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BackgroundPsoriasis is a chronic immune-mediated inflammatory skin disease which can also involve joints. It is often associated with burdensome comorbidities which negatively impact prognosis and quality of life (QoL). Biologic agents have been shown to be effective in controlling disease progression, but their use is associated with higher costs compared with traditional systemic treatments. The economic analysis of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: an obserVAtional longitudinal study of real-life clinical practice) study aims to assess the costs and cost-effectiveness of biologics in a real-world context in Italy.MethodsThe annualised overall direct costs of moderate-to-severe plaque psoriasis management, the annualised cost of biologic drugs and the cost per responder in the Italian National Health System perspective were assessed. More specifically, the cost per response and cost per sustained response of the most prescribed biologic therapies for the treatment of moderate-to-severe plaque psoriasis within the CANOVA study were assessed using the Psoriasis Area Severity Index (PASI) at several score levels (75, 90 and 100%).ResultsThe most frequently used biologic therapies for plaque psoriasis were secukinumab, ustekinumab, adalimumab originator, and ixekizumab. Cost of biologics was the driver of expenditure, accounting for about 98% of total costs. Adalimumab originator was the biologic with the lowest cost per responder ratio (range: €7848 - €31,378), followed by secukinumab (range: €9015 - €33,419). Ustekinumab (range: €11,689 – €39,280) and ixekizumab (range: €11,092 – €34,289) ranked respectively third and fourth, in terms of cost-effectiveness ratio. As concerns the cost per sustained response analysis, secukinumab showed the lowest value observed (€21,375) over the other options, because of its high response rate (86% vs. 60–80%), which was achieved early in time.ConclusionBiologic therapy is a valuable asset for the treatment of moderate-to-severe plaque psoriasis. Concomitant assessment of treatment costs against the expected therapeutic response over time can provide physicians and payers additional insights which can complement the traditional risk-benefit profile assessment and drive treatment decisions.

EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: An obserVAtional (CANOVA) study was aimed at providing real-world evidence of the effectiveness of biologics in Italian patients with moderate-severe psoriasis. It was an observational, retro-prospective cohort study conducted in 17 Italian dermatology clinics. Adult patients with moderate-severe plaque psoriasis, who started a biologic treatment between 24 weeks and 24 months before enrolment, were included. With a follow-up visit at 6 months after enrolment, each patient had at least 12 months of observation. The primary objective was to describe the clinical response rates (PASI 75) after 16/24/52 weeks from biologic treatment start. Secondary outcomes were sustained response, quality of life, and treatment satisfaction. Of the 669 eligible patients (64% males), 52% were naive to biologics, though a mean duration of psoriasis since first diagnosis of 18.6 years (SD 13.2). The most frequently prescribed biologics were secukinumab (41%), ustekinumab (25%), TNF-inhibitors (22%) and ixekizumab (12%). PASI 75 was achieved by 86% of patients (95% CI: 82%-89%) at 16 weeks, 90% (87%-93%) at 24 weeks, and 91% (89%-94%) at 52 weeks. Patients achieving PASI 90 and PASI 100 at 52 weeks were 75% (71%-79%) and 53% (49%-57%), respectively. Sustained PASI 75 response after 1 year from treatment start was achieved by 78% (74%-82%) of patients. Mean DLQI total score was 2.3 (SD 3.9) at enrollment and decreased at the final visit to 1.8 (3.6). A high level of treatment satisfaction was expressed by patients over the study period. This large real-world study confirms in the clinical practice the good effectiveness and acceptability of biologics in psoriasis patients.

