H1-antihistamine up-dosing in chronic spontaneous urticaria: patients' perspective of effectiveness and side effects--a retrospective survey study

Background

The guidelines recommend that first line treatment of chronic spontaneous urticaria should be second generation non-sedating H₁-antihistamines with a positive recommendation against the use of old sedating first generation antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended. The objective of this study was to obtain the chronic spontaneous urticaria-patient perspective on the effectiveness and unwanted effects of H₁-antihistamines in standard and higher doses.

Methodology/Principal Findings

This was a questionnaire based survey, initially completed by 368 individuals. 319 (248 female, 71 male, median age 42 years) had a physician-confirmed diagnosis of chronic spontaneous urticaria and were included in the results. Participants believed standard doses (manufacturers recommended dose) of second generation antihistamines to be significantly (P<0.005) more effective than first generation drugs. Furthermore, they believed that second generation drugs caused significantly (P<0.001) fewer unwanted effects and caused significantly (P<0.001) less sedation than first generation antihistamines. Three-quarters of the patients stated that they had up-dosed with antihistamines with 40%, 42% and 54% reporting significant added benefit from taking 2, 3 or 4 tablets daily respectively. The number of reports of unwanted effects and sedation following up-dosing were not significantly different from those reported for standard doses.

Conclusions

This survey supports the urticaria guidelines recommendations that the first line treatment for chronic spontaneous urticaria should be second generation rather than first generation H₁-antihistamines and that, if standard dosing is not effective, the dosage should be increased up to four-fold.     

Methodology in Aristotle’s Theory of Spontaneous Generation

Aristotle’s theory of spontaneous generation offers many puzzles to those who wish to understand his theory both within the context of his biology and within the context of his more general philosophy of nature. In this paper, I approach the difficult and vague elements of Aristotle’s account of spontaneous generation not as weaknesses, but as opportunities for an interesting glimpse into the thought of an early scientist struggling to reconcile evidence and theory. The paper has two goals: (1) to give as charitable and full an account as possible of what Aristotle’s theory of spontaneous generation was, and to examine some of its consequences; and (2) to reflect on Aristotle as a scientist, and what his comments reveal about how he approached a difficult problem. In particular, I propose that the well-recognized problem of the incompatibility between Aristotle’s concept of spontaneity and his theory of spontaneous generation presents an opportunity for insight into his scientific methodology when approaching ill-understood phenomena.     

Interstitial cells of Cajal in the urethra

The smooth muscle layer of the urethra generates spontaneous myogenic tone that is thought to make a major contribution to urinary continence. The mechanisms underlying generation of tone remain unclear, however recent studies from our laboratory highlighted a role for a specialised population of pacemaker cells which we originally referred to as interstitial cells (IC) and now term ICC. Urethra ICC possess an electrical pacemaker mechanism characterised by rhythmic activation of Ca(2+)-activated Cl(-) channels leading to spontaneous transient inward currents (STICs) under voltage clamp and spontaneous transient depolarisations (STDs) under current clamp conditions. Both STICS and STDs are now known to be associated with spontaneous Ca(2+) oscillations that result from a complex interplay between release of Ca(2+) from intracellular stores and Ca(2+) influx across the plasma membrane. In this review we will consider some of the precise mechanisms involved in the generation of pacemaker activity and discuss how these are modulated by excitatory and inhibitory neurotransmitters.     

ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension

Arteries from hypertensive animals and humans have increased spontaneous tone. Increased superoxide anion (superoxide) contributes to elevated blood pressure (BP) and spontaneous tone in hypertension. The association between the extracellular signaling-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK) signaling pathway and generation of superoxide and spontaneous tone in isolated aorta was studied in angiotensin II (ANG II)-infused hypertensive (HT) rats. Systolic BP, phosphorylation of ERK, aortic superoxide formation, and aortic spontaneous tone were compared in sham normotensive and HT rats. Infusion of ANG II (0.5 mg x kg(-1) x day(-1) for 6 days) significantly elevated the systolic BP (P<0.01). The phosphorylation of ERK1/2 vs. total ERK1/2 in thoracic aorta was enhanced, and superoxide was increased in the HT vs. the sham group (P<0.01). Spontaneous tone developed in the HT group, but not in the normotensive group. MAPK/ERK1/2 (MEK1/2)-ERK1/2 signaling pathway inhibitors, PD-98059 (10 micromol/l), and U-0126 (10 micromol/l), significantly reduced the phosphorylation of ERK1/2, superoxide generation (P<0.01), and spontaneous tone (P<0.01) in HT. These findings suggest that ANG II infusion induces the production of superoxide and spontaneous tone and that both are dependent on ERK-MAPK activation. In endothelium-denuded aorta, however, MEK1/2 inhibitors did not inhibit the spontaneous tone, even though they significantly reduced superoxide generation similar to endothelium-intact aorta. These data suggest that inhibition of ERK1/2 signaling pathway, via PD-98059 or U-0126, may regulate spontaneous tone in an endothelium-dependent manner. In conclusion, these findings support the importance of the ERK1/2 signaling pathway in modulating vascular oxidative stress and subsequently mediating spontaneous tone in HT.     

Boyle on seminal principles

This paper presents a comprehensive study of Robert Boyle’s writings on seminal principles or seeds. It examines the role of seeds in Boyle’s account of creation, the generation of plants and animals, spontaneous generation, the generation of minerals and disease. By an examination of all of Boyle’s major extant discussions of seeds it is argued that there were discernible changes in Boyle’s views over time. As the years progressed Boyle became more sceptical about the role of seminal principles in the generation of minerals and he came to reject the spontaneous generation of insects and animals from putrefying matter. It is also argued that Boyle’s notion of a generative or ‘plastick’ principle creates a tension within his mechanical philosophy. He appeals to a plastick power in order to explain those phenomena of generation that are beyond the explanatory resources of the corpuscular hypothesis. However, when pressed to explain the nature of this power he either hints, somewhat paradoxically, that it too can be explained mechanically or admits his nescience.     

The role of metarhodopsin in the generation of spontaneous quantum bumps in ultraviolet receptors of Limulus median eye. Evidence for reverse reactions into an active state

The origin of spontaneous quantum bumps has been examined in the ultraviolet photoreceptors of Limulus median eye. These cells have a rhodopsin with a lambda max at 360 nm and a stable photoproduct, metarhodopsin, with a lambda max at 470 nm. The steady state rate of spontaneous quantum bumps was found to be higher when the metarhodopsin concentration was high than when the rhodopsin concentration was high. This result implicates metarhodopsin in the generation of spontaneous quantum bumps. Furthermore, this result is consistent with the idea that the reaction which inactivates metarhodopsin (terminates the ability of metarhodopsin to initiate the reactions leading to a quantum bump) is reversible and that such reversions can be a significant source of spontaneous quantum bumps. Given that the rate of spontaneous quantum bumps is approximately 1/s under conditions where the number of inactive metarhodopsin molecules is approximately 10(9), it follows that the molecular switch that inactivates metarhodopsin reverses with a probability of less than 10(-9). A model is presented of how a molecular switch with this reliability might be constructed.     

Specific subunits of voltage-gated sodium channel underlying the subthreshold membrane potential oscillations: Potential therapeutic targets for neuropathic pain

The treatment of neuropathic pain remains a major challenge to pain clinicians. Certain nociceptive and non-nociceptive dorsal root ganglion (DRG) neurons may develop abnormal spontaneous activities following peripheral nerve injury, which is believed to be a major contributor to chronic pain. Subthreshold membrane potential oscillation (SMPO) observed in injured DRG neurons was reported to be involved in the generation of abnormal spontaneous activity. Tetrodotoxin-sensitive sodium (Na⁺) channels were testified to be involved in the generation of SMPO, but their specific subunits have not been clarified. We hypothesize that the subunits of voltage-gated sodium channel, Na_v1.3 and Na_v1.6, are involved in the generation of SMPO. An attempt to test this hypothesis may lead to a new therapeutic strategy for neuropathic pain.     

