CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non-associative learning.

Carnitine palmitoyltransferase 1c (CPT1C) is a neuron-specific protein widely distributed throughout the CNS and highly expressed in discrete brain areas including the hypothalamus, hippocampus, amygdala and different motor regions. Its deficiency has recently been shown to disrupt dendritic spine maturation and AMPA receptor synthesis and trafficking in the hippocampus, but its contribution to synaptic plasticity and cognitive learning and memory processes remains mostly unknown. Here, we aimed to explore the molecular, synaptic, neural network and behavioural role of CPT1C in cognition-related functions by using CPT1C knockout (KO) mice. CPT1C-deficient mice showed extensive learning and memory deficits. The CPT1C KO animals exhibited impaired motor and instrumental learning that seemed to be related, in part, to locomotor deficits and muscle weakness but not to mood alterations. In addition, CPT1C KO mice showed detrimental hippocampus-dependent spatial and habituation memory, most probably attributable to inefficient dendritic spine maturation, impairments in long-term plasticity at the CA3-CA1 synapse and aberrant cortical oscillatory activity. In conclusion, our results reveal that CPT1C is not only crucial for motor function, coordination and energy homeostasis, but also has a crucial role in the maintenance of learning and memory cognitive functions. KEY POINTS: CPT1C, a neuron-specific interactor protein involved in AMPA receptor synthesis and trafficking, was found to be highly expressed in the hippocampus, amygdala and various motor regions. CPT1C-deficient animals exhibited energy deficits and impaired locomotion, but no mood changes were found. CPT1C deficiency disrupts hippocampal dendritic spine maturation and long-term synaptic plasticity and reduces cortical γ oscillations. CPT1C was found to be crucial for motor, associative and non-associative learning and memory.

Association between an oxidative balance score and mortality: a prospective analysis in the SUN cohort.

PURPOSE: We aimed to prospectively investigate the association of an overall oxidative balance score (OBS) with all-cause death and cause-specific mortality among participants in the Seguimiento Universidad de Navarra (SUN) Study, a Mediterranean cohort of Spanish graduates. METHODS: Using baseline information on 12 a priori selected dietary and non-dietary lifestyle pro- and antioxidants exposures-vitamins C and E, ß-carotenes, selenium, zinc, heme iron, polyphenols, total antioxidant capacity, body mass index, alcohol, smoking, and physical activity-we constructed an equally weighted OBS categorized into quartiles, with higher scores representing greater antioxidant balance. Cox proportional hazards models were fitted to evaluate the association between the OBS and mortality. RESULTS: A total of 18,561 participants (mean [SD] age, 38.5 [12.4] years; 40.8% males) were included in the analysis. During a median follow-up of 12.2 years (interquartile range 8.3-14.9), 421 deaths were identified, including 80 deaths from cardiovascular disease (CVD), 215 from cancer, and 126 from other causes. After adjustment for potential confounders, the hazard ratios and 95% confidence interval (CIs) between the highest quartile (predominance of antioxidants) vs. the lowest quartile (reference category) were 0.35 (95% CI 0.22-0.54, P-trend < 0.001) for all-cause mortality, 0.18 (95% CI 0.06-0.51, P-trend = 0.001) for CVD mortality, 0.35 (95% CI 0.19-0.65, P-trend = 0.002) for cancer mortality, and 0.45 (95% CI 0.20-1.02, P-trend = 0.054) for other-cause mortality. CONCLUSION: Our findings suggest a strong inverse association between the OBS and all-cause, CVD, and cancer mortality. Individuals exposed to both antioxidant dietary and lifestyle factors may potentially experience the lowest mortality risk. STUDY REGISTRY NUMBER: Dynamic Mediterranean Prospective Cohort: the SUN Project; NCT02669602. https://clinicaltrials.gov/ct2/show/NCT02669602 . https://proyectosun.es.

G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3-CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3-CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

Allocation costs of regeneration: tail regeneration constrains body growth under low food availability in juvenile lizards.