Background: Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as “may contain traces of” is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. Methods: MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. Results: In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. Conclusion: Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement “this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product” for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged. © 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

As primary aim the study evaluated the monthly average dose for biologic drugs used for psoriasis (PSO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) in real-world settings.This retrospective analysis was based on administrative databases of Italian Entities. Adult patients diagnosed PSO, PsA or AS with ≥1 prescription of biologic drugs indicated for these diseases were included during 01/01/2011 - 30/06/2017. Monthly average dose and persistence were evaluated during 6-months after inclusion (follow-up).Overall, 6,179 patients prescribed biologic drugs were included: 2,373 represented the 1.1% of PSO-patients, 2,756 the 37.4% of PsA-patients, 1,050 the 17.8% of AS-patients. Monthly average dose was: 69 mg (PSO), 73 mg (PsA), 70 mg (AS) for adalimumab; 152 mg (PSO), 155 mg (PsA), 147 mg (AS) for etanercept; 140 mg (PSO), 133 mg (PsA), 166 mg (AS) for infliximab; 255 mg (PSO), 183 mg (PsA), 154 mg (AS) for secukinumab. Persistance to adalimumab was 76%(PSO), 78%(PsA), 74%(AS); with etanercept 77% in each disease-cohort; with infliximab 67%(PSO), 71%(PsA), 88%(AS); with secukinumab 91%(PSO) and 85%(PsA).The study described real-world dosing patterns of biologics indicated for PSO, PsA, or AS, suggesting a trend of monthly average dose generally lower than the dosage indicated in the datasheet.

Background: The current COVID-19 pandemic has changed many medical practices in order to provide additional protection to both our patients and healthcare providers. In many cases this includes seeing patients through electronic means such as telehealth or telephone rather than seeing them in person. Asthma exacerbations cannot always be treated in this way. Problem: Current emergency unit asthma guidelines recommend bronchodilators be administered by metered dose inhaler (MDI) and spacer for mild-moderate asthma and include it as a choice even in severe asthma, but many emergency units continue to prefer nebulised therapy for patients who urgently require beta-agonists. The utilization of nebulised therapy potentially increases the risk of aerosolization of the coronavirus. Since nosocomial transmission of respiratory pathogens is a major threat in the context of the SARS-CoV-2 pandemic, use of nebulised therapy is of even greater concern due to the potential increased risk of infection spread to nearby patients and healthcare workers. Practical implications: We propose a risk stratification plan that aims to avoid nebulised therapy, when possible, by providing an algorithm to help better delineate those who require nebulised therapy. Protocols that include strategies to allow flexibility in using MDIs rather than nebulisers in all but the most severe patients should help mitigate this risk of aerosolised infection transmission to patients and health care providers. Furthermore, expedient treatment of patients with high dose MDI therapy augmented with more rapid initiation of systemic therapy may help ensure patients are less likely to deteriorate to the stage where nebulisers are required. © 2020 The Author(s)

During the month of 2009 December, the blazar 3C 454.3 became the brightest gamma-ray source in the sky, reaching a peak flux F 2000 × 10 -8 photons cm-2 s-1 for E > 100 MeV. Starting in 2009 November intensive multifrequency campaigns monitored the 3C 454 gamma-ray outburst. Here, we report on the results of a two-month campaign involving AGILE, INTEGRAL, Swift/XRT, Swift/BAT, and Rossi XTE for the high-energy observations and Swift/UVOT, KANATA, Goddard Robotic Telescope, and REM for the near-IR/optical/UV data. GASP/WEBT provided radio and additional optical data. We detected a long-term active emission phase lasting 1 month at all wavelengths: in the gamma-ray band, peak emission was reached on 2009 December 2-3. Remarkably, this gamma-ray super-flare was not accompanied by correspondingly intense emission in the optical/UV band that reached a level substantially lower than the previous observations in 2007-2008. The lack of strong simultaneous optical brightening during the super-flare and the determination of the broadband spectral evolution severely constrain the theoretical modeling. We find that the pre- and post-flare broadband behavior can be explained by a one-zone model involving synchrotron self-Compton plus external Compton emission from an accretion disk and a broad-line region. However, the spectra of the 2009 December 2-3 super-flare and of the secondary peak emission on 2009 December 9 cannot be satisfactorily modeled by a simple one-zone model. An additional particle component is most likely active during these states. © 2010. The American Astronomical Society. All rights reserved.

