Sailor-Boy Scavenger Suit

The efficiency with which I work tends to decrease as the semester progresses, but that's obviously not always a bad thing. I'm hoping that switching to the pharmacology class will work out, in part because the pharmacology department--and the people associated with it--at the U. is/are spectacular, obviously. I always feel like I don't need to say things and that the best way I'm likely to be able to communicate, personally, in some of these areas is to do the most thorough work that I can on things. This blog has always been like a recycling dump or landfill, basically, and I wade around in it and look for gems in the material that's being processed or is old or whatever. I don't show up to a landfill with a starched shirt--that's one way of looking at it. I'll stumble around a recycling plant, and I'm liable to swear like a @#$%&%$ sailor in a cracker-jack suit and gun the engine on the bobcat. Vrrrrrrroom...Vrrrroom-Vrroom. "Put it in first gear...I said, put the bobcat in first. I SAID, PUT THE @#$%*& thing in FIRST, OR IT'LL STALL when...SUM @#%&*'LL STALL WHEN...mmm-hmm...when you run it over the old piles and heaps." Anyway, that's basically the way I have to approach it, if I'm going to do a blog. And if I find a nice clean area, I might gun the bobcat and stir up some old junk and get the ball rolling in the clean spot. "Put that stuff over...OVER IN THE CLEAN AREA, I...said, YASSSS, THERE. Bec--Because it's...THAAA F$#@@!# thing--LIGE-THIZ...VRROOM, VROOM. I said, dump THAA JUNK on it....STIR tha-tuh-s#$%-tuh-up-uh." I don't know--a neat and tidy spot might be just the place to find some old gems that have been swept over and trampled over into a spick-n-span surface. Obviously, I'm exaggerating, but I'm liable to show up at the blog like Cracker Jack, and he's swaying around because he's toasted out of his mind. He can't walk a straight line, and, though I don't drink and run the bobcat, I won't think twice about wearing that toy sailor suit, given that it helps me stumble around rull good.

More Obnoxious Prattling About Influenza and Viral Transmission

The traffic was bad today, and the evening commute took 2.25 hours. I didn't get a live, attenuated flu vaccine, and the reason is basically that I decided not to try to sweet-talk my way into getting one. I'm not very good at that. The high-risk categories that the CDC has created are really problematic and have just really been defined in a nebulous way. The categories give the impression that a person needs to be quite ill to qualify, if one isn't 24 years old or younger. Of course, the "24-year-old" cut-off is totally arbitrary and has not a smidgen of credible evidence to support its validity. I think someone heard it in a folk song, passed down through the generations, as part of the oral storytelling tradition. The categories seem inclusive of a lot of sick people, but, as one looks at the illnesses included in the "high-risk" category, one realizes that a sick person is likely to be left wondering if he or she is actually sick enough to qualify. The person might think, "I have x disease, but I'm more or less healthy. Maybe I'm not sick enough. Maybe I should 'let a sick person have my vaccine,'" or some such thing. Of course, the sick person isn't going to get it, either. The people who thought up this type of approach seem to have no understanding of psychology, when one thinks about it. Who wants to think of himself or herself as being someone who's sick enough to get a complication from influenza? What doctor ever discusses the risks of influenza complications with his or her patients, especially those that are "sick" with those conditions? The person might think, "What am I going to have to tell the person, in order to establish that I'm sick enough to be at risk of complications? What's the actual procedure? Is the person going to flash the "shark eyes" at me, the blank stare? That's a little joke, but there are so many factors that are conspiring to decrease the likelihood that a person is going to get one of these early vaccines. If someone doesn't make the big decision to scrap this absurdly restrictive plan and hold a big press conference that no reporters may even attend, now that some of the decision-makers at the CDC have lost whatever credibility they might have initially had, then no one's going to get any vaccines this winter.

I was thinking about the educational system, and it's not even that the professors who teach science classes are not really good. The science professors I've had have been really articulate and terrific (although I've found that the professors in the humanities and rhetoric/writing classes surpass the science professors and are obviously superb), but the science textbooks and curricula are stuck in the 1950's or something, in terms of methodologies. It's almost as if it's the fact that the methods for teaching science haven't kept pace with the degree of complexity and vastness of the subject matter. One aspect of that problem is that one doesn't really learn much of anything, even when one gets an A or a B in a class. If one is told to memorize a fact, one can do it and answer questions about that fact. But, in most cases, one isn't going to remember it after the test is over, and the fact may, in actuality, be objectively incorrect, according to many of the different sets of standards by which one might evaluate the objective accuracy of the statement. For example, if I'm told to memorize that a hormone is usually released with such-and-such a serum-concentration-dependence, in response to x and y as stimuli for the hormone's release, I might remember that. But there may well be 500 articles calling that fact into question, and the sheer mass of information that contradicts that "textbook fact" will basically cause the statement in the textbook to be incorrect. There just isn't any purpose that's served by memorizing something, in the sciences, that's given such a superficial and lacking-in-subjective-nuance treatment in a textbook. It's like something out of 1920 or something. I'm exaggerating with that, but it gets to be upsetting to see. I always find writing to be a valuable use of my time, and it doesn't matter what things I'm writing, in many ways. It's always beneficial. But writing incorrect questions and answers on note cards, as a way of remembering material from a science textbook, is not beneficial and can...leave...a bad taste in one's mouth. If I were able to actually get a sense of the reality of the area of science, I...might "not get a bad taste" from the information. "Remember that, 'boy.' Now, go wash them @#%^&#$ hands, too, and don't take too long with the disinfectant, because I used to get sick and found that it helped warm my @#$%&$$ bones up in the wintertime--you hear--I say I sh-sh-sh-shivered me timbers, by jumpin' jehosaphat."

