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1.
Rev Sci Instrum ; 94(5)2023 May 01.
Article in English | MEDLINE | ID: mdl-37184347

ABSTRACT

We report on progress implementing and testing cryogenically cooled platforms for Magnetized Liner Inertial Fusion (MagLIF) experiments. Two cryogenically cooled experimental platforms were developed: an integrated platform fielded on the Z pulsed power generator that combines magnetization, laser preheat, and pulsed-power-driven fuel compression and a laser-only platform in a separate chamber that enables measurements of the laser preheat energy using shadowgraphy measurements. The laser-only experiments suggest that ∼89% ± 10% of the incident energy is coupled to the fuel in cooled targets across the energy range tested, significantly higher than previous warm experiments that achieved at most 67% coupling and in line with simulation predictions. The laser preheat configuration was applied to a cryogenically cooled integrated experiment that used a novel cryostat configuration that cooled the MagLIF liner from both ends. The integrated experiment, z3576, coupled 2.32 ± 0.25 kJ preheat energy to the fuel, the highest to-date, demonstrated excellent temperature control and nominal current delivery, and produced one of the highest pressure stagnations as determined by a Bayesian analysis of the data.

2.
Chem Commun (Camb) ; 57(95): 12804-12807, 2021 Nov 30.
Article in English | MEDLINE | ID: mdl-34783334

ABSTRACT

Silica is widely used in industrial applications and its performance is partially decided by its surface hydroxyl density αOH. Here we report a quick, simple liquid 1H NMR method to determine αOH using a benchtop 1H NMR spectrometer. The results show excellent agreement with the literature with an αOH range from 4.16 to 6.56 OH per nm2.

3.
Epilepsy Res ; 178: 106805, 2021 12.
Article in English | MEDLINE | ID: mdl-34768048

ABSTRACT

Many people with epilepsy suffer from comorbid sleep disorders and sleep fragmentation. While the disruptive nature of seizures on sleep is well documented, it is unclear how diurnal seizures impact sleep quality and for how long these changes persist during the following nights. To better understand this relationship, the sleep architecture of two rhesus macaques were studied before and several nights after penicillin-induced diurnal seizures. These focal seizures stopped naturally, and none occurred at night. We scored sleep-stage during the nights immediately following the seizures, as well as several nights after seizure induction. We noted a significant increase in movement along with a decrease in sleep efficiency, both limited to the night of seizure induction. For both animals, we observed a significant decrease in the number of REM periods that manifested as a decrease in total REM sleep duration, and this phenomenon persisted up to 2 nights after the seizures. We also found a significant increase in the probability to transition from stage N2 to stage N1 on the night of the seizures. This study shows for the first time that the NHP model of penicillin-induced cortical seizures exhibits significant changes in sleep architecture, including an increase in nocturnal movement, change in sleep architecture and a prolonged decrease in REM activity. The prolonged decrease in REM periods compared to the temporary enhanced movement and reduction of sleep efficiency suggest that these seizures may affect two neural circuits, one controlling REM sleep entry and the other controlling nocturnal wakefulness.


Subject(s)
Sleep Deprivation , Sleep, REM , Animals , Electroencephalography , Humans , Macaca mulatta , Seizures/chemically induced , Sleep , Sleep Deprivation/complications , Wakefulness
5.
Rev Sci Instrum ; 92(7): 073505, 2021 Jul 01.
Article in English | MEDLINE | ID: mdl-34340419

ABSTRACT

A deuterium-ice extruder has been developed for inertial confinement fusion experiments on the Sandia National Laboratories Z Facility. The screw-driven extruder is filled via desublimation, where a slow flow of deuterium gas enters the extruder cavity and freezes to the walls without entering the liquid phase. Ice generated in this manner is optically clear, demonstrating its high uniformity. When the extruder cavity is filled with ice, the screw is driven downward, closing off the gas-fill line. With the ice cavity isolated, further screw rotation compresses the deuterium through a nozzle, extruding a fiber. Fiber diameters ranging from 200 to 500 µm have been extruded to lengths of 1.5 feet before hitting the vacuum chamber floor. The fiber straightness improves with the nozzle length-to-diameter aspect ratio. Deuterium-ice fibers can persist in high vacuum for more than 10 min before breaking free from the nozzle. The peripheral infrastructure required for Z experimental operations is under development. An in-vacuum stepper-motor-based drive system will allow remote operation, and a translating cathode will ensure proper placement of the fiber in the powerflow hardware.

