William James gets very high on nitrous oxide and then writes about it.

Continuous recordings of brain electrical activity were obtained from a group of 176 patients throughout surgical procedures using general anesthesia. Artifact-free data from the 19 electrodes of the International 10/20 System were subjected to quantitative analysis of the electroencephalogram (QEEG). Induction was variously accomplished with etomidate, propofol or thiopental. Anesthesia was maintained throughout the procedures by isoflurane, desflurane or sevoflurane (N = 68), total intravenous anesthesia using propofol (N = 49), or nitrous oxide plus narcotics (N = 59). (...) A set of QEEG measures were found which reversibly displayed high heterogeneity of variance between four states as follows: (1) during induction; (2) just after loss of consciousness (LOC); (3) just before return of consciousness (ROC); (4) just after ROC. Homogeneity of variance across all agents within states was found. Topographic statistical probability images were compared between states. At LOC, power increased in all frequency bands in the power spectrum with the exception of a decrease in gamma activity, and there was a marked anteriorization of power. Additionally, a significant change occurred in hemispheric relationships, with prefrontal and frontal regions of each hemisphere becoming more closely coupled, and anterior and posterior regions on each hemisphere, as well as homologous regions between the two hemispheres, uncoupling. All of these changes reversed upon ROC. Variable resolution electromagnetic tomography (VARETA) was performed to localize salient features of power anteriorization in three dimensions. A common set of neuroanatomical regions appeared to be the locus of the most probable generators of the observed EEG changes. (shrink)

Psychogenic depersonalization is an altered mental state consisting of an unusual discontinuity in the phenomenological perception of personal being; the individual is engulfed by feelings of unreality, self-detachment and unfamiliarity in which the self is felt to lack subjective perspective and the intuitive feeling of personal embodiment. A new sub-feature of depersonalization is delineated. 'Prosthesis' consists in the thought that the thinker is a 'mere thing'. It is a subjectively realized sense of the specific and objective 'thingness' of the particular (...) object thought about. I show that prosthesis is an important cognitive feature of depersonalization, and may be psychologically connected with the tendency of depersonalized individuals to report 'philosophical' types of thinking. Indeed, several philosophical issues concerning the identity of the self appear to have been enhanced by prosthesis experiences. Thus, far more efficient than William James's experimental attempts to uncover philosophical truths under the influence of nitrous oxide intoxication, prosthesis may be a safe and recommended experience for philosophers. The history of depersonalization theories is presented from Krishaber to Freud, and the main approaches to prosthesis criticized. Finally, a fresh approach to psychogenic depersonalization is outlined on the basis of certain cognitive similarities with visual agnosia. This paper may be understood as continuing the Jamesian tradition 'experimental abnormal psychology', that is, of examining extraordinary mental states with an eye to their philosophical implications. (shrink)

_Pluriverse_, the final work of the American poet and philosopher Benjamin Paul Blood, was published posthumously in 1920. After an experience of the anaesthetic nitrous oxide during a dental operation, Blood came to the conclusion that his mind had been opened, that he had undergone a mystical experience, and that he had come to a realisation of the true nature of reality. This title is the fullest exposition of Blood’s esoteric Christian philosophy-cum-theology, which, though deemed wildly eccentric by (...) commentators both during his lifetime and later in the twentieth century, was nonetheless one of the most influential sources for American mystical-empiricism. In particular, Blood’s thought was a major inspiration for William James, and can be seen to prefigure the latter’s concept of Sciousness directly. (shrink)

_Pluriverse_, the final work of the American poet and philosopher Benjamin Paul Blood, was published posthumously in 1920. After an experience of the anaesthetic nitrous oxide during a dental operation, Blood came to the conclusion that his mind had been opened, that he had undergone a mystical experience, and that he had come to a realisation of the true nature of reality. This title is the fullest exposition of Blood’s esoteric Christian philosophy-cum-theology, which, though deemed wildly eccentric by (...) commentators both during his lifetime and later in the twentieth century, was nonetheless one of the most influential sources for American mystical-empiricism. In particular, Blood’s thought was a major inspiration for William James, and can be seen to prefigure the latter’s concept of Sciousness directly. (shrink)

