Differential effects of ivabradine and ryanodine on pacemaker activity in canine sinus node and purkinje fibers

Effects of Ivabradine and Ryanodine on Cardiac Pacemakers . Introduction: It is generally accepted that at least 2 major mechanisms contribute to sinus node (SN) pacemaking: a membrane voltage (mainly I_f) clock and a calcium (Ca) clock (localized submembrane sarcoplasmic reticulum Ca²⁺ release during late diastolic depolarization). The aim of this study was to compare the contributions of each mechanism to pacemaker activity in SN and Purkinje fibers (PFs) exhibiting normal or abnormal automaticity. Methods and Results: Conventional microelectrodes were used to record action potentials in isolated spontaneously beating canine SN and free running PF in control and in the presence of 0.1 μM isoproterenol. Ryanodine (0.1–3 μM) and ivabradine (3 μM) were used to inhibit sarcoplasmic reticulum Ca²⁺ release or I_f, respectively. To induce automaticity at low membrane potentials, PFs were superfused with BaCl₂. In SN, ivabradine reduced the rate whereas ryanodine had no effect. Isoproterenol significantly accelerated automatic rate, which was decreased by ivabradine and ryanodine. In normally polarized PFs, ryanodine had no effects on the automatic rate in the absence or presence of isoproterenol, whereas ivabradine inhibited both control and isoproterenol‐accelerated automaticity. In PF depolarized with BaCl₂, ivabradine decreased BaCl₂‐induced automatic rate while ryanodine had no effect. Conclusion: In canine SN, I_f contributes to both basal automaticity and β‐adrenergic‐induced rate acceleration while the ryanodine‐inhibited Ca clock appears more involved in β‐adrenergic regulation of pacemaker rate. In PF, normal automaticity depends mainly on I_f. Inhibition of basal potassium conductance results in high automatic rates at depolarized membrane potentials with SN‐like responses to inhibition of membrane and Ca clocks. (J Cardiovasc Electrophysiol, Vol. 23, pp. 650–655, June 2012)     

Blood pressure responses to hypertension treatment and trends in cognitive function in patients with initially difficult-to-treat hypertension: a retrospective subgroup analysis of the Observational Study on Cognitive Function and SBP Reduction (OSCAR) study

J Clin Hypertens (Greenwich). 2012;14:78–84. ©2012 Wiley Periodicals, Inc.The Observational Study on Cognitive Function and SBP Reduction (OSCAR) provided opportunities to examine the influence of eprosartan on trends in cognitive performance in a large population of patients with difficult‐to‐treat hypertension (DTTH). A total of 4649 patients diagnosed retrospectively with DTTH, defined as systolic/diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg despite use of at least 3 antihypertensive drugs during the month preceding the baseline visit comprised the intention‐to‐treat (ITT) cohort. The patients were given eprosartan‐based antihypertension therapy (EBT; 600 mg/d). Blood pressure and cognitive function parameters included significant (P<.001) differences for DTTH vs non‐DTTH patients such as older age, body mass index, SBP and pulse pressure (PP), and lower Mini‐Mental State Examination (MMSE) score. After EBT for 6 months, SBP/DBP in DTTH was 138.8±12.2/81.9±7.4 (ΔSBP−26±15.7; ΔDBP−11.4±9.8); PP was 57.0±10.8 (ΔPP−14.5±13.8) (all P<.001 vs baseline and non‐DTTH group). A total of 2576 patients (87.4%) responded to EBT (ie, SBP <140 mm Hg and/or ΔSBP ≥15 mm Hg, or DBP <90 mm Hg and/or ΔDBP ≥10 mm Hg); 1426 DTTH patients (48.4%) achieved normalized SBP/DBP (ie, SBP <140 mm Hg and DBP <90 mm Hg). ΔPP in DTTH‐isolated systolic hypertension (ISH) was −18.0±13.3 mm Hg (P=.003 vs DTTH‐systolic‐diastolic hypertension). End‐of‐EBT mean MMSE was 27.5±3.0 (P<.001 vs baseline). Blood pressure responses after EBT coincided with stabilization/improvement of MMSE in this retrospective investigation in DTTH patients. The average improvement in MMSE in DTTH patients was similar to that in non‐DTTH patients. EBT effects on PP may be relevant to the evolution of MMSE in DTTH‐ISH patients.