6.
J Cardiothorac Surg ; 16(1): 205, 2021 Jul 28.
Article in English | MEDLINE | ID: mdl-34321019

ABSTRACT

BACKGROUND: Postoperative vasoplegia with minimal responsiveness to vasopressors is common after cardiac surgery. Called cardiac vasoplegic syndrome (CVS), it is caused by multiple factors. Treating CVS involves a high dose of fluids and catecholamines, however high doses of catecholamines and fluids are associated with serious side effects. There is evidence that new therapeutic strategies can lead to a reduction in norepinephrine doses and mortality in CVS. Specifically, the use of non-adrenergic vasopressors such as methylene blue (MB) can be beneficial. METHODS: We retrospectively analyzed the electronic records of 8716 adult cardiac surgery patients from November 2008 to December 2016. Medication, hemodynamic and outcome parameter data were analyzed for CVS until discharge. We determined CVS according to the following parameters: a postoperative onset of ≤24 h, a reduced mean arterial pressure (MAP) of < 70 mmHg, a dose of norepinephrine ≥0.8 mg*h- 1 and a continuously increasing need for catecholamine, without ventricular dysfunction. RESULTS: We identified 513 patients with CVS. Perioperative risk factors were higher in patients treated with methylene blue (MB). Before MB administration patients had a significantly higher dose of norepinephrine, and MAP increased after MB administration. Norepinephrine could be reduced after MB administration and MAP remained stable at the same level even after the reduction of norepinephrine. CONCLUSIONS: CVS patients have a severe systemic disease accompanied by significant operative stress and a high catecholamine requirement. The administration of MB in addition to standard treatment for CVS in the first 24 h was accompanied by an increase in MAP followed by a decrease in vasopressor requirement, indicating that early MB administration can be beneficial.


Subject(s)
Cardiac Surgical Procedures , Vasoplegia , Aged , Cardiac Surgical Procedures/adverse effects , Female , Humans , Male , Methylene Blue , Middle Aged , Retrospective Studies , Stroke Volume , Vasoplegia/drug therapy , Vasoplegia/etiology , Ventricular Function, Left
7.
J Neurosci ; 41(15): 3462-3478, 2021 04 14.
Article in English | MEDLINE | ID: mdl-33664133

ABSTRACT

Clinical and experimental data from the last nine decades indicate that the preoptic area of the hypothalamus is a critical node in a brain network that controls sleep onset and homeostasis. By contrast, we recently reported that a group of glutamatergic neurons in the lateral and medial preoptic area increases wakefulness, challenging the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic. However, the precise role of these subcortical neurons in the control of behavioral state transitions and cortical dynamics remains unknown. Therefore, in this study, we used conditional expression of excitatory hM3Dq receptors in these preoptic glutamatergic (Vglut2+) neurons and show that their activation initiates wakefulness, decreases non-rapid eye movement (NREM) sleep, and causes a persistent suppression of rapid eye movement (REM) sleep. We also demonstrate, for the first time, that activation of these preoptic glutamatergic neurons causes a high degree of NREM sleep fragmentation, promotes state instability with frequent arousals from sleep, decreases body temperature, and shifts cortical dynamics (including oscillations, connectivity, and complexity) to a more wake-like state. We conclude that a subset of preoptic glutamatergic neurons can initiate, but not maintain, arousals from sleep, and their inactivation may be required for NREM stability and REM sleep generation. Further, these data provide novel empirical evidence supporting the hypothesis that the preoptic area causally contributes to the regulation of both sleep and wakefulness.SIGNIFICANCE STATEMENT Historically, the preoptic area of the hypothalamus has been considered a key site for sleep generation. However, emerging modeling and empirical data suggest that this region might play a dual role in sleep-wake control. We demonstrate that chemogenetic stimulation of preoptic glutamatergic neurons produces brief arousals that fragment sleep, persistently suppresses REM sleep, causes hypothermia, and shifts EEG patterns toward a "lighter" NREM sleep state. We propose that preoptic glutamatergic neurons can initiate, but not maintain, arousal from sleep and gate REM sleep generation, possibly to block REM-like intrusions during NREM-to-wake transitions. In contrast to the long-standing notion in sleep neurobiology that the preoptic area is exclusively somnogenic, we provide further evidence that preoptic neurons also generate wakefulness.