Modafinil increases waking and labeling of Fos, a marker of neuronal activation. In the present study, armodafinil, the R-enantiomer of racemic modafinil, was administered to rats at 30 or 100 mg/kg i.p. about 5 h after lights on (circadian time 5 and near the midpoint of the sleep phase of the sleep:wake cycle) to assess its effects on sleep/wake activity and Fos activation. Armodafinil at 100 mg/kg increased wakefulness for 2 h, while 30 mg/kg armodafinil only briefly increased wakefulness. Armodafinil (30 and 100 mg/kg) also increased latencies to the onset of sleep and motor activity. Armodafinil had differential effects in increasing neuronal Fos immunolabeling 2 h after administration. Armodafinil at 100 mg/kg increased numbers of Fos-labeled neurons in striatum and anterior cingulate cortex, without affecting nucleus accumbens. Armodafinil at 30 mg/kg only increased numbers of light Fos-labeled neurons in the anterior cingulate cortex. In brainstem arousal centers, 100 mg/kg armodafinil increased numbers of Fos-labeled neurons in the tuberomammillary nucleus, pedunculopontine tegmentum, laterodorsal tegmentum, locus coeruleus, and dorsal raphe nucleus. Fos activation of these brainstem arousal centers, as well as of the cortex and striatum, is consistent with the observed arousal effects of armodafinil.

Starting from a complete sample of type I AGN observed by INTEGRAL in the 20-40 keV band, we have selected a set of 8 AGN which can be classified as radio loud objects according to their 1.4 GHz power density, radio to hard X-ray flux flux density ratio and radio morphology. The sample contains 6 Broad Line Radio Galaxies and 2 candidate ones. Most of the objects in our sample display a double lobe morphology, both on small and large scales. For all the objects, we present broad-band (1-110 keV) spectral analysis using INTEGRAL observations together with archival XMM-Newton, Chandra, Swift/XRT and Swift/BAT data. We constrain the primary continuum (photon index and cut-off energy), intrinsic absorption and reprocessing features (iron line and reflection) in most of the objects. The sources analysed here show remarkable similarities to radio quiet type 1 AGN with respect to most of the parameters analysed; we only find marginal evidence for weaker reprocessing features in our objects compared to their radio quiet counterparts. Similarly we do not find any correlation between the spectral parameters studied and the source core dominance or radio to 20-100 keV flux density ratios, suggesting that what makes our objects radio loud has no effect on their high energy characteristics.

In this paper we report on the third soft gamma-ray source catalog obtained with the IBIS/ISGRI gamma-ray imager on board the INTEGRAL satellite. The scientific dataset is based on more than 40 Ms of high quality observations performed during the first three and a half years of Core Program and public IBIS/ISGRI observations. Compared to previous IBIS/ISGRI surveys, this catalog includes a substantially increased coverage of extragalactic fields, and comprises more than 400 high-energy sources detected in the energy range 17-100 keV, including both transients and faint persistent objects which can only be revealed with longer exposure times.

Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards. © 2015 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Multiwavelength variability of blazars offers indirect insight into their powerful engines and on the mechanisms through which energy is propagated from the centre down the jet. The BL Lac object Mkn 421 is a TeV emitter, a bright blazar at all wavelengths, and therefore an excellent target for variability studies. Mkn 421 was observed by INTEGRAL and Fermi-LAT in an active state on 16-21 April 2013. Well sampled optical, soft, and hard X-ray light curves show the presence of two flares. The average flux in the 20-100 keV range is 9.1e-11 erg/s/cm2 (~4.5 mCrab) and the nuclear average apparent magnitude, corrected for Galactic extinction, is V ~12.2. In the time-resolved X-ray spectra (3.5-60 keV), which are described by broken power laws and, marginally better, by log-parabolic laws, we see a hardening that correlates with flux increase, as expected in refreshed energy injections in a population of electrons that later cool via synchrotron radiation. The hardness ratios between the JEM-X fluxes in two different bands and between the JEM-X and IBIS/ISGRI fluxes confirm this trend. During the observation, the variability level increases monotonically from the optical to the hard X-rays, while the large LAT errors do not allow a significant assessment of the MeV-GeV variability. The cross-correlation analysis during the onset of the most prominent flare suggests a monotonically increasing delay of the lower frequency emission with respect to that at higher frequency, with a maximum time-lag of about 70 minutes, that is however not well constrained. The spectral energy distributions from the optical to the TeV domain are satisfactorily described by homogeneous models of blazar emission based on synchrotron radiation and synchrotron self-Compton scattering, except in the state corresponding to the LAT softest spectrum and highest flux., Comment: 11 pages, 6 figures, in press in A&A

