First Dark Matter Search with Nuclear Recoils from the XENONnT Experiment.

We report on the first search for nuclear recoils from dark matter in the form of weakly interacting massive particles (WIMPs) with the XENONnT experiment, which is based on a two-phase time projection chamber with a sensitive liquid xenon mass of 5.9 ton. During the (1.09±0.03) ton yr exposure used for this search, the intrinsic ^{85}Kr and ^{222}Rn concentrations in the liquid target are reduced to unprecedentedly low levels, giving an electronic recoil background rate of (15.8±1.3) events/ton yr keV in the region of interest. A blind analysis of nuclear recoil events with energies between 3.3 and 60.5 keV finds no significant excess. This leads to a minimum upper limit on the spin-independent WIMP-nucleon cross section of 2.58×10^{-47} cm^{2} for a WIMP mass of 28 GeV/c^{2} at 90% confidence level. Limits for spin-dependent interactions are also provided. Both the limit and the sensitivity for the full range of WIMP masses analyzed here improve on previous results obtained with the XENON1T experiment for the same exposure.

Searching for Heavy Dark Matter near the Planck Mass with XENON1T.

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10^{12} and 2×10^{17} GeV/c^{2}. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale.

Search for New Physics in Electronic Recoil Data from XENONnT.

We report on a blinded analysis of low-energy electronic recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 ton liquid xenon target reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(ton×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 ton-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter.

Material radiopurity control in the XENONnT experiment.

The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and 222 Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background ( ∼ 17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected 222 Rn activity concentration in XENONnT is determined to be 4.2 ( - 0.7 + 0.5 )  µ Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.

First Directional Measurement of Sub-MeV Solar Neutrinos with Borexino.

We report the measurement of sub-MeV solar neutrinos through the use of their associated Cherenkov radiation, performed with the Borexino detector at the Laboratori Nazionali del Gran Sasso. The measurement is achieved using a novel technique that correlates individual photon hits of events to the known position of the Sun. In an energy window between 0.54 to 0.74 MeV, selected using the dominant scintillation light, we have measured 10 887_{-2103}^{+2386}(stat)±947(syst) (68% confidence interval) solar neutrinos out of 19 904 total events. This corresponds to a ^{7}Be neutrino interaction rate of 51.6_{-12.5}^{+13.9} counts/(day·100 ton), which is in agreement with the standard solar model predictions and the previous spectroscopic results of Borexino. The no-neutrino hypothesis can be excluded with >5σ confidence level. For the first time, we have demonstrated the possibility of utilizing the directional Cherenkov information for sub-MeV solar neutrinos, in a large-scale, high light yield liquid scintillator detector. This measurement provides an experimental proof of principle for future hybrid event reconstruction using both Cherenkov and scintillation signatures simultaneously.

Improved Measurement of Solar Neutrinos from the Carbon-Nitrogen-Oxygen Cycle by Borexino and Its Implications for the Standard Solar Model.

We present an improved measurement of the carbon-nitrogen-oxygen (CNO) solar neutrino interaction rate at Earth obtained with the complete Borexino Phase-III dataset. The measured rate, R_{CNO}=6.7_{-0.8}^{+2.0} counts/(day×100 tonnes), allows us to exclude the absence of the CNO signal with about 7σ C.L. The correspondent CNO neutrino flux is 6.6_{-0.9}^{+2.0}×10^{8} cm^{-2} s^{-1}, taking into account the neutrino flavor conversion. We use the new CNO measurement to evaluate the C and N abundances in the Sun with respect to the H abundance for the first time with solar neutrinos. Our result of N_{CN}=(5.78_{-1.00}^{+1.86})×10^{-4} displays a ∼2σ tension with the "low-metallicity" spectroscopic photospheric measurements. Furthermore, our result used together with the ^{7}Be and ^{8}B solar neutrino fluxes, also measured by Borexino, permits us to disfavor at 3.1σ C.L. the "low-metallicity" standard solar model B16-AGSS09met as an alternative to the "high-metallicity" standard solar model B16-GS98.