Subject(s)
Glutamic Acid/metabolism , Hypothalamus/physiology , Neurons/physiology , Sleep, REM , Wakefulness , Animals , Brain Waves , Hypothalamus/cytology , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Vesicular Glutamate Transport Protein 2/genetics , Vesicular Glutamate Transport Protein 2/metabolism
8.
Nat Commun ; 12(1): 1200, 2021 02 22.
Article in English | MEDLINE | ID: mdl-33619256

ABSTRACT

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.


Subject(s)
Fear/physiology , Memory Consolidation/physiology , Memory/physiology , Sleep/physiology , Animals , Conditioning, Psychological/physiology , Cues , Electrodes , Fiber Optic Technology , Mice, Transgenic , Neuronal Plasticity/physiology , Neurons/physiology , Optogenetics , Sleep Deprivation/physiopathology , Visual Cortex/physiopathology
9.
PLoS One ; 16(2): e0246724, 2021.
Article in English | MEDLINE | ID: mdl-33571258

ABSTRACT

OBJECTIVES: Surgery for acute type A aortic dissection is associated with several perioperative complications, such as acute respiratory dysfunction (ARD). The aim of this study was to investigate perioperative risk factors involved in the development of ARD and whether antibiotic treatment has an impact. METHODS: 243 patients underwent surgery for acute type A aortic dissection between 2008 and 2017. The patients were retrospectively divided into the ARD and NON-ARD group. ARD was defined as PaO2/FiO2 ≤ 200 mmHg (PF ratio) within 48 hours after surgery. All patients received either narrow- or broad-spectrum antibiotics. RESULTS: After the exclusion of 42 patients, 201 patients were analyzed. The PF ratio of the ARD group was significantly lower than of the NON-ARD group within the first 7 days. ARD patients (n = 111) were significantly older (p = .031) and had a higher body mass index (BMI) (p = .017). ARD patients required longer postoperative ventilation (2493 vs. 4695 [min], p = .006) and spent more days in the intensive care unit (7.0 vs. 8.9 [days], p = .043) compared to NON-ARD. The mortality was significantly lower for ARD than for NON-ARD patients (p = .030). The incidence of pneumonia was independent of the antibiotic treatment regime (p = .391). Renal and neurological complication rate was higher in patients treated with broad-spectrum antibiotic. CONCLUSION: ARD is the main complication (55%) that occurs approximately 24 hours after surgery for acute type A aortic dissection. The preoperative risk factors for ARD were higher age and increased BMI. Patients on broad-spectrum antibiotics did not show an improved postoperative outcome compared to patients with narrow-spectrum antibiotics.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Aortic Dissection/surgery , Respiration Disorders/drug therapy , Aged , Female , Humans , Male , Middle Aged , Postoperative Complications/drug therapy , Postoperative Complications/etiology , Respiration Disorders/etiology , Retrospective Studies
10.
J Neurosci Methods ; 346: 108915, 2020 12 01.
Article in English | MEDLINE | ID: mdl-32822694

ABSTRACT

Radio telemetry systems are a useful way to continuously monitor broad electrical neuronal activity in behaving animals. It can also be used to study sleep disturbances or monitor seizure activity. Many different telemeter styles are available, but the more versatile and cost-efficient ones are the head mounted systems. They permit long-term recordings and allow more flexibility in the recordings. However, there are currently no such system available for non-human primate (NHP). In fact, the choices for NHP telemetry solutions are very limited. Here, we present a chronically implantable 3D printed chamber specifically designed to accommodate a rodent head-mounted system (RodentPACK) onto a NHP's head. We recorded EEG signal for more than a year, confirmed quality of the signal, and the ability to use the data to monitor sleep activity. We also used two of our epileptic animals to validate the embedded alarm system for real time seizure monitoring. While initially not designed for NHP, but with a minimum number of adaptions, this telemeter is in fact perfectly suitable for NHP experiments. Since early medical intervention during seizures is critical to avoid status epilepticus and to save the animal's life, real time seizures monitoring is becoming a safety requirement in many NHP studies. This method refines the current seizure monitoring methods for NHP and creates a flexible telemetry solution.