The Observational Study on Cognitive Function and SBP Reduction (OSCAR) was designed to examine the safety and tolerability of once‐daily therapy with eprosartan in a very large community‐dwelling population of patients with arterial hypertension recruited in 28 countries and managed in routine primary care. This study provided opportunities to examine the influence of the angiotensin receptor blocker (ARB) eprosartan on trends in cognitive performance in a large population of patients with high blood pressure (BP).The principal findings of OSCAR have been reported previously. ¹ A 6‐month period of antihypertensive therapy based on eprosartan was associated with a significant reduction in mean systolic BP (SBP) and a significant improvement in mean Mini‐Mental State Examination (MMSE) score (P<.0001 for both outcomes). In multiple linear regression, cognitive decline was demonstrated to be independently and inversely correlated with SBP reduction (odds ratio, 0.77; 95% confidence interval [CI], 0.73–0.82).The intention‐to‐treat (ITT) cohort of OSCAR comprised 25,745 adult patients with hypertension. This large number of patients enabled us to identify several large subgroups for further investigation, with the intention of adding to what are still sometimes limited epidemiologic data on specific types of patients.Recent revisions to extant European hypertension guidelines and first reports of new treatment options for this condition ² , ³ , ⁴ are indications that resistant hypertension is a pressing clinical priority. Poorly controlled high BP may be a factor in cognitive decline in older patients. Observations from several thousand patients in a real‐world survey may be instructive for the better management of this condition. Accordingly, we report here our findings in a retrospectively identified cohort of almost 3000 patients from the OSCAR population classified as having difficult‐to‐treat hypertension (DTTH) at baseline.     

Optimization of filtering correctors for autopilot control laws with special structures

The paper is devoted to the problem of control law optimization for marine ships, which are steered by autopilots under the action of sea disturbances, mainly determined by bias terms and high‐frequency wave components. The essence of the problem is to find a transfer function of the adjustable corrective item (filter) for the autopilot with a special structure, minimizing the functional, which characterizes the intensity of a ship's rudders action. The correspondent dynamic of a closed‐loop system provides an economical regime of the ship motion, with the aim to reduce general fuel consumption and to prevent the wear of actuator elements. A specialized approach to the filter design is proposed based on the modern H_∞ optimization theory, and its applicability and effectiveness are illustrated by the practical example of autopilot synthesis for a transport ship. Copyright © 2015 John Wiley & Sons, Ltd.     

Dopamine transporter mutant animals: a translational perspective

The dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby providing effective control over activity of dopaminergic transmission. Since brain dopamine is known to be involved in numerous neuropsychiatric disorders, investigations using mice with genetically altered DAT function and thus intensity of dopamine-mediated signaling have provided numerous insights into the pathology of these disorders and novel pathological mechanisms that could be targeted to provide new therapeutic approaches for these disorders. In this brief overview, we discuss recent investigations involving animals with genetically altered DAT function, particularly focusing on translational studies providing new insights into pathology and pharmacology of dopamine-related disorders. Perspective applications of these and newly developed models of DAT dysfunction are also discussed.     

Direct determination of carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa from positive blood cultures using laser scattering technology

Delays in appropriate antimicrobial treatment contribute to increased mortality of septic patients. We aimed to develop a methodology for detection of carbapenem resistance in Gram-negative bacteria directly from positive blood cultures (BCs). Initially, meropenem-resistant Enterobacteriaceae (n?=?13) and Pseudomonas aeruginosa (n?=?32) isolates as well as the same numbers of meropenem-susceptible isolates were used to establish the detection of carbapenem resistance from agar cultures. Growth-based phenotypic detection of meropenem resistance was performed by a laser scattering (LS) method using a BacterioScan?216R instrument. A subset of the strain collection consisting of meropenem-susceptible and -resistant isolates (each comprising seven P. aeruginosa and three Klebsiella pneumoniae) was used for determination of carbapenem resistance directly from positive BCs. Lysis/centrifugation and filtration/dilution methods were investigated for processing of positive BCs. Four different statistical approaches to discriminate between susceptible and resistant bacteria in real-time were applied and were compared regarding their sensitivity and specificity. After 3?h and 4?h of incubation, respectively, detection of carbapenem resistance in Enterobacteriaceae (sensitivity, 100%; specificity, 100%) and P. aeruginosa (sensitivity, 100%; specificity, ≥90%) agar cultures was attainable. Detection of carbapenem resistance directly from positive BCs was achievable with 100% sensitivity and 100% specificity after 4?h and 5?h, respectively, applying lysis/centrifugation and filtration/dilution methods. In conclusion, LS technology combined with lysis/centrifugation and appropriate statistical real-time analyses represents a promising option for rapid detection of carbapenem resistance in Gram-negative rods directly from positive BCs.     

