Bounds on Lorentz Invariance Violation from MAGIC Observation of GRB 190114C.

On January 14, 2019, the Major Atmospheric Gamma Imaging Cherenkov telescopes detected GRB 190114C above 0.2 TeV, recording the most energetic photons ever observed from a gamma-ray burst. We use this unique observation to probe an energy dependence of the speed of light in vacuo for photons as predicted by several quantum gravity models. Based on a set of assumptions on the possible intrinsic spectral and temporal evolution, we obtain competitive lower limits on the quadratic leading order of speed of light modification.

First Experimental Characterization of Microwave Emission from Cosmic Ray Air Showers.

We report the first direct measurement of the overall characteristics of microwave radio emission from extensive air showers. Using a trigger provided by the KASCADE-Grande air shower array, the signals of the microwave antennas of the Cosmic-Ray Observation via Microwave Emission experiment have been read out and searched for signatures of radio emission by high-energy air showers in the GHz frequency range. Microwave signals have been detected for more than 30 showers with energies above 3×10^{16} eV. The observations presented in this Letter are consistent with a mainly forward-directed and polarized emission process in the GHz frequency range. The measurements show that microwave radiation offers a new means of studying air showers at E≥10^{17} eV.

The zebrafish embryo derivative affects cell viability of epidermal cells: a possible role in the treatment of psoriasis.

In patients affected by psoriasis, use of a topical formula containing a derivative of zebrafish embryos was associated with reduced skin inflammation and dermal turnover, as well as a generally better outcome. In an attempt to understand the molecular mechanisms lying beyond these findings, we investigated the anti-proliferative effects of the zebrafish embryos derivative by addressing the mitochondrial function (MTT assay) and cell nuclei distribution (Hoestch staining). In cell cultures stimulated with fetal calf serum (FCS) or epidermal growth factor (EGF), the zebrafish derivative significantly inhibited cell proliferation induced by either approach, although the effect was stronger in cells stimulated with FCS. These results suggest that the zebrafish embryos derivative may dampen increased cell proliferation; this observation may be relevant to cutaneous pathologies related to altered proliferative mechanisms, including psoriasis.

Kneelike structure in the spectrum of the heavy component of cosmic rays observed with KASCADE-Grande.

We report the observation of a steepening in the cosmic ray energy spectrum of heavy primary particles at about 8×10(16) eV. This structure is also seen in the all-particle energy spectrum, but is less significant. Whereas the "knee" of the cosmic ray spectrum at 3-5×10(15) eV was assigned to light primary masses by the KASCADE experiment, the new structure found by the KASCADE-Grande experiment is caused by heavy primaries. The result is obtained by independent measurements of the charged particle and muon components of the secondary particles of extensive air showers in the primary energy range of 10(16) to 10(18) eV. The data are analyzed on a single-event basis taking into account also the correlation of the two observables.

Detection and imaging of atmospheric radio flashes from cosmic ray air showers.

The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10(20) eV remains a mystery. They are likely to be of extragalactic origin, but should be absorbed within approximately 50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics. Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or gamma-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect. Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing.

A naturally-inspired, curcumin-based lecithin formulation (Meriva® formulated as the finished product Algocur®) alleviates the osteo-muscular pain conditions in rugby players.

