Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review

Neurocritical Care - For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral...     

Bovine NK cells can produce gamma interferon in response to the secreted mycobacterial proteins ESAT-6 and MPP14 but not in response to MPB70

Bovine NK cells have recently been characterized and the present study describes the interaction between NK cells, antigen-presenting cells, and secreted mycobacterial proteins. Gamma interferon (IFN-gamma) production by NK cells was seen in approximately 30% of noninfected calves in response to the Mycobacterium tuberculosis complex-specific protein ESAT-6, MPP14 from Mycobacterium avium subsp. paratuberculosis, and purified protein derivative (PPD) from M. tuberculosis. In contrast, no response was induced by MPB70, which is another M. tuberculosis complex-specific secreted antigen. The production of IFN-gamma by NK cells in whole blood in response to ESAT-6 and MPP14 was demonstrated using intracellular staining together with surface labeling for the NK cell-specific receptor, NKp46, or CD3. Furthermore, the depletion of NK cells from peripheral blood mononuclear cells completely abolished the IFN-gamma production. The response was mediated through stimulation of adherent cells and was largely independent of contact between adherent cells and the NK cells. Neutralization of interleukin-12 only partly inhibited IFN-gamma production, showing that other cytokines were also involved. The demonstration of NK cell-mediated IFN-gamma production in young cattle provides an explanation for the nonspecific IFN-gamma response frequently encountered in young cattle when using the IFN-gamma test in diagnosis of mycobacterial infections.     

Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond

Structures of alternative pathway proteins have offered a comprehensive structural basis for understanding the molecular mechanisms governing activation and regulation of the amplification pathway of the complement cascade. Although properdin (FP) is required in vivo to sustain a functional alternative pathway, structural studies have been lagging behind due to the extended structure and polydisperse nature of FP. We review recent progress with respect to structure determination of FP and its proconvertase/convertase complexes. These structures identify in detail regions in C3b, factor B and FP involved in their mutual interactions. Structures of FP oligomers obtained by integrative studies have shed light on how FP activity depends on its oligomerization state. The accumulated structural knowledge allows us to rationalize the effect of point mutations causing FP deficiency. The structural basis for FP inhibition by the tick CirpA proteins is reviewed and the potential of alphafold2 predictions for understanding the interaction of FP with other tick proteins and the NKp46 receptor on host immune cells is discussed. The accumulated structural knowledge forms a comprehensive basis for understanding molecular interactions involving FP, pathological conditions arising from low levels of FP, and the molecular strategies used by ticks to suppress the alternative pathway.     

Symptoms and healthcare contact preceding sudden cardiac death in persons aged 1–49 years

Sudden Cardiac Death (SCD) is a leading cause of death among persons in their youth and early middle-age. To prevent SCD it is crucial to identify persons at high-risk of SCD. Knowledge of symptoms and medical contact prior to SCD could potentially aid in the identification of high-risk persons in the general population who would benefit from further investigation. This review aims to summarize the current knowledge of symptoms and healthcare contact preceding SCD in persons aged 1–49 years, and to explore how the symptoms differ according to SCD cause and age of the deceased.There was a high frequency of both cardiac and non-specific symptoms prior to SCD. Additionally, many SCD victims contacted the healthcare system prior to death on the basis of their symptoms and only a few were diagnosed with cardiovascular disease. This information underlines that young persons reporting potential cardiac symptoms should also be thoroughly examined. Furthermore, such symptoms could be used in combination with other easily accessible information in non-invasive prediction models aiming at identifying persons at high risk of SCD that would benefit from further investigation and possibly treatment.     

Structural basis for activation of the complement system by component C4 cleavage

An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.     

Preferences predict who commits crime among young men

Understanding who commits crime and why is a key topic in social science and important for the design of crime prevention policy. In theory, people who commit crime face different social and economic incentives for criminal activity than other people, or they evaluate the costs and benefits of crime differently because they have different preferences. Empirical evidence on the role of preferences is scarce. Theoretically, risk-tolerant, impatient, and self-interested people are more prone to commit crime than risk-averse, patient, and altruistic people. We test these predictions with a unique combination of data where we use incentivized experiments to elicit the preferences of young men and link these experimental data to their criminal records. In addition, our data allow us to control extensively for other characteristics such as cognitive skills, socioeconomic background, and self-control problems. We find that preferences are strongly associated with actual criminal behavior. Impatience and, in particular, risk tolerance are still strong predictors when we include the full battery of controls. Crime propensities are 8 to 10 percentage points higher for the most risk-tolerant individuals compared to the most risk averse. This effect is half the size of the effect of cognitive skills, which is known to be a very strong predictor of criminal behavior. Looking into different types of crime, we find that preferences significantly predict property offenses, while self-control problems significantly predict violent, drug, and sexual offenses.