The balance of energy allocated to development and growth of different body compartments may incur allocation conflicts and can thereby entail physiological and evolutionary consequences. Regeneration after autotomy restores the functionality lost after shedding a body part but requires a strong energy investment that may trade-off with other processes, like reproduction or growth. Caudal autotomy is a widespread antipredator strategy in lizards, but regeneration may provoke decreased growth rates in juveniles that could have subsequent consequences. Here, we assessed the growth of intact and regenerating hatchling wall lizards (Podarcis muralis) exposed to different food regimens. Regenerating juveniles presented slightly but significantly lower body growth rates than individuals with intact tails when facing low food availability, but there were no differences when food was supplied ad libitum. Regenerating individuals fed ad libitum increased their ingestion rates compared to intact ones during the period of greatest tail growth, which also reveals a cost of tail regeneration. When resources were scarce, hatchlings invested more in tail regeneration in relation to body growth, rather than delay regeneration to give priority to body growth. We propose that, in juvenile lizards, regeneration could be prioritized even at the expense of body growth to restore the functionality of the lost tail, likely increasing survivorship and the probability to reach reproductive maturity. Our study indicates that food availability is a key factor for the occurrence of trade-offs between regeneration and other growth processes, so that environmental conditions would be determinant for the severity of the costs of regeneration.

Heating of metallic biliary stents during magnetic hyperthermia of patients with pancreatic ductal adenocarcinoma: an in silico study.

OBJECTIVE: To investigate the eddy current heating that occurs in metallic biliary stents during magnetic hyperthermia treatments and to assess whether these implants should continue to be an exclusion criterion for potential patients. METHODS: Computer simulations were run on stent heating during the hyperthermia treatment of local pancreatic tumors (5-15 mT fields at 300 kHz for 30 min), considering factors such as wire diameter, type of stent alloy, and field orientation. Maxwell's equations were solved numerically in a bile duct model, including the secondary field produced by the stents. The heat exchange problem was solved through a modified version of the Pennes' bioheat equation assuming a temperature dependency of blood perfusion and metabolic heat. RESULTS: The choice of alloy has a large impact on the stent heating, preferring those having a lower electrical conductivity. Only for low field intensities (5 mT) and for some of the bile duct tissue layers the produced heating can be considered safe. The orientation of the applied field with respect to the stent wires can give rise to the onset of regions with different heating levels depending on the shape that the stent has finally adopted according to the body's posture. Bile helps to partially dissipate the heat that is generated in the lumen of the bile duct, but not at a sufficient rate. CONCLUSION: The safety of patients with pancreatic cancer wearing metallic biliary stents during magnetic hyperthermia treatments cannot be fully assured under the most common treatment parameters.

Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3-CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance.

First female with Allan-Herndon-Dudley syndrome and partial deletion of X-inactivation center.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.

Iron Availability Modulates the Response of Endosymbiotic Dinoflagellates to Heat Stress.

Warming and nutrient limitation are stressors known to weaken the health of microalgae. In situations of stress, access to energy reserves can minimize physiological damage. Because of its widespread requirements in biochemical processes, iron is an important trace metal, especially for photosynthetic organisms. Lowered iron availability in oceans experiencing rising temperatures may contribute to the thermal sensitivity of reef-building corals, which rely on mutualisms with dinoflagellates to survive. To test the influence of iron concentration on thermal sensitivity, the physiological responses of cultured symbiotic dinoflagellates (genus Breviolum; family Symbiodiniaceae) were evaluated when exposed to increasing temperatures (26 to 30°C) and iron concentrations ranging from replete (500 pM Fe') to limiting (50 pM Fe') under a diurnal light cycle with saturating radiance. Declines in photosynthetic efficiency at elevated temperatures indicated sensitivity to heat stress. Furthermore, five times the amount of iron was needed to reach exponential growth during heat stress (50 pM Fe' at 26-28°C vs. 250 pM Fe' at 30°C). In treatments where exponential growth was reached, Breviolum psygmophilum grew faster than B.minutum, possibly due to greater cellular contents of iron and other trace metals. The metal composition of B.psygmophilum shifted only at the highest temperature (30°C), whereas changes in B.minutum were observed at lower temperatures (28°C). The influence of iron availability in modulating each alga's response to thermal stress suggests the importance of trace metals to the health of coral-algal mutualisms. Ultimately, a greater ability to acquire scarce metals may improve the tolerance of corals to physiological stressors and contribute to the differences in performance associated with hosting one symbiont species over another.