OBJECTIVE: Curcumin is one of the most investigated phytochemical products because of its low toxicity and its broad spectrum of bioactivity, including anti-inflammatory and analgesic properties. A new delivery form of curcumin, resorting to phosphatidylcholine (Meriva®, formulated as the finished product Algocur®) has been developed to increase its bioavailability. In this study, we tested the efficacy and safety of a Meriva®-based product in rugby players suffering by different osteo-muscular pain conditions PATIENTS AND METHODS: In this pilot study, 50 male rugby players with osteo-muscular pain due to traumatic injuries, physical overload or acute episode of chronic pain were recruited and treated with conventional analgesic drugs (n = 25) or Meriva®-based product (n = 25) for a maximum of 10 days. The pain perception and the functio laesa were evaluated at baseline and after 1, 3, 6, 10 and 20 days from the initiation of the treatment protocol. Treatment tolerability, compliance, and adverse events were also reported. RESULTS: During the study, the analgesic effect decreased in both treated group compared to baseline, starting from the third day of treatment. Similarly, the impaired physical function evaluated after 3, 6, 10 and 20 days improved in Meriva®-based product treated group and in subjects treated with conventional analgesic drugs, compared to the baseline condition. The percentage of excellent adherence to treatment or tolerability was higher in the Meriva®-based product treated group. Only 1 (4%) subject treated with Meriva®-based product experienced adverse events whereas 4 (16%) subjects treated with conventional analgesic drugs reported gastric pain as an adverse event. CONCLUSIONS: Despite the small sample size and the group heterogeneity, this study suggests that the naturally-derived, curcumin-based delivery form, Meriva® (formulated as the finished product Algocur®), could represent a promising safe, analgesic remedy in painful osteo-muscular conditions associated with intense, high impact, physical activities.

From single-objective to multiple-objective multiple-rainfall events automatic calibration of urban storm water runoff models using genetic algorithms.

The calibration of storm water runoff models is a complex task. Early attempts focused on the choice of a performance criterion function that could capture all the facets of the problem into a single-objective framework. Subsequently, the awareness that a good calibration must necessarily take into account conflicting objectives led to the adoption of more sophisticated multi-objective approaches. Only recently, the focus has shifted towards effective ways of exploiting the mounting information provided by the availability of many sets of concurrent rainfall and flow measurements. This paper revisits through a case study the transition just elucidated: the calibration of a SWMM model applied to a catchment in Singapore is tackled through a single-objective, a multi-objective and a multi-objective multiple-event (MOME) paradigm respectively. A new approach to support the latter is presented herein. It consists in formulating the problem of model calibration as a multi-objective problem with m x r objective functions, where m and r are the number of performance criteria and rainfall events respectively, that must be optimized simultaneously. Results suggest that the new MOME framework performs significantly better than the others tested on the case study presented.

Protective and curative potential of vaccination with interleukin-2-gene-transfected cells from a spontaneous mouse mammary adenocarcinoma.

The potential of interleukin 2-gene-transfected tumor cells to prevent tumor growth and cure established tumors was evaluated using cells from a spontaneous, invasive, and metastasizing mouse mammary adenocarcinoma. Tumor cells engineered to secrete interleukin 2 initially trigger a local inflammatory reaction that leads to inhibition of established parental adenocarcinomas, as well as an antigenically unrelated fibrosarcoma. The ensuing systemic immunity selectively inhibits subsequent parental cell challenges and cures established parental adenocarcinomas and their lung metastases, although less effectively as the neoplastic mass increases. Multiple injections of interleukin 2-gene-transfected tumor cells may thus be considered a new form of vaccination in the management of minimal residual disease and incipient metastases.

Effect of administration of Streptococcus salivarius K12 on the occurrence of streptococcal pharyngo-tonsillitis, scarlet fever and acute otitis media in 3 years old children.

OBJECTIVE: Streptococcus salivarius K12 (BLIS K12) is a probiotic strain strongly antagonistic to the growth of Streptococcus pyogenes, the most important bacterial cause of pharyngeal infections in humans. Shown to colonize the oral cavity and to be safe for human use, BLIS K12 has previously been reported to reduce pharyngo-tonsillitis episodes in children or adults known to have experienced recurrent streptococcal infection. The present study was focussed upon evaluating the role of BLIS K12 in the control of streptococcal disease and acute otitis media in children attending the first year of kindergarten. PATIENTS AND METHODS: By randomization, 222 enrolled children attending the first year of kindergarten were divided into a treated group (N = 111) receiving for 6 months a daily treatment with BLIS K12 (Bactoblis®) and a control group (N = 111) who were monitored as untreated controls. During the 6 months of treatment and 3 months of follow-up, the children were evaluated for treatment tolerance, and for episodes of streptococcal pharyngo-tonsillitis, scarlet fever and acute otitis media. RESULTS: During the 6-month trial (N = 111 per group) the incidence of streptococcal pharyngo-tonsillitis, scarlet fever and acute otitis media was approximately 16%, 9% and 44% respectively in the treated group and 48%, 4% and 80% in the control group. During the 3-months follow-up (N = 29 per group) the corresponding rates of infection were 15%, 0% and 12% in the treated group and 26%, 6% and 36% in the controls. No apparent side effects were detected in the treated group either during treatment or follow-up. All of the enrolled children completed the study. CONCLUSIONS: The daily administration of BLIS K12 to children attending their first year of kindergarten was associated with a significant reduction in episodes of streptococcal pharyngitis and acute otitis media. No protection against scarlet fever was detected.

