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STAMBUK : 11020170024

Many nociceptive, inflammatory, and neuropathic pathways contribute to perioperative pain.
Although opioids have long been a mainstay for perioperative analgesia, other non-opioid
therapies, and dexmedetomidine, in particular, have been increasingly used as part of a
multimodal analgesic regimen to provide improved pain control while minimizing opioid-
related side effects. This article reviews the evidence supporting the preoperative,
intraoperative, and postoperative efficacy of dexmedetomidine as an adjuvant, and the
efficacy of intravenous, spinal canal, and nerve block analgesia with dexmedetomidine for
perioperative acute pain treatment. While there have not been any large-scale clinical trials
conducted, the current body of evidence suggests that dexmedetomidine is suitable for use
as an adjuvant analgesic at all perioperative stages. However, there are potential adverse
effects, such as hypotension and bradycardia, which must be taken into consideration by

Rationale: Downregulation of the pacemaking ion channel, HCN4, and the corresponding
ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this
occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran
athletes and it will be important to understand the underlying processes. Objective: To test
the role of HCN4 in the training-induced bradycardia in human athletes and investigate the
role of micro-RNAs (miRs) in the repression of HCN4. Methods and Results: As in rodents,
the intrinsic heart rate was significantly lower in human athletes than non-athletes and in all
subjects the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly
correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next
generation sequencing and qPCR showed remodelling of miRs in the sinus node of swim-
trained mice. Computational predictions highlighted a prominent role for miR-423-5p.
Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in
HCN4 3'-UTR luciferase reporter activity on co-transfection with precursor miR-423-5p
(abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with
antimiR-423-5p reversed training-induced bradycardia via rescue of HCN4 and If Further
experiments showed that, in the sinus node of swim-trained mice, upregulation of miR-423-
5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription
factor Nkx2.5. Conclusions: HCN remodelling likely occurs in human athletes as well as
rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4.
This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p
could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.

Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity
syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and
incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin
obesity syndrome may be protective with respect to obesity-associated cardiovascular
disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes
dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular
diameter. This cardiomyopathy is independent of obesity as weight matched diet induced
obese mice do not display systolic dysfunction. Mc4r cardiomyopathy is characterized by
ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization.
Remarkably, testing of myocardial tissue from Mc4r-/-mice exhibited increased ADP
stimulated respiratory capacity. However, this increase in respiration correlates with
increased reactive oxygen species production - a canonical mediator of tissue damage.
Together this study identifies MC4R deletion as a novel and potentially clinically important
cause of heart failure.

Intraoperative nausea and vomiting (IONV) or postoperative nausea and vomiting (PONV)
affecting women undergoing regional anesthesia for cesarean section is an important clinical
problem since these techniques are used widely. There are burdens of literature about
IONV/PONV and several in parturient and cesarean. However, it needs more attention. The
underlying mechanisms of IONV and PONV in the obstetrical setting mainly include
hypotension due to sympathicolysis during neuraxial anesthesia, bradycardia owing to an
increased vagal tone, the visceral stimulation via the surgical procedure and intravenously
administered opioids.
Given the high and even increasing rate of cesarean sections and the sparse information on
the etiology, incidence and severity of nausea and vomiting and the impact of prophylactic
measures on the incidence of PONV/IONV, this article aims to review the available
information and provide pragmatic suggestions on how to prevent nausea and vomiting in
this patient cohort. Current literature and guidelines were identified by electronic database
searching (MEDLINE via PubMed and Cochrane database of systematic reviews) up to
present, searching through reference lists of included literature and personal contact with
Taking into account the current guidelines and literature as well as everyday clinical
experience, the first step for decreasing the incidence of IONV and PONV is a
comprehensive management of circulatory parameters. This management includes liberal
perioperative fluid administration and the application of vasopressors as the circumstances
require. By using low-dose local anesthetics, an additional application of intrathecal or spinal
opioids or hyperbaric solutions for a sufficient controllability of neuraxial distribution,
maternal hypotension might be reduced. Performing a combined spinal-epidural anesthesia
or epidural anesthesia may be considered as an alternative to spinal anesthesia. Antiemetic
drugs may be administered restrainedly due to off-label use in pregnant women for IONV or
PONV prophylaxis and may be reserved for treatment.

