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At a time when over 65 million people are forcibly displaced worldwide, Latin America and the Caribbean offer examples of good practices from a region which continues to uphold a long-standing commitment to protect those in need.

SummaryBackgroundIf carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA.MethodsBetween 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3–2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6–11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392.Findings1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7% versus 4·8% at 1 year (and 92·1% vs 16·5% at 5 years). Perioperative risk of stroke or death within 30 days was 3·0% (95% CI 2·4–3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1% versus 10·0% at 5 years (gain 5·9%, 95% CI 4·0–7·8) and 10·8% versus 16·9% at 10 years (gain 6·1%, 2·7–9·4); ratio of stroke incidence rates 0·54, 95% CI 0·43–0·68, p

Angiogenesis is a complex multistep process by which new blood vessels are formed from pre-existent ones. It’s a fundamental process in tissue development and it’s directly correlated with tumor growth and aggressivity. Tumors appear to activate an angiogenesis switch from vascular quiescence by changing the balance between angiogenesis inhibitors and promoters. The multimodular protein angiostatin physiologically inhibits angiogenesis by suppressing endothelial cell growth and migration (1). Being angiostatin already in clinical trials, it is essential to understand the underlying molecular mechanism of inhibition. The scanning force microscope in the force spectroscopy mode allows to mechanically unfold multimodular proteins by working at the single molecule level. In this kind of experiments, a single protein bridge is settled between the microscope tip and a substrate; the force required to strech the protein is monitored as a function of its extension, showing a typical saw tooth profile in which each peak corresponds to the unfolding of a single domain (2). In a recent work (3) we have demonstrated by means of single molecule force spectroscopy that angiostatin mechanical properties can be modulated by the controlled reduction of its internal disulphide bonds. In the same work we have also shown how this technique allows to identify the different thiol/disulphide intermediates at the single domain level. Here we demonstrate by force spectroscopy techniques that angiostatin disulphide bonds reduction can be performed by human thioredoxin, an extracellular reductase overexpressed in the proximity of tumor tissues. This result indicate that angiostatin mechanical properties might be modulated in vivo and that angiostatin might play a mechanochemical role in angiogenesis. On this basis a mechanochemical model of the angiostatin inhibitory effect on angiogenesis is proposed. We investigated the dependence of the unfolding forces on the natural logarithm of the pulling speed and found the expected linear dependence (4). We performed kinetic Monte Carlo simulations of the stretching experiments (5) and (in collaboration with Rita Casadio and Emidio Capriotti, University of Bologna) we carried out steered molecular dynamics simulations of the forced unfolding of angiostatin domains (6). The comparison between the simulations results and the experimental data allowed us to get quantitative information about the free energy profile along the unfolding pathway and to identify a structural unfolding intermediate that could play a mechanochemical role in the angiostatin inhibitory effect on angiogenesis. 1. Folkman, J. (2002) Semin Oncol 29, 15-18. 2. Samori, B. (2000) Chemistry 6, 4249-4255. Best, R. B., and Clarke, J. (2002) Chem Commun (Camb), 183-192. 3. Bustanji, Y., and Samorì, B. (2002) Angew. Chem. Int. Ed. 41, 1546-1548. 4. Bustanji, Y., Arciola, C. R., Conti, M., Mandello, E., Montanaro, L., and Samori, B. (2003) Proc Natl Acad Sci U S A 100, 13292-13297. 5. Carrion-Vazquez, M., Oberhauser, A. F., Fowler, S. B., Marszalek, P. E., Broedel, S. E., Clarke, J., and Fernandez, J. M. (1999) Proc Natl Acad Sci U S A 96, 3694-3699. 6. Lu, H., Isralewitz, B., Krammer, A., Vogel, V., and Schulten, K. (1998) Biophys J 75, 662-671.

Background and aims: Quality monitoring has great relevance in stroke care. The Project "How to guarantee adherence to effective interventions in stroke care" aimed to estimate adherence to acute-phase guidelines in stroke care in Italy. Methods: A prospective observational study was performed in 27 hospitals of 13 Italian Regions. Adherence to 15 process indicators was evaluated, comparing also stroke units (SU) with conventional wards. An overall score of care, defined as the sum of achieved indicators, was calculated. A multilevel hierarchical model described performance at patient, hospital and regional level. Results: Overall, 484 consecutive stroke patients (mean age, 73.4 years; 52.7% males) were included. Total score ranged from 2 to 15 (mean 8.5 ± 2.4). SU patients were more often evaluated with the National Institutes of Health Stroke Scale (NIHSS) within 24 h, had more frequently an assessment of pre- and post-stroke disability, and a CT scan the same or the day after admission. Regional-hospital- and patient-level variability explained, respectively, 25, 34, and 41% of total score variance. In multivariate models, patients >80 years vs. younger showed a change in total score of -0.45 (95% CI -0.79 to -0.12), and those with NIHSS ≥14 vs. ≤5 of -0.92 (95% CI -1.53 to -0.30). A negative change means a worse adjusted average adherence to process indicators. SU admission increased total score of 1.55 (95% CI 0.52-2.58). Conclusions: Our data confirm the need of quality monitoring in stroke care. Although SU patients showed a better adherence to quality indicators, overall compliance was unsatisfactory. © Springer International Publishing 2013.