Anyway, the other point is that "virions" can be transferred, for example, from a contaminated surface to one's hands and then to another, non-contaminated surface and could, after "the transfer," conceivably survive for days and infect one with something like influenza. If one supposes that the "5-minute-survival" estimate [Collignon and Carnie (2006) mentioned that in the article I cited in a past posting: Collignon and Carnie, 2006: (https://www.mja.com.au/public/issues/185_10_201106/col10881_fm.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17115953)] is likely to not be written in stone and that the estimate may be incorrect by as large a factor as the "surivival-on-porous-surface" estimate was for influenza A [Collignon and Carnie (2006) estimated 6-12 hours for that, if I remember correctly, and Thomas et al. (2008) found the survival time, on a porous surface, of 17 days: (http://hardcorephysiologyfun.blogspot.com/2009/12/another-rambler-on-influenza.html)], then influenza might be able to live on one's hands for as long as [17/0.25 (as in the time of 6 hours that's the lower limit of the estimate for the survival on a porous surface) = 68, and 68 times 5 minutes = 340 minutes] 5.67 hours. That's about the length of time the rotavirus can survive and remain infectious for, I think. I would personally assume that influenza can survive for longer than 5 minutes on one's hands. But it doesn't really matter, as far as the issue of surface-to-hand-to-surface transfers go. Anyway, I just think this type of concept can be alien to a lot of people, and it doesn't hurt to practice thinking about these things. It's an "unreasonable" type of consideration, but I guess viruses have never been reasonable. It's easy to see that controlling some types of infections of patients in hospitals is unlikely to ever be possible, with all of these people running all over the place. I remember reading that the tv remotes (commonly, according to some research) in hospital rooms and stuffed animals passed out to patients can transmit the infectious particles that ultimately kill them, and that's sort of a concept that's almost "hostile" to human social interaction and is just hard for me and, presumably, a lot of other people to be cognizant of and also be a "reasonable" human. It basically seems like it would create something akin to cognitive dissonance, as if a person might think, unconsciously (I'm obviously exaggerating with this), "A good person wouldn't allow potentially lethal infections to be transmitted via a remote control or stuffed teddy bear, and a reasonable person wouldn't even think that that would be a reasonable possibility. The viruses couldn't do that and simultaneously be reasonable, but I know, from my readings, that viruses can be made to behave in reasonable ways, in the context of medicine. I need to think of myself as being a good person, and, therefore (here's the little "tweak" that fixes the dissonance), since I know I am a good person, the viruses must not be that unreasonable." I mean, that's the type of thought process that sometimes crosses my mind. "Now, let's see, here. I've got some crisp papers with information on pathology and horrors, and, over here, I've got some lethal viral infections and calculations of viral transmission. Alll right, now, this looks interesting..."

Multiple Revisions of an Old Paper of Mine

I guess this is the end of this [(http://www.mediafire.com/?410jmzmrjjm); (http://hardcorephysiologyfun.blogspot.com/2009/06/folate-and-uvb-papers-in-pdf-format.html); (http://hardcorephysiologyfun.blogspot.com/2009/05/another-old-paper-of-mine.html); (http://hardcorephysiologyfun.blogspot.com/search/label/UVB)]. Maybe I'll try it elsewhere, at some point in the future. In any case, it wasn't really for my benefit that I did these, and it's not going to benefit me in the future. The dermatologists wouldn't like it, and the neurologists wouldn't like it, either. But the mechanisms are relevant to biology in general.


Multiple Sclerosis and Ultraviolet Radiation (UVR): Can UVR Exert Immunomodulatory Effects in the CNS Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Bains [1], in a recent and very interesting article, noted that excessively-direct exposure of the eyes to ultraviolet radiation (UVR) could cause optic neuritis and contribute to the development of multiple sclerosis (MS) in some people, and additional research lends credence to that hypothesis and sheds light on some mechanisms by which neurogenic effects of UVR could influence immunological processes in the brain. Cutaneous exposure to either ultraviolet B (UVB) or ultraviolet A (UVA) increases the concentrations of inflammatory mediators in the skin [2,3], and these mediators can then act on primary afferent neurons (PAN’s) innervating the skin and increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by direct or indirect, neurogenic mechanisms [6-13], and UVR could, by increasing the percentages of spontaneously-active PAN’s, either augment or suppress the immune and inflammatory responses of microglia and dendritic cells in the central nervous system (CNS).
UVR can increase the release of cytokines and neurotrophins and other mediators from keratinocytes and mast cells in the skin [14, 15], and these mediators can then depolarize and induce spontaneous action potentials (APs) in C-fibers [2,16,17] and A-fibers [16] innervating the exposed skin [2,16,17]. The APs are likely to be largely asynchronous [18], can begin as soon as 30 minutes after exposure [17] and persist for five days [2,16], and can occur at low frequencies of 0.8-1.25 Hz [2] or at comparable freqencies [16,17]. Thus, UVA-induced APs in trigeminal ganglion (TG) neurons may have contributed to the visual-evoked potentials measured in humans [19] and the rapid emergence of changes in the pineal gland [20] or suprachiasmatic nucleus [9] in hamsters or rats, respectively.