In silico assessment of collateral eddy current heating in biocompatible implants subjected to magnetic hyperthermia treatments.

Purpose: Bearing partially or fully metallic passive implants represents an exclusion criterion for patients undergoing a magnetic hyperthermia procedure, but there are no specific studies backing this restrictive decision. This work assesses how the secondary magnetic field generated at the surface of two common types of prostheses affects the safety and efficiency of magnetic hyperthermia treatments of localized tumors. The paper also proposes the combination of a multi-criteria decision analysis and a graphical representation of calculated data as an initial screening during the preclinical risk assessment for each patient.Materials and methods: Heating of a hip joint and a dental implant during the treatment of prostate, colorectal and head and neck tumors have been assessed considering different external field conditions and exposure times. The Maxwell equations including the secondary field produced by metallic prostheses have been solved numerically in a discretized computable human model. The heat exchange problem has been solved through a modified version of the Pennes' bioheat equation assuming a temperature dependency of blood perfusion and metabolic heat, i.e. thermorregulation. The degree of risk has been assessed using a risk index with parameters coming from custom graphs plotting the specific absorption rate (SAR) vs temperature increase, and coefficients derived from a multi-criteria decision analysis performed following the MACBETH approach.Results: The comparison of two common biomaterials for passive implants - Ti6Al4V and CoCrMo - shows that both specific absorption rate (SAR) and local temperature increase are found to be higher for the hip prosthesis made by Ti6Al4V despite its lower electrical and thermal conductivity. By tracking the time evolution of temperature upon field application, it has been established that there is a 30 s delay between the time point for which the thermal equilibrium is reached at prostheses and tissues. Likewise, damage may appear in those tissues adjacent to the prostheses at initial stages of treatment, since recommended thermal thresholds are soon surpassed for higher field intensities. However, it has also been found that under some operational conditions the typical safety rule of staying below or attain a maximum temperature increase or SAR value is met.Conclusion: The current exclusion criterion for implant-bearing patients in magnetic hyperthermia should be revised, since it may be too restrictive for a range of the typical field conditions used. Systematic in silico treatment planning using the proposed methodology after a well-focused diagnostic procedure can aid the clinical staff to find the appropriate limits for a safe treatment window.

An integrative analysis of the short-term effects of tail autotomy on thermoregulation and dehydration rates in wall lizards.

Maintaining body temperature is essential for the optimal performance of physiological functions. Ectotherms depend on external heat sources to thermoregulate. However, thermoregulation may be constrained by body condition and hydration state. Autotomy (i.e., the voluntary shed of a body part) evolved in various animal lineages and allowed surviving certain events (such as predator attacks), but it may affect body condition and volume/surface ratios, increase dehydration and constrain thermoregulation. In the framework of a general analysis of the evolution of autotomy, here we assessed the effects of tail loss on the thermal preferences and evaporative water loss rates (EWL) in the lizard Podarcis bocagei, integrating the thermal and hydric factors. We did not observe shifts in the thermal preferences of experimentally autotomized lizards when compared to the controls, which contradicted the hypothesis that they would raise preferred temperature to increase metabolic rates and accelerate regeneration. Evaporative water loss rates were also similar for tailed and tailless individuals, suggesting negligible increase of water loss through the injury and no specific ecophysiological responses after autotomy. Therefore, the changes observed in autotomized lizards in the field are to be considered primarily behavioural, rather than physiological, and thermoregulation could be secondarily affected by behavioural compensations for an increased predation risk after autotomy. Functional studies are necessary to understand how lizards' interaction with the environment is altered after autotomy, and further studies including different dehydration levels would be useful to fully understand the effect of water shortage on lizards' performance after caudal autotomy.

Apoptosis Pathways Triggered by a Potent Antiproliferative Hybrid Chalcone on Human Melanoma Cells.

