Search for Daily Modulation of MeV Dark Matter Signals with DAMIC-M.

Dark matter (DM) particles with sufficiently large cross sections may scatter as they travel through Earth's bulk. The corresponding changes in the DM flux give rise to a characteristic daily modulation signal in detectors sensitive to DM-electron interactions. Here, we report results obtained from the first underground operation of the DAMIC-M prototype detector searching for such a signal from DM with MeV-scale mass. A model-independent analysis finds no modulation in the rate of 1 e^{-} events with sidereal period, where a DM signal would appear. We then use these data to place exclusion limits on DM in the mass range [0.53,2.7] MeV/c^{2} interacting with electrons via a dark photon mediator. Taking advantage of the time-dependent signal we improve by ∼2 orders of magnitude on our previous limit obtained from the total rate of 1 e^{-} events, using the same dataset. This daily modulation search represents the current strongest limit on DM-electron scattering via ultralight mediators for DM masses around 1 MeV/c^{2}.

First Constraints from DAMIC-M on Sub-GeV Dark-Matter Particles Interacting with Electrons.

We report constraints on sub-GeV dark matter particles interacting with electrons from the first underground operation of DAMIC-M detectors. The search is performed with an integrated exposure of 85.23 g days, and exploits the subelectron charge resolution and low level of dark current of DAMIC-M charge-coupled devices (CCDs). Dark-matter-induced ionization signals above the detector dark current are searched for in CCD pixels with charge up to 7e^{-}. With this dataset we place limits on dark matter particles of mass between 0.53 and 1000 MeV/c^{2}, excluding unexplored regions of parameter space in the mass ranges [1.6,1000] MeV/c^{2} and [1.5,15.1] MeV/c^{2} for ultralight and heavy mediator interactions, respectively.

Results on Low-Mass Weakly Interacting Massive Particles from an 11 kg d Target Exposure of DAMIC at SNOLAB.

We present constraints on the existence of weakly interacting massive particles (WIMPs) from an 11 kg d target exposure of the DAMIC experiment at the SNOLAB underground laboratory. The observed energy spectrum and spatial distribution of ionization events with electron-equivalent energies >200 eV_{ee} in the DAMIC CCDs are consistent with backgrounds from natural radioactivity. An excess of ionization events is observed above the analysis threshold of 50 eV_{ee}. While the origin of this low-energy excess requires further investigation, our data exclude spin-independent WIMP-nucleon scattering cross sections σ_{χ-n} as low as 3×10^{-41} cm^{2} for WIMPs with masses m_{χ} from 7 to 10 GeV c^{-2}. These results are the strongest constraints from a silicon target on the existence of WIMPs with m_{χ}<9 GeV c^{-2} and are directly relevant to any dark matter interpretation of the excess of nuclear-recoil events observed by the CDMS silicon experiment in 2013.

Constraints on Light Dark Matter Particles Interacting with Electrons from DAMIC at SNOLAB.

We report direct-detection constraints on light dark matter particles interacting with electrons. The results are based on a method that exploits the extremely low levels of leakage current of the DAMIC detector at SNOLAB of 2-6×10^{-22} A cm^{-2}. We evaluate the charge distribution of pixels that collect <10e^{-} for contributions beyond the leakage current that may be attributed to dark matter interactions. Constraints are placed on so-far unexplored parameter space for dark matter masses between 0.6 and 100 MeV c^{-2}. We also present new constraints on hidden-photon dark matter with masses in the range 1.2-30 eV c^{-2}.

First Direct-Detection Constraints on eV-Scale Hidden-Photon Dark Matter with DAMIC at SNOLAB.

We present direct detection constraints on the absorption of hidden-photon dark matter with particle masses in the range 1.2-30 eV c^{-2} with the DAMIC experiment at SNOLAB. Under the assumption that the local dark matter is entirely constituted of hidden photons, the sensitivity to the kinetic mixing parameter κ is competitive with constraints from solar emission, reaching a minimum value of 2.2×10^{-14} at 17 eV c^{-2}. These results are the most stringent direct detection constraints on hidden-photon dark matter in the galactic halo with masses 3-12 eV c^{-2} and the first demonstration of direct experimental sensitivity to ionization signals <12 eV from dark matter interactions.

A metabolic fragment of bradykinin, Arg-Pro-Pro-Gly-Phe, protects against the deleterious effects of lipopolysaccharide in rats.