Author Correction: Anak Krakatau triggers volcanic freezer in the upper troposphere.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anak Krakatau triggers volcanic freezer in the upper troposphere.

Volcanic activity occurring in tropical moist atmospheres can promote deep convection and trigger volcanic thunderstorms. These phenomena, however, are rarely observed to last continuously for more than a day and so insights into the dynamics, microphysics and electrification processes are limited. Here we present a multidisciplinary study on an extreme case, where volcanically-triggered deep convection lasted for six days. We show that this unprecedented event was caused and sustained by phreatomagmatic activity at Anak Krakatau volcano, Indonesia during 22-28 December 2018. Our modelling suggests an ice mass flow rate of ~5 × 106 kg/s for the initial explosive eruption associated with a flank collapse. Following the flank collapse, a deep convective cloud column formed over the volcano and acted as a 'volcanic freezer' containing ~3 × 109 kg of ice on average with maxima reaching ~1010 kg. Our satellite analyses reveal that the convective anvil cloud, reaching 16-18 km above sea level, was ice-rich and ash-poor. Cloud-top temperatures hovered around -80 °C and ice particles produced in the anvil were notably small (effective radii ~20 µm). Our analyses indicate that vigorous updrafts (>50 m/s) and prodigious ice production explain the impressive number of lightning flashes (~100,000) recorded near the volcano from 22 to 28 December 2018. Our results, together with the unique dataset we have compiled, show that lightning flash rates were strongly correlated (R = 0.77) with satellite-derived plume heights for this event.

Prevalence of Simkania negevensis in chlorinated water from spa swimming pools and domestic supplies.

AIMS: This study aimed to investigate the prevalence of Simkania negevensis in the chlorinated water of spa swimming pools and domestic network systems. METHODS AND RESULTS: A total of 10 and 36 samples were collected from two domestic water supplies and four spa facilities, respectively. Simkania negevensis was isolated in Acanthamoeba castellanii monolayers and detected by Gimenez staining and immunofluorescence test. Simkania negevensis DNA, extracted from the positive samples, was confirmed by a nested PCR assay followed by sequencing. Simkania negevensis was detected in 41·3% of samples (domestic water: 50%; untreated spa supply water: 25%; chlorinated spa pool water: 42·9%) from all the examined water systems in successive samplings performed in 1 year. The presence of S. negevensis was not correlated with the counts of Heterotrophic Bacteria and Pseudomonas aeruginosa. Unlike Legionella spp., which were never isolated from the swimming-pool water samples, S. negevensis was also detected in chlorinated spa water. CONCLUSIONS: This investigation shows that Simkania is widespread in natural and man-made aquatic environments, which may represent possible sources of infection: in the swimming pools, in particular, the aerosol generated by the water movement could increase the risk of inhalation of infected particles. SIGNIFICANCE AND IMPACT OF THE STUDY: This study represents the first evidence of the presence of S. negevensis in spa pool water. Sero-epidemiological surveys on spa users could help to clarify its transmission in this environment.

Oxidative stress in pathological pregnancies.

Oxidative stress (OS) plays a role in pregnancy at risk of pre-eclampsia, diabetes and premature labour. We measured three markers of OS: total antioxidant capacity (TAC), thiolyte capacity and pro-oxidant capacity in 45 women: 15 normal pregnancies, 17 pathological pregnancies (pre-eclampsia and pregestational diabetes) and 13 delivered pre-term. Plasma TAC (µmol/ml) values in patients with pathological pregnancies (235.67 ± 70.08) (p(1) = 0.0086) and pre-term labour (243.51 ± 50.52) (p(2) = 0.0479) were significantly reduced as compared with the controls (306.78 ± 70.08). Thiolyte capacity (µmol/ml) in the pathological pregnancies (326.03 ± 78.24) (p(3) = 0.0029) and in pre-term labour (335.94 ± 76.63) (p(4) = 0.0084) groups were significantly reduced compared with the control group (417.48 ± 39.76) (p < 0.05). Pro-oxidant capacity (mg/100 ml) in the pathological pregnancies (94.11 ± 26.13) (p(5) = 0.00034) and in pre-term labour (87.18 ± 20.28) (p(6) = 0.00044) groups were significantly higher compared with the controls (60.27 ± 6.33). Elevated OS values were seen in pathological pregnancies. This supports the important role of OS in diseases in pregnancy, particularly pre-eclampsia, diabetes and pre-term birth.