The World Health Organization reported that approximately 324,000 new cases of melanoma skin cancer were diagnosed worldwide in 2020. The incidence of melanoma has been increasing over the past decades. Targeting apoptotic pathways is a potential therapeutic strategy in the transition to preclinical models and clinical trials. Some naturally occurring products and synthetic derivatives are apoptosis inducers and may represent a realistic option in the fight against the disease. Thus, chalcones have received considerable attention due to their potential cytotoxicity against cancer cells. We have previously reported a chalcone containing an indole and a pyridine heterocyclic rings and an α-bromoacryloylamido radical which displays potent antiproliferative activity against several tumor cell lines. In this study, we report that this chalcone is a potent apoptotic inducer for human melanoma cell lines SK-MEL-1 and MEL-HO. Cell death was associated with mitochondrial cytochrome c release and poly(ADP-ribose) polymerase cleavage and was prevented by a non-specific caspase inhibitor. Using SK-MEL-1 as a model, we found that the mechanism of cell death involves (i) the generation of reactive oxygen species, (ii) activation of the extrinsic and intrinsic apoptotic and mitogen-activated protein kinase pathways, (iii) upregulation of TRAIL, DR4 and DR5, (iv) downregulation of p21Cip1/WAF1 and, inhibition of the NF-κB pathway.

The Complex Structure of the Pharmacological Drug-Disease Network.

The complexity of drug-disease interactions is a process that has been explained in terms of the need for new drugs and the increasing cost of drug development, among other factors. Over the last years, diverse approaches have been explored to understand drug-disease relationships. Here, we construct a bipartite graph in terms of active ingredients and diseases based on thoroughly classified data from a recognized pharmacological website. We find that the connectivities between drugs (outgoing links) and diseases (incoming links) follow approximately a stretched-exponential function with different fitting parameters; for drugs, it is between exponential and power law functions, while for diseases, the behavior is purely exponential. The network projections, onto either drugs or diseases, reveal that the co-ocurrence of drugs (diseases) in common target diseases (drugs) lead to the appearance of connected components, which varies as the threshold number of common target diseases (drugs) is increased. The corresponding projections built from randomized versions of the original bipartite networks are considered to evaluate the differences. The heterogeneity of association at group level between active ingredients and diseases is evaluated in terms of the Shannon entropy and algorithmic complexity, revealing that higher levels of diversity are present for diseases compared to drugs. Finally, the robustness of the original bipartite network is evaluated in terms of most-connected nodes removal (direct attack) and random removal (random failures).

Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity.

Hippocampal synaptic plasticity disruption by amyloid-ß (Aß) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G-protein-gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G-protein-coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aß1-42 . In vitro electrophysiological recordings from slices showed that Aß1-42 alters synaptic plasticity by switching high-frequency stimulation (HFS) induced long-term potentiation (LTP) to long-term depression (LTD), which led to in vivo hippocampal-dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS-induced LTP and habituation memory from Aß1-42 action. Moreover, when GirK channels were specifically blocked by Tertiapin-Q, their activation with ML297 failed to rescue LTP from the HFS-dependent LTD induced by Aß1-42 . On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aß1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aß1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aß-mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS-induced LTP into LTD.

Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls.

IMPORTANCE: The magnitude and variability of cytokine alterations in depression are not clear. OBJECTIVE: To perform an up to date meta-analysis of mean differences of immune markers in depression, and to quantify and test for evidence of heterogeneity in immune markers in depression by conducting a meta-analysis of variability to ascertain whether only a sub-group of patients with depression show evidence of inflammation. DATA SOURCES: Studies that reported immune marker levels in peripheral blood in patients with depression and matched healthy controls in the MEDLINE database from inception to August 29th 2018 were examined. STUDY SELECTION: Case-control studies that reported immune marker levels in peripheral blood in patients with depression and healthy controls were selected. DATA EXTRACTION AND SYNTHESIS: Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis. MAIN OUTCOMES AND MEASURES: Hedges g was used to quantify mean differences. Relative variability of immune marker measurements in patients compared with control groups as indexed by the coefficient of variation ratio (CVR). RESULTS: A total of 107 studies that reported measurements from 5,166 patients with depression and 5,083 controls were included in the analyses. Levels of CRP (g = 0.71; 95%CI: 0.50-0.92; p < 0.0001); IL-3 (g = 0.60; 95%CI: 0.31-0.89; p < 0.0001); IL-6 (g = 0.61; 95%CI: 0.39-0.82; p < 0.0001); IL-12 (g = 1.18; 95%CI: 0.74-1.62; p < 0.0001); IL-18 (g = 1.97; 95%CI: 1.00-2.95; p < 0.0001); sIL-2R (g = 0.71; 95%CI: 0.44-0.98; p < 0.0001); and TNFα (g = 0.54; 95%CI: 0.32-0.76; p < 0.0001) were significantly higher in patients with depression. These findings were robust to a range of potential confounds and moderators. Mean-scaled variability, measured as CVR, was significantly lower in patients with depression for CRP (CVR = 0.85; 95%CI: 0.75-0.98; p = 0.02); IL-12 (CVR = 0.61; 95%CI: 0.46-0.80; p < 0.01); and sIL-2R (CVR = 0.85; 95%CI: 0.73-0.99; p = 0.04), while it was unchanged for IL-3, IL-6, IL-18, and TNF α. CONCLUSIONS AND RELEVANCE: Depression is confirmed as a pro-inflammatory state. Some of the inflammatory markers elevated in depression, including CRP and IL-12, show reduced variability in patients with depression, therefore supporting greater homogeneity in terms of an inflammatory phenotype in depression. Some inflammatory marker elevations in depression do not appear due to an inflamed sub-group, but rather to a right shift of the immune marker distribution.

