Demonstration of event position reconstruction based on diffusion in the NEXT-white detector.

Noble element time projection chambers are a leading technology for rare event detection in physics, such as for dark matter and neutrinoless double beta decay searches. Time projection chambers typically assign event position in the drift direction using the relative timing of prompt scintillation and delayed charge collection signals, allowing for reconstruction of an absolute position in the drift direction. In this paper, alternate methods for assigning event drift distance via quantification of electron diffusion in a pure high pressure xenon gas time projection chamber are explored. Data from the NEXT-White detector demonstrate the ability to achieve good position assignment accuracy for both high- and low-energy events. Using point-like energy deposits from 83mKr calibration electron captures (E∼45 keV), the position of origin of low-energy events is determined to 2 cm precision with bias <1mm. A convolutional neural network approach is then used to quantify diffusion for longer tracks (E≥1.5 MeV), from radiogenic electrons, yielding a precision of 3 cm on the event barycenter. The precision achieved with these methods indicates the feasibility energy calibrations of better than 1% FWHM at Qßß in pure xenon, as well as the potential for event fiducialization in large future detectors using an alternate method that does not rely on primary scintillation.

Effect of breed body-size on leptin amniotic fluid concentrations at term pregnancy in dogs.

Because of the need to improve the knowledge about canine perinatology, and given the major role of fetal fluids in sustaining the course of pregnancy and fetal development, an in-depth analysis to better understand the role of some hormones in these compartments is essential. Among all, leptin is recognized to play a key role not only on the energetic homeostasis, but also at multiple levels, influencing the control of reproduction, food assumption and metabolism. Even if in humans and other species it is reported the presence of leptin receptors during fetal development, very little is known about the canine species, in which the role of leptin still needs to be fully understood. The present study aimed to assess the amniotic fluid leptin (AFL) concentrations at term pregnancy in healthy dogs, and to evaluate the possible influence played by breed body-size (after assessment of correlation with maternal bodyweight and placental weight), or other maternal (age, parity, and the so-called "litter effect") and neonatal (gender, birth weight, litter size) parameters on AFL concentrations, analyzed by ELISA test. The study was performed on 90 healthy, viable and normal weighted puppies, 39 small-sized (adult body weight < 10 kg) and 51 large-sized (adult body weight > 25 kg), born by 29 purebred, healthy bitches, submitted to elective Caesarean section because of breed-related or individual high risk for dystocia. The results showed that the mean AFL concentration in the small-sized puppies was significantly (p < 0.05) higher in comparison to large-sized puppies (867.48 vs 698.42 pg/ml), while all the other studied parameters did not show to influence AFL concentrations. In conclusions, the present study showed significant higher at term AFL concentrations in small-sized as compared to large-sized breeds, suggesting an influence of breed body-size on fetal metabolism, as previously reported for NEFA and IGF-I.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

Plasma and synovial fluid concentrations of nimesulide and its main metabolite after a single or repeated oral administration in patients with knee osteoarthritis.

The aim of this study was to evaluate plasma and synovial fluid concentrations of the non-steroidal anti-inflammatory drug nimesulide and its major metabolite (hydroxynimesulide, M1), after a single 100 mg dose of nimesulide and a repeated (14 day) administration, 100 mg twice a day, in patients with osteoarthritis of the knee and joint effusion. Nimesulide was rapidly absorbed in plasma and distributed in synovial fluid. On day 1, effective concentrations were present 30 min after the first dose and on day 14, the synovial fluid concentration of nimesulide was significantly higher than that measured on day 1; no accumulation was observed in plasma. After 14 days of treatment, both the plasma and synovial fluid concentrations of M1 were significantly higher than those measured on day 1. These data may help to explain the rapid onset of the analgesic effect of nimesulide demonstrated in several clinical conditions, including painful osteoarthritis.

Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis: comparison with paracetamol.

Both the analgesic drugs tramadol and paracetamol are widely used for the symptomatic therapy of osteoarthritis (OA). The aim of this double-blind, randomised study in patients with knee OA was to compare their effects on synovial fluid concentrations of interleukin (IL)-6 and substance P (SP). Moreover, we evaluated plasma and synovial fluid concentrations of tramadol and its active metabolite (O-desmethyl-tramadol, M1) after oral treatment with this drug. Twenty patients were enrolled. A group of 10 patients received tramadol (50 mg three times a day), and another group of 10 patients were treated with paracetamol (500 mg three times a day) for 7 days. Both drugs significantly reduced the intensity of joint pain. The synovial fluid concentrations of SP were significantly reduced only by the treatment with tramadol. In this group of patients, IL-6 synovial fluid concentrations were slightly, but not significantly, decreased. Paracetamol did not significantly change the synovial fluid concentrations of SP and IL-6. After oral administration, a considerable amount of tramadol was measurable in synovial fluid. Both in plasma and synovial fluid the concentrations of M1 were markedly lower than those of tramadol, with a T/M1 ratio of 14.7+/-4.6 and 9.3+/-3.9, respectively. These data demonstrate that the activity of tramadol may involve the modulation of inflammatory mediators. Moreover, they indicate that after oral treatment with tramadol, both the parent drug and its active metabolite can penetrate into synovial fluid.