Open comparison study of oxidative stress markers between patients with chronic renal failure in conservative therapy and patients in haemodialysis.

AIMS: Oxidative stress is defined as tissue damage caused by an imbalance between the excessive production of the oxidant components and an insufficient defence mechanism. It has been observed, as in patients with chronic kidney failure, that there exists a pro-oxidant state characterised by a higher level of reactive oxygen species (ROS), and that oxidative stress in dialysis patients can be aggravated by the activation of neutrophils associated with the production of free radicals. In patients undergoing dialysis even the molecules other than those of cytokines can accumulate and provoke an inflammatory response. This study proposes an analysis based on the total antioxidant capacity (TAC), thiol concentration (TC) and pro-oxidant capacity (POC) in the serum of various groups of patients: one group of dialysis subjects who had been undergoing substitutive treatment for more than ten years at the time of the study; one group of subjects with chronic renal insufficiency in its pre-terminal stage and subjected to conservative therapy; and the control group consisting of healthy volunteers. MATERIALS AND METHODS: Three types of tests were employed to assess the level of oxidative stress: oxy-adsorbent test, d-ROMS test, and SHp- test. Thirty-three subjects were selected: 11 undergoing haemodialysis for over then years; 14 patients with chronic kidney failure in its pre-terminal stage, and 8 normal subjects. In patients undergoing renal substitutive treatment, the serum levels (mean±sd) of TAC were 272.98±20.54; TC, 249.19±92.48, and POC, 95.06±15.70. In patients with chronic renal insufficiency in its pre-terminal stage and undergoing conservative treatment, the value of TAC was 226.5±27.89; TC, 336.42±102.08; and POC, 80.78±15.69. The levels of TAC in the serum of the controls were 335.62±46.35; TC, 434.09±22.23; and POC, 56.31±7.41. CONCLUSION: The analysed data suggest that in dialysis the patients with chronic kidney failure, whether undergoing conservative therapy during its pre-terminal stage or in substitution treatment during its terminal stage, there is a reduction in the antioxidant defence (in terms of TAC and thiolic barrier) and an increase in POC compared to the healthy subjects in the control group. Uraemia and haemodialysis increase the inflammatory response: an initial signal provokes the inflammatory state with the production of cytokines and free radicals or reactive oxygen, so that the lack of an antioxidant defence mechanism can bring about a vicious circle with the continual production of other free radicals.

Assessment of the oxidative stress markers in patients with chronic renal insufficiency undergoing dialysis treatment.

AIMS: Uraemia is a disease characterised by a significant oxidative stress, and it is a wide agreement that oxidative stress which accompanies uraemia, increases the inflammatory state and promotes the alterations of tiny molecules such as amino acids, proteins, lipids, and carbohydrates. There are numerous records of how ROS are connected to the pathology of end stage renal disease (ESRD). The aim of this study is to assess the Total Antioxidant Capacity (TAC), the Thiolic Capacity (TC) and the Pro-Oxidant Capacity (POC) in the serum of patients undergoing dialysis treatment. MATERIALS AND METHODS: Forthy-six patients have been recruited (32 men, 14 women; mean age 68.5±15.8) who received hemodialytic treatment triweekly. Three methods have been used: oxy adsorbent test (mmol/l) to determine TAC values; d-ROM test (mg/100 mg/H2O2) to determine POC; SHp-test (mmol/l) to determine TC. RESULTS: In patients who underwent hemodialysis, TAC levels were: pre-dialysis, 265.9±30.5; post-dialysis, 300.0±40.6; TC levels: pre-dialysis, 267.4±59.1; post-dialysis, 303.2±116.7; POC levels: predialysis, 86.2±16.9; post-dialysis, 98.6±17.0; NS: TAC, 335.6±46.3; TC, 434.0±22.2; POC, 56.3±7.4. TAC in both pre- and post-dialysis is reduced compared to the NS (p < 0.05); moreover TAC increases after dialysis (p < 0.05). Pre- and post-dialysis TC is reduced compared to NS (p < 0.05); available TC increases after dialysis, although not statistically significant. Pre- and post-dialysis POC in patients undergoing dialysis is increased compared to the NS (p < 0.05); moreover, POC tends to increase after dialysis ( p < 0.05). The data obtained from our study also show that the TAC is reduced in the patients subjected to hemodialysis compared to the NS, both before and after dialysis treatment; TAC increased after dialysis, even though it did not reach the level of the control group. CONCLUSION: Our study has demonstrated that exists a profound imbalance between antioxidants and the production of ROS in ESRD patients, which determines oxidative stress and eventually leads to atherosclerosis and cardiovascular complications. This, in turn, represents the major cause of morbidity and mortality in these patients.

