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Background: Tumour-released DNA in blood represents a promising biomarker for cancer detection. Although epigenetic alterations such as aberrant promoter methylation represent an appealing perspective, the discordance existing between frequencies of alterations found in DNA extracted from tumour tissue and cell-free DNA (cfDNA) has challenged their practical clinical application. With the aim to explain this bias of agreement, we investigated whether protocadherin 10 ( PCDH10 ) promoter methylation in tissue was associated with methylation pattern in matched cfDNA isolated from plasma of patients with colorectal cancer (CRC), and whether the strength of concordance may depend on levels of cfDNA, integrity index, as well as on different clinical–pathological features. Methods: A quantitative methylation-specific PCR was used to analyse a selected CpG site in the PCDH10 promoter of 67 tumour tissues, paired normal mucosae, and matched plasma samples. The cfDNA integrity index and cfDNA concentration were assessed using a real-time PCR assay. Results: The PCDH10 promoter methylation was detected in 63 out of 67 (94.0%) surgically resected colorectal tumours and in 42 out of 67 (62.7%) plasma samples. The median methylation rate in tumour tissues and plasma samples was 43.5% (6.3–97.8%) and 5.9% (0–80.9%), respectively. There was a significant correlation between PCDH10 methylation in cfDNA and tumour tissue in patients with early CRC ( P <0.0001). The ratio between plasma and tissue methylation rate increases with increasing cfDNA integrity index in early-stage cancers ( P =0.0299) and with absolute cfDNA concentration in advanced cancers ( P =0.0234). Conclusion: Our findings provide new insight into biological aspects modulating the concordance between tissues and plasma methylation profiles.

Blood doping is an illegal and unfair way of enhancing athletic performance by increasing the oxygen carrying capacity of the blood. Currently used methods usually involve stimulation of erythropoiesis. Gene therapy targeting the hypoxia inducible factor pathway may be an attractive alternative to traditional blood doping techniques. Hypoxia activates a large number of genes with essential roles in cell and tissue adaptation to low oxygen. Cobalt chloride is a well established chemical inducer of hypoxia-like responses such as erythropoiesis. Cobalt supplementation is not banned and therefore would not be detected by current anti-doping testing. Although there is as yet no direct or anecdotal evidence of cobalt chloride administration to athletes, its use should be warned against as being not only unfair but potentially dangerous.

A wide range of rheumatic and peripheral nervous system disorders may develop in patients with HIV infection, leading to pain, sensory symptoms, and muscle weakness. Over the past three decades, the progress in management of HIV disease with anti-retroviral therapy (ART) has resulted in increased life expectancy for people living with HIV disease. With this new chronicity of the disease has a constellation of chronic musculoskeletal, orthopaedic and rheumatic manifestations has emerged, as potential complications of the disease itself and/or the results of ART treatment regimen and/or because of expected age-related symptoms/manifestations. The incidence of CTS in the general population is around 3.8% with clinical examination and, when electroneuromyography is used, it is 2.7%. In the HIV-positive population, the incidence is very close to that of the general population. The aim of this study was to evaluate the incidence of CTS and to identify factors influencing the development of CTS in HIV-infected patients attending our clinic. This syndrome has been associated with advanced HIV disease and the use of ART possibly due to an increased inflammatory state and the presence of concurrent HCV infection.

The detection of cosmic neutrinos with energies above a teraelectronvolt (TeV) offers a unique exploration into astrophysical phenomena 1 , 2 – 3 . Electrically neutral and interacting only by means of the weak interaction, neutrinos are not deflected by magnetic fields and are rarely absorbed by interstellar matter: their direction indicates that their cosmic origin might be from the farthest reaches of the Universe. High-energy neutrinos can be produced when ultra-relativistic cosmic-ray protons or nuclei interact with other matter or photons, and their observation could be a signature of these processes. Here we report an exceptionally high-energy event observed by KM3NeT, the deep-sea neutrino telescope in the Mediterranean Sea 4 , which we associate with a cosmic neutrino detection. We detect a muon with an estimated energy of 12 0 − 60 + 110 petaelectronvolts (PeV). In light of its enormous energy and near-horizontal direction, the muon most probably originated from the interaction of a neutrino of even higher energy in the vicinity of the detector. The cosmic neutrino energy spectrum measured up to now 5 , 6 – 7 falls steeply with energy. However, the energy of this event is much larger than that of any neutrino detected so far. This suggests that the neutrino may have originated in a different cosmic accelerator than the lower-energy neutrinos, or this may be the first detection of a cosmogenic neutrino 8 , resulting from the interactions of ultra-high-energy cosmic rays with background photons in the Universe. A very high-energy muon observed by the KM3NeT experiment in the Mediterranean Sea is evidence for the interaction of an exceptionally high-energy neutrino of cosmic origin.  