Dexmedetomidine (Precedex) may be used as an alternative sedative in children,
maintaining spontaneous breathing, and avoiding tracheal intubation in a non-intubated
moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter
study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in
an operating room or a procedure room, with an intensivist or anesthesiologist in attendance,
for elective diagnostic or therapeutic procedures expected to take at least 30 min. The
primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients
received one of two doses dependent on age: patients aged 28 weeks' gestational age to
<1 month postnatal received dose level 1 (0.1 g/kg load; 0.05-0.2 g/kg/h infusion); those
aged 1 month to <17 years received dose level 2 (1 g/kg load; 0.2-2.0 g/kg/h infusion).
Sedation efficacy was assessed and defined as adequate sedation for at least 80% of the
time and successful completion of the procedure without the need for rescue medication. In
all, 91 patients were enrolled (dose level 1, n = 1; dose level 2, n = 90); of these, 90 received
treatment and 82 completed the study. Eight patients in dose level 2 discontinued treatment
for the following reasons: early completion of diagnostic or therapeutic procedure (n = 3);
change in medical condition (need for intubation) requiring deeper level of sedation (n = 2);
adverse event (AE; hives and emesis), lack of efficacy, and physician decision (patient not
sedated enough to complete procedure; n = 1 each). Sixty-seven patients experienced 147
TEAEs. The two most commonly reported AEs were respiratory depression (bradypnea;
reported per protocol-defined criteria, based on absolute respiratory rate values for age or
relative decrease of 30% from baseline) and hypotension. Four patients received
glycopyrrolate for bradycardia and seven patients received intravenous fluids for
hypotension. SpO2 dropped by 10% in two patients, but resolved without need for manual
ventilation. All other reported AEs were consistent with the known safety profile of
dexmedetomidine. Two of the 78 patients in the efficacy-evaluable population met all
sedation efficacy criteria. Dexmedetomidine was well-tolerated in pediatric patients
undergoing procedure-type sedation.

This study focused on the potential toxicity of silver nanoparticles (AgNPs) on cardiac
electrophysiology which is rarely investigated. We found that AgNPs (10-9-10-6g/ml)
concentration-dependently depolarized the resting potential, diminished the action potential,
and finally led to loss of excitability in mice cardiac papillary muscle cells in vitro. In cultured
neonatal mice cardiomyocytes, AgNPs (10-9-10-7g/ml) concentration-dependently decreased
the Na+ currents (INa), accelerated the activation, and delayed the inactivation and recovery
of Na+ channels from inactivation within 5min. AgNPs at 10-8g/ml also rapidly decreased the
inwardly rectifying K+ currents (IK1) and delayed the activation of IK1channels. Intravenous
injection of AgNPs at 3mg/kg only decreased the heart rate, while at 4mg/kg sequentially
induced sinus bradycardia, complete atrio-ventricular conduction block, and cardiac
asystole. AgNPs at 10-10-10-6g/ml did not increase reactive oxygen species (ROS)
generation and only at 10-6g/ml mildly induced lactate dehydrogenase (LDH) release in the
cardiomyocytes within 5min. Endocytosis of AgNPs by cardiomyocytes was not observed
within 5min, but was observed 1h after exposing to AgNPs. Comparative Ag+ (0.02% of
the AgNPs) could not induce above toxicities. We conclude that AgNPs exert rapid toxic
effects on myocardial electrophysiology and induce lethal bradyarrhythmias. These acute
toxicities are likely due to direct effects of AgNPs on ion channels at the nano-scale level,
but not caused by Ag+, ROS, and membrane injury. These findings provide warning to the
nanomedical practice using AgNPs.

