Ca(2+)-activated K(+) (K(Ca)) channels of small (SK) and intermediate (IK) conductance are present in a wide range of excitable and non-excitable cells. On activation by low concentrations of Ca(2+), ...they open, which results in hyperpolarization of the membrane potential and changes in cellular excitability. K(Ca)-channel activation also counteracts further increases in intracellular Ca(2+), thereby regulating the concentration of this ubiquitous intracellular messenger in space and time. K(Ca) channels have various functions, including the regulation of neuronal firing properties, blood flow and cell proliferation. The cloning of SK and IK channels has prompted investigations into their gating, pharmacology and organization into calcium-signalling domains, and has provided a framework that can be used to correlate molecularly identified K(Ca) channels with their native currents.
Sepsis is a leading cause of mortality and morbidity in neonates. Presenting clinical symptoms are unspecific. Sensitivity and positive predictive value of biomarkers at onset of symptoms are ...suboptimal. Clinical suspicion therefore frequently leads to empirical antibiotic therapy in uninfected infants. The incidence of culture confirmed early-onset sepsis is rather low, around 0.4-0.8/1000 term infants in high-income countries. Six to 16 times more infants receive therapy for culture-negative sepsis in the absence of a positive blood culture. Thus, culture-negative sepsis contributes to high antibiotic consumption in neonatal units. Antibiotics may be life-saving for the few infants who are truly infected. However, overuse of broad-spectrum antibiotics increases colonization with antibiotic resistant bacteria. Antibiotic therapy also induces perturbations of the non-resilient early life microbiota with potentially long lasting negative impact on the individual's own health. Currently there is no uniform consensus definition for neonatal sepsis. This leads to variations in management. Two factors may reduce the number of culture-negative sepsis cases. First, obtaining adequate blood cultures (0.5-1 mL) at symptom onset is mandatory. Unless there is a strong clinical or biochemical indication to prolong antibiotics physician need to trust the culture results and to stop antibiotics for suspected sepsis within 36-48 h. Secondly, an international robust and pragmatic neonatal sepsis definition is urgently needed. Neonatal sepsis is a dynamic condition. Rigorous evaluation of clinical symptoms ("organ dysfunction") over 36-48 h in combination with appropriately selected biomarkers ("dysregulated host response") may be used to support or refute a sepsis diagnosis.
The slow afterhyperpolarising current, sIAHP, is a Ca2+-dependent current that plays an important role in the late phase of spike frequency adaptation. sIAHP is activated by voltage-gated Ca2+ ...channels, while the contribution of calcium from ryanodine-sensitive intracellular stores, released by calcium-induced calcium release (CICR), is controversial in hippocampal pyramidal neurons. Three types of ryanodine receptors (RyR1-3) are expressed in the hippocampus, with RyR3 showing a predominant expression in CA1 neurons. We investigated the specific role of CICR, and particularly of its RyR3-mediated component, in the regulation of the sIAHP amplitude and time course, and the activity-dependent potentiation of the sIAHP in rat and mouse CA1 pyramidal neurons. Here we report that enhancement of CICR by caffeine led to an increase in sIAHP amplitude, while inhibition of CICR by ryanodine caused a small, but significant reduction of sIAHP. Inhibition of ryanodine-sensitive Ca2+ stores by ryanodine or depletion by the SERCA pump inhibitor cyclopiazonic acid caused a substantial attenuation in the sIAHP activity-dependent potentiation in both rat and mouse CA1 pyramidal neurons. Neurons from mice lacking RyR3 receptors exhibited a sIAHP with features undistinguishable from wild-type neurons, which was similarly reduced by ryanodine. However, the lack of RyR3 receptors led to a faster and reduced activity-dependent potentiation of sIAHP. We conclude that ryanodine receptor-mediated CICR contributes both to the amplitude of the sIAHP at steady state and its activity-dependent potentiation in rat and mouse hippocampal pyramidal neurons. In particular, we show that RyR3 receptors play an essential and specific role in shaping the activity-dependent potentiation of the sIAHP. The modulation of activity-dependent potentiation of sIAHP by RyR3-mediated CICR contributes to plasticity of intrinsic neuronal excitability and is likely to play a critical role in higher cognitive functions, such as learning and memory.