Rate of spontaneous chromosome aberration occurrence in cultured Chinese hamster cells

The spontaneous chromosome mutation rate was studied in cultured aneuploid Chinese hamster cells (clone 237(1)) using the method of slowing down the rate of cell division in a limiting medium containing 0.1% of serum. It was shown that during one cell generation (which lasted 14 days in limiting medium) the accumulation of chromosome aberrations with time took place. The data obtained are in keeping with the assumption of a linear dependence of this accumulation on time. The spontaneous chromosome rearrangement rate was 1.2 X 10(-2) mutations per cell per 24 hours. Proceeding from this value the spontaneous chromosome aberration rate in cells with a normal duration of the cell cycle was 0.6 X 10(-2) per cell per generation.     

Spontaneous activity of living cells

The purpose of this article is to give a theoretical framework to describe the mechanism of internal signal generation and discuss the physiological significance of spontaneous activities of certain living cells [Oosawa, F., 2001. Spontaneous signal generation in living cells. Bull. Math. Biol. 63, 643].     

Effects of external calcium, magnesium, and temperature on spontaneous contractions of pregnant human myometrium

Spontaneous isometric contractions of small isolated segments from the isthmic region of pregnant human myometrium were recorded to clarify the characteristics of and influences of experimental conditions on contractions. There is a spontaneous periodicity in membrane activity of human myometrium, and contractions evoked with a sustained electric stimulus were affected by spontaneous rhythmic contractions. The frequency of contractions increased markedly, but their duration decreased when temperature of the bathing fluid was increased from 26 degrees C to 39 degrees C. Both excess (7 mM) and low (0.5 mM) calcium levels suppressed the generation of spontaneous contraction. Frequency and half-duration gradually decreased when external magnesium was increased from 0 mM to 3.6 mM. These results indicate that the pattern of contraction depends on the frequency of and intervals between each action potential, and that spontaneous contractility-particularly its frequency-is extremely sensitive to external temperature and ionic conditions.     

Ionic mechanisms underlying spontaneous CA1 neuronal firing in Ca2+-free solution

Hippocampal CA1 neurons exposed to zero-[Ca(2+)] solutions can generate periodic spontaneous synchronized activity in the absence of synaptic function. Experiments using hippocampal slices showed that, after exposure to zero-[Ca(2+)](0) solution, CA1 pyramidal cells depolarized 5-10 mV and started firing spontaneous action potentials. Spontaneous single neuron activity appeared in singlets or was grouped into bursts of two or three action potentials. A 16-compartment, 23-variable cable model of a CA1 pyramidal neuron was developed to study mechanisms of spontaneous neuronal bursting in a calcium-free extracellular solution. In the model, five active currents (a fast sodium current, a persistent sodium current, an A-type transient potassium current, a delayed rectifier potassium current, and a muscarinic potassium current) are included in the somatic compartment. The model simulates the spontaneous bursting behavior of neurons in calcium-free solutions. The mechanisms underlying several aspects of bursting are studied, including the generation of triplet bursts, spike duration, burst termination, after-depolarization behavior, and the prolonged inactive period between bursts. We show that the small persistent sodium current can play a key role in spontaneous CA1 activity in zero-calcium solutions. In particular, it is necessary for the generation of an after-depolarizing potential and prolongs both individual bursts and the interburst interval.     