Subject(s)
Electroencephalography , Seizures , Animals , Primates , Seizures/diagnosis , Sleep , Telemetry
11.
Acta Psychol (Amst) ; 205: 103054, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32151791

ABSTRACT

The Stroop effect is typically much larger than the reverse Stroop effect. One explanation for this asymmetry asserts that interference between the attended feature and an incongruent unattended feature depends on which feature is more strongly associated with the processing typically needed to complete the task. Accordingly, because identification of the target's color or the target word (as in the traditional Stroop paradigm) is more strongly associated with verbal processing than visual processing, the target's meaning should interfere with identification of the target's color (Stroop) more than vice versa (reverse Stroop). In contrast, localization is more strongly associated with visual processing, so strength-of-association predicts that the target's color should interfere with localizing the target word (reverse Stroop) more than vice versa (Stroop). Experiments 1 and 2 supported the strength-of-association account: compared to Stroop, the reverse Stroop effect was smaller for an identification task, but larger for a localization task. Because overall responses were slower for the reverse Stroop condition than the Stroop condition in Experiment 2, we entertained two alternative explanations for the reverse Stroop effect being larger than the Stroop effect. Experiments 3 and 4 showed that the larger reverse Stroop effect could not have been due to scaling, and Experiment 5 showed that it could not have been due to covert translation. Taken together, these experiments demonstrate the role of strength of association in generating the classic Stroop asymmetry, and pave the way for future exploration of the reverse Stroop effect using localization tasks.


Subject(s)
Color Perception , Stroop Test , Attention/physiology , Female , Humans , Male , Reaction Time/physiology , Task Performance and Analysis , Young Adult
12.
Mediators Inflamm ; 2019: 8274903, 2019.
Article in English | MEDLINE | ID: mdl-30804708

ABSTRACT

INTRODUCTION: Recent studies have shown that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may serve as important diagnostic and therapeutic targets in sepsis. Since polymorphonuclear neutrophils (PMNs) play a pivotal role in the early phase of sepsis, we evaluated the potential therapeutic effects of cholinesterase inhibitors on PMN functions during cecal ligation and puncture- (CLP-) induced sepsis and investigated the roles of AChE and BChE as inflammatory markers under standardized experimental conditions. METHODS: Sham surgery or CLP was performed in male Wistar rats (n = 60). Animals were randomized into four groups: physostigmine, 100 µg/kg; neostigmine, 75 µg/kg; 0.9% saline (control group); and sham group, each applied four times over 24 h. The levels of reactive oxygen species (ROS) production and CD11b/CD62l expression were quantified by flow cytometry at t = 0, 6, 15, 20, and 24 h. Blood gas analysis as well as AChE and BChE activity levels was measured by validated point-of-care measurements. Clinical scores and survival times were determined. RESULTS: CLP induced a significant increase in ROS production and CD11b upregulation by rat PMNs. Treatment with physostigmine or neostigmine significantly reduced ROS production and CD11b upregulation by PMNs 20 h after CLP induction. In physostigmine-treated animals, survival times were significantly improved compared to the control animals, but not in neostigmine-treated animals. While AChE activity significantly decreased in the control animals at t > 6 h, AChE activity did not change in the sham group. BChE activity decreased at t > 20 h in the control animals. CONCLUSION: While AChE activity may serve as an acute inflammatory marker, BChE activity shows a delayed decrease. Administration of centrally acting physostigmine in CLP-induced sepsis in rats has protective effects on PMN functions and improves survival times, which may be of interest in clinical practice.