Antibiotic exposure at the beginning of life can lead to increased antimicrobial resistance and perturbations of the developing microbiome. Early-life microbiome disruption increases the risks of ...developing chronic diseases later in life. Fear of missing evolving neonatal sepsis is the key driver for antibiotic overtreatment early in life. Bias (a systemic deviation towards overtreatment) and noise (a random scatter) affect the decision-making process. In this perspective, we advocate for a factual approach quantifying the burden of treatment in relation to the burden of disease balancing antimicrobial stewardship and effective sepsis management.
The value of critical incident reporting systems (CIRSs) has been shown before but data for paediatric facilities are scarce. We aimed to evaluate a CIRS in a paediatric hospital to analyse its ...benefits, weaknesses and opportunities.
In a qualitative analysis, all incidents reported in 2018 with the anonymous reporting tool (CIRS) of the Children's Hospital Lucerne were evaluated. In an iterative process, categories to group the incidents were created and the data analysed accordingly. The focus was on the problem created through the incident, the type of error and possible avoidance.
496 incidents were reported in 2018: 307 incidents led to medical errors directly effecting patients, 82 incidents led to organisational problems increasing expenditure and 107 incidents were found to not result in any problem. In the majority of cases (398/496) there was no evidence that the caregiver responsible was informed. Personal feedback was documented in 46 cases. Fifty-two incidents were self-reported.
A number of reported incidents helped to identify system-based errors and for these the reporting system proved indispensable. Many of the reported errors were found to have an individual component, or only organisational or no consequences. Our data give evidence that instead of giving direct personal feedback, the anonymous reporting system was utilised. The CIRS is essential to identify system-based errors, but personal feedback needs to become obligatory so caregivers can learn from their error: an additional tool to ensure individual feedback and overcome communication difficulties needs to be created.
Ca(2+)-activated K(+) (K(Ca)) channels of small (SK) and intermediate (IK) conductance are present in a wide range of excitable and non-excitable cells. On activation by low concentrations of Ca(2+), ...they open, which results in hyperpolarization of the membrane potential and changes in cellular excitability. K(Ca)-channel activation also counteracts further increases in intracellular Ca(2+), thereby regulating the concentration of this ubiquitous intracellular messenger in space and time. K(Ca) channels have various functions, including the regulation of neuronal firing properties, blood flow and cell proliferation. The cloning of SK and IK channels has prompted investigations into their gating, pharmacology and organization into calcium-signalling domains, and has provided a framework that can be used to correlate molecularly identified K(Ca) channels with their native currents.
Abstract
Childhood obesity continues to escalate worldwide and may affect left ventricular (LV) geometry and function. The aim of this study was to investigate the impact of obesity on prevalence of ...left ventricular hypertrophy (LVH) and diastolic dysfunction in children. In this analysis of prospectively collected cross-sectional data of children between 5 and 16 years of age from randomly selected schools in Peru, parameters of LV geometry and function were compared according to presence or absence of obesity (body mass index z-score > 2). LVH was based on left ventricular mass index (LVMI) adjusted for age and sex and defined by a z-score of > 2. LV diastolic function was assessed using mitral inflow early-to-late diastolic flow (E/A) ratio, peak early diastolic tissue velocities of the lateral mitral annulus (E′), early diastolic transmitral flow velocity to tissue Doppler mitral annular early diastolic velocity (E/E′) ratio, and left atrial volume index (LAVI). Among 1023 children, 681 children (mean age 12.2 ± 3.1 years, 341 male (50.1%)) were available for the present analysis, of which 150 (22.0%) were obese. LVH was found in 21 (14.0%) obese and in 19 (3.6%) non-obese children (p
adjusted
< 0.001). LVMI was greater in obese than that in non-obese children (36.1 ± 8.6 versus 28.7 ± 6.9 g/m
2.7
, p < 0.001). The mean mitral E/E′ ratio and LAVI were significantly higher in obese than those in non-obese individuals (E/E′: 5.2 ± 1.1 versus 4.9 ± 0.8, p
adjusted
= 0.043; LAVI 11.0 ± 3.2 versus 9.6 ± 2.9, p
adjusted
= 0.001), whereas E′ and E/A ratio were comparable. Childhood obesity was associated with left ventricular hypertrophy and determinants of diastolic dysfunction.
ClinicalTrials.gov Identifier: NCT02353663.