Oxidant/antioxidant status in patients with chronic HIV infection.

The infection caused by HIV leads to an activation of the immune system, which involves local and systemic oxidative stress. In HIV-positive (HIV+) patients, oxidative damage is the result of HIV infection and its progression through the replication of the virus. We have examined 52 subjects: 26 HIV+ patients, and 26 healthy subjects (NC). Analysis of the parameters of the oxidant/antioxidant status (total antioxidant capacity (TAC), hydroperoxides (free radicals, PRO), thiols as thiolic capacity, TC) was carried out by means of the OXY-Absorbent test, the d-Rom test, and the -SHp test, respectively. Healthy subjects presented the following values: TAC (micromol/ml) 259.5+/-40.5; TC (micromol/l) 434.09+/-18.31; PRO (mg/dl) 54.09+/-7.3; CD4+ cells (cells/ml) 850+/-333. Values of HIV+ patients were the following: TAC 218.73+/-18.55 (ns vs NC; TC 250.88+/-93.11 (p 0.001 vs NC); PRO 110.5+/-23.61 (p 0.0005 vs NC); CD4+ cells 354+/-323.35 (p 0.0005 vs NC). The statistical analysis shows a direct correlation between TAC vs CD4+ cells; an indirect correlation between hydroperoxides vs CD4+ cells; not significant result between thiolic capacity vs CD4+ cells; finally, good correlations between TAC, hydroperoxides, and thiolic capacity vs HIV-RNA. The data obtained have proven that HIV+ patients present a condition of important oxidative stress. We may affi rm that this disease concurs with an increase of extreme stress; a condition in which the antioxidant defences are present, but are insufficient in neutralising the damaging actions of reactive species of oxygen, thus contributing to an acceleration in the natural history of HIV infections.

Evaluation of oxidative stress in rheumatoid and psoriatic arthritis and psoriasis.

INTRODUCTION: The aim of the present study is to discuss the importance of the processes of oxidative stress in the pathogenesis of certain autoimmune diseases, to search for an appropriate assessment marker, and to debate current approaches which have been proposed for the treatment of Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), and Psoriasis (Ps). MATERIALS AND METHODS: The total antioxidant capacity (TAC), the thiolic capacity (TC), and the serum hydroperoxide concentration (SHC) were measured in 37 subjects: 13 with RA, 8 with PsA, 8 with Ps, and 8 healthy controls. RESULTS: SHC levels were significantly higher in patients with RA (p = 0.01), as well as in those with PsA (p = 0.005) and Ps (p = 0.002) in comparison with the control group. However, a significant reduction in the TAC values in the serum of all three groups (RA, p = 0.03; PsA, p = 0.005; Ps, p = 0.001) were observed in comparison with the healthy controls. The thiolic concentration were found to have significantly diminished in patients with RA (p =0.0005) and Ps (p = 0.0005) in comparison with the control group. Our findings have brought out the fact that the therapeutic treatment of RA using biological drugs is more than satisfactory in accord with the considerable increase in the TAC values, although not significantly, compared to those patients treated with DMARDs. CONCLUSIONS: The determination of the parameters of oxidative stress utilising these methods may be useful as a quick test, and as routine in monitoring the state of oxidative stress in patients suffering from RA, PsA, and Ps, so that a more effective treatment for ROS can be undertaken accordingly. The administration of biological drugs seems to have a role in increasing the mechanism of the barrier which the body possesses against oxidative stress.