Extensive research has provided few therapeutic agents for the treatment of septicemia. Bradykinin, an endogenous vasodepressor hormone, is a key mediator in the hypotension seen with septicemia. The present investigation shows that a stable metabolic fragment of bradykinin, arginine-proline-proline-glycine-phenylalanine (RPPGF), prevents the deleterious effects of endotoxin [lipopolysaccharide (LPS); a component of the membrane of Gram negative bacteria], the signaling agent responsible for the effects of septicemia, in both anesthetized rats and in isolated rat aortic segments. Survival time of rats treated with LPS (12 mg/kg) was significantly (p < 0.05) prolonged by pretreatment with RPPGF [140.3 +/- 16 min (n = 10)] compared with rats receiving saline and LPS [93.2 +/- 8 min (n = 39)]. Prolongation of survival was not seen when rats were pretreated with either bradykinin or with PRGFP (proline-arginine-glycine-phenylalanine-proline). Isolated aortic segments treated with LPS (30 microg/ml) showed a significantly reduced ability to contract in response to phenylephrine compared with control segments not receiving LPS. Pretreatment of the segments with RPPGF significantly reversed the LPS-induced reduction in contractile response of the segments. Removal of the endothelial layer did not alter the protection provided by RPPGF. These results demonstrate the ability of a stable metabolic fragment of bradykinin, RPPGF, to protect against the deleterious effects produced by LPS. The findings presented here may provide the basis for a new developmental area for novel therapeutic agents in the treatment of septicemia.

Evaluation of cardiovascular parameters by continuous 24 hour monitoring in diabetic hypertensive patients with autonomic neuropathies.

Correlations between scores of autonomic neuropathy severity in diabetic hypertensive subjects and behaviour of cardiovascular parameters detected by continuous 24 hour monitoring were investigated in order to reveal any alterations hat indicated onset and progression of disautonomy. R-R and Q-T patterns, circadian pressure rhythm and ECG Holter over 24 hours were analysed in 30 patients divided into various groups (age, duration of disease, treatment) and 10 controls. Three autonomic tests (deep breathing, postural hypotension, lying to standing) were performed and the relative Ewing scores recorded. Data obtained were analysed using Pearson's correlation test and simple linear regression. The results not only confirm circadian rhythm demodulation of arterial pressure, but also show progressive correlation between the scores obtained and modified cardiovascular parameters. According to the authors, detection of these intermediate alterations may be useful in forecasting possible onset or evolution of dysautonomic pathologies.

Hypertensive effect of tissue kallikrein in rostral ventrolateral medulla is mediated by brain kinins.

Microinjections of kallikrein, 0.5-2.0 units, in the rostral ventrolateral medulla (RVLM) of brain increased arterial pressure in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). This effect was significantly greater in SHR. The kinin B2 receptor antagonist icatibant (Hoe 140) blocked the hypertensive responses to kallikrein in both groups and caused greater hypotension and bradycardia in SHR. These results suggest that local kinins in the RVLM act to alter cardiovascular function and may be involved in the maintenance of blood pressure in the SHR.

Brain kallikrein-kinin system abnormalities in spontaneously hypertensive rats.

The objective of the present study was to determine whether the brain kallikrein-kinin system differs between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and if so, whether any detected differences occur before the development of hypertension in SHR. We measured cerebrospinal fluid levels of various components of the system in adult and young prehypertensive SHR and WKY. Cerebrospinal fluid kinin concentration and appearance rate were higher in SHR. Cerebrospinal fluid active kallikrein level and kininogenase activity were also higher in adult SHR. In addition, cerebrospinal fluid kinin concentration and appearance rate were higher in prehypertensive, 5- to 6-week-old SHR compared with age-matched WKY. However, no differences in cerebrospinal fluid kallikrein or kininogenase activity were observed between the two strains of young rats. Cerebrospinal fluid kinin concentration was higher in young versus adult rats of the same strain. In WKY, cerebrospinal fluid kallikrein also decreased with age although cerebrospinal fluid kallikrein concentration did not decrease in young and adult SHR. Together, these data suggest that there is a hyperactive kallikrein-kinin system in the brain of SHR that may contribute to the hypertensive state in this animal model.

Rostral ventrolateral medulla as a site for the central hypertensive action of kinins.