Objectives To compare laboratory and clinical parameters in patients with biopsy proven and not biopsy proven temporal arteritis. To evaluate if the incidence of neurologic complications would be influenced by other clinical factors including the modality of referral to rheumatologist. Methods We retrospectively examined the clinical records of patients who had been diagnosed with giant cell arteritis in our rheumatology unit from February 2007 to December 2012. We recorded data, procedures for referral, time interval between onset of symptoms and diagnosis, clinical features and comorbidities, laboratory exams. Neurologic complications (visual loss, optic and peripheral nerves paralysis) were examined. Biopsy proven and not biopsy proven cases were compared. For the statistical analysis t-Student and Fisher tests were used. Results Thirty six patients (F 27, M 9, age 75.6 yrs) affected by temporal arteritis were included; twenty four 66.6%) had positive arterial biopsy. Fourteen patients (38.8%) were referred to us from other Units: Neurology 6 pts, Ophtftalmology 5 pts, Otorinolaryngology 2 pts, Infectious Disease 1 pt; the other 22 patients (61.2%) went from the General Practitioner (GP). The time interval between onset of symptoms and diagnosis was shorter in the group with not biopsy proven diagnosis (4.0 and 5.7 months respectively). Biological markers of inflammation were more increased in biopsy positive patients, with statistic relevance for C-reactive protein (p=0.0002). No significant differences were found regarding the presence of polymyalgia rheumatica (p=1), temporal/jaw pain (p=0.37), fever (p=0.48), complications (p=0.47). In the biopsy proven group, complications were more frequent in the presence of arterial hypertension (p=0.31), polymyalgia rheumatica (p=0.25) and when diagnosis was later (p=0.11). Rate of complications was higher in patients from ophthalmologist and otorinolaryngologist (100%) than patients from neurologist (50%), GP (13.6%) and infectivologist (none). Among complicated patients, biopsy was performed less frequently in patients referred to us from ophthalmologist (60%), than from neurologist and GP (66.6%). Among uncomplicated patients, however, the majority of biopsies was performed in those sent from GP (86.3%) compared with those sent from neurologist (66.6%). Conclusions In our study, C-reactive protein was the only laboratory test significantly higher in the group of biopsy proven patients. No significant clinical correlations have been found between the two groups regarding to polymyalgia rheumatica, temporal/jaw pain or fever. In biopsy proven patients, late diagnosis seemed to be more predictive of complications than arterial hypertension and polymyalgia rheumatica, but the difference is not significant. Patients referred to rheumatologist by other specialists (mostly ophthalmologists) had the higher rate of complications. Disclosure of Interest None Declared

The next generation of water Cherenkov neutrino telescopes in the Mediterranean Sea are under construction offshore France (KM3NeT/ORCA) and Sicily (KM3NeT/ARCA). The KM3NeT/ORCA detector features an energy detection threshold which allows to collect atmospheric neutrinos to study flavour oscillation. This paper reports the KM3NeT/ORCA sensitivity to this phenomenon. The event reconstruction, selection and classification are described. The sensitivity to determine the neutrino mass ordering was evaluated and found to be 4.4σ if the true ordering is normal and 2.3σ if inverted, after 3 years of data taking. The precision to measure Δm322 and θ23 were also estimated and found to be 85.10-6eV2 and (-3.1+1.9)∘ for normal neutrino mass ordering and, 75.10-6eV2 and (-7.0+2.0)∘ for inverted ordering. Finally, a unitarity test of the leptonic mixing matrix by measuring the rate of tau neutrinos is described. Three years of data taking were found to be sufficient to exclude event rate variations larger than 20% at 3σ level.