Reintubation in the ICU following cardiac surgery: is it more difficult than first-time intubation in the operating room?: A prospective observational study.

BACKGROUND: After cardiac surgery, a patient's trachea is usually extubated; however, 2 to 13% of cardiac surgery patients require reintubation in the ICU. OBJECTIVE: The objective of this study was to compare the initial intubation in the cardiac operating room with reintubation (if required) in the ICU following cardiac surgery. DESIGN: A prospective, observational study. SETTING: Department of Anesthesiology and Intensive Care Medicine, Clinical Hospital of Santiago, Spain. PATIENTS: With approval of the local ethics committee, over a 44-month period, we prospectively enrolled all cardiac surgical patients who were intubated in the operating room using direct laryngoscopy, and who required reintubation later in the ICU. MAIN OUTCOME MEASURES: The primary endpoint was to compare first-time success rates for intubation in the operating room and ICU. Secondary endpoints were to compare the technical difficulties of intubation (modified Cormack-Lehane glottic view, operator-reported difficulty of intubation, need for support devices for direct laryngoscopy) and the incidence of complications. RESULTS: A total of 122 cardiac surgical patients required reintubation in the ICU. Reintubation was associated with a lower first-time success rate than in the operating room (88.5 vs. 97.6%, P = 0.0048). Reintubation in the ICU was associated with a higher incidence of Cormack-Lehane grades IIb, III or IV views (34.5 vs. 10.7%, P < 0.0001), a higher incidence of moderate or difficult intubation (17.2 vs. 6.5%, P = 0.0001) and a greater need for additional support during direct laryngoscopy (20.5 vs. 10.7%, P = 0.005). Complications were more common during reintubations in the ICU (39.3 vs. 5.7%, P < 0.0001). CONCLUSION: Compared with intubations in the operating room, reintubation of cardiac surgical patients in the ICU was associated with more technical difficulties and a higher incidence of complications. CLINICAL TRIAL NUMBER: Ethics committee of Galicia number 2015-012.

Generation of renal Epo-producing cell lines by conditional gene tagging reveals rapid HIF-2 driven Epo kinetics, cell autonomous feedback regulation, and a telocyte phenotype.

Erythropoietin (Epo) is essential for erythropoiesis and is mainly produced by the fetal liver and the adult kidney following hypoxic stimulation. Epo regulation is commonly studied in hepatoma cell lines, but differences in Epo regulation between kidney and liver limit the understanding of Epo dysregulation in polycythaemia and anaemia. To overcome this limitation, we have generated a novel transgenic mouse model expressing Cre recombinase specifically in the active fraction of renal Epo-producing (REP) cells. Crossing with reporter mice confirmed the inducible and highly specific tagging of REP cells, located in the corticomedullary border region where there is a steep drop in oxygen bioavailability. A novel method was developed to selectively grow primary REP cells in culture and to generate immortalized clonal cell lines, called fibroblastoid atypical interstitial kidney (FAIK) cells. FAIK cells show very early hypoxia-inducible factor (HIF)-2α induction, which precedes Epo transcription. Epo induction in FAIK cells reverses rapidly despite ongoing hypoxia, suggesting a cell autonomous feedback mechanism. In contrast, HIF stabilizing drugs resulted in chronic Epo induction in FAIK cells. RNA sequencing of three FAIK cell lines derived from independent kidneys revealed a high degree of overlap and suggests that REP cells represent a unique cell type with properties of pericytes, fibroblasts, and neurons, known as telocytes. These novel cell lines may be helpful to investigate myofibroblast differentiation in chronic kidney disease and to elucidate the molecular mechanisms of HIF stabilizing drugs currently in phase III studies to treat anemia in end-stage kidney disease.

