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The article intends to analyze the role of Jewish merchants in the grain trade in the Mediterranean area of the eighteenth century, with a focus on the case of the Papal States and the middle Adriatic Sea. The starting question is the following: is it possible to identify (if there are any) specific elements, connected to the characteristics of a discriminated minority, which connect the Jewish mercantile network and the trade in cereals and food products in general? The ability to circulate information and goods is a determining factor, not only for Jewish merchants; equally central appears to be the ability to establish relationships with local authorities, which are essential for obtaining licenses, concessions and orders. Specific to the Jewish world, on the other hand, is the context of political and religious limitations and discrimination exercised by the authorities of the respective territories. Rather, the arrival of emergency conditions, dictated by famines or war events, such as the passage of troops, seems to constitute a terrain in which some of the main Jewish merchants of the State managed to activate the relational and economic resources necessary to supply the cities of the cereals necessary for the survival of populations.

Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra-ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach.

Future Internet Testbed with Security (FITS) is a testbed for experimenting Next-Generation Internet proposals that provides two virtualization schemes based on Xen and on OpenFlow. Experimenting new protocol proposals for the Future Internet requires a realistic condition environment for packet forwarding. FITS nodes are spread in Brazilian and European universities. In this paper, we present FITS and we use it to test a Content Centric Network (CCN), which is one of the main proposals for the Future Internet. The experiment creates a virtual network on the testbed with CCNx stack and measure the file transfer performance under real Internet traffic conditions. The results show that CCN presents an overhead of 19% when compared with the conventional TCP/IP stack. Nevertheless, CCN outperforms TCP as the number of consumers increases and CCN download time is approximately 25% smaller than TCP on the Internet.

Background: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. Methods: The UmanDiagnostics NF-light ®enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68 kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories' accuracy and preparation of standards were documented and used for the statistical analyses. Results: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R = 0.60, p < 0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R = 0.98, p < 0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss' multi-rater kappa and Gwet's AC1 statistics. Conclusion: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online. © 2009 Elsevier B.V.

In 2002–2003, the Italian Association for Neuroimmunology (AINI) ran a program for procedure and method standardization in neuroimmunology. The main purposes of the program were: a) to improve the overall quality of analytical performance and, simultaneously, to reduce costs by resource optimization; b) to establish the bases for clinical guidelines in neurology; c) to promote the formation of laboratory networks and of joint research projects; d) to facilitate the procedures for certification required by governmental/non-governmental agencies. This report summarizes the consensus recommendations of a panel of AINI neuroimmunologists/biochemists involved in the field of cerebrospinal fluid examination. The collection process for said recommendations was guided by ‘‘impact-factored’’ literature and the knowledge of the experts involved. Communication was by email and face-to-face at two dedicated AINI workshops.

This paper introduces the Special Issue ‘Minorities and Grain Trade in Early Modern Europe’. While an area’s traditional supply circuits benefitted from satisfactory harvests and a stable food demand, minorities’ contribution became crucial during crisis. Due to their commercial networks, facilities, and capital, minorities and their agents were able to cope with market disruption, especially when inflation and the reconfiguration of supply areas rendered ‘traditional’ grain merchants unable to face the emergency. The papers included in the Special Issue focus on the geographical and financial scope of legal grain-trading minorities’ businesses and their degree of specialisation and analyse how political authorities’ reliance on minorities to face food scarcity not only represented an economic opportunity for minorities but also contributed to shaping their relationship with public authorities.

The exploitation of sunlight as a clean, renewable, and distributed energy source is key to facing the energetic demand of modern society in a sustainable and affordable fashion. In the past few decades, chemists have learned to make molecular machines, that is, synthetic chemical systems in which energy inputs cause controlled movements of molecular components that could be used to perform a task. A variety of artificial molecular machines operated by light have been constructed by implementing photochemical processes within appropriately designed (supra)molecular assemblies. These studies could open up new routes for the realization of nanostructured devices and materials capable to harness, convert, and store light energy.