Subject(s)
Acetylcholinesterase/metabolism , Biomarkers/metabolism , Butyrylcholinesterase/metabolism , Neostigmine/therapeutic use , Neutrophils/drug effects , Physostigmine/therapeutic use , Sepsis/drug therapy , Sepsis/metabolism , Animals , Blood Gas Analysis , Male , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism
13.
Phys Chem Chem Phys ; 20(17): 11976-11986, 2018 May 03.
Article in English | MEDLINE | ID: mdl-29670963

ABSTRACT

The diffusion of ammonia in the small pore zeolite and potential commercial NH3-SCR catalyst levynite (LEV) was measured and compared with its mobility in the chabazite (CHA) topology (more established in NOx abatement catalysis), using quasielastic neutron scattering (QENS) and molecular dynamics (MD) simulations at 273, 323 and 373 K. The QENS experiments suggest that mobility in LEV is dominated by jump diffusion through the 8-ring windows between cages (as previously observed in CHA) which takes place at very similar rates in the two zeolites, yielding similar experimental self-diffusion coefficients (Ds). After confirming that the same characteristic motions are observed between the MD simulations and the QENS experiments on the picosecond scale, the simulations suggest that on the nanoscale, the diffusivity is higher by a factor of ∼2 in the CHA framework than in LEV. This difference between zeolites is primarily explained by the CHA cages having six 8-ring windows in the building unit, compared to only three such windows in the LEV cage building unit, thereby doubling the geometric opportunities to perform jump diffusion between cages (as characterised by the QENS experiments) leading to the corresponding increase in the MD calculated Ds. The techniques illustrate the importance of probing both pico- and nanoscale dynamics when studying intracrystalline diffusion in both NH3-SCR catalyst design, and in porous materials generally, where notable consistencies and differences may be found on either scale.

14.
PLoS One ; 13(4): e0193558, 2018.
Article in English | MEDLINE | ID: mdl-29652895

ABSTRACT

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a minimally invasive procedure used to treat degenerative heart valve disease. The implantation requires a highly specific and interdisciplinary management approach. Currently, TAVI is performed with the patient under local or general anaesthesia. METHODS: This study was a retrospective analysis of all TAVI procedures performed at the University Hospital of Regensburg between January 2009 and July 2015. All pre-, intra and postoperative data focusing on perioperative complications were recorded. RESULTS: A total of 853 transfemoral- and transapical-TAVI patients were included in the study. All patients underwent general anaesthesia. The ASA classifications were primarily 3-4. The average logistic EuroScores for the transfemoral- and transapical-TAVI patients were 18 ± 12% and 21 ± 15% (p = 0.002), respectively. The anaesthesia coverage time was 170 ± 49 min., including 37 ± 12 minutes for anaesthetic management. Overall, 458 complications were recorded; with pneumonia, acute renal failure, indication for a permanent pacemaker and non-extubation in the operating theatre the most frequently recorded complications. CONCLUSION: In the present study, we showed that our patients' outcomes are comparable to those reported in the available literature. Compared to TF, TA patients show an overall worse physical condition as well as a higher perioperative morbidity and mortality. Consequently TA patients need additional care and should only be operated in appropriately experienced medical centres.


Subject(s)
Anesthesia, General/adverse effects , Aortic Valve/surgery , Heart Valve Diseases/surgery , Pneumonia/etiology , Renal Insufficiency/etiology , Transcatheter Aortic Valve Replacement/adverse effects , Aged , Aged, 80 and over , Anesthesia, General/methods , Female , Humans , Male , Postoperative Complications/etiology , Retrospective Studies , Risk Factors , Transcatheter Aortic Valve Replacement/methods , Treatment Outcome
15.
Breast Cancer Res Treat ; 166(3): 681-693, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28808806

ABSTRACT

PURPOSE: We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity ("BRCA1-mimetics"), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 ("NSC35446.HCl"), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. METHODS: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ERα-negative (MDA-MB-231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in silico analysis of the IKKB gene, and ChIP assays. RESULTS: SC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen-resistant LCC9, T47DCO, MCF-7/RR, and LY2 cells but not in ERα-negative breast cancer cell lines. IKKB (IKKß, IKBKB), an upstream activator of NF-κB, was identified as a BRCA1-mimetic-regulated gene based on an RNA-seq analysis. NSC35446.HCl inhibited IKKB, IKKA, and IKKG/NEMO mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-κB activity and expression of NF-κB target genes. In silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ERα was recruited to the ERE-like full-site and five of the nine half-sites and that ERα recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. CONCLUSIONS: These studies identify functional EREs in the IKKB promoter and identify IKKB as an ERα and NSC35446.HCl-regulated gene, and they suggest that NF-κB and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance.