Structure and Properties of Heat-Resistant Alloys NiAl–Cr–Co–X (X = La,Mo, Zr,Ta, Re) and Fabrication of Powders for Additive Manufacturing

The NiAl–Cr–Co–X alloys were produced by centrifugal self-propagating high-temperature synthesis (SHS) casting. The effects of dopants X = La, Mo, Zr, Ta, and Re on combustion, as well as the phase composition, structure, and properties of the resulting cast alloys, have been studied. The greatest improvement in overall properties was achieved when the alloys were co-doped with 15% Mo and 1.5% Re. By forming a ductile matrix, molybdenum enhanced strength characteristics up to the values σ_ucs = 1604 ± 80 MPa, σ_ys = 1520 ± 80 MPa, and ε_pd = 0.79%, while annealing at T = 1250 ℃ and t = 180 min improved strength characteristics to the following level: σ_ucs = 1800 ± 80 MPa, σ_ys = 1670 ± 80 MPa, and ε_pd = 1.58%. Rhenium modified the structure of the alloy and further improved its properties. The mechanical properties of the NiAl, ZrNi₅, Ni_0.92Ta_0.08, (Al,Ta)Ni₃, and Al(Re,Ni)₃ phases were determined by nanoindentation. The three-level hierarchical structure of the NiAl–Cr–Co+15%Mo alloy was identified. The optimal plasma treatment regime was identified, and narrow-fraction powders (fraction 8–27 µm) characterized by 95% degree of spheroidization and the content of nanosized fraction <5% were obtained.     

Vertical Transmission of SARS-CoV-2 in Second Trimester Associated with Severe Neonatal Pathology

The effects of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in women on the gestation course and the health of the fetus, particularly in the first and second trimesters, remain very poorly explored. This report describes a case in which the normal development of pregnancy was complicated immediately after the patient had experienced Coronavirus disease 2019 (COVID-19) at the 21st week of gestation. Specific conditions included critical blood flow in the fetal umbilical artery, fetal growth restriction (1st percentile), right ventricular hypertrophy, hydropericardium, echo-characteristics of hypoxic-ischemic brain injury (leukomalacia in periventricular area) and intraventricular hemorrhage at the 25th week of gestation. Premature male neonate delivered at the 26th week of gestation died after 1 day 18 h due to asystole. The results of independent polymerase chain reaction (PCR), mass spectrometry and immunohistochemistry analyses of placenta tissue, umbilical cord blood and child blood jointly indicated vertical transmission of SARS–CoV-2 from mother to the fetus, which we conclude to be the major cause for the development of maternal vascular malperfusion in the studied case.     

Clinical aspects of ballistic peripheral nerve injury: shrapnel versus gunshot

Objectives

Ballistic injuries to peripheral nerves pose special challenges in terms of indications, timing and type of surgical intervention. The aim of the present work was to analyze our experience in the surgical treatment of peripheral nerve ballistic injuries with respect to the mechanism of injury (gunshot versus shrapnel), and identify common and dissimilar prognostic factors in both types of injury.

Methods

This study was conducted on 42 patients totaling 58 nerves. Twenty-two patients (32 nerves) were injured by gunshot and 20 patients (26 nerves) by shrapnel. Median postoperative follow-up was 33 months (range 12 months to 14 years).

Results

Overall postoperative outcome appears to be more favorable for gunshot-wound (GSW) patients than shrapnel-injured patients, especially in terms of neuropathic pain relief (75 % vs. 58 % respectively, p < 0.05). Presence of foreign particles in shrapnel injured patients has a negative impact on the surgical outcome in terms of rate of pain improvement (28 % compared to 67 % in patients with and without foreign particles, respectively). Nerve graft reconstruction, rather than neurolysis, seems to be the more beneficial treatment for shrapnel-induced neuropathic pain (100 % vs. 47 % in improvement rate, respectively). Early surgical intervention (median 2 months after injury) significantly relieved neuropathic pain in 83 % of shrapnel-injured patients compared to 58 % in patients operated later.

Conclusions

This study suggests that shrapnel injury is more destructive for nerve tissue than gunshot injury. Our impression is that early surgical intervention in shrapnel injuries and split nerve grafting (especially when small fragments are recognized in the nerve) significantly improve the patient’s functional activity and quality of life.     

Existential neuroscience: effects of mortality salience on the neurocognitive processing of attractive opposite-sex faces

Being reminded of the inherently finite nature of human existence has been demonstrated to elicit strivings for sexual reproduction and the formation and maintenance of intimate relationships. Recently, it has been proposed that the perception of potential mating partners is influenced by mortality salience. Using functional magnetic resonance imaging, we investigated the neurocognitive processing of attractive opposite-sex faces after priming with death-related words for heterosexual men and women. Significant modulations of behavioral and neural responses were found when participants were requested to decide whether they would like to meet the presented person. Men were more in favor of meeting attractive women after being primed with death-related words compared to a no-prime condition. Increased neural activation could be found under mortality salience in the left anterior insula and the adjacent lateral prefrontal cortex (lPFC) for both men and women. As previously suggested, we believe that the lPFC activation reflects an approach-motivated defense mechanism to overcome concerns that are induced by being reminded of death and dying. Our results provide insight on a neurocognitive level that approach motivation in general, and mating motivation in particular is modulated by mortality salience.