In vitro and in vivo immune stimulating effects of a new standardized Echinacea angustifolia root extract (Polinacea).

Polinacea is a new standardized hydroethanolic extract obtained from Echinacea angustifolia roots containing echinacoside (>4%), the high molecular weight polysaccharide IDN 5405 (>5%) and a isobutylamide fraction (<0.1%). For in vitro tests, a bacterial lipopolysaccharide-free (LPS-free) Polinacea has been prepared in order to avoid non-specific responses of immunocompetent cells. LPS-free Polinacea enhanced the immune functions as highlighted by the proliferation rate and gamma-interferon production in murine T-lymphocyte cell cultures stimulated by anti-CD3. LPS-free Polinacea did not have a direct role on macrophage response as measured in the nitric oxide production test using the J774 macrophage cells line. In vivo, Polinacea showed an immune stimulating activity by reducing the Candida albicans induced mortality both in normal and in cyclosporin A-treated mice.

Automatic calibration of urban drainage model using a novel multi-objective genetic algorithm.

In order to successfully calibrate an urban drainage model, multiple calibration criteria should be considered. This raises the issue of adopting a method for comparing different solutions (parameter sets) according to a set of objectives. Amongst the global optimization techniques that have blossomed in recent years, Multi Objective Genetic Algorithms (MOGA) have proved effective in numerous engineering applications, including sewer network modelling. Most of the techniques rely on the condition of Pareto efficiency to compare different solutions. However, as the number of criteria increases, the ratio of Pareto optimal to feasible solutions increases as well. The pitfalls are twofold: the efficiency of the genetic algorithm search worsens and decision makers are presented with an overwhelming number of equally optimal solutions. This paper proposes a new MOGA, the Preference Ordering Genetic Algorithm, which alleviates the drawbacks of conventional Pareto-based methods. The efficacy of the algorithm is demonstrated on the calibration of a physically-based, distributed sewer network model and the results are compared with those obtained by NSGA-II, a widely used MOGA.

Functional study on Boswellia phytosome as complementary intervention in asthmatic patients.

OBJECTIVE: The combination of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs) is recommended for the treatment of patients with mild-to-severe persistent asthma. However, given the lack of definite and safe therapies, complementary or alternative medicines are frequently used by asthmatic patients in combination with standard treatments. PATIENTS AND METHODS: A group of asthmatic subjects have been enrolled in this multicenter study; after having verified the compliance to their current medical therapy (ICS + LABAs), the subjects have been randomized to receive Casperome® 500 mg/day or no additional treatment for a period of 4 weeks. They were also asked to keep track of the number of inhalations required per day and any adverse events through a daily form. RESULTS: A total of 32 subjects were enrolled in the study. Subjects receiving Casperome® 500 mg/day in addition to the standard ICS + LABAs treatment showed a decrease in the number of inhalations needed compared to patients who did not receive Casperome® therapy. The treatment was well tolerated and only mild-moderate adverse events were registered. CONCLUSIONS: The use of Casperome® 500 mg/day is beneficial for asthmatic patients as it helps reduce the need for inhalation therapy with ICS + LABA.