In the present study, we focused on the rostral ventrolateral medulla as a possible site of action for kinins because of its established importance in the central regulation of the cardiovascular system. Unilateral microinjections of 100 pmol to 4 nmol bradykinin into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure in Sprague-Dawley (SD) rats, Wistar-Kyoto (WKY) rats, and spontaneously hypertensive rats (SHR). The dose-response curves for the hypertensive responses to bradykinin in SD and WKY rats were essentially the same, whereas the hypertensive effect of bradykinin was significantly greater in SHR than in either SD or WKY rats. The kinin B2 receptor antagonists D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin and Hoe 140 inhibited the hypertensive responses to bradykinin in both SHR and WKY rats. The hypertensive effect of 500 pmol bradykinin was reduced 65 +/- 5% after 4 nmol of D-Arg0, Hyp3,Thi5,8,D-Phe7-bradykinin in SHR and 50 +/- 16% in WKY rats, whereas 1 nmol Hoe 140 abolished the hypertensive effect of 500 pmol bradykinin injected into the rostral ventrolateral medulla. Microinjection of D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin produced prolonged dose-dependent decreases in mean arterial pressure and heart rate. Blood pressure decreased 70 +/- 8 mm Hg and heart rate decreased 49 +/- 9 beats per minute in SHR, whereas in WKY rats mean arterial pressure decreased 12 +/- 4 mm Hg, with no change in heart rate. In a similar fashion, Hoe 140 caused a 51 +/- 7 and 17 +/- 3 mm Hg reduction in blood pressure in SHR and WKY rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid kallikrein in spontaneously hypertensive and desoxycorticosterone acetate-salt hypertensive rats.

OBJECTIVE: To determine whether immunoreactive tissue kallikrein levels in cerebrospinal fluid (CSF) of spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)--salt-treated hypertensive rats are elevated compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats. DESIGN: The present study was designed to test the hypothesis that the activity of the brain tissue kallikrein-kinin system is enhanced in hypertensive states. METHODS: Age-matched 18- to 19-week-old SHR and WKY rats, and Sprague-Dawley rats treated for 6 weeks either with 2 mg/kg per day DOCA subcutaneously and 0.9% saline in the drinking water, or with vehicle and tap water to drink, were studied. CSF was collected from a cannula inserted into the cisterna magna, and was frozen until the tissue kallikrein in the samples was measured by radioimmunoassay. Arterial pressure in the SHR and WKY rats was measured directly via a cannula inserted in the femoral artery or by tail-cuff plethysmography. RESULTS: In adult 18- to 19-week-old SHR the CSF kallikrein concentration was higher than in WKY rats. The CSF flow rate in SHR was also higher than in WKY rats. The rate of appearance of kallikrein in the CSF of SHR was twice that in WKY rats. Moreover, CSF kininogenase activity in SHR was significantly higher than that in age-matched WKY rats. In DOCA--salt hypertensive rats the CSF kallikrein concentration was higher than in vehicle-treated control rats. Acute elevation of blood pressure with a 120-min intravenous phenylephrine infusion did not change the CSF kallikrein concentration in 50 rats compared with vehicle-treated control rats. This is the first study to quantitate immunoreactive tissue kallikrein in the CSF of rats and to show elevated levels of CSF kallikrein in hypertensive rats compared with normotensive rats. CONCLUSION: The present data suggest that higher brain kallikrein activity in hypertensive rats may play a role in the development of elevated blood pressure.

Autoradiographic visualization and characteristics of [125I]bradykinin binding sites in guinea pig brain.

The present study was undertaken to localize and characterize bradykinin (BK) binding sites in 10 microns serial sections of guinea pig brain by in vitro quantitative receptor autoradiography. Specific binding of [125I-Tyr8]bradykinin ([125I]BK) was localized in the medulla oblongata to the regions of the nucleus of the solitary tract (nTS), the area postrema (AP), the dorsal motor nucleus of the vagus (X) and the caudal subnucleus of the spinal trigeminal nucleus. No significant specific [125I]BK binding was seen in other brain regions. The specific binding (85-90% of total binding) was of high affinity and saturable with a KD of 73.5 +/- 9.9 pM and a Bmax of 27.8 +/- 1.9 amol per mm2 of tissue. In competition studies, the rank order of potencies was: BK greater than Met-Lys-BK greater than Lys-BK much greater than Des-Arg9-BK. The B2 receptor antagonist D-Arg0-Hyp3-Thi5,8-D-Phe7-BK inhibited [125I]BK binding with a Ki value of 3.5 +/- 1.5 nM while Des-Arg9-[Leu8]-BK, a B1 receptor antagonist did not significantly inhibit [125I]BK binding in concentrations up to 10 microM. Our finding of specific high affinity [125I]BK binding sites in the nTS, AP and the X is important because these brain areas are known to be involved in central cardiovascular regulation. Moreover, our results suggest that the specific [125I]BK binding sites in the guinea pig medulla are of the bradykinin B2 receptor type.

