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.

[Identification of individuals with high coronary risk in the Italian population: indications of the Epidemiologic Cardiovascular Observatory]. / L'identificazione degli individui ad elevato rischio coronarico nella popolazione italiana: indicazioni dall'Osservatorio Epidemiologico Cardiovascolare.

BACKGROUND: The absolute global coronary risk has recently been introduced as an indicator of the incidence predicted by the main risk factors. It offers numerous options for the treatment of individuals at high risk. The identification of the absolute global coronary risk is produced through the application of functions obtained by longitudinal studies; their adequacy depends on the characteristics of the population from which they were estimated. The aim of this work was to evaluate the impact of the application of the absolute global coronary risk evaluation using the chart of risk proposed to the Italian physicians and to compare it with the results obtained from the application of other risk functions. METHODS: The database of the Osservatorio Epidemiologico Cardiovascolare (OEC), consisting of men and women aged 35-74 years, has been considered as being representative of the Italian population. The individual risk has been computed using the functions and coefficients from the Framingham study, the PROCAM study and the Seven Countries Study-Italy. The prevalence of high risk factors has been estimated on the basis of the recommendations on coronary prevention of the Task Force of the European Societies. RESULTS: The prevalence of high risk factors estimated by the Framingham function is 23.7% among men and 3.8% among women aged 35-74 years. In men aged 35-64 years, this estimated prevalence decreases from 14.2 to 8.7% when the Framingham function is adjusted using the mean value of the risk factors of the OEC, to 5.2% when the PROCAM function is applied, and to 1.1% when the function of the Seven Countries Study-Italy is employed. CONCLUSIONS: The application of the risk function suggested to the Italian physicians implies that more than 2,700,000 men and more than 500,000 women aged 35-74 years are potential candidates for treatment with lipid-lowering drugs. The comparison between the use of different functions in the OEC sample produces high numerical differences. The over-evaluation of the individual at high risk implies significant human and social costs. It is therefore essential to determine risk functions and coefficients derived from recent Italian studies including all age groups, both sexes and taking into account the different geographic characteristics of our country.

Prognostic value of midwall shortening fraction and its relation with left ventricular mass in systemic hypertension.

We followed 1,778 subjects (up to 12 years) with essential hypertension who underwent echocardiography at the time of their initial diagnostic workup. There were 166 major cardiovascular events during follow-up and the prognostic value of the midwall shortening fraction did not remain significant after controlling for left ventricular mass.

[Cardiovascular risk stratification. Systolic, diastolic or pulse pressure?]. / Definizione del rischio cardiovascolare. Pressione arteriosa sistolica, diastolica o differenziale?