Clinical evaluation of safety and efficacy of Boswellia-based cream for prevention of adjuvant radiotherapy skin damage in mammary carcinoma: a randomized placebo controlled trial.

OBJECTIVE: Acute radiation erythema and other skin reactions are common adverse effects experienced by breast carcinoma patients undergoing radiotherapy treatment. Boswellic acids are pentacyclic triterpenes extracted from the resins of the tropical tree Boswellia serrata with strong anti-inflammatory properties. This study was designed to evaluate the safety and the efficacy of the application of a base cream containing boswellic acids in a proprietary formulation (Bosexil(R)) for the prevention and relief of radiation-induced adverse effects in breast cancer patients. PATIENTS AND METHODS: The acute skin reactions were clinically evaluated by visual intensity and computer-assisted skin color analysis, and toxicity was assessed by the Radiation Therapy Oncology Group (RTOG) rating scale. RESULTS: These findings indicate that the use of a boswellia-based cream is effective in reducing the use of topical corticosteroids and is able to reduce the grade of erythema and the skin superficial symptoms, being well tolerated by the patients. CONCLUSIONS: Further studies comparing boswellia cream with other topical agents will be appropriate to confirm the effectiveness of this treatment for breast cancer patients under radiation therapy.

Potential role of bioavailable curcumin in weight loss and omental adipose tissue decrease: preliminary data of a randomized, controlled trial in overweight people with metabolic syndrome. Preliminary study.

OBJECTIVE: This randomized, controlled study aims to evaluate the tolerability and the efficacy of curcumin in overweight subjects affected from metabolic syndrome, with a focus on impaired glucose intolerance and android-type fat accumulation. PATIENTS AND METHODS: Forty-four subjects, selected among those who after 30 days of diet and intervention lifestyle have shown a weight loss < 2%, have been treated for further 30 days either with curcumin complexed with phosphatidylserine in phytosome form or with pure phosphatidylserine. Outcomes concerning anthropometric measurements and body composition were analyzed at enrollment and after 30 and 60 days. RESULTS: Curcumin administration increased weight loss from 1.88 to 4.91%, enhanced percentage reduction of body fat (from 0.70 to 8.43%), increased waistline reduction (from 2.36 to 4.14%), improved hip circumference reduction from 0.74 to 2.51% and enhanced reduction of BMI (from 2.10 to 6.43%) (p < 0.01 for all comparisons). Phosphatidylserine did not show any statistical significant effect. Tolerability was very good for both treatments, and no drop-out was reported. CONCLUSIONS: Although preliminary, our findings suggest that a bioavailable form of curcumin is well-tolerated and can positively influence weight management in overweight people.

A new rational hypothesis for the pharmacophore of the active metabolite of leflunomide, a potent immunosuppressive drug.

Leflunomide is one of the most promising disease-modifying antirheumatic drug now in clinical trials for the treatment of rheumatoid arthritis. Metabolic studies have indicated that leflunomide is rapidly processed in vivo to an active metabolite, A771726 (2). To identify the chemical characteristics necessary for the immunosuppressive activity of 2, configurational and conformational studies were carried out on the latter and its inactive analogues (ethyl 3-hydroxy-2-((4-(trifluoromethyl)phenyl)carbamoyl)but-2-enoate, 3a, and 3-hydroxy-2-nitro-N-(4-(trifluoromethyl)phenyl)but-2-enamide, 3b). These studies suggested that the pharmacophore responsible for the immunosuppressive activity of 2 is a beta-keto amide with the enolic hydroxy group cis to the amidic moiety. To verify this hypothesis, a new class of immunosuppressive agents was designed and synthesized. Their testing in vitro and in vivo identified compounds which were more potent than both leflunomide and 2 and above all confirmed our hypothesis as to the key structural and chemical determinants for the immunosuppressive properties of 2 and our compounds.

Use of type I and type IV hypersensitivity responses to define the immunopharmacological profile of drugs.