Heteroditopic calix[6]arenes are extensively exploited as synthetic receptors and as molecular components of supramolecular threaded and interlocked structures. We describe the synthesis of two novel calix[6]arene macrocycles, the upper rim of which is functionalized with either two or three phenylthioureido groups. These moieties are excellent hydrogen-bond donors and largely affect the conformation of the macrocycle, both in solution and in the solid state. Alternate conformers are observed in solution, and they give rise to supramolecular chains in the solid state. Moreover, and because of this conformational freedom, also the recognition properties toward the formation of pseudorotaxanes with bipyridinium-based axles are strongly affected. The number of phenylthioureido units of the macrocyclic host and the nature of the counterions of the bipyridinium guest determine the stability of the complexes. NMR, UV-Vis and electrochemical measurements revealed that very stable 1 : 1 inclusion complexes are formed between the triphenylthioureido calix[6]arene and a bipyridinium guest with tosylate counterions, whereas no complex is observed between the diphenylthioureido macrocycle and a hexafluorophosphate bipyridinium salt.

OBJECTIVES: to describe the epidemic trends of COVID-19 over time and by area in the territory covered by Milan's Agency for Health Protection (ATS-MI) from February to May 2020. DESIGN: descriptive study of COVID-19 cases. SETTING AND PARTICIPANTS: a new information system was developed to record COVID-19 cases with positive nasopharyngeal swab. Patients resident in the area covered by ATS-MI with symptom onset between February and May 2020 were selected. Different epidemic periods were considered based on the timeline of the various regional and national containment measures. MAIN OUTCOME MEASURES: case fatality ratios, incidence rates, and reproduction number by epidemic period and sub-area of ATS-MI. RESULTS: a total of 27,017 swab-positive COVID-19 cases were included. Mean age was 65 years and males were 45%. Incidence in the ATS-MI area was 776 per 100,000 population. The number of deaths was 4,660, the crude case fatality ratio was 17.3%, higher in males (21.2%) than in females (14.0%). The estimated reproduction number registered its peak (3.0) in the early stages of the epidemic and subsequently decreased. Territorial differences were observed in the epidemic spread, with a higher incidence in the Lodi area. CONCLUSIONS: estimated incidence and case fatality ratios were higher than national estimates for Italy. Each ATS-MI area had different epidemic spread patterns.

Background COVID-19 epidemic has paralleled with the so called infodemic, where countless pieces of information have been disseminated on putative risk factors for COVID-19. Among those, emerged the notion that people suffering from autoimmune diseases (AIDs) have a higher risk of SARS-CoV-2 infection. Methods The cohort included all COVID-19 cases residents in the Agency for Health Protection (AHP) of Milan that, from the beginning of the outbreak, developed a web-based platform that traced positive and negative cases as well as related contacts. AIDs subjects were defined ad having one the following autoimmune disease: rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren disease, ankylosing spondylitis, myasthenia gravis, Hashimoto’s disease, acquired autoimmune hemolytic anemia, and psoriatic arthritis. To investigate whether AID subjects are at increased risk of SARS-CoV-2 infection, and whether they have worse prognosis than AIDs-free subjects once infected, we performed a combined analysis of a test-negative design case–control study, a case–control with test-positive as cases, and one with test-negative as cases (CC-NEG). Results During the outbreak, the Milan AHP endured, up to April 27th 2020, 20,364 test-positive and 34,697 test-negative subjects. We found no association between AIDs and being positive to COVID-19, but a statistically significant association between AIDs and being negative to COVID-19 in the CC-NEG. If, as likely, test-negative subjects underwent testing because of respiratory infection symptoms, these results imply that autoimmune diseases may be a risk factor for respiratory infections in general (including COVID-19), but they are not a specific risk factor for COVID-19. Furthermore, when infected by SARS-CoV-2, AIDs subjects did not have a worse prognosis compared to non-AIDs subjects. Results highlighted a potential unbalance in the testing campaign, which may be correlated to the characteristics of the tested person, leading specific frail population to be particularly tested. Conclusions Lack of availability of sound scientific knowledge inevitably lead unreliable news to spread over the population, preventing people to disentangle them form reliable information. Even if additional studies are needed to replicate and strengthen our results, these findings represent initial evidence to derive recommendations based on actual data for subjects with autoimmune diseases.