Assessing maternal dietary habits across Europe during pregnancy in relation to their national pregnancy recommendations. A collaborative, multi-centre, birth cohort study in nine European countries was conducted as part of European Union funded EuroPrevall project. Standardised baseline questionnaire data included details of food intake, nutritional supplement use, exposure to cigarette smoke during pregnancy and socio-demographic data. Pregnancy recommendations were collected from all nine countries from the appropriate national organisations. The most commonly taken supplement in pregnancy was folic acid (55.6 % Lithuania–97.8 % Spain) and was favoured by older, well-educated mothers. Vitamin D supplementation across the cohort was very poor (0.3 % Spain–5.1 % Lithuania). There were significant differences in foods consumed in different countries during pregnancy e.g. only 2.7 % Dutch mothers avoided eating peanut, while 44.4 % of British mothers avoided it. Some countries have minimal pregnancy recommendations i.e. Lithuania, Poland and Spain while others have similar, very specific recommendations i.e. UK, the Netherlands, Iceland, Greece. Allergy specific recommendations were associated with food avoidance during pregnancy [relative rate (RR) 1.18 95 % CI 0.02–1.37]. Nutritional supplement recommendations were also associated with avoidance (RR 1.08, 1.00–1.16). Maternal dietary habits and the use of dietary supplements during pregnancy vary significantly across Europe and in some instances may be influenced by national recommendations. © 2014, Springer Science+Business Media New York.

We have constructed a new sample of magnetic cataclysmic variables (mCVs) by cross‐correlating candidate sources detected in INTEGRAL/IBIS observations against catalogues of known CVs and included mCVs observed with either Swift/BAT or SUZAKU/HXD. Here we review the properties arising from this hard X‐ray selected sample and find that most hard X‐ray detected mCVs have Pspin/Porb

Hard X-ray surveys have proven remarkably efficient in detecting intermediate polars and asynchronous polars, two of the rarest type of cataclysmic variable (CV). Here we present a global study of hard X-ray selected intermediate polars and asynchronous polars, focusing particularly on the link between hard X-ray properties and spin/orbital periods. To this end, we first construct a new sample of these objects by cross-correlating candidate sources detected in INTEGRAL/IBIS observations against catalogues of known CVs. We find 23 cataclysmic variable matches, and also present an additional 9 (of which 3 are definite) likely magnetic cataclysmic variables (mCVs) identified by others through optical follow-ups of IBIS detections. We also include in our analysis hard X-ray observations from Swift/BAT and SUZAKU/HXD in order to make our study more complete. We find that most hard X-ray detected mCVs have P_{spin}/P_{orb}, 14 pages, 8 figures and 3 tables. Accepted for publication in MNRAS

INTEGRAL is continuing the deep observations of the Galactic Plane and, at level of a mCrab, of the whole sky in the soft Gamma ray range. The new IBIS catalogue contains more than 420 sources detected in 20–40 and 40–100 keV range. We present a view of the INTEGRAL high energy sky with particular regard to sources emitting beyond 100 keV, including Blazar and HESS couterpart.