It is well known that hypertension is a highly prevalent condition in the population, carries a significant risk of adverse cardiovascular events and is therapeutically difficult to control. These factors render it "a major unsolved - but soluble - mass public health problem". One of the present-day aspects of the complexity of managing patients with high blood pressure (BP) derives from clinical and epidemiological data that have emerged over the past 10 years: the growing importance of the clinical significance of systolic and pulse BP. The pathophysiological basis of these data is based, on the one hand, on a better articulated definition of the components of BP, and on the other, on precise information concerning age-related modifications. The common definition of BP does not take into account pressure fluctuations occurring during the cardiac cycle; in fact, systolic and diastolic BP denote the extreme values of continuous variations in differential pressure. Diastolic BP reflects, to a greater extent, the trend of arterial resistances and mean BP (usually calculated as diastolic BP plus one third of the differential BP, and considered the "stable component" of the arterial sphygmogram) and has long been used as a diagnostic and therapeutic target. Systolic BP is more closely linked to variations in pulse BP (given from the difference between systolic and diastolic BP and considered the "dynamic component" of the arterial sphygmogram) and is produced by a group of factors including left ventricular ejection and the reflection of the sphygmic wave. As age increases, the walls of the aorta and the large elastic arteries progressively harden due to senile degenerative phenomena and the loss of elasticity as well as the progressive diffusion of atherosdclerotic lesions. This leads to the reduced capacity of the arterial wall to distend during the systole with a consequent increase in both systolic and pulse BP. These pathophysiological data have important clinical and prognostic implications and account for the possible diversity of significance to attribute to systolic, diastolic, mean and pulse BP, factors which, in their entirety, can represent an element, albeit partial, of resolvability of problems in managing hypertension. In fact, possibilities of diversification in the stratification of risk of the hypertensive patients may be considered on a pathophysiological basis, with the prospect of better aimed therapeutic interventions. On the whole, it appears that the clinical significance to attribute to pulse BP should be considered not as an alternative to that of systolic and diastolic BP, but rather in complementary terms, with age kept in careful consideration. In practice, by simplifying to a maximum the state of present knowledge, the values of systolic, diastolic, mean and pulse BP are all important in subjects under 60 years old. This indicates that the clinical significance to attribute to diastolic hypertension in young or middle-aged patients, which have been so accurately described by well-known meta-analyses, is not presently under discussion. What seems to change, with respect to the past, is the importance that should be attributed to the systolic and pulse BP in subjects of all ages and in particular to pulse BP in subjects over 60 years old: in these persons, the increase in pulse BP summarizes and integrates the adverse prognostic value of an elevated systolic BP and a low diastolic BP. It should be clearly understood that, in subjects over 60 years old, a high systolic BP and a low diastolic BP mean rigidity of the wall of the aorta and of the main elastic arteries; in these subjects, the isolated increase in diastolic BP, usually easily controllable by antihypertensive treatment, should not cause excessive clinical concern; instead, an increase in systolic BP - even if isolated - and, above all, an increase in pulse BP, should cause greater preoccupation, inasmuch as they are signs of consistent serious structural lesions. In other words, a 60-year-old subject with 150/90 mmHg would have a lesser risk of cardiovascular events, particularly cardiological events, than a contemporary with equal risk factors who has 150/50 mmHg. A large number of clinical studies suggest that an increase in pulse BP seems to predict cardiac ischemic events to a greater extent than the cerebrovascular events, which seem to be predicted to a greater extent by the mean BP. On the therapeutic level, the reference datum is represented by the unequivocal demonstration, furnished by wide scale interventional studies, that in hypertensive patients adequate pharmacological control of both the diastolic and systolic BP, particularly in the elderly, significantly reduces adverse consequences linked to the progression of atherosclerotic disease in the heart, brain and kidney. A degree of complexity is represented by the modest percent of patients in treatment who have BP values < 140/90 mmHg. Only a series of ad hoc studies will enable us to know when and if this negative situation can be resolved, even partially, by the clinical application of new knowledge in the pathophysiological field. From this point of view, it should be kept in mind that ACE-inhibitors, diuretics, dihydropyridinic calcium antagonists and vasopeptidase inhibitors seem to be more effective than beta-blockers in terms of preferential reduction of pulse BP. The contents of the reports that make up the Symposium constitute a valid base of knowledge and represent a concrete stimulus for research initiatives, which in the spirit of "operativeness" of the Area Prevenzione of the Italian Association of Hospital Cardiologists, follow the objective of bringing together scientific and managerial needs.

Subclinical left ventricular dysfunction in systemic hypertension and the role of 24-hour blood pressure.

The relation between blood pressure (BP) and left ventricular (LV) systolic function in systemic hypertension is controversial. We assessed the relation of LV midwall fractional shortening (FS) to 24-hour BP in 1,702 never-treated hypertensive subjects (age 48 +/- 12 years), who underwent 24-hour BP monitoring and echocardiography. Stress-corrected endocardial and midwall FS (the latter calculated taking into account the epicardial migration of midwall during systole) were predicted in hypertensives on the basis of the values observed in 130 healthy normotensives (age 43 +/- 13 years, office BP 126/78 mm Hg). Subjects below the fifth percentile of observed-to-predicted FS had depressed LV function. The use of midwall FS resulted in an increase from 3.5% to 17.5% in the proportion of patients with depressed chamber function. Compared with the group with normal function, subjects with low midwall LV function had similar office systolic BP (155 +/- 21 vs 154 +/- 17 mm Hg), but increased 24-hour systolic BP (140 +/- 17 vs 133 +/- 12 mm Hg, p <0.001). Midwall FS had a closer negative relation to 24-hour systolic BP than to office systolic BP (r = -0.27 vs -0.08, p <0.001), whereas this difference was not apparent for diastolic BP (r = -0.23 vs -0.20). Compared with endocardial FS, midwall FS had a stronger inverse association to LV mass (r = -0.45 vs -0.16, p <0.001). Thus, an increased 24-hour BP load may chronically lead to depressed myocardial function in systemic hypertension in the absence of clinically overt heart disease.