Oxidant/antioxidant status in patients with Raynaud's disease.

OBJECTIVE: Despite several studies concerning the oxidative stress in Raynaud's phenomenon secondary to systemic sclerosis (secondary Raynaud, SR), little is known regarding the relationship between Raynaud's disease (primary Raynaud, PR) and oxidative stress at present. The aim of the present research was to study the parameters of oxidative stress in PR patients and to compare them to those of SR patients. MATERIALS AND METHODS: Serum hydroperoxide (Hydrop) level, serum total antioxidant capacity (TAC) and serum total thiol (-SHp) barrier were measured in 19 patients with SR, 15 patients with PR and 14 healthy control subjects (CS). The statistical contrasts were performed via one-way ANOVA. RESULTS: The serum Hydrop concentrations were significantly higher in SR (p = 0.0043) and PR (p = 0.0038) groups in comparison with CS. A significant decrease in serum TAC level in SR (p = 0.00005) and PR (p = 0.00128) patients in respect to the CS was revealed. No significant change in the -SHp barrier in SR and PR patients in respect to CS has been demonstrated. However, there were no significant differences in serum Hydrop and TAC levels between the groups of patients. CONCLUSIONS: The study of serum oxidative stress parameters, in terms of Hydro and TAC levels may be used as a routine and rapid test to verify the oxidative stress status in SR and PR patients and to undertake a strategy of treatments by a supplementation of antioxidant molecules.

Evaluation of telomerase in non-melanoma skin cancer.

Telomerase, a ribonucleoprotein, is capable of adding telomeric sequences (TTAGGG hexameric repeats) to the ends of chromosomes and, thereby, halting the erosion of chromosome at each cell division. Whereas most normal somatic cells contain minimal or no detectable telomerase activity, most immortal and tumour cells exhibit significant levels of telomerase activity and show no net loss of telomere length during proliferation. The evaluation of telomerase has been proposed for diagnostic and therapeutic purposes in human cancer. Skin cancer is the most common cancer in humans; the precise molecular events in skin carcinogenesis are numerous and complicated and not yet completely clarified. In this study, we evaluated telomerase in 35 basal cell carcinomas and in 14 squamous cell carcinomas in order to determine if activation of the telomerase enzyme was a pivotal step in the development of skin cancer and whether telomerase activity levels were different between the two histotypes. A higher enzymatic level was shown to be associated with squamous cell carcinomas, while low levels were mainly detected in the basal cell histotype (chi2 test; p=0.02). Telomerase complex activity is dependent on its catalytic subunit, telomerase reverse transcriptase hTERT. By reverse transcription-PCR, using primers within the reverse transcriptase domain of hTERT, we observed a significant correlation between hTERT expression and telomerase activity in our skin tumour samples (p=0.0003). We detected the presence of multiple, alternately spliced transcripts, corresponding to full-length messages as well as spliced messages with critical reverse transcriptase motifs deleted. A higher telomerase messenger level was shown to be associated with squamous cell carcinomas (chi2 test; p<0.0001), as for telomerase activity. Our results provide arguments supporting the role of telomerase in skin cancer and suggest RT-PCR of telomerase RNA as a tool easier and faster than TRAP assay to identify more aggressive malignancies among non-melanoma skin specimens.

Changes in plasma level of human leukocyte elastase during leukocytosis from physical effort.