In choice theory of crime, individuals trade off their benefits from criminal activity against the opportunity costs of legitimate activity and the risks of future costs due to apprehension and punishment (1–3). People can face different trade-offs, for instance, due to differences in how much they can otherwise earn in the labor market, or they can evaluate the trade-offs differently due to differences in preferences. A large empirical literature documents that variation in the trade-off people face predicts who commits crime (3–6). In contrast, little is known about the role of preferences.Key preference parameters are risk tolerance and impatience. Intuitively, crime provides a benefit now but at the risk of a cost in the future which makes crime less attractive for people who dislike risk and care more about future well-being (3). Thus, more risk-tolerant and more impatient people are more prone to commit crime than others (see SI Appendix, SI Text, for a formal derivation in a basic model of criminal behavior). In standard choice theory, people are entirely driven by self-interest, but the theory can be extended to allow for altruistic motives or more sophisticated, other-regarding preferences (7–9). More altruistic people will commit less crime because they care about the costs they inflict on others.In this paper, we ask whether preferences predict who commits crime among young men. We focus on young men (age 18 to 19) who are known to have much higher crime rates than women and older people (3, 10, 11). To answer the question, we leverage a unique combination of data where we use incentivized experiments to elicit the preferences of young men in Denmark and link this experimental data to administrative records with information about all criminal offenses.We examine the association between preferences and crime while also controlling for other differences across people that can explain criminal behavior. The link between experimental data and administrative records enables us to include an extraordinary rich set of relevant control variables. This includes school performance, area of residence, immigrant status, family size, birth order, parental socioeconomic status, criminal records of parents, and family stress as measured by parental divorce or unemployment. Moreover, when we collected the experimental data on preferences, we also asked about self-control which is known to be a strong predictor of crime (12–14). We use this information to control for behavioral factors other than risk, time, and social preferences. We also investigate the relation between preferences and different types of criminal offenses. Arguably, the hypothesis that cost-benefit considerations help explain crime seems more appropriate for property crimes than violent, drug, and sexual offenses where lack of self-control may be a more important driver.This study links experimentally elicited risk, time, and social preferences to actual criminal behavior. We follow a large literature in experimental economics that elicits people’s preferences using incentivized choice experiments, where participants receive payments according to their decisions in the experiment. This literature documents pervasive variation in preferences including that some people are more risk tolerant, impatient, and motivated by self-interest than others (15–17). Studies also show that these parameters are correlated with real-life behavior and outcomes in accordance with theoretical predictions, for example, savings, high school graduation, disciplinary referrals of school children, entrepreneurship, body mass index, and smoking (18–25). The number of participants in our elicitation experiment is large compared to previous studies, and the participants are sampled randomly from the population in contrast to many previous studies which are based on samples of students (26). A large population sample is important for our purpose because crime frequency is low and because students differ significantly from the population at large with respect to their crime propensity.Most closely related to our work is a recent study that finds a significant relationship between patience and criminal offenses (27). The study uses a nonincentivized survey question to measure patience and demonstrates that this predicts crime. Interestingly, the authors find that the predictive power of patience is about one-third of the power of cognitive skills and that patience is most predictive of property crime, which is similar to our findings. Our study differs 1) by providing a more comprehensive and experimentally elicited set of preference measures that include risk preferences and social preferences and 2) by including a self-control measure in the set of predictors. This enables us to 1) show that risk tolerance is the strongest predictor of crime among the preference parameters and 2) document that risk and time preferences significantly predict property crime where self-control is not a significant predictor, whereas in the domain of violent, drug, and sexual offenses, self-control is a key predictor, while risk and time preferences are not significantly predictive.     

Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioural studies in the rat

Rationale. A substantial number of patients do not respond sufficiently to antidepressant drugs and are therefore often co-medicated with lithium as an augmentation strategy. However, the neurochemical rationale behind this strategy needs to be further clarified. Objectives. We examined the effect of chronic citalopram and subchronic lithium, alone or in combination, on (a) serum levels of citalopram and lithium, (b) animal behaviour and (c) hippocampal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels. Furthermore, we examined the serum level of citalopram and hippocampal 5-HT following one acute citalopram injection. Methods. Microdialysis in the freely moving animals was used to determine hippocampal 5-HT and 5-HIAA. The animal behaviour was examined in the open field and forced swim test. Results. We found that chronic administration of citalopram (20 mg/kg/24 h s.c.) significantly increased the 5-HT baseline relative to vehicle-treated rats. Addition of subchronic lithium (60 mmol/kg chow pellet p.o.) to chronic citalopram therapy further elevated the 5-HT levels. Moreover, we found acute citalopram (5 mg/kg s.c.) to increase the 5-HT level. The immobility time in the FST and the locomotion in the OF were unaffected by any treatments. Conclusions. The present results support the assumption that increases in hippocampal 5-HT neurotransmission may be important in the augmentatory effect of lithium. Electronic Publication     

Antidepressant-like effect of agmatine is not mediated by serotonin

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light-dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.