Clinical relevance of office underestimation of usual blood pressure in treated hypertension.

Average 24-h blood pressure (BP) is more representative of usual BP than office BP. However, the clinical relevance of 24-h BP in treated hypertensive subjects is incompletely known. Thus, we studied 395 uncomplicated hypertensive subjects (209 men, 53+/-10 years) who were receiving antihypertensive drug therapy from >1 year. All subjects underwent 24-h ambulatory BP monitoring and M-mode echocardiography. Subjects were classified by tertile of the difference between observed and predicted 24-h systolic BP (the latter determined by regressing 24-h systolic BP on office systolic BP): higher-than-predicted (III tertile), around the regression line (II tertile), and lower-that-predicted (I tertile) 24-h BP. Despite similar office BP (144/89, 141/88, and 144/89 mm Hg in the III, II, and I tertile, P = not significant), age, body mass index, and duration of hypertension, left ventricular mass was greater in the subjects with higher-than-predicted 24-h systolic BP (50+/-14 g x m(-2.7)) than in the other two groups (46+/-13 g x m(-2.7) and 42+/-10 g x m(-2.7), both P < .05). The III tertile also showed a more concentric left ventricular geometric pattern (relative wall thickness was 0.42+/-0.08, 0.40+/-0.07, and 0.38+/-0.07 in the III, II, and I tertile, P < .001) and a reduced systolic function at the midwall level (16.8+/-3, 17.7+/-3, and 18.2+/-3, P < .001). In conclusion, treated hypertensive subjects whose 24-h BP is notably higher than one would predict from office BP are more likely to develop left ventricular hypertrophy, a strong adverse prognostic marker. In a sizable subset of treated hypertensive subjects, BP measured in the physician's office underestimates usual BP and its impact on left ventricular structure.

Effects of fatty acids, nucleotides and reactive oxygen species on durum wheat mitochondria.

Linoleic acid (LA) and other fatty acids added to respiring durum wheat mitochondria (DWM) were found to cause a remarkable membrane potential (deltaPsi) decrease, as monitored by measuring safranin fluorescence. The rate of deltaPsi decrease showed (i) saturation dependence on LA concentration; (ii) fatty acid specificity; (iii) inhibition by externally added ATP, GDP, GTP and Mg(2+) and (iv) sigmoid dependence upon initial DeltaPsi, thus suggesting the existence of an active plant mitochondrial uncoupling protein (PUMP) in mitochondria from monocotyledonous species (durum wheat, Triticum durum Desf.). Surprisingly, the rate of the linoleate dependent DeltaPsi decrease was found to be activated by reactive oxygen species (ROS) (hydrogen peroxide and superoxide anion) and, moreover, linoleate proved to lower the mitochondrial generation of superoxide anion. These results suggest that ROS can activate PUMP, thus protecting the cell against mitochondrial ROS production.

Ambulatory pulse pressure: a potent predictor of total cardiovascular risk in hypertension.

A wide pulse pressure (PP) is a marker of increased artery stiffness and high cardiovascular (CV) risk. To investigate the prognostic value of ambulatory PP, which is currently unknown, we studied 2010 initially untreated subjects with uncomplicated essential hypertension (mean age, 51.7 years; 52% men). All subjects underwent baseline procedures including 24-hour noninvasive ambulatory blood pressure (BP) monitoring. The mean duration of follow-up was 3.8 years (range, 0 to 11 years), and CV morbidity and mortality were the outcome measures. There were 200 major CV events (2.61 per 100 person-years), 36 of which were fatal (0.47 per 100 person-years). In the 3 tertiles of the distribution of office PP, the rate of total CV events (per 100 persons per year) was 1.38, 2. 12, and 4.34, respectively, and that of fatal events was 0.12, 0.30, and 1.07 (log-rank test, both P<0.01). In the 3 tertiles of the distribution of average 24-hour PP, the rate of total CV events was 1.19, 1.81, and 4.92, and that of fatal events was 0.11, 0.17, and 1. 23 (log-rank test, both P<0.01). After controlling for several independent risk markers including white coat hypertension and nondipper status, we found that ambulatory PP was associated with the biggest reduction in the -2 log likelihood statistics for CV morbidity (P<0.05 versus office PP). In each of the 3 tertiles of office PP, CV morbidity and mortality increased from the first to the third tertile of average 24-hour ambulatory PP (log-rank test, all P<0.01). Age, left ventricular hypertrophy, and nondipper status were independent predictors of CV mortality, and the further predictive effect of ambulatory PP (P<0.001) was marginally but not significantly superior to that of office PP and average 24-hour systolic BP. We conclude that ambulatory PP is a potent risk marker in essential hypertension. CV morbidity is more closely predicted by ambulatory than by office PP even after control for multiple risk factors.