Alpine cold ice caps are sensitive indicators of local climate. The adequate interpretation of this information in an ice core requires detailed in situ glaciological and meteorological records, of ...which there are few. The Weißseespitze summit ice cap (3499 m) presents an ideal case to compare past and present climate and mass balance, with limited ice flow, but close to 6000 years locked into about 10 m of ice. First-ever meteorological observations at the ice dome have revealed that over 3 years of observation most of the accumulation took place between October and December and from April to June. In the colder winter months, between January and March, wind erosion prevents accumulation. Melt occurred between June and September, ice was only affected during short periods, mainly in August, which caused ice losses of up to 0.6 m (i.e. ~ 5% of the total ice thickness). Historical data points at a loss of of 34.9 ± 10.0 m between 1893 and 2018 and almost balanced conditions between 1893 and 1914. The local evidence of ice loss lays the basis for the interpretation of past gaps in the ice core records as past warm/melt events.
Diagnosis of neonatal early-onset sepsis is difficult because clinical signs and laboratory tests are non-specific. Early antibiotic therapy is crucial for treatment success.
To evaluate the effect ...of procalcitonin (PCT)-guided decision-making on duration of antibiotic therapy in suspected neonatal early-onset sepsis.
This single-center, prospective, randomized intervention study was conducted in a tertiary neonatal and pediatric intensive care unit in the Children's Hospital of Lucerne, Switzerland, between June 1, 2005 and December 31, 2006. All term and near-term infants (gestational age >or=34 weeks) with suspected early-onset sepsis were randomly assigned either to standard treatment based on conventional laboratory parameters (standard group) or to PCT-guided treatment (PCT group). Minimum duration of antibiotic therapy was 48-72 h in the standard group, whereas in the PCT group antibiotic therapy was discontinued when two consecutive PCT values were below predefined age-adjusted cut-off values.
121 newborns were randomly assigned either to the standard group (n = 61) or the PCT group (n = 60). The two groups were similar for baseline demographics, risk factors for early-onset sepsis, likelihood of infection as assessed by the attending physician and early conventional laboratory findings. There was a significant difference in the proportion of newborns treated with antibiotics >or=72 h between the standard group (82%) and the PCT group (55%) (absolute risk reduction 27%; odds ratio 0.27 (95% CI 0.12-0.62), p = 0.002). On average, PCT-guided decision-making resulted in a shortening of 22.4 h of antibiotic therapy. Clinical outcome was similar and favorable in both groups but sample size was insufficient to exclude rare adverse events.
Serial PCT determinations allow to shorten the duration of antibiotic therapy in term and near-term infants with suspected early-onset sepsis. Before this PCT-guided strategy can be recommended, its safety has to be confirmed in a larger cohort of neonates.
Simulation-based medical training (SBMT) is a powerful tool for continuing medical education. In contrast to the Anglo-Saxon medical education community, up until recently, SBMT was scarce in ...continental Europe's pediatric health care education: In 2009, only 3 Swiss pediatric health care institutions used SBMT. The Swiss catalogue of objectives in Pediatrics does not acknowledge SBMT. The aim of this survey is to describe and analyze the current state of SBMT in Swiss pediatric hospitals and health care departments.
A survey was carried out with medical education representatives of every institution. SBMT was defined as any kind of training with a mannequin excluding national and/or international standardized courses. The survey reference day was May 31st 2015.
Thirty Swiss pediatric hospitals and health care departments answered our survey (response rate 96.8%) with 66.6% (20 out of 30) offering SBMT. Four of the 20 hospitals offering SMBT had two independently operating training simulation units, resulting in 24 educational units as the basis for our SBMT analysis. More than 90% of the educational units offering SBMT (22 out of 24 units) were conducting in-situ training and 62.5% (15 out of 24) were using high-technology mannequins. Technical skills, communication and leadership ranked among the top training priorities. All institutions catered to inter-professional participants. The vast majority conducted training that was neither embedded within a larger educational curriculum (19 out of 24: 79.2%) nor evaluated (16 out of 24: 66.6%) by its participants. Only 5 institutions (20.8%) extended their training to at least two thirds of their hospital staff.
Two thirds of the Swiss pediatric hospitals and health care departments are offering SBMT. Swiss pediatric SBMT is inter-professional, mainly in-situ based, covering technical as well as non-technical skills, and often employing high-technology mannequins. The absence of a systematic approach and reaching only a small number of healthcare employees were identified as shortcomings that need to be addressed.
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