodes for ERa, and represents a major target gene for miR-18a and miR-18b, previously found to be overexpressed in mammary carcinomas. A loss in ERa expression in CMTs is commonly associated with poor prognosis, and it is noteworthy that the downregulation of the ESR1 would appear to be more epigenetic than genetic in nature. In this study, the expression of ESR1 mRNA in formalin-fixed, paraffin-embedded (FFPE) canine mammary tumors (CMTs) was evaluated and compared with the expression levels of miR18a and miR18b, both assessed via RT-qPCR. Furthermore, the possible correlation between the miRNA expression data and the immunohistochemical prognostic factors (ERa immunoexpression; Ki67 proliferative index) was explored. A total of twenty-six FFPE mammary samples were used, including 22 CMTs (7 benign; 15 malignant) and four control samples (three normal mammary glands and one case of lobular hyperplasia). The obtained results demonstrate that miR-18a and miR-18b are upregulated in malignant CMTs, negatively correlating with the expression of target ESR1 mRNA. Of note, the upregulation of miRNAs strictly reflects the progressive loss of ERa immunoexpression and increased tumor cell proliferation as measured using the Ki67 index. The results suggest a central role of miR-18a and miR-18b in the pathophysiology of canine mammary tumors as potential epigenetic mechanisms involved in ERa downregulation. Moreover, as miRNA expression reflects ERa protein status and a high proliferative index, miR-18a and miR-18b may represent promising biomarkers with prognostic value. More detailed investigations on a larger number of cases are needed to better understand the influence of these miRNAs in canine mammary tumors

Labelling and clinical performance of human leukocytes labelled with 99m Tc-HMPAO using leukokit® with gelofusine versus leukokit® with HES as sedimentation agent

The scintigraphy with radiolabelled autologous leukocytes (WBCs) is considered the gold-standard technique for imaging infections. Leukokit (R) is a commercially available, disposable, sterile kit for labelling WBCs ex vivo. In this kit, WBCs isolation from red blood cells (RBCs) was performed using poly(O-2-hydroxyethyl)starch (HES) as the RBCs sedimentation agent. Due to its poor availability, HES has been recently replaced by Gelofusine as the RBC sedimentation agent. The aim of this study was to compare the labelling efficiency and the diagnostic accuracy of WBCs labelled with Leukokit (R) with HES vs Leukokit (R) with Gelofusine. WBCs were isolated using HES or Gelofusine for 45minutes and then purified from platelets (PLTs) and labelled with 1.1 +/- 0.3 GBq of freshly prepared Tc-99m- HMPAO. The following parameters were evaluated: the number and type of recovered WBCs, RBCs contamination, PLTs contamination, vitality of neutrophils, and chemotactic properties of neutrophils. Clinical comparison was performed between 80 patients (33 males; age 67.5 +/- 14.2) injected with Tc-99m-HMPAO-WBCs, using HES as the sedimentation agent, and 92 patients (38 males; age 68.2 +/- 12.8) injected with Tc-99m-HMPAO-WBCs using Gelofusine as the sedimentation agent. Patients were affected by prosthetic joint infections, peripheral bone osteomyelitis, or vascular graft infection. We compared radiolabelling efficiency (LE), final recovery yield (RY), and diagnostic outcome based on microbiology or 2-year follow-up. Results showed that HES provides the lowest RBCs and PLTs contamination, but Gelofusine provides the highest WBC recovery. Both agents did not influence the chemotactic properties of WBCs, and no differences were found in terms of LE and RY. Sensitivity, specificity, and accuracy were also not significantly different for WBCs labelled with both agents (diagnostic accuracy 90.9%, CI = 74.9-96.1 vs 98.3%, CI = 90.8-100, for HES and Gelofusine, respectively). In conclusion, Gelofusine can be considered a suitable alternative of HES for WBCs separation and labelling

Case report: De novo mutation of a-galactosidase A in a female patient with end-stage renal disease: report of a case of late diagnosis of Anderson–Fabry disease