A stereoselective central hypotensive action of atenolol.

Previous studies have demonstrated that propranolol can lower arterial pressure through an action within the central nervous system. The purpose of this study was to determine 1) whether the hydrophilic beta blocking drug atenolol which is devoid of membrane stabilizing activity can reduce arterial pressure through a central action and 2) whether this action is stereoselective for the (-)-, or beta receptor blocking enantiomer. Studies were conducted in the anesthetized spontaneously hypertensive (SH) rats in which the cardiovascular effects of (-)- and (+)- atenolol were compared after i.v. or intracisternal administration. Intravenous injection of 100 micrograms/kg of (-)-atenolol reduced mean arterial pressure 25 +/- 5 mm Hg (P less than .02) and lowered heart rate 58 +/- 7 bpm (P less than .02). The same dose of (+)-atenolol i.v. produced no significant changes in either mean arterial pressure or heart rate. Similarly, intracisternal (-)-atenolol, 66 micrograms/kg, significantly (P less than .05) reduced mean arterial pressure and heart rate whereas the same dose of the (+)-isomer was without effect. When the i.v. dose of (-)-atenolol was lowered to 33 micrograms/kg, heart rate was decreased markedly but mean arterial pressure was not reduced. In contrast, 33 micrograms/kg of intracisternal (-)- atenolol significantly reduced mean arterial pressure 17 +/- 6 mm Hg and reduced heart rate. These results suggest that atenolol possesses a central hypotensive action that is selective for the (-)-, beta receptor blocking enantiomer.

[Plasma lipids, insulin, C-peptide, and glucagon levels in cirrhosis: personal observations]. / Frazioni lipidiche plasmatiche, insulina, C-peptide e glucagone in gruppi di cirrotici: considerazioni su osservazioni personali.

The authors report preliminary data on the behavior of some lipid fractions in cirrhosis of the liver and correlate them with the changes in the insulin, glucagon and C-peptide levels. Elevated FFA (Free Fatty Acids) and normal cholesterol, triglyceride and total lipid values indicate a prevalent insulin induced effect and a reduction of liver metabolism of these fractions. This hypothesis is supported by the fact that L-carnitine, which reestablishes the carnitine-dependent intracellular transport system, reduces the levels of all the lipid fractions studied. The normal C-peptide values in these patients with liver cirrhosis show that hyperinsulinemia is caused by impaired metabolism of this hormone and not by hyperincretion. This hyperinsulinemia seems to react positively to the improvement of the intracellular transport systems. A fall in the hyperglucagonemia follows the decreased hyperinsulinemia leading to a hormone balance with lower values and a consequent reduction of the hormonal stimuli on the lipid metabolism. The possibility of administering drugs, which can act on the metabolic pathways responsible for the high FFA plasma levels, which seem to play a role in the physiopathology of encephalopathies and hepatic coma is clinically interesting.

Stereochemistry of tissue distribution of racemic propranolol in the dog.

Only limited information is available on the stereochemistry of the in vivo distribution of beta-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)-vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.

C1 area of the rostral ventrolateral medulla as a site for the central hypotensive action of propranolol.

Previous studies suggest that the hypotensive response to centrally administered propranolol results from a drug-induced release of norepinephrine which then stimulates central alpha adrenergic receptors and, as a consequence, arterial pressure is lowered. Inasmuch as the C1 area of the rostral ventrolateral medulla is known to contain noradrenergic nerve terminals and participate in arterial pressure regulation, we determined whether this medullary region is a site mediating the hypotensive response to centrally administered propranolol. Bilateral microinjections (0.1 microliter) of dl-propranolol (0.25-2 nmol) into the C1 area of urethane-anesthetized rats resulted in a gradual reduction in mean arterial pressure which was sustained throughout the 120-min experimental period. The injection site was verified pharmacologically at the end of each experiment by bilateral microinjection of 10 nmol of tyramine and observing a further decrease in mean arterial pressure and a reduction in heart rate. Pretreatment of the C1 area bilaterally with reserpine 24 hr earlier significantly reduced the hypotensive responses to microinjections of both propranolol and tyramine whereas the hypotensive response to the direct acting agonist clonidine was unchanged. These results demonstrate that the C1 area of the rostral ventrolateral medulla is a site for a central hypotensive action of propranolol. Moreover, the data provide further evidence that the hypotensive action of centrally administered propranolol results from a drug-induced release of norepinephrine from central noradrenergic neurons.