The history of the dyestuffs industry during the period 1775–1860 is interesting for three reasons. In the first place it was in connection with the manufacture of synthetic dyestuffs, begun in 1856, that the industrial research laboratory and the organization scientist first unmistakably appeared in the last decades of the nineteenth century. Secondly, there are the enigmas of W. H. Perkin, the man who discovered and manufactured the first coal-tar colours, but who retired somewhat abruptly from the industry in 1874: (...) just after the synthesis of alizarine. Thirdly, the dyestuffs industry was in intimate association with the textile industries which had for a long time been subject to frequent radical scientific and technological innovation. Among the most important of these we may mention John Smeaton's classic paper of 1759 on the maximum work obtainable from a given fall of water: a problem important not only for the abstract science of mechanics, but also for the design of waterwheels—the main source of power for the early textile mills. (The waterwheel was not, during the eighteenth century, the epitome of the quaint and picturesque: it was in the van of scientific and technical progress.) Again, the textile industries were quick to employ the Watt rotative engine; previously a two cylinder Newcomen engine had been tried out. Bleaching powders, based on Scheele's discovery of chlorine and its properties, were rapidly adopted: in this context one cannot help contrasting the indifference of medical science to Davy's early suggestion of using nitrous oxide as an anaesthetic; or Faraday's comment in 1818 on the anaesthetic power of sulphuric ether. The textile industries saw, over this period, a rapid succession of new machines, the pace of invention being so hot that in 1832 Charles Babbage reported that machines became obsolete long before they wore out. A Salford cotton mill was the first industrial establishment to use gas lighting: James Thomson, calico printer, introduced gas lighting to the town of Clitheroe when he installed it in his works. And there were many other important technical and scientific innovations. It was to supply these industries, so well accustomed to change, that the synthetic coal-tar dyestuffs were introduced from 1856 onwards. It is interesting that, so far as we can see, the appearance of these synthetic dyestuffs was the last in the series of major innovations in the textiles and related industries: at least until recent times. (shrink)

This chapter contains sections titled: Philosophical Prohibitions Religious Arguments A Defense of Altered States Cannabis in Particular.

The idea that oxidative stress may underpin life history trade‐offs has become extremely popular. However, experimental support for the concept has proved equivocal. It has recently been suggested that this might be because of flaws in the design of existing studies. Here, we explore the background to the oxidative stress hypothesis and highlight some of the complexities in testing it. We conclude that the approach recently suggested to be least useful in this context (comparing reproducing to non‐reproducing animals) may in (...) fact be the most powerful. Moreover, suggested alternative approaches of limiting food supply or manipulating litter sizes have many complexities and problems. We suggest some useful alternative approaches that have not been previously advocated, particularly the study of individuals reproducing at greater parity later in life. Finally, the measures of oxidative stress and tissues that are analysed influence the experimental outcome. This suggests our conceptual model of the trade‐off is currently too simplistic, and that studies based on single or limited numbers of assays, or restricted to single tissues, whether they support or refute the theory, should be interpreted with great caution. (shrink)

The theory stating that oxidative stress is at the root of several diseases is extremely popular. However, so far, no antioxidant is recommended or offered by healthcare systems neither approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this (...) review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging reactive oxygen species might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and with different timing. Aggregating this plurality of systems in a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories, as this will allow big data approaches or meta-analyses without the blinders of the publication bias. (shrink)