We report a case of symptomatic bradycardia caused by consumption of a Chinese herbal
medicine which was initially undisclosed to the attending emergency physician. The scientific
name of the herb is Panax japonicus. Electrocardiogram revealed sinus bradycardia.
Laboratory tests were normal except for the detection of a high serum digoxin level. Further
interrogation of the patient eventually disclosed ingestion of the herb which, however, did not
contain any digoxin. Other active ingredients in the herb include various types of
ginsenoside. These are digoxin-like substances that had caused the observed false-positive
detection of digoxin by fluorescence polarization immunoassay due to cross-reactivity. Our
case-report provides an important insight about a blind-spot in the field of laboratory
medicine (clinical pathology), namely, the false positive detection of digoxin due to
crossreactivity in the immunoassay when we come across digoxin-like substances in clinical
scenarios, which has barely received attention in the medical literature. It also conveys a
clear educational message that with full understanding of the laboratory methodology and its
mechanistic rationale there are actually some tricks-of-the-trade that allow us to optimize the
specificity of the biochemical tests and the treatment of digoxin-like substances overdose.

Hypoxemic episodes commonly occur in very preterm infants and may be associated with
several adverse effects. Cerebral tissue oxygen saturation (StO2) as measured by near
infrared spectroscopy (NIRS) may be a useful measure to assess brain oxygenation.
However, knowledge on variability of StO2 is currently limited in preterm infants at this time,
so StO2 dependency on arterial oxygenation (SpO2) and heart rate (HR) was assessed in
preterm infants using statistical methods of time series analysis.
StO2, SpO2, and HR were recorded from 15 preterm infants every 2 seconds for six hours.
Statistical methods of time series and longitudinal data analysis were applied to the data.
The mean StO2 level was found as 72% (95% confidence interval (CI) 55.5% -85.5%) based
on a moving average process with a 5 minute order. Accordingly, longitudinal SpO2
measurements showed a mean level of 91% (95% CI 69% -98%). Generally, compensation
strategies to cope with both StO2 and SpO2 desaturations were observed in the studied
patients. SpO2 had a significant effect on cerebral oxygenation (p<0.001), but HR did not,
which led to inconclusive results considering different time intervals.
In infants with intermittent hypoxemia and bradycardia, we found a mean StO2 level of 72%
and a strong correlation with SpO2. We observed large differences between individuals in
the ability to maintain StO2 at a stable level.

Temporary parent vessel clip occlusion in aneurysm surgery is not always practical or
feasible. Adenosine-induced transient cardiac arrest may serve as an alternative. We
retrospectively reviewed our clinical database between September 2011 and July 2014. All
patients who underwent microsurgical clipping of intracranial aneurysms under adenosine-
induced asystole were included. A total of 18 craniotomies were performed, and 18
aneurysms were clipped under adenosine-induced asystole (7 basilar arteries, 8 internal
carotid arteries, 1 middle cerebral artery, and 1 anterior communicating artery) in 16 patients
(10 females, 6 males). Nine cases were elective and seven after subarachnoid hemorrhage.
Mean age was 54 years (range 39-70). The indications for adenosine use were proximal
control in narrow surgical corridors in 13 cases and "aneurysm softening" in 4 cases. A
single dose was used in 14 patients; 3 patients had multiple boluses. The median (range)
total dose was 30 (18-135) mg. Adenosine induced a bradycardia with concomitant arterial
hypotension in all patients, and the majority also had asystole for 5-15 sec. Transient cardiac
arrhythmias were noted in one patient (AFib in need of electroconversion after two boluses).
Nine clinical scenarios where adenosine-induced temporary cardiac arrest and deep
hypotension was an effective adjunct to temporary clipping during microsurgical clipping of
intracranial aneurysms were identified.