Background: Anderson-Fabry disease (AFD) is an X-linked disease that results from reduced activity of the enzyme galactosidase alpha (GLA). When the GLA gene sequence is altered by mutations that alter the normal DNA sequence, variants of the alpha-galactosidase A enzyme are produced, which may or may not function. These mutations are responsible for Fabry disease, and to date, over 800 different mutations of the gene have been described in patients with Anderson-Fabry disease. In this case, we report the case of a woman who is the sole family member with this type of mutation.Case presentation: We report a case of a 52-year-old woman with end-stage chronic kidney disease in dialysis treatment. The patient's alpha-galactosidase activity was 6.6 nmol/ml/h in whole blood, and lyso-GB3 levels were 11.45 nmol/L (normal range < 2.3 nmol/L). Alpha-galactosidase A gene sequence analysis revealed a pathogenic variant of c.947dupT in exon 6, leading to the p. I317NfsTer16 amino acid substitution. The genetic analysis did not detect the same mutation in any of the other screened family members.Conclusion: The international Fabry disease genotype-phenotype database (dbFGP) reports a pathogenic variant c.947dupT in exon 6 that is probably associated with a classical phenotype of Fabry disease. In this case report, we report the case of a woman who is the sole family member with this type of pathogenic variant. Similar situations have not been described in the literature for this pathogenic variant, and it represents an important case of inter- and intrafamilial variability in patients with Fabry disease. The literature shows that de novo pathogenic variants are frequently found in the context of Fabry disease

Insect-based aquafeeds modulate the fatty acid profile of zebrafish: a comparison on the different life stages

Insects are considered as an alternative and sustainable ingredient for feed production. In this study, Hermetia illucens (Hi) prepupae (fed on coffee roasted by-product added with 10% Schyzochytrium sp., a marine protist rich in polyunsaturated fatty acids) was processed into meal and included at graded levels in five experimental diets to replace dietary fish meal (0, 25, 50, 75, 100%) offered to zebrafish (Danio rerio) as experimental model. The fatty acids (FAs) profile of fish larvae (20 days), juveniles (2 months, deprived of the viscera) and adults (6 months, male and female, deprived of the viscera) specimens was investigated to evaluate the impact of dietary FM replacement with full-fat Hi prepupae meal. For the first time, the quantification of FAs in Danio rerio, performed by gas chromatography-mass spectrometry, was computed in absolute terms (mg 100g-1 dw), identifying the real variation in the content of any single FA. In fish, quantified total FAs in larvae, juvenile, adult male and adult female were 134±2, 235±8, 266±3 and 266±8 mg g-1 dw, respectively. With respect to zebrafish fed the control diet, specimens fed diet with increasing level of Hi prepupae meal showed significantly higher content of saturated and omega6 FAs, and significantly lower content of poly-unsaturated and omega3 FAs, reflecting partially the FAs composition of the administered diets. At the same time, the docosahexaenoic/eicosapentaenoic acid ratio increased significantly. Moreover, adult female showed a higher content of PUFA with respect to adult male, which could be justified by the needs of physiological reproductive processes. The principal component analysis demonstrated that the FAs composition in Danio rerio depends on both the life stage and the diet

Molecular Pathogenesis of Central and Peripheral Nervous System Complications in Anderson–Fabry Disease

Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications of the GLA gene may cause the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriasylsphingosine (lyso-Gb3), in lysosomes of several types of cells of the heart, kidneys, skin, eyes, peripheral and central nervous system (not clearly and fully demonstrated), and gut with different and pleiotropic clinical symptoms. Among the main symptoms are acroparesthesias and pain crisis (involving the peripheral nervous system), hypohidrosis, abdominal pain, gut motility abnormalities (involving the autonomic system), and finally, cerebrovascular ischemic events due to macrovascular involvement (TIA and stroke) and lacunar strokes and white matter abnormalities due to a small vessel disease (SVS). Gb3 lysosomal accumulation causes cytoplasmatic disruption and subsequent cell death. Additional consequences of Gb3 deposits are inflammatory processes, abnormalities of leukocyte function, and impaired trafficking of some types of immune cells, including lymphocytes, monocytes, CD8+ cells, B cells, and dendritic cells. The involvement of inflammation in AFD pathogenesis conflicts with the reported poor correlation between CRP levels as an inflammation marker and clinical scores such as the Mainz Severity Score Index (MSSI). Also, some authors have suggested an autoimmune reaction is involved in the disease's pathogenetic mechanism after the alpha-galactosidase A deficiency. Some studies have reported a high degree of neuronal apoptosis inhibiting protein as a critical anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Notably, this apoptotic upregulation did not change after treatment with enzymatic replacement therapy (ERT), with a further upregulation of the apoptosis-inducing factor after ERT started. Gb3-accumulation has been reported to increase the degree of oxidative stress indexes and the production of reactive oxygen species (ROS). Lipids and proteins have been reported as oxidized and not functioning. Thus, neurological complications are linked to different pathogenetic molecular mechanisms. Progressive accumulation of Gb3 represents a possible pathogenetic event of peripheral nerve involvement. In contrast, central nervous system participation in the clinical setting of cerebrovascular ischemic events seems to be due to the epitheliopathy of Anderson-Fabry disease with lacunar lesions and white matter hyperintensities (WMHs). In this review manuscript, we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease. The management of Fabry disease may be improved by the identification of biomarkers that reflect the clinical course, severity, and progression of the disease. Intensive research on biomarkers has been conducted over the years to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. Recent proteomic or metabolomic studies are in progress, investigating plasma proteome profiles in Fabry patients: these assessments may be useful to characterize the molecular pathology of the disease, improve the diagnostic process, and monitor the response to treatment

Pathogenesis and molecular mechanisms of anderson–fabry disease and possible new molecular addressed therapeutic strategies

Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approxi-mately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a signif-icant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the au-tophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal oc-clusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-de-pendent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibro-blasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in ad-dition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy

Common Variable Immunodeficiency and Autoimmune Diseases: A Retrospective Study of 95 Adult Patients in a Single Tertiary Care Center

Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency in adulthood, which presents a broad spectrum of clinical manifestations, often including non-infectious complications in addition to heightened susceptibility to infections. These protean manifestations may significantly complicate the differential diagnosis resulting in diagnostic delay and under-treatment with increased mortality and morbidity. Autoimmunity occurs in up to 30% of CVID patients, and it is an emerging cause of morbidity and mortality in this type of patients. 95 patients (42 males and 53 females) diagnosed with CVID, basing on ESID diagnostic criteria, were enrolled in this retrospective cohort study. Clinical phenotypes were established according to Chapel 2012: i) no other disease-related complications, ii) cytopenias (thrombocytopenia/autoimmune hemolytic anemia/neutropenia), iii) polyclonal lymphoproliferation (granuloma/lymphoid interstitial pneumonitis/persistent unexplained lymphadenopathy), and iv) unexplained persistent enteropathy. Clinical items in the analysis were age, gender, and clinical features. Laboratory data included immunoglobulin (Ig)G, IgM and IgA levels at diagnosis, flow-cytometric analysis of peripheral lymphocytes (CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD4+CD25highCD127low, CD19hiCD21loCD38lo, and follicular T helper cell counts). Comparisons of continuous variables between groups were performed with unpaired t-test, when applicable. 39 patients (41%) showed autoimmune complications. Among them, there were 21 females (53.8%) and 18 males (46.2%). The most prevalent autoimmune manifestations were cytopenias (17.8%), followed by arthritis (11.5%), psoriasis (9.4%), and vitiligo (6.3%). The most common cytopenia was immune thrombocytopenia, reported in 10 out of 95 patients (10.5%), followed by autoimmune hemolytic anemia (n=3, 3.1%) and autoimmune neutropenia (n=3, 3.1%). Other autoimmune complications included thyroiditis, coeliac disease, erythema nodosum, Raynaud’s phenomenon, alopecia, recurring oral ulcers, autoimmune gastritis, and primary biliary cholangitis. There were no statistically significant differences comparing immunoglobulin levels between CVID patients with or without autoimmune manifestations. There was no statistical difference in CD3+, CD8+, CD4+CD25highCD127low T, CD19, CD19hiCD21loCD38lo, and follicular T helper cell counts in CVID patients with or without autoimmune disorders. In conclusion, autoimmune manifestations often affect patients with CVID. Early recognition and tailored treatment of these conditions are pivotal to ensure a better quality of life and the reduction of CVID associated complications