Nitric oxide (NO) is a pleiotropic signalling molecule that subserves a wide variety of basic cellular functions and also manifests itself pathophysiologically. As regards cancer and its progression, however, the reported role of NO appears surprisingly inconsistent. In this review, we focus on metastasis, the process of cancer cell spread and secondary tumour formation. In a ‘reductionist’ approach, we consider the metastatic cascade to be made up of a series of basic cellular behaviours (such as proliferation, apoptosis, adhesion, secretion (...) migration, invasion and angiogenesis). We evaluate how NO controls such behaviours, in comparison with normal cells. The available information suggests strongly that NO signalling would be expected to regulate these behaviours both positively and negatively and this probably leads to the observed apparent variability in the NO status of cancer cells and tissues. Thus, the role of NO in cancer is more complex than previously thought. A number of suggestions are made, including consideration of novel mechanisms, such as ion channels, in order to achieve a more consistent and integrated understanding of NO signalling in cancer and to realise its clinical potential. BioEssays 27:1228–1238, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The environment can elicit biological responses such as oxidative stress (OS) and inflammation as a consequence of chemical, physical, or psychological changes. As population studies are essential for establishing these environment-organism interactions, biomarkers of OS or inflammation are critical in formulating mechanistic hypotheses. By using examples of stress induced by various mechanisms, we focus on the biomarkers that have been used to assess OS and inflammation in these conditions. We discuss the difference between biomarkers that are the result of a (...) chemical reaction (such as lipid peroxides or oxidized proteins that are a result of the reaction of molecules with reactive oxygen species) and those that represent the biological response to stress, such as the transcription factor NRF2 or inflammation and inflammatory cytokines. The high-throughput and holistic approaches to biomarker discovery used extensively in large-scale molecular epidemiological exposome are also discussed in the context of human exposure to environmental stressors. We propose to consider the role of biomarkers as signs and to distinguish between signs that are just indicators of biological processes and proxies that one can interact with and modify the disease process. (shrink)

Interest in the role of nitric oxide (NO) in the nervous system began with the demonstration that glutamate receptor activation in cerebellar slices causes the formation of a diffusible messenger with properties similar to those of the endothelium-derived relaxing factor. It is now clear that this is due to the Ca2+/calmodulin-dependent activation of the enzyme NO synthase, which forms NO and citrulline from the amino acid L-arginine. The cerebellum has very high levels of NO synthase, and although it has (...) low levels of guanylyl cyclase, cerebellar cyclic guanosine monophosphate (cGMP) levels are an order of magnitude higher than in other brain regions. A transcellular metabolic pathway is also present in the cerebellar cortex to recycle citrulline back to arginine. The NO formed binds to and activates soluble guanylyl cyclase to elevate cGMP levels in target cells. Studies employing NADPH-diaphorase, a selective histochemical marker for NO synthase, together with immunohistochemistry, in situ hybridization and biochemical studies have indicated that NO production occurs in granule and basket cells in the cerebellar cortex, whereas cGMP formation appears to occur largely in other cells, including Purkinje cells. Given that a long-term depression of AMPA currents can be seen in isolated Purkinje cells, this anatomical localization suggests that NO cannot play an essential role in the induction of this form of synaptic plasticity. (shrink)

Widespread expression of the transcription factor, nuclear factor (erythroid‐derived 2)‐like 2 (NRF2), which maintains redox homeostasis, has recently been identified in the hair follicle (HF). Small molecule activators of NRF2 may therefore be useful in the management of HF pathologies associated with redox imbalance, ranging from HF greying and HF ageing via androgenetic alopecia and alopecia areata to chemotherapy‐induced hair loss. Indeed, NRF2 activation has been shown to prevent peroxide‐induced hair growth inhibition. Multiple parameters can increase the levels of reactive (...) oxygen species in the HF, for example melanogenesis, depilation‐induced trauma, neurogenic and autoimmune inflammation, toxic drugs, environmental stressors such as UV irradiation, genetic defects and aging‐associated mitochondrial dysfunction. In this review, the potential mechanisms whereby NRF2 activation could prove beneficial in treatment of redox‐associated HF disorders are therefore discussed. (shrink)

In this essay I share some of the lessons I have learned over the last 25 years studying how the vascular endothelium via nitric oxide contributes to the regulation of the cardiovascular system in humans. My motivation for this effort is that in an era of molecular reductionism in biomedical research I believe that the lessons from the vascular endothelium and NO are instructive in a larger sense. These discoveries might also be among the "last" big biomedical discoveries made (...) by traditional physiology and pharmacology using primarily organ baths, pharmacological blockers, and in... (shrink)