The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes [21-23] or dorsal root reflexes. In an axon reflex, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a dorsal root reflex, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24]. The complex, UVR-induced changes in the expression, formation, and release of CGRP and SP, in the DH, are likely to result from changes in the patterns of orthodromic and antidromic APs that PAN’s, in the dorsal root ganglia (DRG) or TG, exhibit following UVR [3-5,25].

TG and DRG neurons are likely to serve as the primary inputs for the apparently-polysynaptic pathways by which UVR can alter neuronal activity in the CNS. UVR can cause neurons in the DH to fire spontaneously [26,27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5,6,9,10,30-35] in animals or humans. The apparent effects of UVB or UVA on the brain [6,9,10,32,35] have sometimes been blocked by ciliary ganglionectomy [10], optic nerve (ON) transection [7] or denervation [8], hypophysectomy [8,10], or orbital enucleation [6,9]. Despite the evidence suggesting that UVR induces APs in ON fibers [6-9], ocular UVB is known to reliably induce Herpes simplex virus reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears [10,32] were likely to have been mediated by the activation of TG neurons, in the ophthalmic branch of the trigeminal nerve (V1), and also by neurons in the ciliary ganglion/ganglia (CG) [10], and, consistent with this, some neurons in the caudal trigeminal nucleus (Vc) project to the hypothalamus and receive monosynaptic inputs from TG neurons innervating the facial skin [37].

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19,20], it is relevant that only ~ 2 percent of UVB reaches the lens in the intact eye and that almost all of the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [38]. Sliney et al. [38] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [39], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19,20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. Most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [38], and any prolonged exposure of the eyes to direct UVR could damage corneal C-fibers or A-fibers, impact neurotransmission in the brain by atypical mechanisms, or, as noted by Bains [1], contribute to the development of optic neuritis.

The axons of many neurons in the TG or CG or accessory CG, in rats [40] and some mice [41] and also humans [42], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [41], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6,8-10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [40], and many of the TG neurons pass through the CG without forming synapses [40].

The neurogenic release of CGRP in the skin contributes to UVB-induced systemic immunosuppression [25,43] and to visible-light-mediated immune privilege in the eyes [44], and the UVR-induced release of SP and CGRP in the CNS could act on microglia or dendritic cells and either promote tolerance to CNS-specific antigens, such as in people who do not have MS, or exacerbate the course of MS. Following UVR exposures to rodents, researchers could evaluate, with an eye to the relevance to MS, phenotypic changes in dendritic cells that migrate from the CNS to the cervical lymph nodes [45] or site-specific changes in microglial activation in the CNS.

References

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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Recently, Brajac et al. [1] noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) [6-9], the ophthalmic branch of the trigeminal nerve (V1) [10], or by incompletely-defined mechanisms [11,12], potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides [13] or in the activities of PAN’s [11]. UVR could influence the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by increasing the percentages of spontaneously-active PAN’s and thereby altering the release of CGRP, SP, and glutamate at different sites in the CNS.

UVR can induce spontaneous action potentials (AP’s) in C-fibers [2,14,15] and A-fibers [14] innervating the exposed skin [2,14,15]. These sensory fibers (SF’s), which are the peripheral branches of PAN’s in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators [16] that are released from keratinocytes and mast cells [17] in UV-exposed skin. The AP’s in PAN’s can begin as soon as 30 minutes after exposure [15] and persist for five days [2,14] or longer. Spontaneous AP’s in SF’s are likely to be largely asynchronous [18], and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz [2] or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) [15] or 6-108 AP’s per minute (~0.1-1.8 Hz) [14]. Thus, UVA-induced AP’s in TG neurons may have contributed to the visual-evoked potentials measured in humans [19] and rapid emergence of changes in the pineal gland [20] and suprachiasmatic nucleus [7].

The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes (AXR) [21-23] or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24].

The AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats [25], and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s [3]. The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central branches of PAN’s, in response to the release of those neuropeptides [4,5]. Those increases in CGRP and SP may also result from adaptive decreases, over the long term [3] or short term [4], in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s [3,4]. For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.

TG and DRG neurons are likely to serve as the primary inputs for the polysynaptic pathways activated by UVR. UVR can cause neurons in the DH to fire spontaneously [26, 27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5-7, 10, 30-35] in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH [10, 32] or in IEG expression [6, 7] or pineal NAT activity [35], have sometimes been blocked by ciliary ganglionectomy [10], ON transection [8] or denervation [9], hypophysectomy [9, 10], or orbital enucleation [6, 7]. Despite the evidence suggesting that UVR induces AP’s in ON fibers [6-9], ocular UVB is known to reliably induce HSV reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) [10]. These effects were more pronounced after exposure to the eyes alone than after exposure to the ears alone [10, 32], and this could be explained by the exceptionally-dense trigeminal innervation of the corneas [37]. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc [38], and the UVR-induced increases in plasma ACTH [32] or -MSH [10] in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus [39] and receive monosynaptic inputs from TG neurons innervating the facial skin [39]. Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of some cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc [36].