Objectives: to describe the overall mortality increase in the provinces of Milan and Lodi – area covered by the Agency for Health Protection of Milan – during the COVID-19 epidemic in the first four months of 2020, compare it with the same time period in the years 2016-2019, and evaluate to what extent the mortality can be directly attributed to the outbreak. Design: cohort study. Setting and participants: using a new information system developed during the pandemic, we gathered data on the number of daily deaths in the population residing in the provinces of Milan and Lodi by Local Health Unit (ASST) and age groups. To describe the case fatality of COVID-19, we performed a record linkage with a database specially constructed during the epidemic to identify deaths that occurred in confirmed cases. Main outcome measures: mortality and excess mortality were analysed by comparing the number of observed deaths in the first 4 months of 2020 with the average deaths of the years 2016-2019 in the same calendar period and with expected deaths, estimated using a Poisson model. Furthermore, a measure of relative risk was calculated as observed/ expected ratio with a 95% confidence interval. Results: the increase in mortality for all causes occurring in the study population in the first 4 months of 2020 was 48.8%, 30.8% for ages between 60 and 69, 43.9% for ages between 70 and 79, and 56.7% for subjects above 80 years of age. Focusing on the epidemic period, from 1 March to 30 April, the excess is quantifiable as more than 2-fold and mainly concerns the population over 60 years of age. The excess mortality was observed in all local health units (ASSTs). The highest increments were in the province of Lodi and the North-East of Milan (ASST Nord). In the ASSTs of Lodi and Melegnano-Martesana the mortality excess was detectable from March 15th, while for the other ASSTs the increase began in the first week of April. Conclusions: evaluation of overall mortality in the provinces of Milan and Lodi during the first wave of the Covid-19 epidemic showed a significant excess compared to the first 4 months of the years 2016-2019, mainly in the population over 60 years of age. However, this excess cannot be completely attributed directly to COVID-19 itself. This phenomenon was more intense in the Lodi ASST, with daily deaths up to 5 times higher than expected.

Emerging evidence points to reactive glia as a pivotal factor in Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of basal ganglia injury, but whether astrocytes and microglia activation may exacerbate dopaminergic (DAergic) neuron demise and/or contribute to DAergic repair is presently the subject of much debate. Here, we have correlated the loss and recovery of the nigrostriatal DAergic functionality upon acute MPTP exposure with extensive gene expression analysis at the level of the ventral midbrain (VM) and striata (Str) and found a major upregulation of pro-inflammatory chemokines and wingless-type MMTV integration site1 (Wnt1), a key transcript involved in midbrain DAergic neurodevelopment. Wnt signaling components (including Frizzled-1 [Fzd-1] and β-catenin) were dynamically regulated during MPTP-induced DAergic degeneration and reactive glial activation. Activated astrocytes of the ventral midbrain were identified as candidate source of Wnt1 by in situ hybridization and real-time PCR in vitro. Blocking Wnt/Fzd signaling with Dickkopf-1 (Dkk1) counteracted astrocyte-induced neuroprotection against MPP(+) toxicity in primary mesencephalic astrocyte-neuron cultures, in vitro. Moreover, astroglial-derived factors, including Wnt1, promoted neurogenesis and DAergic neurogenesis from adult midbrain stem/neuroprogenitor cells, in vitro. Conversely, lack of Wnt1 transcription in response to MPTP in middle-aged mice and failure of DAergic neurons to recover were reversed by pharmacological activation of Wnt/β-catenin signaling, in vivo, thus suggesting MPTP-reactive astrocytes in situ and Wnt1 as candidate components of neuroprotective/neurorescue pathways in MPTP-induced nigrostriatal DAergic plasticity.

The two chemokines, monocyte chemoattractant protein (MCP)-1 and gamma -interferon inducible protein (IP)-10, are thought to be involved in the pathogenesis of multiple sclerosis (MS). We measured MCP-1 and IP-10 levels in serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls. The latter consisted in patients with other inflammatory neurological diseases (OIND) or with non-inflammatory neurological diseases, and healthy controls. CSF MCP-1 levels exceeded those found in serum in all the patients studied as well as in healthy controls. CSF MCP-1 levels were significantly Lower in acute MS [468 +/- (S.E.M.) 18 pg/ml] than in stable MS (857 +/- 104 pg/ml). When detectable, serum and CSF IP-10 levels were significantly higher in acute MS (serum 331 +/- 66 pg/ml; CSF 118 +/- 16 pg/ml) than in stable MS (serum 69 +/- 7 pg/ml; CSF 25 +/- 2 pg/ml). Among OIND patients, those with HIV-1-associated dementia showed high serum and CSF levels of both MCP-1 and IP-10. Those with encephalitis showed high serum and CSF levels of IP-10 and CSF mononuclear pleiocytosis. We also evaluated the effects of 6-methylprednisolone or IFN-beta 1a therapy on circulating MCP-1 and IP-10 levels. Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values. Our findings suggest that (a) MCP-1 could be constitutively produced within the brain; (b) MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS. and these variations are inverse: and (c) current MS therapies do not modify circulating levels of MCP-1 and IP-10. (C) 2001 Elsevier Science B.V. All rights reserved.