Subject(s)
Breast Neoplasms/drug therapy , Estrogen Antagonists/administration & dosage , Estrogen Receptor alpha/genetics , I-kappa B Kinase/genetics , Apoptosis/genetics , BRCA1 Protein/antagonists & inhibitors , BRCA1 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/genetics , Drug Resistance, Neoplasm/genetics , Estrogens/genetics , Estrogens/metabolism , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , NF-kappa B/genetics , Promoter Regions, Genetic
16.
Cardiovasc Drugs Ther ; 30(6): 551-558, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27757725

ABSTRACT

INTRODUCTION: Mechanical and morphological ischemia and reperfusion (I/R) injury is reduced in septic hearts. The mechanism behind this "cardioprotection" is less well understood. As adenosine receptors play a major role for cardioprotection in non-septic hearts, we investigated the influence of adenosine receptors in a model of I/R in septic hearts. METHODS: SHAM operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats (n = 60). After 24 h of incubation, hearts were isolated and randomly assigned to a group with or without adenosine receptor (Ador) antagonists (SCH 58261 and MRS 1706) administered before reperfusion. Ischemia and reperfusion lasted for 40 min each. Cardiac function of the heart was determined by measuring left ventricular pressure (LVP). RESULTS: Before I/R, CLP hearts showed a significant mechanical left ventricular impairment (CLP: 63 ± 5 mmHg vs. SHAM: 104 ± 6 mmHg. After I/R, left ventricular function was significantly reduced in SHAM (24 ± 32 mmHg), but not in CLP hearts (65 ± 13 mmHg). mRNA expression for the AdorA2a and AdorA2b was significantly increased in CLP, but not in SHAM hearts. LVP of CLP hearts deteriorated when AdorA2a and AdorA2b were blocked. CONCLUSIONS: The morphological and functional I/R injury in septic animals is less pronounced compared to non-septic animals. By a combined blockade of AdorA2a and AdorA2b this "cardioprotective" effect is nearly abolished in septic hearts. This is the first study showing, that AdorA2a and AdorA2b may play an important role for a reduced functional I/R injury in the septic heart.


Subject(s)
Myocardial Reperfusion Injury/physiopathology , Receptor, Adenosine A2A/physiology , Receptor, Adenosine A2B/physiology , Sepsis/physiopathology , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/therapeutic use , Animals , Cardiotonic Agents/pharmacology , Cardiotonic Agents/therapeutic use , Coronary Circulation/drug effects , Heart/drug effects , Heart/physiology , Male , Myocardial Reperfusion Injury/drug therapy , Myocardial Reperfusion Injury/metabolism , Myocardium/metabolism , RNA, Messenger/metabolism , Rats, Wistar , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2B/genetics , Sepsis/drug therapy , Sepsis/metabolism , Ventricular Function, Left/drug effects , Ventricular Pressure/drug effects
17.
Climacteric ; 19(2): 198-203, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26857354

ABSTRACT

OBJECTIVES: This prospective study was designed to investigate the effect of testosterone, delivered by subcutaneous implants, on the female voice. METHODS: Ten women who had opted for testosterone therapy were recruited for voice analysis. Voices were recorded prior to treatment and at 3 months, 6 months, and 12 months while on testosterone therapy. Acoustic samples were collected with subjects reading a sentence, reading a paragraph, and participating in a conversation. Significant changes in the voice over time were investigated using a repeated-measures analysis of variance with the fundamental frequency (F0) as a response variable. Demographic variables associated with characteristics of the voice were assessed. RESULTS: There were no significant differences in average F0 related to smoking history, menopausal status, weight, or body mass index. There was no difference in average fundamental speaking frequency (sentence, paragraph, conversation) between the pre-treatment group and any post-treatment group at 3 and 12 months. There was an increase in sentence speech F0 at 6 months. Two of three patients with lower than expected F0 at baseline improved on testosterone therapy. CONCLUSION: Therapeutic levels of testosterone, delivered by subcutaneous implant, had no adverse affect on the female voice including lowering or deepening of the voice.