in English, Spanish

To compare the efficacy and safety of endotracheal intubation (ETI) in a simulated clinical
environment in motion vs a motionless one.
Clinical simulation trial of ETI with 3 endotracheal tubes (Airtraq, Fast-trach, Macintosh
laryngoscope) in mannequins with realistic physiological responses (MetiMan) in 2
scenarios: an environment in motion vs a motionless one. Thirty-six physicians expert in
prehospital ETI participated. Outcome variables were successful intubation, effective
intubation, number of attempts, maximum apnea time, and total maneuver time. The safety
variables were the presence of bradycardia, tachycardia, or high or low systolic blood
pressures (ie, 20% variation from baseline); hypoxemia (decrease in oxygen saturation to
<90% or 10% below baseline), tube placement in the esophagus or main bronchus, and
dental trauma.
No statistically significant differences between the 2 scenarios were found in the numbers of
successful ETI (motionless, 71 [65.7%]; in motion, 67 [62.0%]; P=.277) or effective ETI
(motionless, 104 [96.3%]; in motion, 105 [97.2%]; P=.108). Likewise, the number of attempts
were similar (motionless, 91 [84.2%]; in motion, 90 [83.3%]; P=.305). Nor did we see
differences in the mean (SD) maximum apnea times (motionless, 14.0 [5.6] seconds; in
motion, 14.9 [8.1] seconds; P=.570) or mean total maneuver times (motionless, 236.7 [73.4]
seconds; in motion, 210.3 [77.9] seconds; P=.164). The prevalences of bradycardia,
tachycardia, high or low systolic blood pressure, hypoxemia, placements in the esophagus
or bronchus, and dental trauma also did not differ significantly between the 2 scenarios.
Neither efficacy nor safety variables differed significantly when ETI was performed in
mannequins in a motionless environment vs one simulating ambulances in motion.

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Cardiomyopathy and Symptomatic Chronic Heart Failure. Journal of the American College of
Cardiology. 2017 Sep 05;70(10):1262-72. PubMed PMID: 28859790.
2. D'Souza A, Pearman CM, Wang Y, Nakao S, Logantha SJR, Cox C, et al. Targeting miR-423-5p
Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia. Circulation
research. 2017 Aug 17. PubMed PMID: 28821541.
3. Litt MJ, Okoye GD, Lark D, Cakir I, Moore C, Barber MC, et al. Loss of the melanocortin-4
receptor in mice causes dilated cardiomyopathy. eLife. 2017 Aug 22;6. PubMed PMID: 28829041.
Pubmed Central PMCID: 5577919.
4. Jelting Y, Klein C, Harlander T, Eberhart L, Roewer N, Kranke P. Preventing nausea and
vomiting in women undergoing regional anesthesia for cesarean section: challenges and solutions.
Local and regional anesthesia. 2017;10:83-90. PubMed PMID: 28860857. Pubmed Central PMCID:
5. Jooste EH, Hammer GB, Reyes CR, Katkade V, Szmuk P. Phase IV, Open-Label, Safety Study
Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation.
Frontiers in pharmacology. 2017;8:529. PubMed PMID: 28848443. Pubmed Central PMCID: 5554485.
6. Lin CX, Yang SY, Gu JL, Meng J, Xu HY, Cao JM. The acute toxic effects of silver nanoparticles
on myocardial transmembrane potential, INa and IK1 channels and heart rhythm in mice.
Nanotoxicology. 2017 Aug 23:1-11. PubMed PMID: 28830271.
7. Liu KT, Lee CW. Clinical judgement perplexed by initially undisclosed use of herbal medicine
and unexpected cross-reactivity of immunoassay. The Malaysian journal of pathology. 2017
Aug;39(2):189-92. PubMed PMID: 28866703.
8. Mayer B, Pohl M, Hummler HD, Schmid MB. Cerebral oxygenation and desaturations in
preterm infants -a longitudinal data analysis. Journal of neonatal-perinatal medicine. 2017 Aug 23.
PubMed PMID: 28854512.
9. Meling TR, Romundstad L, Niemi G, Narum J, Eide PK, Sorteberg AG, et al. Adenosine-
assisted clipping of intracranial aneurysms. Neurosurgical review. 2017 Aug 17. PubMed PMID:
10. Castejon de la Encina Mf, Sanjuan Quiles A, Del Moral Vicente-Mazariegos I, Garcia Aracil N,
Jose Alcaide L, Richart Martinez M. [Efficacy and safety of endotracheal intubation performed in
moving vs motionless environments]. Emergencias : revista de la Sociedad Espanola de Medicina de
Emergencias. 2017 Feb;29(1):5-10. PubMed PMID: 28825262. Estudio comparativo de la eficacia y
seguridad de la intubacion endotraqueal en movimiento y en estatico.