Administration of antigen suspended in incomplete Freund's adjuvant supplemented with either heat-killed Mycobacterium tuberculosis (complete Freund's adjuvant, CFA) or Bordetella pertussis toxin sensitizes animals so that subsequent antigen challenge leads to delayed-type (DTH) or immediate type hypersensitivity (ITH) responses, named type IV and type I, respectively. Appropriate timing of administration of drugs with respect to immunization or antigen challenge allowed to detect predominantly immunosuppressive, antiinflammatory or antianaphylactic activities. Among the reference drugs tested, only cyclosporin A (CsA) and dexamethasone (Dex) markedly inhibited DTH reaction, due to their immunosuppressive and antiinflammatory activities, respectively, whereas leflunomide and indomethacin resulted less potent. On the other hand, only dexchlorpheniramine, a histamine-receptor antagonist, afforded significant protection against anaphylactic shock, a form of ITH. Two new chemical entities were studied according to this protocol: ITF 1697, a chemically stabilized C-reactive protein-derived tetrapeptide, and ITF 2018, a leflunomide analogue. Data obtained with these new compounds showed that ITF 1697 has antianaphylactic activity, while ITF 2018 is endowed, mainly, with antiinflammatory activity. These results show that, through appropriate timing of administration, established in vivo models of immunologically mediated disease states allow an accurate profiling of the effects of pharmacologically active molecules and the detection of unsuspected activities for new drugs.

Botanical derivatives for the prostate.

The prostate, after the age of 45 years, may undergo benign hyperplasia (BPH). Its etiology has not yet been completely explained, but different factors play a major role in its occurrence, among them, the sexual hormones (with a fundamental role of 5 alpha reductase). The 5-alpha reductase activity and inflammatory aspects in the prostate tissue can be effectively controlled with the use of highly standardized plant extracts (Pygeum africanum, Serenoa repens, etc.), which yield excellent results in the prophylaxis and treatment of the symptoms linked to prostate hypertrophy. The prostate tissue is not affected only by benign diseases but may also be subject to neoplastic transformation. From an epidemiological point of view, a vegetable derivative, lycopene, was linked with a lower occurrence of prostate carcinoma. A recent clinical study demonstrated that lycopene might not only prevent prostate cancer but also have therapeutic effects.

Strategies for cytokine utilisation in tumor therapy.

The state of the art with regard to the employment of various cytokine-based tumor immunotherapy strategies and their mechanisms of action are critically reviewed. As matters now stand, adoptive transfer of LAK cells or tumor infiltrating lymphocytes together with high doses of IL-2 constitutes the only immunologic way to hinder tumor growth in advanced stages of cancer. On the other hand, many experimental data show that the local presence of cytokines, either injected repeatedly at tumor site or released by cytokine-gene engineered tumor cells, arouses immunogenicity in apparently nonimmunogenic spontaneous tumors. By strengthening the notion that most tumors are potentially immunogenic, these findings offer substantial evidence to stress the potential use of cytokines as a component of new tumor vaccines.

Growth and spread of human malignant T lymphoblasts in immunosuppressed nude mice: a model for meningeal leukemia.

Previous work has shown that nude (nu/nu) mice additionally immunosuppressed by splenectomy, sublethal irradiation, and treatment with antiasialo GM1 antiserum (SIA-nu/nu mice) have no detectable natural killer activity and allow the growth of human malignant lymphoblasts. We show here that all SIA-nu/nu mice engrafted intravenously with 5 x 10(6) malignant lymphoblasts originally derived from a child with a T-cell acute lymphoblastic leukemia (PF382) and from a boy with a T-cell lymphoma (ST-4) develop lethal meningeal leukemia and die within 35 days. Histologic examination of moribund SIA-nu/nu mice showed that vertebral and skull bone marrow was always replaced by proliferating human T lymphoblasts. From the spinal canal, lymphoblasts spread to the meninges, causing hind leg paralysis. Leaving the skull, they permeated the meninges and then invaded the nervous parenchyma. This efficient and reproducible experimental model may be suitable for experimental studies on the pathogenesis of meningeal leukemia.