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19, 20], it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [40]. Sliney et al. [40] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [41], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19, 20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [40], and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.

The axons of many neurons in the TG or CG or accessory CG, in rats [42] and some mice [43] and also humans [44], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [43], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6, 7, 9, 10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [42], and many of the TG neurons pass through the CG without forming synapses [42].

UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans [34] or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.

References

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(2) Eschenfelder CC, Benrath J, Zimmermann M, Gillardon F. Involvement of substance P in ultraviolet irradiation-induced inflammation in rat skin. Eur J Neurosci 1995;7(7):1520-6.
(3) Legat FJ, Griesbacher T, Schicho R, et al. Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats. Neurosci Lett 2002;329(3):309-13.
(4) Gillardon F, Schrock H, Morano I, Zimmermann M. Long-term increase in CGRP levels in rat spinal dorsal horn following skin ultraviolet irradiation. A mechanism of sunburn pain? Ann N Y Acad Sci 1992;657:493-6.
(5) Polgar E, Szucs P, Urban L, Nagy I. Alterations of substance P immunoreactivity in lumbar and thoracic segments of rat spinal cord in ultraviolet irradiation induced hyperalgesia of the hindpaw. Brain Res 1998;786(1-2):248-51.
(6) Amir S and Robinson B. Fos expression in rat visual cortex induced by ocular input of ultraviolet light. Brain Res 1996;716(1-2):213-8.
(7) Amir S and Robinson B. Ultraviolet light entrains rodent suprachiasmatic nucleus pacemaker. Neuroscience 1995;69(4):1005-11.
(8) Hiramoto K, Mashita Y, Katada T, Konishi H, Sugiura M, Hayakawa R. Immunosuppression by ultraviolet B rays via eyes in mice. Arch Dermatol Res 1997;289(12):709-11.
(9) Inoue M, Hiramoto K, Park A, Sato EF. UV-Irradiation down-regulates immune functions and causes fatigue by photo-optico-neuronal network: lessons from iNOS-knockout mice. Neurochem Res 2004;29(8):1582.
(10) Hiramoto K, Yanagihara N, Sato EF, Inoue M. Ultraviolet B irradiation of the eye activates a nitric oxide-dependent hypothalamopituitary proopiomelanocortin pathway and modulates functions of alpha-melanocyte-stimulating hormone-responsive cells. J Invest Dermatol 2003;120(1):123-7.
(11) Ericsson AD, Dora J, Cao S. Melanocytes: morphological basis for an exteroceptive sensory system for monitoring ultraviolet radiation. Physiol Chem Phys Med NMR 2003;35(1):27-42.
(12) Taylor SL, Kaur M, LoSicco K, et al. Pilot study of the effect of ultraviolet light on pain and mood in fibromyalgia syndrome. J Altern Complement Med 2009;15(1):15-23.
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(14) Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58(4):793-8.
(15) Szolcsanyi J. Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 1987;388:9-23.
(16) Saade NE, Farhat O, Rahal O, Safieh-Garabedian B, Le Bars D, Jabbur SJ. Ultraviolet-induced localized inflammatory hyperalgesia in awake rats and the role of sensory and sympathetic innervation of the skin. Brain Behav Immun 2008;22(2):245-56.
(17) Streilein JW, Alard P, Niizeki H. Neural influences on induction of contact hypersensitivity. Ann N Y Acad Sci 1999;885:196-208.
(18) Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006;312(5780):1659-62.
(19) Brainard GC, Beacham S, Sanford BE, Hanifin JP, Streletz L, Sliney D. Near ultraviolet radiation elicits visual evoked potentials in children. Clin Neurophysiol 1999;110(3):379-83.
(20) Brainard GC, Podolin PL, Leivy SW, Rollag MD, Cole C, Barker FM. Near-ultraviolet radiation suppresses pineal melatonin content. Endocrinology 1986;119(5):2201-5.
(21) Benrath J, Gillardon F, Zimmermann M. Differential time courses of skin blood flow and hyperalgesia in the human sunburn reaction following ultraviolet irradiation of the skin. Eur J Pain 2001;5(2):155-67.
(22) Eisenbarth H, Rukwied R, Petersen M, Schmelz M. Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin. Pain 2004;110(1-2):197-204.
(23) Koppert W, Brueckl V, Weidner C, Schmelz M. Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine. Eur J Pain 2004;8(3):237-44.
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(26) Chapman V and Dickenson AH. Enhanced responses of rat dorsal horn neurons after UV irradiation of the hindpaw; roles of the NMDA receptor. Neurosci Lett 1994;176(1):41-4.
(27) Urban L, Perkins MN, Campbell E, Dray A. Activity of deep dorsal horn neurons in the anaesthetized rat during hyperalgesia of the hindpaw induced by ultraviolet irradiation. Neuroscience 1993;57(1):167-72.
(28) Boxall SJ, Berthele A, Tolle TR, Zieglgansberger W, Urban L. mGluR activation reveals a tonic NMDA component in inflammatory hyperalgesia. Neuroreport 1998;9(6):1201-3.
(29) Thompson SW, Dray A, Urban L. Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro. J Neurosci 1994;14(6):3672-87.
(30) Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998;82(2):591-602.
(31) Davis CL, Naeem S, Phagoo SB, Campbell EA, Urban L, Burgess GM. B1 bradykinin receptors and sensory neurones. Br J Pharmacol 1996;118(6):1469-76.
(32) Hiramoto K. Ultraviolet A irradiation of the eye activates a nitric oxide-dependent hypothalamo-pituitary pro-opiomelanocortin pathway and modulates the functions of Langerhans cells. J Dermatol 2009;36(6):335-45.
(33) Gillardon F, Wiesner RJ, Zimmermann M. Expression of the junD proto-oncogene in the rat spinal cord and skin following noxious cutaneous ultraviolet irradiation. Neurosci Lett 1992;136(1):87-90.
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(38) Bereiter DA, Bereiter DF, Tonnessen BH, Maclean DB. Selective blockade of substance P or neurokinin A receptors reduces the expression of c-fos in trigeminal subnucleus caudalis after corneal stimulation in the rat. Neuroscience 1998;83(2):525-34.
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Recently, Brajac et al. (13) noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin (21,39) and also in the dorsal horn (DH) of the spinal cord (26, 46). The increases in the DH are likely to result from increases in the release of CGRP and SP from the central terminals of PAN’s (27,48). Similarly, exposure of the facial skin to UVR is likely to induce the release of CGRP, SP, and glutamate in the trigeminal nucleus caudalis (Vc), in the brainstem (51). Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) (1,2,30,33), the ophthalmic branch of the trigeminal nerve (V1) (31), or by incompletely-defined mechanisms (20,57), potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides (47) or in the activities of PAN’s (20). There is evidence that cutaneous UVR can influence peptidergic and glutamatergic transmission in the spinal cord (9,10,15,17,46,59,60,61) and brain (2,31) along polysynaptic pathways, and these effects are likely to result from prolonged increases in low-frequency, spontaneous action potentials (AP’s) induced in PAN’s, in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), innervating the UV-irradiated skin (3,21,56). Those mechanisms (3,21,26,27,29,30,31) imply that the neuroendocrinological effects (12,29,31), increases in immediate-early gene (IEG) expression in the suprachiasmatic nucleus (SCN) and other sites in the brain (1,2), or decreases in pineal melatonin content (12) or serotonin N-acetyltransferase (NAT) activity (65), induced by UVR exposure to only the eyes (1,2,29,30,31) or ears (29,31), could have resulted from increases in the percentages of spontaneously-active PAN’s, in the TG or cervical DRG, innervating the corneas or ears, respectively. UVR may influence, via PAN’s, the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by altering the release of CGRP, SP, and glutamate at different sites in the brain.