Here we describe a rare clinical manifestation of canine pododemodicosis. A dog was presented with pedal erythema, scaling, crusting, severe edema and digit loss. The following diseases were taken into account for the differential diagnosis: pododemodicosis, lethal acrodermatitis, zinc responsive dermatosis and pemphigus foliaceus. Results from skin biopsies revealed the presence of Demodex spp. of mites in the follicular infundibula and a severe inflammatory process (pododemodicosis). Upon the acaricidal treatment, the patient exhibited favorable signs of clinical improvement.Keywords: Acaricidal treatment, Canine, Parasite, Pododemodicosis, Skin

Many historical city centers are changing their demographic composition and their urban planning at the same time. This paper analyzes Brescia's case study as an example of temporary urban transformation and investigates cohabitation between immigrant people, university students and other city users, focusing on specific strategies of public and private players who on the same «ground» are developing different processes and programmes, looking for a new prospective for the city. According to the authors the challenge of middle Italian cities is rethinking its urban policies in a more comprehensive perspective, able to take account of social, cultural, economical complexity as a critical success factor for city development.

Potassium ion (K+) kinetics in intra and extracellular compartments during hemodialysis was studied by means of a double-pool computer model which included potassium-dependent active transport (Na-K-ATPase pump) in thirty-four patients (21M/13F; aged 66 plusmn 22 years old, dry weight 68 plusmn 18 kg, height 160 plusmn 15 cm) on renal replacement therapy with thrice weekly 4 hour double-needle hemodialysis. Each patient was studied during acetate free biofiltration (AFB) with a constant K+ dialysate concentration (KCONST therapy) and with a time-varying (profiled) K+ dialysate concentration (KPROF therapy). The two therapies induced different levels of K+ plasma concentration (KCONST: 3.6plusmn0.8 vs. KPROF: 4.0plusmn0.7 mmol/L, time-averaged values, p

Evidence is emerging that a mechanical tension can alter the functional states of proteins. It has been proved that a mechanical force can switch on the binding of PECAM-1 with a kinase (1), and the self-assembly of fibronectin into a fibrillar form by the exposure of cryptic binding sites (2). We previously reported that angiostatin modules mechanical unfolding was controlled by redox conditions (3). Here we report the first experimental evidence of a hierarchical coupling of redox and mechanical switches that controls the access to partially unfolded structures of biological significance in the multimodular protein angiostatin. We provide evidence that these structures can act as the antiangiogenic active forms of this protein, rather than the native fully oxidized and folded one as commonly considered so far. Among these structures we have identified a metastable intermediate that can account for unexplained data on the antiangiogenic activity of several angiostatin fragments (4) and for angiostatin binding to one of its receptors (5). The mechanochemical paradigm herein proposed could apply to other kringle fragments of multimodular proteins whose role in angiogenesis was proved, like prothrombin, apolipoprotein(a) and hepatocyte growth factor (6,7). 1. Osawa, M., Masuda, M., Kusano, K. & Fujiwara, K. Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule? J. Cell. Biol. 158, 773-85 (2002). 2. Baneyx, G., Baugh, L. & Vogel, V. Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension. Proc. Natl. Acad. Sci. USA 99, 5139-43 (2002). 3. Bustanji, Y. & Samorì, B. The mechanical properties of human angiostatin can be modulated by means of its disulfide bonds: A single-molecule force-spectroscopy study. Angew. Chem. Int. Ed. 41, 1546-1548 (2002). 4. Dettin, M. et al. Synthetic peptides derived from the angiostatin K4 domain inhibit endothelial cell migration. Chembiochem 4, 1238-42 (2003). 5. Veitonmaki, N. et al. Endothelial cell surface ATP synthase-triggered caspase-apoptotic pathway is essential for K1-5-induced antiangiogenesis. Cancer Res. 64, 3679-86 (2004). 6. Cao, Y., Cao, R. & Veitonmaki, N. Kringle structures and antiangiogenesis. Curr. Med. Chem. Anti-Canc. Agents 2, 667-81 (2002). 7. Sengupta, S. et al. Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler. Thromb. Vasc Biol 23, 69-75 (2003).

A novel mechanism is proposed by which the triggering of a biochemical signal can be controlled by the hierarchical coupling between a protein redox equilibrium and an external mechanical force. We have characterized this mechanism in angiostatin, where the access to partially unfolded structures is controlled by mechanochemical switches. We provide evidence that these structures can act as the antiangiogenic active forms of this protein, rather than the native fully oxidized and folded one as commonly considered so far.We have identified a metastable intermediate that is specifically accessible in the thioredoxin-rich reducing conditions like those met by angiostatin on the surface of a tumor cell. The structure of the same intermediate accounts for unexplained data on the antiangiogenic activity of angiostatin. The mechanochemical paradigm herein proposed constitutes, to our knowledge, the first example of the coupling of a redox and a mechanical regulation and has broad implications for redox biology. It applies in particular to the large set of proteins that are composed by independent modules containing internal disulfide bonds and experience environmental mechanical stresses in-vivo.

In Italy, the prevalence of Corynebacterium diphtheriae carriage is unknown. Throat swabs from 1970 healthy chil- dren, 6 to 14 years of age, were investigated. Three non-toxi- genic strains of Corynebacterium diphtheriae biotype mitis, were isolated from as many healthy children. Molecular char- acterization of the these strains indicates that they have been persisting for at least 25 years and are endemic rather than having been imported from countries with current endemic or epidemic diphtheria. Although non-toxigenic strains of C. diphtheriae occurring in the community are usually thought to be of little or no epidemiological importance, it may be possible to convert a non-toxigenic diphtheria strain into a toxigenic one by lysogenization with a specific temperate bacteriophage. Despite the virtual elimination of diphtheria in Italy, this long-standing circulation of non-toxigenic C. diphtheriae poses a potentially significant risk to public health and could result in the re-emergence of diphtheria in our country, even though the high proportion of younger population with protective levels of immunity is probably significant in preventing diphtheria spread. Therefore, it is important to maintain mandatory vaccination in childhood and to offer periodical re-vaccination of adults.