Afferent vagal stimulation, vasopressin, and nitroprusside alter cerebrospinal fluid kinin.

The effects of afferent vagal stimulation, cerebroventricular vasopressin, and intravenous nitroprusside on cerebrospinal fluid (CSF) kinin levels, mean arterial pressure (MAP), and heart rate (HR) were determined in anesthetized dogs in which a ventriculocisternal perfusion system (VP) was established. Following bilateral vagotomy, stimulation of the central ends of both vagi for 60 min significantly increased MAP and CSF perfusate levels of kinin and norepinephrine (NE). MAP was increased a maximum of 32 +/- 4 mmHg, and the rates of kinin and NE appearance into the CSF perfusate increased from 4.2 +/- 1.4 to 22.1 +/- 6.9 and from 28 +/- 5 to 256 +/- 39 pg/min, respectively. A significant correlation was found between CSF kinin and NE levels in these experiments. In other experiments the addition of arginine vasopressin to the VP system caused a significant increase in CSF perfusate kinin without affecting MAP or HR. Intravenous infusion of nitroprusside lowered MAP without affecting kinin levels in the CSF. However, on cessation of nitroprusside infusion, CSF kinin increased significantly in association with the return in MAP to predrug level. Collectively the data are consistent with the hypothesis that central nervous system kinins have some role in cardiovascular regulation, and furthermore that this role may involve an interaction between brain kinin and central noradrenergic neuronal pathways.

Site and mechanism of the centrally mediated hypotensive action of propranolol.

Ventriculocisternal perfusion of propranolol (25 micrograms/kg/min for 30 min) throughout the entire brain ventricular system in anesthetized dogs decreased arterial pressure and increased cerebrospinal fluid (CSF) norepinephrine. Localized perfusion of propranolol into the fourth ventricle produced increased CSF norepinephrine levels and a hypotensive response comparable to that seen with whole-brain ventriculocisternal perfusion. In comparison, perfusion of propranolol through the forebrain (lateral-third) ventricles resulted in changes in CSF norepinephrine comparable to those observed with the administration of the drug into the fourth ventricle but resulted in a reduced hypotensive response. Increased CSF norepinephrine levels and a hypotensive response were also observed after peripheral i.v. infusion of propranolol (100 micrograms/kg/min for 45 min). Collectively, these results support the hypothesis that an interaction of propranolol at noradrenergic nerve terminals in the hindbrain area results in a hypotensive effect which may contribute to the antihypertensive action of the drug.

Effects of captopril on limiting infarct size in conscious dogs.

The effects of angiotensin-converting enzyme inhibitor captopril on infarct size and cardiovascular hemodynamics were studied in 35 conscious dogs subjected to 24 h of coronary occlusion. Following occlusion of the left anterior descending coronary artery, 10 dogs were infused with captopril 0.25 mg/kg/h i.v. (group 1), eight dogs received captopril 0.5 mg/kg/h i.v. (group 2), and 17 dogs served as saline-infused controls. All infusions were started 10 min following occlusion and continued for 15 h. Eighty-eight percent of untreated dogs and 80% of group 1 captopril dogs survived the 24-h duration of the study. No experimental deaths occurred in group 2 captopril dogs. Arterial blood pressure had decreased 10-12 mm Hg in both captopril groups by 4 h and remained relatively stable for the remainder of the study period. In untreated dogs, blood pressure was unchanged for 6 h, then began a gradual decline. There were no significant differences in infarct size among the groups. When infarct size is expressed as percent of left ventricle at risk the values were: control, 39.9 +/- 5.6; captopril group 1, 44.8 +/- 4.9; and captopril group 2, 43.8 +/- 7.8%. Creatine kinase levels were not different among the groups. Heart rate and incidence of arrhythmias also did not differ among the groups. These data show that captopril had no detrimental or beneficial effects on infarct size or on cardiovascular hemodynamics associated with myocardial infarction in conscious dogs.