In pathological conditions associated with persistent increases in hemodynamic workload (old myocardial infarction, high blood pressure, valvular heart disease), a number of signalling pathways are activated in the heart, all of which promote hypertrophic growth of the heart, characterised at the cellular level by increases in individual cardiac myocyte size. Some of these pathways are required for a successful adaptation to cardiac injury. Other pathways are maladaptive, however, as they lead to progressive contractile dysfunction and heart failure. The free radical (...) gas nitric oxide and natriuretic peptides, both of which are produced in the heart, have emerged as endogenous inhibitors of maladaptive hypertrophy signalling. Overall, it appears that cardiac hypertrophy is controlled by an interplay of pro‐ and antihypertrophic signalling networks. This delicate balance can tip towards adaptation or heart failure. In the future, patients living with cardiac disease may benefit from therapeutic strategies targeting maladaptive hypertrophy signalling pathways. BioEssays 26:608–615, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene have, however, (...) led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The involvement of nitric oxide in cerebellar long-term depression is supported by the observation that nitric oxide is released by climbing fiber stimulation and by pharmacological tool usage. Two forms of long-term depression should be distinguished by their physiological relevance. [CRÉPEL et al.; LINDEN; VINCENT].

Oxidised bases, such as 8-oxo-guanine, occur in cellular DNA as a result of attack by oxygen free radicals. The cancer-protective effect of vegetables and fruit is attributed to the ability of antioxidants in them to scavenge free radicals, preventing DNA damage and subsequent mutation. Antioxidant supplements (e.g., β-carotene, vitamin C) increase the resistance of lymphocytes to oxidative damage, and a negative correlation is seen between antioxidant concentrations in tissues and oxidised bases in DNA. Large-scale intervention trials with β-carotene have, however, (...) led to increases in cancer. Recent measurements of the frequency of oxidised DNA bases indicate that earlier estimates were greatly exaggerated; there may be only a few thousand 8-oxo-guanines per cell. Convincing evidence for mutations resulting from oxidative damage, in tumours or cultured cells, is lacking. It seems that efficient antioxidant defences together with DNA repair maintain a steady-state level of damage representing minimal risk to cell or organism. BioEssays 21:238–246, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The ubiquitous nature of mitochondria, the dual genetic foundation of the respiratory chain in mitochondrial and nuclear genome, and the peculiar rules of mitochondrial genetics all contribute to the extraordinary heterogeneity of clinical disorders associated with defects of oxidative phosphorylation (mitochondrial encephalomyopathies). Here, we review recent findings about nuclear gene defects in isolated OXPHOS enzyme complex deficiency. This information should help in identifying patients with mitochondrial disease and defining a biochemical and molecular basis of the disorder found in each patient. (...) This knowledge is indispensable for accurate genetic counseling and prenatal diagnosis, and is a prerequisite for the development of rational therapies, which are still, at present, woefully inadequate. BioEssays 23:518–525, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

We investigate the context of discovery of two significant achievements of twentieth century biochemistry: the chemiosmotic mechanism of oxidative phosphorylation and the dark reaction of photosynthesis. The pursuit of these problems involved discovery strategies such as the transfer, recombination and reversal of previous causal and mechanistic knowledge in biochemistry. We study the operation and scope of these strategies by careful historical analysis, reaching a number of systematic conclusions: even basic strategies can illuminate “hard cases” of scientific discovery that go far (...) beyond simple extrapolation or analogy; the causal–mechanistic approach to discovery permits a middle course between the extremes of a completely substrate-neutral and a completely domain-specific view of scientific discovery; the existing literature on mechanism discovery underemphasizes the role of combinatorial approaches in defining and exploring search spaces of possible problem solutions; there is a subtle interplay between a fine-grained mechanistic and a more coarse-grained causal level of analysis, and both are needed to make discovery processes intelligible. (shrink)

We investigate the context of discovery of two significant achievements of twentieth century biochemistry: the chemiosmotic mechanism of oxidative phosphorylation and the dark reaction of photosynthesis. The pursuit of these problems involved discovery strategies such as the transfer, recombination and reversal of previous causal and mechanistic knowledge in biochemistry. We study the operation and scope of these strategies by careful historical analysis, reaching a number of systematic conclusions: even basic strategies can illuminate “hard cases” of scientific discovery that go far (...) beyond simple extrapolation or analogy; the causal–mechanistic approach to discovery permits a middle course between the extremes of a completely substrate-neutral and a completely domain-specific view of scientific discovery; the existing literature on mechanism discovery underemphasizes the role of combinatorial approaches in defining and exploring search spaces of possible problem solutions; there is a subtle interplay between a fine-grained mechanistic and a more coarse-grained causal level of analysis, and both are needed to make discovery processes intelligible. (shrink)