Interleukin-6 affects scopolamine-induced amnesia, but not brain amino acid levels in mice.

We have previously shown that, after peripheral administration, different cytokines affect cognitive functions in mice. In this study, we evaluated the effects of mouse interleukin-6 (IL-6) on the classical behavioural test of scopolamine-induced amnesia for a passive avoidance response in the mouse. Pretraining i.p. administration of this cytokine (0.125 and 0.5 microgram/mouse) significantly reduced the amnesic action of the muscarinic receptor antagonist. As it is well known that brain amino acids are deeply involved in the modulation of cognitive processes we measured the levels of glutamine, aspartic acid, glutamic acid and GABA in the hippocampus and hypothalamus of mice treated with IL-6. At both doses which affected the cognitive functions, this cytokine had no effect on brain levels of measured amino acids. Neither nociceptive thresholds to a thermal stimulus, nor spontaneous locomotor activity were modified by the acute administration of IL-6 (0.5 microgram/mouse). Our data confirm previous observations indicating that peripheral administration of cytokines affects some, but not other brain functions and suggest the involvement of IL-6 in the central modifications induced by the immune activation.

GM-CSF affects hypothalamic neurotransmitter levels in mice: involvement of interleukin-1.

We studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on the brain levels of several neurotransmitters in mice. Administration of GM-CSF (5.0 and 10 microg, i.p.) significantly reduced the hypothalamic levels of glutamine, glutamic acid, GABA and aspartic acid. GM-CSF (5.0 microg, i.p.) also induced a significant reduction of norepinephrine and serotonin levels in the hypothalamus, without affecting dopamine levels. The hippocampal levels of neurotransmitters were not modified by GM-CSF administration. The peripheral administration of a specific interleukin-1 receptor antagonist (IL-1ra, 50 microg, i.p.) blocked the effects of GM-CSF. These results confirm our previous behavioural data suggesting that GM-CSF is able to exert neuromodulatory actions.

[Daily survey of procedures as markers of resources utilization]. / Rilevazione giornaliera di procedure come tracciante dell'utilizzo di risorse.

OBJECTIVE: To assess and to follow along the time-span of ICU stay the process of resources allocation and utilization. DESIGN: Prospective study. PATIENTS: A cohort of 778 patients consecutively admitted to 7 multipurpose general ICU in the Milano area were enrolled in a survey of the daily performed interventions/procedures. MEASUREMENTS AND MAIN RESULTS: The majority of diagnostic procedure/interventions were performed during the first two days. The number and quality of interventions were transferred into points obtaining a score system in non-monetary units. The resource allocation process shows a regular trend in the sub-intensive patients who were only monitorized. On the contrary the 258 patients who were intensively treated and survived show a phase of high resource-consumption (about 30 daily points: roughly twice the score of monitorized patients) then followed by a post-intensive phase with a resource consumption resulting in a daily score absolutely equal to the sub-intensive patients. The intensive patients who die show a significantly higher score than survived patients. Both daily and cumulative scores do not show differences among different type of patients. CONCLUSION: The evaluation of the process of resources allocation, even if in non-monetary units enables the knowledge of the trend of ICU costs and allows the elaboration of the appropriate budget mechanism.

Effects of interleukin-1 beta and interleukin-2 on amino acids levels in mouse cortex and hippocampus.

We measured the levels of glutamine, aspartic acid, glutamic acid and GABA in cortex and hippocampus of mice acutely treated with i.p. human recombinant interleukin-2 (IL-2) or human recombinant interleukin-1 beta (IL-1 beta). Administration of IL-2 (5.0 micrograms kg-1) induced a slight but statistically significant increase in glutamine concentrations in both brain areas, while similar administration of IL-1 beta (20 micrograms kg-1) significantly reduced the hippocampal levels of glutamine, glutamic acid and GABA. Our data suggest that brain amino acid pathways are involved in the central modifications induced by IL-1 beta.

Neurochemical changes of long-term adrenalectomy in rat brain: effects on neurotransmitter amino acids.

The levels of five amino acids together with glutamine synthetase activity, were measured in brain regions of rats with bilateral adrenalectomy, performed in newly weaning rats on postnatal day 22 and sacrificed 3 months later. Adrenalectomy caused a general decrease of glutamine concentration in three hippocampal regions (CA1-CA2, CA3, CA4-dentate gyrus), in hypothalamus, striatum and cerebellum. This reduction, which was particularly significant in hippocampus and cerebellum, was paralleled by a decrease of glutamine synthetase activity. Treatment with corticosterone reversed the effect of adrenalectomy. Little or no change was observed in the tissue levels of taurine, aspartic, glutamic or gamma-amino butyric acids.

Susceptibility to seizures produced by chemical convulsants and maximal electric shock in rats after electrolytic lesions into the red nucleus.