Role of GirK Channels in Long-Term Potentiation of Synaptic Inhibition in an In Vivo Mouse Model of Early Amyloid-ß Pathology.

Imbalances of excitatory/inhibitory synaptic transmission occur early in the pathogenesis of Alzheimer's disease (AD), leading to hippocampal hyperexcitability and causing synaptic, network, and cognitive dysfunctions. G-protein-gated potassium (GirK) channels play a key role in the control of neuronal excitability, contributing to inhibitory signaling. Here, we evaluate the relationship between GirK channel activity and inhibitory hippocampal functionality in vivo. In a non-transgenic mouse model of AD, field postsynaptic potentials (fPSPs) from the CA3⁻CA1 synapse in the dorsal hippocampus were recorded in freely moving mice. Intracerebroventricular (ICV) injections of amyloid-ß (Aß) or GirK channel modulators impaired ionotropic (GABAA-mediated fPSPs) and metabotropic (GirK-mediated fPSPs) inhibitory signaling and disrupted the potentiation of synaptic inhibition. However, the activation of GirK channels prevented Aß-induced changes in GABAA components. Our data shows, for the first time, the presence of long-term potentiation (LTP) for both the GABAA and GirK-mediated inhibitory postsynaptic responses in vivo. In addition, our results support the importance of an accurate level of GirK-dependent signaling for dorsal hippocampal performance in early amyloid pathology models by controlling the excess of excitation that disrupts synaptic plasticity processes.

ROS-Induced JNK and p38 Signaling Is Required for Unpaired Cytokine Activation during Drosophila Regeneration.

Upon apoptotic stimuli, epithelial cells compensate the gaps left by dead cells by activating proliferation. This has led to the proposal that dying cells signal to surrounding living cells to maintain homeostasis. Although the nature of these signals is not clear, reactive oxygen species (ROS) could act as a signaling mechanism as they can trigger pro-inflammatory responses to protect epithelia from environmental insults. Whether ROS emerge from dead cells and what is the genetic response triggered by ROS is pivotal to understand regeneration of Drosophila imaginal discs. We genetically induced cell death in wing imaginal discs, monitored the production of ROS and analyzed the signals required for repair. We found that cell death generates a burst of ROS that propagate to the nearby surviving cells. Propagated ROS activate p38 and induce tolerable levels of JNK. The activation of JNK and p38 results in the expression of the cytokines Unpaired (Upd), which triggers the JAK/STAT signaling pathway required for regeneration. Our findings demonstrate that this ROS/JNK/p38/Upd stress responsive module restores tissue homeostasis. This module is not only activated after cell death induction but also after physical damage and reveals one of the earliest responses for imaginal disc regeneration.

Patient reported outcome measures in child and adolescent mental health services: associations between clinician demographic characteristics, attitudes and efficacy.

BACKGROUND: Policy recommends using patient reported outcome measures (PROMs), yet their use is persistently low. Our aim was to examine the association between PROM use and clinician demographic characteristics, attitudes and efficacy. METHOD: A sample of N = 109 clinicians completed an online survey. RESULTS: Clinicians who reported higher levels of use of cognitive behaviour or humanistic approaches had higher levels of PROM use than clinicians who reported lower levels of use of these approaches. Clinicians who reported having received training had higher levels of self-efficacy regarding PROMs than clinicians who reported not having received training, but the effects of training on PROM attitudes and use were not significant. Still, clinicians with more positive attitudes or self-efficacy regarding PROMs had higher levels of PROM use than clinicians with less positive attitudes or self-efficacy regarding PROMs. CONCLUSION: Clinicians should be supported to have the knowledge, skills and confidence to effectively use PROMs in their clinical practice.