Serum amylase and lipase concentrations were determined in 78 patients with chronic liver diseases [26 chronic active hepatitis (CAH) and 52 liver cirrhosis] and in 15 healthy subjects. Pancreatic isoamylase concentrations and macroamylase complexes were assayed in hyperamylasemic sera. Serum amylase levels were abnormally elevated in 27 patients (35%; 22 liver cirrhosis, 5 CAH), whereas serum lipase levels were elevated in 16 patients (21%; 15 liver cirrhosis, 1 CAH). In 9 of the 27 hyperamylasemic patients, the hyperamylasemia was of pancreatic type. Macroamylasemic complexes were not detected in hyperamylasemic sera. Patients with liver cirrhosis had serum levels of amylase and lipase significantly higher than both the healthy subjects and the patients with CAH, while no significant differences were found in serum levels of these enzymes in patients with CAH as compared to the healthy subjects. A decreased liver metabolism of serum amylase and lipase in patients with chronic infective liver disease, especially in those having liver cirrhosis, may lead to an accumulation of these enzymes in the blood.

The aim of this study was to evaluate the incidence in the serum of elevated levels of amylase, pancreatic isoamylase, and lipase in acute alcohol intoxication among occasional drinkers and chronic alcoholics, and to assess the diagnostic ability of the three enzymes for acute alcoholic pancreatitis.One-hundred and seventeen consecutive subjects with acute alcohol intoxication but no abdominal pain (47 occasional drinkers, 70 chronic alcoholics), and 17 with acute alcoholic pancreatitis were studied. For all subjects serum amylase, pancreatic isoamylase, and lipase were determined using commercially available kits.Among occasional drinkers, serum amylase levels were abnormally high in 6 subjects (13%), whereas serum pancreatic isoamylase and lipase were abnormally high in one, (2%). In chronic alcoholics without abdominal pain serum amylase and lipase were abnormally high in 10 subjects (14%) but serum pancreatic isoamylase in only 7 (10%). In patients with acute alcoholic pancreatitis, serum amylase and pancreatic isoamylase were abnormally high in 16 of the 17 patients (94%), whereas serum lipase was abnormally high in all.Chronic alcohol abuse, but not occasional alcohol intoxication, may cause pancreatic damage. Amylase, pancreatic isoamylase and lipase determinations in the serum are all equally useful in the diagnosis of acute alcoholic pancreatitis.

Serum amylase and lipase were measured in 32 patients with cerebral ischemia, 19 with spontaneous cerebral hemorrhage, 15 with head injury and intracranial bleeding, and 22 with head injury without intracranial bleeding; 20 healthy subjects were also studied as controls. Serum pancreatic isoamylase concentrations were assayed in hyperamylasemic sera. The overall incidence of hyperamylasemia was 14% (12 of 88 patients: 4 with cerebral ischemia, 4 with spontaneous cerebral hemorrhage, 1 with head injury and intracranial bleeding, and 3 with head injury without intracranial bleeding). In 4 of the 12 patients the hyperamylasemia was of pancreatic origin: 1 patient with cerebral ischemia, 1 patient with spontaneous cerebral hemorrhage, 1 patient with head injury and intracranial bleeding, and 1 patient with head injury without intracranial bleeding. The incidence of hyperlipasemia was 7% (6 of the 88 patients: 1 patient with cerebral ischemia, 2 with spontaneous cerebral hemorrhage, and 3 with head injury without intracranial bleeding). We conclude that hyperamylasemia is more frequent than hyperlipasemia in patients with an altered state of consciousness due to head injury or stroke and is usually of non-pancreatic origin. This knowledge may save these patients from invasive and costly examinations.