Bilateral electrolytic lesions into the red nucleus (RN) of rat elicit an increase in susceptibility to seizures induced by pilocarpine, kainic acid, isoniazid, pentylenetetrazole, bicuculline and maximal electric shock (MES). It was also observed that carbachol-induced wet-dog shakes were increased in the RN-lesioned rats. The brain acetylcholine (ACh) and gamma-aminobutyric acid (GABA) concentrations were significantly decreased in the striatum and substantia nigra, respectively. There were no changes in electroencephalogram (EEG) recordings in the RN-lesioned group compared with sham-operated rats. Based on the results it is proposed that the RN is involved in the generalization and acceleration of seizure activity through the cholinergic and GABA-ergic system.

Neurotransmitter amino acid variations in striatum of rats exposed to 50 Hz electric fields.

Concentration of neurotransmitter amino acids (Tau, Gly, Asp, Glu, Gln, Ala, GABA) were measured in rat striatum following varying exposure (320 to 1408 h) to high intensity (50 Hz) electric fields. Tissue extracts in methanol, after drying, were derivatized with dansyl chloride and the amino acids quantitated by high-pressure liquid chromatography with ultraviolet detection. Short exposures (320 h) to 100 kV/m field induced a decrease in almost all tested amino acids. Longer exposure times (640 h) to 25 and 100 kV/m were only associated with a decrease in Tau. A further increase of the exposure time (1240 and 1408 h) both at 25 and 180 kV/m were mainly associated with a reduction of the amino acid levels. It is concluded that electric fields in the range 20-180 kV/m generate bimodal variations in neurotransmitter amino acids with troughs at very short and longer exposure times, independent from the field strength.

Determination of diclofenac and its metabolites in plasma and cerebrospinal fluid by high-performance liquid chromatography with electrochemical detection.

A reversed-phase high-performance liquid chromatographic method with electrochemical detection for the quantitation of diclofenac and metabolites in plasma and cerebrospinal fluid has been developed. Pirprofen is employed as internal standard. Samples are extracted with C18 solid-phase extraction columns and eluted with methanol. Oxidation potentials for detection were established by constructing voltammograms for each compound. In the concentration range found in human studies, the intra-day coefficients of variation were always less than 6%. The procedure allows the simultaneous determination of diclofenac and its four major metabolites with very low detection limits (less than 1 ng/ml), which were sufficient even for kinetic studies in cerebrospinal fluid.

Effects of diazepam on nociception in rats.

Acute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg-1 day-1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency. Diazepam injected intracerebroventricularly (1, 5, 20 micrograms/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 micrograms/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency. These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

In vivo metabolism and kinetics of 99mTc-HMPAO.

The cerebral distribution of 99mTc-labeled d, l, hexamethyl-propylene-amine-oxime (99mTc-HMPAO) as a function of rCBF and time was examined in rats and in man. The results of this study confirm that 99mTc-HMPAO is distributed in brain in proportion to rCBF. However, the rapid systemic breakdown of the tracer in blood results in considerable difficulties in the assessment of the arterial concentration of the parent compound; incomplete extraction of 99mTc-HMPAO from blood to brain and significant efflux from brain represent further limitations in the use of this tracer for quantification of rCFB. Despite these limitations 99mTc-HMPAO is of potential interest for a qualitative assessment of rCBF in specific clinical conditions.

Analysis of pirprofen in cerebrospinal fluid, plasma, and synovial fluid by high-performance liquid chromatography with electrochemical detection.

We describe a high-performance liquid chromatographic method, using electrochemical detection, for the determination of pirprofen in cerebrospinal fluid (CSF), plasma, and synovial fluid (SF). A C-18 column with a mobile phase containing acetonitrile acetate:phosphate buffer (pH 3.0) was employed. Samples were added with phosphoric acid, then extracted into dichloromethane, evaporated, and injected into the chromatograph. A detection potential of +0.85 V was applied on the basis of current-potential curves. Good linearity was found for each fluid in the expected range of therapeutic concentrations. The detection limit was 0.1 ng/mL for CSF, and 1 ng/mL for plasma and SF, with a recovery greater than 96% and intraday coefficient of variation less than 5% in all cases. The main advantages of this method include high specificity and sensitivity which allow the analysis of CSF and the use of small volumes of plasma and SF. The application of the method for the analysis of plasma and SF samples and the kinetic profile in CSF are shown.

Pharmacokinetics of buflomedil after various dosage forms.

The pharmacokinetic disposition of buflomedil was compared in humans after oral administration of solution, tablets and film tablets. Six healthy male volunteers received a single oral dose of the three different dosage formulations. Blood and urine samples were taken before dosing and at selected times over 24 h and 72 h, resp., after dosing. The concentration of the drug in samples was measured by gas-chromatography with nitrogen detector. The absorption of buflomedil was faster after solution administration, while other plasma parameters did not show any major differences. Also the amount of drug excreted in urines was higher with solution dosing.