The dorsal root reflex in isolated mammalian spinal cord

1. The dorsal root reflex has been investigated in an isolated preparation of adult mammalian spinal cord. 2. Both evoked and spontaneous activity can be recorded from the cord in the dorsal spinal roots. 3. The spontaneous activity has a characteristic pattern of firing in bursts of action potentials. Spontaneous and evoked activity are optimum at temperatures between 25 and 27 degrees C; little activity can be detected above 35 degrees C. 4. The spontaneous dorsal root activity has been shown to be correlated with negative potentials in the dorsal horn of the cord, and intracellular recordings made from primary afferent fibres have shown spontaneous primary afferent depolarizations (PAD) which underlie the generation of the spontaneous dorsal root activity. 5. The evoked dorsal root reflex has been shown to spread up to 16 spinal segments both rostrally and caudally from the stimulated dorsal root, and to the contralateral side of the cord. 6. The spontaneous dorsal root activity in widely separated segments has been shown by cross-correlation analysis to be linked both ipsi- and contra-laterally. 7. The significance of such a widespread system for the generation of PAD is discussed.     

Spontaneous high-frequency action potential

Action potential, which is the foundation of physiology and electrophysiology, is most vital in physiological research. This work starts by detecting cardiac electrophysiology (tachyarrhythmias), combined with all spontaneous discharge phenomena in vivo such as wound currents and spontaneous neuropathic pain, elaborates from generation, induction, initiation, to all of the features of spontaneous high-frequency action potential—SSL action potential mechanism, i.e., connecting-end hyperpolarization initiates spontaneous depolarization and action potential in somatic membrane. This work resolves the conundrums of in vivo spontaneous discharge in tachyarrhythmias, wounds, denervation supersensitivity, neurogenic pain (hyperalgesia and allodynia), epileptic discharge and diabetic pain in pathophysiological and clinical researches that have puzzled people for a hundred years.     

Stretch-induced calcium sensitization of rat lymphatic smooth muscle

The relationships between smooth muscle calcium and isometric tension generation to spontaneous lymphatic pump activity and its modulation by stretch equivalent from 0 to approximately 6 cmH2O were investigated. Excised preparations of the rat thoracic duct were mounted on a wire myograph and loaded with the calcium-sensitive fluorochrome indo-1. Calcium-dependent fluorescence and isometric force were simultaneously recorded. The thoracic duct segments developed spontaneous rhythmic contractile activity. Each contraction was preceded by an increase in intracellular calcium. When the vessels were normalized and stabilized at a preload equal to 3 cmH2O, the peak generation in tension occurred 0.70 +/- 0.11 s after that of calcium. Incremental stretch enhanced the frequency of the phasic activity and amplitude of isometric force generation but not the basal calcium level or the amplitude of the calcium transient. These findings suggest that stretch enhances lymphatic pump activity by increasing the pacemaker activity and the calcium sensitivity of the contractile apparatus.     

The Role of Cellular Coupling in the Spontaneous Generation of Electrical Activity in Uterine Tissue

The spontaneous emergence of contraction-inducing electrical activity in the uterus at the beginning of labor remains poorly understood, partly due to the seemingly contradictory observation that isolated uterine cells are not spontaneously active. It is known, however, that the expression of gap junctions increases dramatically in the approach to parturition, by more than one order of magnitude, which results in a significant increase in inter-cellular electrical coupling. In this paper, we build upon previous studies of the activity of electrically excitable smooth muscle cells (myocytes) and investigate the mechanism through which the coupling of these cells to electrically passive cells results in the generation of spontaneous activity in the uterus. Using a recently developed, realistic model of uterine muscle cell dynamics, we investigate a system consisting of a myocyte coupled to passive cells. We then extend our analysis to a simple two-dimensional lattice model of the tissue, with each myocyte being coupled to its neighbors, as well as to a random number of passive cells. We observe that different dynamical regimes can be observed over a range of gap junction conductances: at low coupling strength, corresponding to values measured long before delivery, the activity is confined to cell clusters, while the activity for high coupling, compatible with values measured shortly before delivery, may spread across the entire tissue. Additionally, we find that the system supports the spontaneous generation of spiral wave activity. Our results are both qualitatively and quantitatively consistent with observations from in vitro experiments. In particular, we demonstrate that the increase in inter-cellular electrical coupling observed experimentally strongly facilitates the appearance of spontaneous action potentials that may eventually lead to parturition.     