Elevated serum concentrations of beta 2-Microglobulin (beta 2-MG) has been reported in a variety of chronic diseases and solid tumors. We determined serum beta 2-MG concentrations in 140 subjects divided into five groups: group 1, 34 patients with proven chronic pancreatitis, 8 of whom were studied during a painful relapse; group 2, 40 patients with pancreatic cancer staged according to the Cubilla-Fitzgerald classification; group 3, 40 healthy subjects; group 4, 10 patients with digestive nonpancreatic carcinomas; group 5, 16 patients with benign digestive nonpancreatic diseases. Serum soluble interleukin-2 receptor (sIL-2R) was also determined in all patients with pancreatic diseases as an index of immune system activation. In addition, serum CA 19-9 was assayed in patients of groups 2 and 4, and C-reactive protein (CRP) of groups 1 and 5. Renal function, evaluated by serum creatinine determination, was normal in all subjects studied. Patients with pancreatic cancer and those with chronic pancreatitis had serum concentrations of beta 2-MG significantly higher than those of healthy subjects (p < 0.001 and p < 0.005, respectively). Patients with stage I and stage III pancreatic cancer had similar serum levels of beta 2-MG, and these concentrations were significantly lower than those of patients with stage II tumors (p < 0.002 and p < 0.05, respectively). In chronic pancreatitis patients, those studied during painful relapse of the disease had serum concentrations of beta 2-MG similar to those studied during clinical remission.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the clinical accuracy of an automated turbidimetric assay for serum lipase determination in order to screen for acute pancreatic damage. Seventy patients with pancreatic and thirty with nonpancreatic digestive diseases were studied. Fifty-two healthy subjects were also studied as controls. Serum lipase concentrations were abnormally high in all patients with acute pancreatitis and in 3 (10%) in the group of 30 patients with nonpancreatic acute abdomen. In the 35 patients with chronic pancreatitis studied during clinical remission, serum lipase levels were abnormally high in 8 (23%), and abnormally low in 3 (9%). In the 9 patients with pancreatic cancer, 4 (44%) had abnormally elevated serum lipase values and 1 (11%) abnormally low. The results indicate that serum lipase determination is useful in the emergency diagnosis of acute pancreatic damage because of its high sensitivity and specificity. In patients with chronic pancreatitis and in patients with pancreatic carcinoma serum lipase determination is of limited value.

CD13/aminopeptidase N is a multifunctional cell surface metalloprotease expressed in myeloid and activated endothelial cells; in epithelial cells of the intestine, liver, and kidney; and in other cells. A growing body of evidence suggests that CD13 has an important role in inflammation and angiogenesis. Furthermore, a CD13 form selectively expressed by the angiogenic endothelium, but not in normal vessels, is recognized by peptides containing the Asn-Gly-Arg (NGR) motif. Because of this property, NGR peptides have been exploited as ligands for the selective delivery of a variety of therapeutic and imaging agents to angiogenic vessels. In this chapter, we discuss the structural and functional properties of NGR peptides and their potential applications as drug delivery systems in diseases with angiogenesis and inflammatory components. In addition, we discuss the experimental evidence suggesting that the asparagine residue of NGR can rapidly undergo deamidation, a spontaneous reaction that changes NGR to isoDGR (an integrin-binding motif), and the potential biological, pharmacological, and toxicological implications of this sequence transition in peptide-drug conjugates.

Since 2005, the blazar 3C 454.3 has shown remarkable flaring activity at all frequencies, and during the last four years it has exhibited more than one gamma-ray flare per year, becoming the most active gamma-ray blazar in the sky. We present for the first time the multi-wavelength AGILE, SWIFT, INTEGRAL, and GASP-WEBT data collected in order to explain the extraordinary gamma-ray flare of 3C 454.3 which occurred in November 2010. On 2010 November 20 (MJD 55520), 3C 454.3 reached a peak flux (E>100 MeV) of F_gamma(p) = (6.8+-1.0)E-5 ph/cm2/s on a time scale of about 12 hours, more than a factor of 6 higher than the flux of the brightest steady gamma-ray source, the Vela pulsar, and more than a factor of 3 brighter than its previous super-flare on 2009 December 2-3. The multi-wavelength data make a thorough study of the present event possible: the comparison with the previous outbursts indicates a close similarity to the one that occurred in 2009. By comparing the broadband emission before, during, and after the gamma-ray flare, we find that the radio, optical and X-ray emission varies within a factor 2-3, whereas the gamma-ray flux by a factor of 10. This remarkable behavior is modeled by an external Compton component driven by a substantial local enhancement of soft seed photons., Accepted for publication in ApJ Letters. 18 Pages, 4 Figures, 1 Table