UVR can induce spontaneous AP’s in C-fibers (3,21,56) and A-fibers (3) innervating the exposed skin (3,21,56). These sensory fibers (SF’s) develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators (48), and the increases in the release of many of these mediators from keratinocytes (KC’s) and mast cells (54), in UV-exposed skin, are likely to produce the AP’s in SF’s (48). The UVR-induced AP’s in PAN’s can begin as soon as 30 minutes after exposure (56) and persist for up to five days (3,21), and the dermal concentrations of bradykinin, a neuropeptide that induces AP’s and not just sensitization in C-fibers (56), in human skin within 21 minutes of exposure (19). Spontaneous AP’s in SF’s are likely to be largely asynchronous (32), and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz (21) or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) (56) or 6-108 AP’s per minute (~0.1-1.8 Hz) (3). Thus, the visual-evoked potentials measured in UVA-exposed humans (11) and rapid emergence of changes in the pineal gland (12) and SCN (2) may, particularly given the use of high intensity UVA (11), have been partially a result of early, UVA-induced AP’s in TG neurons.

The UVR-induced release of neuropeptides into the skin is likely to occur through axon reflexes (AXR) (4,18,37) or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent, or orthodromic, AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent, or antidromic, direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber (64). In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber (64).

The UVR-induced afferent AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats (25), and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s (39). The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central terminals of DRG neurons, in response to the UVR-induced release of CGRP and SP from those terminals (26,46). Those increases in CGRP and SP may also result from adaptive decreases, over the long term (39) or short term (26), in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s (26,39). For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.

The apparent polysynaptic pathways by which UVR can produce changes in the CNS have not been precisely delineated, but TG and DRG neurons are likely to serve as the primary inputs for those changes. UVR can also cause neurons in the DH to fire spontaneously (15,61), to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission (10,15,60,61), and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS (1,2,9,17,29,31,46,50,65) in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH (29,31) or on IEG expression (1,2) or NAT activity (65) in parts of the brain, have sometimes been blocked by ciliary ganglionectomy (31), ON transection (30) or denervation (33), hypophysectomy (31,33), or orbital enucleation (1,2). Despite the evidence suggesting that UVR induces AP’s in ON fibers (1,2,30,33), ocular UVB is known to reliably induce HSV reactivation in the TG (52) and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. (31) suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) (31). The apparent effects of UVR on the CNS were more pronounced after exposure to the eyes alone than after exposure to the ears alone (29,31), and this could be explained by the exceptionally-dense trigeminal innervation of the corneas {{771}}. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc (6), and the UVR-induced increases in plasma ACTH (29) or -MSH (31) in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus (42) and receive monosynaptic inputs from TG neurons innervating the facial skin (42). Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc (52).