Effect of channel block on the spiking activity of excitable membranes in a stochastic Hodgkin-Huxley model

The influence of intrinsic channel noise on the spontaneous spiking activity of poisoned excitable membrane patches is studied by use of a stochastic generalization of the Hodgkin-Huxley model. Internal noise stemming from the stochastic dynamics of individual ion channels is known to affect the collective properties of the whole ion channel cluster. For example, there exists an optimal size of the membrane patch for which the internal noise alone causes a regular spontaneous generation of action potentials. In addition to varying the size of ion channel clusters, living organisms may adapt the densities of ion channels in order to optimally regulate the spontaneous spiking activity. The influence of a channel block on the excitability of a membrane patch of a certain size is twofold: first, a variation of ion channel densities primarily yields a change of the conductance level; second, a down-regulation of working ion channels always increases the channel noise. While the former effect dominates in the case of sodium channel block resulting in a reduced spiking activity, the latter enhances the generation of spontaneous action potentials in the case of a tailored potassium channel blocking. Moreover, by blocking some portion of either potassium or sodium ion channels, it is possible to either increase or decrease the regularity of the spike train.     

Darwinism and the Origin of Life: The Role of H.C. Bastian in the British Spontaneous Generation Debates, 1868--1873

Henry Charlton Bastian's support for spontaneous generation is shown to have developed from his commitment to the new evolutionary science of Darwin, Spencer, Huxley and Tyndall. Tracing Bastian's early career development shows that he was one of the most talented rising young stars among the Darwinians in the 1860s. His argument for a logically necessary link between evolution and spontaneous generation was widely believed among those sympathetic to Darwin's ideas. Spontaneous generation implied materialism to many, however, and it had associations in Britain with radical politics and amateur science. Huxley and the X Club were trying to create a public posture of Darwinism that kept it at arm's length from those negative associations. Thus, the conflict that developed when Huxley and the X Club opposed Bastian was at least as much about factional in-fighting among the Darwinians as it was about the experiments under dispute. Huxley's strategy to defeat Bastian and define his position as “non-Darwinian” contributed significantly to the shaping of Huxley's famous address “Biogenesis and Abiogenesis.” Rhetorically separating Darwinism from Bastian was thus responsible for Huxley's first clear public statement that a naturalistic origin of life was compatible with Darwin's ideas, but only in the earth's distant past. The final separation of the discourse on the meaning of Brownian movement and “active molecules” from any possible link with spontaneous generation also grew out of Huxley's strategy to defeat Bastian. Clashes between Bastian and the X Club are described at the BAAS, the Royal Society, and in the pages of Nature and other journals. This revised version was published online in July 2006 with corrections to the Cover Date.     

A note on the nature and origin of life

Some relational aspects of the property of self-reproduction of biological systems are studied. If in addition to the requirement of the property of self-reproduction we add also the requirement of adaptability of the organism to changing environment, this imposes certain conditions on the topology of the graphs which represent such systems. A further study of the relational properties of such systems seems to offer the possibility of deriving the principle of biological mapping from the requirement of self-reproduction and adaptability. An examination of the problem of the original formation of such self-reproducing systems in connection with the established fact of impossibility of spontaneous generation leads to the conclusion that an organism must inhibit such processes which, in the absence of organisms, would lead to spontaneous generation.     

Amplification and loss of repeat units of the human minisatellite MS1 integrated in chromosome III of a haploid yeast strain

Minisatellites comprise arrays of tandemly repeated short DNA sequences which show extensive variation in repeat unit number. The mechanisms that underlie this length variation are not understood. In order to study processes influencing length changes of minisatellites, we integrated the human minisatellite MS1 into a haploid strain of the yeast Saccharomyces cerevisiae. Frequent spontaneous generation of MS1 alleles with new lengths were observed in this yeast strain. Hence it is concluded that recombination between members of a pair of homologous chromosomes is not a prerequisite for the generation of length changes in MS1 in yeast.