Subject(s)
Menopause , Testosterone/adverse effects , Testosterone/therapeutic use , Voice/drug effects , Drug Implants , Female , Humans , Middle Aged , Prospective Studies , Testosterone/administration & dosage
18.
Neuropharmacology ; 109: 1-6, 2016 10.
Article in English | MEDLINE | ID: mdl-26772968

ABSTRACT

Previous and more recent studies show that cholinesterase inhibitors (ChE-Is) are an important possibility for therapeutic intervention in Alzheimer's Disease, sepsis and other inflammatory syndromes. ChE-Is maintain high levels of acetylcholine (ACh) determining beneficial effects on the disease process. Despite numerous efforts to identify the appropriate choice of agents and dose of ChE-Is, a common protocol regarding concentration- and species-dependent differences in inhibitory potency (IC 50) of clinical relevant ChE-Is is still not available. To evaluate the in vitro sensitivity of Acetyl- and Butyrylcholinesterase (AChE, BChE), we compared the concentration-response effects of physostigmine and neostigmine on cholinesterases in whole blood from rat and human. A spectrophotometrical test system based on in vitro Ellman's reagent has been used to determine the kinetic properties of clinical relevant ChE-Is. In vitro, the enzyme activity of human AChE and BChE was inhibited in a concentration-dependent manner until a residual activity of 4-6% for AChE and 20-30% for BChE (IC 50 human AChE: 0.117 ± 0.007 µM physostigmine, 0.062 ± 0.003 µM neostigmine; IC 50 human BChE: 0.373 ± 0.089 µM neostigmine; 0.059 ± 0.012 µM physostigmine). The inhibition curve of rat BChE in contrast showed no concentration-dependency for physostigmine and neostigmine (87% residual activity even at high inhibitor concentrations). Rat AChE was inhibited in a concentration-dependent manner until a residual activity of 53%. The results suggest that cholinesterases from human and rat show marked species- and inhibitor-dependent differences in sensitivity to physostigmine and neostigmine. Knowledge of such differences may be critical in assessing the possible therapeutic effects of ChE-Is in both species and may guide researchers in the optimal design of future experiments regarding the application of ChE-Is.


Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Neostigmine/pharmacology , Physostigmine/pharmacology , Acetylcholinesterase/blood , Animals , Butyrylcholinesterase/blood , Dose-Response Relationship, Drug , Humans , Male , Rats , Rats, Wistar , Species Specificity
19.
J Magn Reson ; 255: 122-31, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25965147

ABSTRACT

Conventional rheological characterisation using nuclear magnetic resonance (NMR) typically utilises spatially-resolved measurements of velocity. We propose a new approach to rheometry using pulsed field gradient (PFG) NMR which readily extends the application of MR rheometry to single-axis gradient hardware. The quantitative use of flow propagators in this application is challenging because of the introduction of artefacts during Fourier transform, which arise when realistic sampling strategies are limited by experimental and hardware constraints and when particular spatial and temporal resolution are required. The method outlined in this paper involves the cumulant analysis of the acquisition data directly, thereby preventing the introduction of artefacts and reducing data acquisition times. A model-dependent approach is developed to enable the pipe-flow characterisation of fluids demonstrating non-Newtonian power-law rheology, involving the use of an analytical expression describing the flow propagator in terms of the flow behaviour index. The sensitivity of this approach was investigated and found to be robust to the signal-to-noise ratio (SNR) and number of acquired data points, enabling an increase in temporal resolution defined by the SNR. Validation of the simulated results was provided by an experimental case study on shear-thinning aqueous xanthan gum solutions, whose rheology could be accurately characterised using a power-law model across the experimental shear rate range of 1-100 s(-1). The flow behaviour indices calculated using this approach were observed to be within 8% of those obtained using spatially-resolved velocity imaging and within 5% of conventional rheometry. Furthermore, it was shown that the number of points sampled could be reduced by a factor of 32, when compared to the acquisition of a volume-averaged flow propagator with 128 gradient increments, without negatively influencing the accuracy of the characterisation, reducing the acquisition time to only 3% of its original value.

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