The paper is aimed at the issues of oxidation state determination and limiting values. The possibility of existence of compounds containing an atom with the oxidation number beyond the current common values, i.e., below −IV and above +VIII are discussed. Three principal modes of preparation of compounds with the oxidation number exceeding VIII, electrochemical anodic oxidation, photoionization, and nuclear β-decay, are evaluated. Failure to prepare compounds containing an atom with the oxidation number below −IV is rationalized. The paper provides an (...) opinion on uncertainties in oxidation state determination in three kinds of compounds: binary compounds, nitrosyl complexes, and compounds containing mutually bonded atoms of the same element. The questions are discussed from the viewpoint of correlation of “man-made” quantities and objective, experimentally obtainable data. (shrink)

In many cells, a nitric oxide (NO) synthase inducible by immunological stimuli produces a sustained flow of NO that lasts a long time. NO is a short‐lived molecule but it is a diffusibel ligand believed to be capable of reaching distal target sites. Further, several lines of evidence indicate that cysteine‐rich motifs of metal‐binding proteins, as well as redox‐sensitive metal clusters of metalloproteins, are natural sensors of bioradicals like NO. In metalloregulatory proteins, metals are often conveniently located at binding (...) sites and bound to cysteine residues. Accordingly, disruption of the metal‐thiolate polymetallic clusters should trigger significant remodelling of the protein structure involved in regulation. We can therefore postulate that the nitrosation reaction occurring at metal centres or cysteine‐rich motifs will preclude correct binding to regulatory sites. Several examples are given of metalloregulatory proteins whose metal is bound to thiols and may then become sensitive to NO. Recent observations indicate that in response to NO synthesis, iron regulatory protein, a eukaryotic bifunctional [Fe‐S] protein, switches from acting as aconitase to being an RNA‐binding regulator, and we suggest that the interplay between NO or a NO‐derived molecule and metal clusters at critical allosteric sites may be a crucial component of the cellular response to environmental stress. (shrink)

The origins of oxidative phosphorylation, initially known as aerobic phosphorylation, grew out of three research areas of muscle metabolism, creatine phosphorylation, aerobic metabolism of lactic acid in muscle, and studies on the nature and role of adenosine triphosphate . Much of this work centred round the laboratory of Otto Meyerhof, and most of those contributing to the study of aerobic phosphorylation were influenced by that laboratory: particularly Lipmann and also Ochoa. The work of Engelhardt on ATP levels in blood also (...) appears to have been influenced by the studies of Meyerhof’s laboratory. However, with the work of Kalckar, influenced by Lipmann, biochemists began to realise the potential importance of the process. This was confirmed and extended by Belitzer and Ochoa and the theoretical contribution of Lipmann. Thus it is not easy to identify a single point that marked the initiation of studies in this field.The early work was based on the use of tissue homogenates and cells but ultimately this approach limited research possibilities. The development of techniques based on mitochondria opened up new possibilities and brought this first phase of the study of oxidative phorphorylation to a close. (shrink)

A modest dc electric field markedly reduced the tensile flow stress at high temperatures in three polycrystalline oxides, i.e. MgO, Al2O3 and yttria-stabilized tetragonal ZrO2 (Y-TZP). The reduction in flow stress ΔσE in Y-TZP consisted of three components: (i) ΔσT due to Joule heating, (ii) a rapid, reversible component obtained in on-off and electric field step tests and (iii) the cumulative effect of the field on microstructure. Only ΔσT and occurred in MgO and Al2O3. It is concluded that results from (...) a reduction in the electrochemical potential for the formation of vacancies corresponding to the diffusion of the rate-controlling ion in the space-charge at the grain boundary. The calculated magnitude of the space-charge zone width and its temperature and solute composition dependence are in accord with theory and experiment; is attributed mainly to the retardation of grain growth by the field. The retardation could be due to one or more of the following effects of the field on the space-charge zone: (i) an increase in the segregated solute ions, (ii) a decrease in grain boundary energy and (iii) a decrease in solute ion mobility. (shrink)