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised (11,12), it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor (53). Sliney et al. (53) noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum (62), can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by the excised ocular tissues of nonprimate, mammalian species (11,12). The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses (11), but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules (53), and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.

The axons of many neurons in the TG or CG or accessory CG, in rats (38) and some mice (45) and also humans (44), extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON (45), and it is possible that the ON denervation or transection procedures (1,2,33) severed some axons of neurons whose cell bodies are in the CG, accessory CG, or TG. Most of the sensory neurons in the TG that innervate parts of the eye are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, and the nasociliary nerve is a subdivision of V1 (38). Many of the TG neurons that project to the corneas, within the ciliary nerves, pass through the CG without forming synapses (38). Despite the anatomical differences among mice, rats, and humans (38,44,45), the short or long ciliary nerves that contain corneal afferents from the TG also extend along sections of the ON, just posterior to the globe, in rats (38), mice (45), and also humans (44) and could have been damaged or severed during the ciliary ganglionectomy (31,33), ON transection (1,2,30) or denervation (31,33), or orbital enucleation (1,2) procedures.

UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans (50) or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.

References

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Another Rambler on Influenza

One of the reasons the CDC's authoritarian approach to dispensing swine flu vaccines is ineffective is that a series of "feed-forward" failures can occur, such that the shortage causes people to become frantic in the short-term and to direct their attention elsewhere in the longer term. I saw one news article in which the author was saying that the state health department basically doesn't appear to trust anyone enough to provide them with the actual information about the locations of the flu clinics. The person was basically saying that the people at the health department are afraid people are going to storm the clinics, in effect, and, therefore, have been restricting information about the locations of the clinics. As a result, the so-called high-risk groups are not getting the vaccines. And now that there's supposedly a "downturn" in the numbers of cases (many of the cases discussed in the Fall were not, in fact, influenza cases, in my opinion, as discussed in many past postings), the CDC has basically lost their chance to vaccinate a lot of people. The so-called high-risk groups are not, really, substantially more likely than anyone else to experience a complication from the flu, given the wild quality with which otherwise healthy individuals' liver or kidney function, for example, can deteriorate in response to a flu infection. There are endless reports of "healthy" people having to go in to get dialysis treatments or being on the verge of liver failure from influenza, given all the hemolysis and thrombogenicity, etc.

I tried using the Google flu shot finder thing, and it didn't work at all. Maybe I used it incorrectly and need to try it again. It looks like very few people would be able to find swine flu vaccines, these days. In any case, I'm going to try to get the live attenuated swine flu vaccine tomorrow, at the U. We'll see if there's room for a little bit of flexibility. I'm not expecting to get one, but it doesn't hurt to try. But there's a strange kind of attitude that seems to accompany that kind of CDC-based authoritarianism. This ties into the concept (a good one, in my opinion) that one should never pass up a chance to vaccinate someone, and it's this assumption that the CDC is going to actually be able to get people's attention when there isn't a shortage of vaccines. There are just all sorts of invalid assumptions underlying their approach, and it's been a failed approach. They wound up with vast numbers of unused vaccines in the 2004-05 season, when they rationed vaccines. Even if they had a perfect system for dispensing the vaccines, there would still be all sorts of problems.

I'm surprised that the CDC and other health officials can't communicate information about effective approaches to hand disinfection. Maybe people still wouldn't get benefit from it, given that so many people end up having to or choosing to touch their faces, etc. But it's not that complicated. A lot of research has shown that it takes a long time (45-120 seconds) and a lot of scrubbing to remove, to an acceptable degree, something like rotavirus from one's hands with soap, but the 62-65-percent alcohol gels don't require any more than 20-30 seconds, at most, and are substantially more reliable, in my opinion, based on the research. There's tons and tons of research on the issue. One thing I was getting at with the last posting is that I think there can be this tendency of people to not want to wash their hands for a long time or disinfect them, for fear of becoming "the boy who couldn't stop washing," as the title of the book went, or something along those lines. ("Suh-loppy boy. Now, do like I tell you and go wash them @#$%&$ HANDS, boy, and do it before you sit down for supper and do your chores, too, like I done when I was a boy. By God, it was good enough for me.") I have no idea what that means, but hand-washing is associated with obsessive-compulsive disorder in a sort-of-specific way. I suppose people might not think it would make a difference to use the alcohol-based sanitizer gel. In a lot of the articles on infectious disease transmission, researchers go through all of these scenarios and calculate the numbers of virions that could be transferred from one surface to another, at each step along a chain of events that might allow for the transfer the virions. I just think it's good to be able to get in the habit of thinking about that, in case one wants to make use of the thorough infection-control methods at specific times. For example, as I've said before, cleaning surfaces, in my opinion, is never going to be as effective, in controlling the transmission of viruses, as hand disinfectant use and individual behaviors are likely to be, in my view. One can't cover the entire surface with disinfectant, and there's research showing, for example, that some high percentage (I forget the number) of home health care workers can have rotavirus on their hands at any one time. One needs to take that seriously in considering the effectiveness of "cleaning a whole building" or cleaning surfaces at all. The person doing the cleaning can essentially, transport the virus from one surface to another, and that could bypass the supposed 5-10-minute limit on the survival of influenza on the hands. Thomas et al. (2008) [Thomas et al., 2008: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394922/pdf/0076-08.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18359825)] found that some strains of influenza A virus can live for 17 days outside of a host, on money ("banknotes"), when respiratory mucus is present along with the virus. A lot of the articles have estimated that influenza viruses can only survive for 6-12 hours on porous surfaces, and money would be an example of that type of surface [Collignon and Carnie, 2006: (https://www.mja.com.au/public/issues/185_10_201106/col10881_fm.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17115953)]. I just wouldn't be inclined to think of these things in terms of strict rules, given that some of these methods for evaluating the capacity of influenza to survive on surfaces can be problematic, depending on the precise conditions (i.e. the presence or absence of respiratory mucus, etc.). Some viruses that cause GI symptoms can live for months at freezing temperatures and remain infectious. I saw one article reporting the survival of a virus for six months outside a host, at cold temperatures, and many of those GI viruses can live for more than a week outside of a host.