Physical exercise is known to induce immunological changes, mainly leukocytosis and neutrophil activation. However, it is not known to what extent the leukocytosis, observed after exertion, is associated with an increase in plasma neutrophil elastase, an early marker of inflammatory response and neutrophil degranulation. In the present study changes in circulating leukocyte and neutrophil counts and human neutrophil elastase plasma levels were evaluated in volley-ball players before and after 2 h and 12 h prolonged training, during a competition season. For comparison, the same parameters were evaluated in untrained subjects before and after a jogging session. Basal white blood cell WBC, polymorpho nuclear PMN, and human polymorpho nuclear-elastase PMN-ELA values were within the normal healthy reference range and no significant differences were found between the two groups studied. Venous blood samples of nine volley-ball players showed a statistically significant increase in blood WBCs after 2 h exercise. This effect was paralleled by a statistically significant increase in PMN-ELA concentration compared to the values observed in the same individuals at rest. The exercise did not significantly change the basal correlation parameters between PMN level and PMN-ELA concentration. More pronounced WBC, PMN, and PMN-ELA increases were observed in the seven inactive subjects after 2 h jogging. There was no linear correlation between increased PMN counts and increased PMN-ELA concentrations in untrained subjects after exercise. The results show that not only the leukocyte count but also PMN-ELA plasma levels can be higher after physical effort. This has a practical significance as regards differential diagnosis demonstrating that determination of these two laboratory parameters can give abnormally high values even in the absence of an existing inflammatory process. Besides, lack of correlation between PMN count and PMN-ELA plasma levels in the untrained group suggest a state in which activation of the neutrophils is not connected with their number in peripheral blood.

Neoangiogenesis in colon cancer: correlation between vascular density, vascular endothelial growth factor (VEGF) and p53 protein expression.

Angiogenesis is an essential requirement for the development, progression and metastasis of malignant tumors. Vascular endothelial growth factor (VEGF) plays an essential role in the development of angiogenesis of numerous solid malignancies, including colon cancer. The tumor suppressor gene p53 is a potent transcriptional regulator of genes which are involved in many cellular activities, including cell-cycle arrest, apoptosis and angiogenesis. In order to better understand the relation among p53 status, VEGF expression and microvessels count (MVC) in colon cancer, we evaluated immunoreactivity for CD34 endothelium-associated antigen, VEGF and p53 proteins in 43 cases of colon adenocarcinoma. Our results demonstrated an association between VEGF expression, p53 status and angiogenesis, suggesting that mutant p53 plays a central role in promoting angiogenesis in colon cancer progression.

Plasma endothelin-1 and big endothelin-1 levels in superior and inferior vena cava during protracted antiorthostatic hypokinetic/hypodynamia in rats.

The plasma levels of endothelin-1 and big endothelin-1 were evaluated in blood of rats in the superior and inferior vena cava, in normal posture (synchronous controls), and after 12 days head-down suspension and 1 day recovery in normal posture. In synchronous controls, the mean plasma concentration of endothelin-1 in inferior vena cava or superior vena cava was almost the same (5.89+/-0.63 pmol/l and 5.67+/-0.64 pmol/l, respectively), whereas the mean plasma concentration of big endothelin-1 was higher (p<0.05) in superior vena cava compared to inferior vena cava (5.49+/-0.75 pmol/l and 1.39+/-0.15 pmol/l, respectively). In samples from superior vena cava of head-down suspended rats big endothelin-1 levels were significantly lower (p<0.05) up to day 9 of suspension, compared to non-suspended synchronous controls, whereas endothelin-1 values were higher (p<0.05). Big endothelin-1 concentration was higher (p<0.05) in inferior vena cava compared to non-suspended synchronous controls. The behaviour of endothelin-1 was more complex, endothelin-1 levels were lower (p<0.05) on day 1 of head-down suspension and higher (p<0.05) in samples taken on days 9 and 12. After 1 day recovery endothelin-1 and big endothelin-1 concentrations returned to normal in both superior vena cava and inferior vena cava. These data indicate that the endothelial system involvement for the two venous beds is different and suggest that local rather than systemic evaluation could better explain endothelial involvement and the contribution of different anatomic sites to the biosynthesis, conversion and clearance of the various involved molecules.