Adverse prognostic value of a blunted circadian rhythm of heart rate in essential hypertension.

BACKGROUND: Previous studies revealed a direct association between resting heart rate and risk of mortality in essential hypertension. However, resting heart rate is a highly variable measure since it is affected by the alerting reaction to the visit. OBJECTIVE: To investigate whether the heart rate values recorded during the 24 h of ambulatory blood pressure monitoring are independent predictors of survival of uncomplicated subjects with essential hypertension. METHODS: We followed up 1942 initially untreated and uncomplicated subjects with essential hypertension (mean age 51.7 years, 52% men) for an average of 3.6 years (range 0-10 years). All subjects underwent baseline procedures including 24 h non-invasive blood pressure monitoring with simultaneous assessment of heart rate, one reading every 15 min for 24 h. MAIN OUTCOME MEASURES: All-cause mortality and cardiovascular morbidity. RESULTS: During follow-up there were 74 deaths from all causes (1.06 per 100 person-years) and 182 total (fatal plus non-fatal) cardiovascular morbid events (2.66 per 100 person-years). Clinic, average 24 h, daytime and night-time heart rates exhibited no association with total mortality. However, the subjects who subsequently died had had a blunted reduction of heart rate on going from day to night during the baseline examination. After adjustment for age (P < 0.001), diabetes (P < 0.001) and average 24 h systolic blood pressure (SBP, P= 0.002) in a Cox model, for each 10% less reduction in the heart rate from day to night the relative risk of mortality was 1.30 (95% confidence interval 1.02-1.65, P = 0.04). Rates of death were 0.38, 0.71, 0.94 and 2.0 per 100 person-years among subjects in the four quartiles of the distribution of the percentage reduction in heart rate from day to night The baseline day-night changes in the heart rate exhibited an inverse correlation to age and to clinic and ambulatory SBP and a direct association with the day-night changes in blood pressure. The degree of reduction of heart rate from day to night also had an independent inverse association with total cardiovascular morbidity after adjustment for age, diabetes and left ventricular hypertrophy, but this association did not remain significant when average 24 h SBP and the degree of day-night reduction in SBP were entered into the equation. CONCLUSIONS: A flattened diurnal rhythm of heart rate in uncomplicated subjects with essential hypertension is a marker of risk for subsequent all-cause mortality and this association persists after adjustment for several risk factors. For assessing these subjects, a limited and uniformly distributed period of ambulatory heart rate recording during the 24 h is clinically valuable.

Release of matrix proteins from mitochondria to cytosol during the prereplicative phase of liver regeneration.

70% partial hepatectomy (PH) in the rat causes a release, into the cytosolic fraction, of mitochondrial matrix proteins, namely the mitochondrial isoform of aspartate aminotransferase (mAAT) and malate dehydrogenase (MDH), during the first 24 h after PH, when no growth of the residual liver is observed. After this time interval, the weight of the liver starts to increase and the normal weight is reached at 96 h after PH. This proliferative phase is characterized by a progressive recovery of the normal levels of intramitochondrial activities of mAAT and MDH. Mitochondria isolated at 24 h after PH show a membrane permeabilization to sucrose accompanied by a release of matrix enzymes; both are blocked by cyclosporin A. These results suggest an alteration of mitochondrial membrane integrity, during the prereplicative phase of liver regeneration, with the occurrence of an increased permeability that allows the passage into the cytosol of matrix enzymes.