Degrees of Freedom in "Personal-Freakshow-Style" Infection Control: Turning Away from the Masses When One Wants To

I meant to post this on here.

When I was dealing with immunosuppression from infectious mono several years ago, I "developed" some methods for preventing viral infections that might be applicable to the prevention of influenza infections. As I've said, it's my opinion that many, if not most, influenza infections are a result of self-inoculation, in which a person touches a surface that contains influenza virions/virus particles and then touches, either indirectly or directly, a mucosal surface on his or her face, such as on the eyes (touching the eyes or eyelids can allow the virions to be transferred to the conjunctival mucosal surfaces, around the eyes) or mouth or nose. The best way I've found to avoid this is to get in the habit of never touching one's face in public. I never touch my face in public, and I've basically gotten so I do touch my face at home, just in passing or in thought, etc., but do not really touch mucosal surfaces, even at home. That's almost not conscious on my part, but it's the type of thing that provides a "redundancy" in the prevention of self-inoculation. But, to be aggressive in the prevention of viral infections, one has to abandon the social pressure to do things in a reasonable way. I'm not saying I use these extreme sorts of approaches anymore, but the fact remains that the "normal" or "average" person, either at a hospital or elsewhere, is not effective at preventing the transmission of infections. If I had ever gotten into the business of trying to adhere to "normal" standards or habits, I would never have learned anything or gotten anything done, basically. In any case, the idea is just to think about ways to recognize that any surface that's entering the house from a public area could contain live viruses. I saw some expert on tv who was saying that influenza can't live for more than 5-10 minutes, or something, on a person's hand but, as is well-known, can live for 48-72 hours on a smooth surface. I can't verify that that's accurate, about the hands, though, because the person was making other statements that were inaccurate. But what constitutes a smooth surface? I would consider anything, such as mail, food packaging, packages that have been delivered, items from a drugstore, etc., to be potentially infectious. There isn't really any downside to treating them as such. It could get kind of excessive to open the food package, disinfect one's hands, and then unload the food, put the package in the cupboard or refrigerator, and then disinfect one's hands again, before eating the food, but I'm just saying that one shouldn't, in my opinion, guide one's behavior and "decisions," in that area, on some fear of being "obsessive" or of going against the sloppy behaviors of the masses. Some viruses can survive freezing and rethawing and can survive winters in barns and remain infectious, and I don't know what length of time influenza may be able to survive in a refrigerator or freezer. I wouldn't trust something an expert says on tv, however, because some people base their statements, inappropriately, on one set of flawed experiments or on 50-year-old research or medical folk wisdom and beliefs or something, etc. The most important thing, in my opinion, is to consider the use of large amounts of the alcohol-containing hand sanitizer gel when returning from a public place or touching items that have definitely been in public areas, in the presence of "other humans," recently. It's basically necessary to cover the entire surface of the hands with alcohol, to avoid rhinovirus or, for example, rotavirus infections, and I don't know if it's true that influenza can't survive on the hands for more than 5-10 minutes. I would assume it's not true, personally. When one uses a disinfectant like that, one does so with the knowledge that there is not likely to be a danger of infection in most instances, on most days. The point is to develop a habit and effective procedure, in the event that one's hands are carrying viruses.

I once saw that Howie Mandell say that he had been told, by a doctor, that the frequent use of hand sanitizer would cause "all the antibodies" to disappear from his hands or some nonsense like that. It's not true and is something that was meant to "scare him straight," to scare him into being "not obsessive." One isn't going to fall down a "slippery slope" of obsessiveness or go "kway-thee" by going outside the boundaries of normal behavior in specific instances or contexts. The pressure on people to behave in the ways everyone else behaves and to be desperately afraid of being obsessive about something is, in my opinion, one of the most destructive forces that exists. If one embraces that approach, there is the risk that everything novel and original and powerful will be stripped away from oneself, over the long term. The normal practices of the masses and drive toward normalization create a stripped-down, beaten-down, powerless state of being and of ignorance, essentially, in many areas. Anyway, I'm exaggerating a little, but it's true in a lot of ways.

