Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first ...discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signaling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans.
•ROS are created during oxidative phosphorylation and by NADPH oxidase complexes.•ROS-induced signaling regulates immune reactions and can prevent autoimmunity.•Prolonged and uncontrolled ROS production can cause collateral tissue damage.•Temporally and spatial balance of ROS levels is essential to sustain homeostasis.
There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews ...the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action ('bad trip'), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.
This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA). Research suggests the potential ...safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. A more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement.
Psilocybin, like other 5-HT2A agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. Nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. Potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. However, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility.
(1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved.
This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.
•Psilocybin mushrooms have been used for millennia for spiritual and medical purposes.•Animal and human studies indicate low abuse and no physical dependence potential.•Major national surveys indicate low rates of abuse, treatment-seeking and harm.•Psilocybin may provide therapeutic benefits supporting its development as a new drug.•Analysis supports the scheduling of psilocybin no more restrictively than Schedule IV.
Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric ...disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 min after blinded oral administration of placebo and 10 mg/70 kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.
Naturally occurring and psychedelic drug-occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared. In this study, five groups of ...individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1184 psilocybin, 1251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. The Non-Drug Group was most likely to choose "God" as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose "Ultimate Reality." Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking. Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in approximately half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience. Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.
Water for wound cleansing Fernandez, R; Griffiths, R
Cochrane database of systematic reviews,
01/2008
1
Journal Article
Recenzirano
Various solutions have been recommended for cleansing wounds, however normal saline is favoured as it is an isotonic solution and does not interfere with the normal healing process. Tap water is ...commonly used in the community for cleansing wounds because it is easily accessible, efficient and cost effective, however, there is an unresolved debate about its use.
The objective of this review was to assess the effects of water compared with other solutions for wound cleansing.
Randomised and quasi-randomised controlled trials were identified by electronic searches of Cochrane Wounds Group Specialised Register (June 2007), MEDLINE (1996-2007), EMBASE (1980-2007), CINAHL (1982-2007) and the Cochrane Controlled Trials Register (Issue 3; 2007). Primary authors, company representatives and content experts were contacted to identify eligible studies. Reference lists from included trials were also searched.
Randomised and quasi randomised controlled trials that compared the use of water with other solutions for wound cleansing were eligible for inclusion. Additional criteria were outcomes that included objective or subjective measures of wound infection or healing.
Trial selection, data extraction and quality assessment were carried out independently by two authors and checked by a third author. Differences in opinion were settled by discussion. Some data were pooled using a random effects model.
Eleven trials were included in this review. Seven trials were identified that compared rates of infection and healing in wounds cleansed with water and normal saline, three trials compared cleansing with no cleansing and one trial compared procaine spirit with water. There were no standard criteria for assessing wound infection across the trials which limited the ability to pool the data. The major comparisons were water with normal saline, and tap water with no cleansing. For chronic wounds, the relative risk of developing an infection when cleansed with tap water compared with normal saline was 0.16, (95% CI 0.01 to 2.96). Tap water was more effective than saline in reducing the infection rate in adults with acute wounds (RR 0.63, 95% CI 0.40 to 0.99). The use of tap water to cleanse acute wounds in children was not associated with a statistically significant difference in infection when compared to saline (RR 1.07, 95% CI 0.43 to 2.64). No statistically significant differences in infection rates were seen when wounds were cleansed with tap water or not cleansed at all (RR 1.06, 95% CI 0.07 to 16.50). Likewise, there was no difference in the infection rate in episiotomy wounds cleansed with water or procaine spirit. The use of isotonic saline, distilled water and boiled water for cleansing open fractures also did not demonstrate a statistically significant difference in the number of fractures that were infected.
There is no evidence that using tap water to cleanse acute wounds in adults increases infection and some evidence that it reduces it. However there is not strong evidence that cleansing wounds per se increases healing or reduces infection. In the absence of potable tap water, boiled and cooled water as well as distilled water can be used as wound cleansing agents.
A large body of evidence, including longitudinal analyses of personality change, suggests that core personality traits are predominantly stable after age 30. To our knowledge, no study has ...demonstrated changes in personality in healthy adults after an experimentally manipulated discrete event. Intriguingly, double-blind controlled studies have shown that the classic hallucinogen psilocybin occasions personally and spiritually significant mystical experiences that predict long-term changes in behaviors, attitudes and values. In the present report we assessed the effect of psilocybin on changes in the five broad domains of personality – Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness. Consistent with participant claims of hallucinogen-occasioned increases in aesthetic appreciation, imagination, and creativity, we found significant increases in Openness following a high-dose psilocybin session. In participants who had mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than 1 year after the session. The findings suggest a specific role for psilocybin and mystical-type experiences in adult personality change.
The Baltic Sea summer phytoplankton community plays an important role in biogeochemical cycling and in the transfer of energy through the food web via zooplankton. We aimed to improve the ...understanding of the degree to which large-scale versus local environmental dynamics regulate phytoplankton dynamics by analyzing time series at the Baltic Sea scale. We used dynamic factor analysis to study if there are common patterns of interannual variation that are shared ("common trends") among summer phytoplankton total and class-level biomass time series observed across Baltic Sea latitudinal gradients in salinity and temperature. We evaluated alternative hypotheses regarding common trends among summer phytoplankton biomass: Baltic Sea-wide common trends; common trends by geography (latitude and basin); common trends differing among functional groups (phytoplankton classes); or common trends driven by both geography and functional group. Our results indicated little support for a common trend in total summer phytoplankton biomass. At a finer resolution, classes had common trends that were most closely associated with the cryptophyte and cyanobacteria time series with patterns that differed between northern and southern sampling stations. These common trends were also very sensitive to two anomalous years (1990, 2008) of cryptophyte biomass. The Baltic Sea Index, a regional climate index, was correlated with two common class trends that shifted in mean state around the mid-1990s. The limited coherence in phytoplankton biomass variation over time despite known, large-scale, ecosystem shifts suggests that stochastic dynamics at local scales limits the ability to observe common trends at the scale of monitoring data collection.
The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and ...repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes. Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.
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