Mechanism of Acyl Migration in an Acyl Glucuronide and Formation of a Lysyl Adduct of a Drug

This shows an acyl migration reaction in an acyl glucuronide conjugate of a drug, R. The acyl migration is separate from the adduct formation and doesn't "lead" to it in any specific way, but the acyl migrations can cause the glucuronide conjugates to be poorer substrate of enzymes that exhibit glucuronidase activity (tissue-specific esterase enzymes, mainly, are the enzymes that the beta-2-O-acyl-glucuronide and beta-3 and beta-4 conjugates are poor substrates of), in the intestinal tract or in "extraintestinal" cells. Those positional isomers of the beta-1-O-acyl glucuronides can (just as the beta-1 isomer can) also allow the drug and the glucuronic acid moiety to be linked to the protein covalently, and that can impact the immunogenicity, etc. (I didn't show that example).

Discussion of Some Issues, Reported in the Literature, Related to the Potential for Contamination in Creatine Supplements

I already discussed this, but I thought I'd mention it here. About 2-3 weeks ago, I switched to a brand of supplemental creatine monohydrate that I hadn't taken in a long time and developed objective and recognizable manifestations of a hypersensitivity reaction to some constituent of that supplement. In my opinion, the brand was contaminated with one or more of the compounds that researchers have sometimes identified in creatine preparations [(http://scholar.google.com/scholar?q=contaminant+%22creatine%22+supplement+OR+commercial&hl=en&as_sdt=2001&as_sdtp=on); (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+cyanoguanidine+OR+dicyandiamide+OR+dihydrotriazole&as_sdt=2000&as_ylo=&as_vis=0)]. I can reasonably rule out a contribution of the excipients in the product, given that I, prior to this incident, had taken another supplement from the same brand for a long time and had experienced no hypersensitivity reaction from the same excipients in that supplement. I actually took this brand of creatine about two or three years ago, for a relatively brief interval of time, and felt strongly, then, that it was contaminated. In my opinion, one or more guanidino/guanidinium or azo-/azide-based contaminants may have led to the formation of covalent adducts on various proteins and produced the hypersensitivity reaction. The symptoms resolved, mostly, within 12-24 hours of switching back to the brand I'd previously taken. I take a very small dose of creatine, and I've discussed the potential for adverse effects from metabolites (not contaminants) of creatine in many past postings on this blog. But many people would not be able to recognize signs of hypersensitivity reactions or make the connection, etc. I see at least one article, in one of those searches I linked to, that sounds like it could also have been a result of an "allergic"/autoreactive hypersensitivity reaction, in which there's an antibody response or even cytotoxic T-cell response, in more extreme cases, to a covalently-bound compound (such as a drug or drug metabolite). One explanation for this type of thing is that free drugs tend to be too small to be immunogenic but can sometimes become immunogenic when covalently bound (or, less commonly, tightly or "pseudoirreversibly") to the larger structure of the protein or other macromolecule, such as DNA. Many guanidinium compounds are well known to be reactive toward the formation of covalent adducts, [Lu et al., 2004: (http://www.unm.edu/~dd39/117.pdf); (http://scholar.google.com/scholar?hl=en&q=nucleophilic+adduct+guanidinium+OR+guanidino&as_sdt=2000&as_ylo=&as_vis=0)] and there are all sorts of reactions that can occur with reactive diamines and other nitrogen-containing compounds in vivo [Kalgutkar et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12093357)]. One could look at some of the other side effects, including rhabdomyolysis and interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+supplement+rhabdomyolysis+OR+nephritis&as_sdt=2000&as_ylo=&as_vis=0), associated with the use of creatine and say that hyperosmotic stress, due to the increase in extracellular fluid volume and electrolyte-derangements that the use of high-dose creatine has been associated with, or creatine-derived creatinine or formate or formaldehyde or some strange, semicarbazide-sensitive-amine-oxidase-derived nitrogen-containing compound was to blame in a given case, but another possibility is that contaminant-induced hypersensitivity reactions produced some of those cases of rhabdomyolysis or interstitial nephritis. Drug-induced (as in xenobiotic-induced) hypersensitivity syndromes are known to be major causes of interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=interstitial+nephritis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0) or rhabdomyolysis, individually (http://scholar.google.com/scholar?hl=en&q=rhabdomyolysis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0). A hypersensitivity syndrome could account for the report of reversible liver dysfunction in a person who had been taking creatine (or who had been taking non-creatine guanidino or azo -containing compounds, etc.) [(http://hardcorephysiologyfun.blogspot.com/2009/04/expression-of-creatine-kinase-by.html);(http://hardcorephysiologyfun.blogspot.com/2009/04/report-of-liver-dysfunction-or-damage.html)]. Why do the supposed hypersensitivity reactions to some creatine-containing supplement preparations appear to not be characterized by the kinds of wild and devastating qualities that drug-induced hypersensitivity reactions can be characterized by? One possibility is that there's thymic tolerance or acquired tolerance to protein adducts, formed as byproducts of normal rates of reactive oxygen species formation, etc., of endogenous guanidinium compounds and that the tolerance causes the xenobiotic-specific antibody response to be dampened or offset by the presence of antibodies to guanidinoacetyl protein adducts, or something like that, that cross-react with the xenobiotic-guanidium-containing adducts, etc. Maybe the abundance of endogenous guanidinium-containing adducts means that there's a high "dose of antigen," in the form of adducts of endogenous guanidino/guanidinium compounds, and that this favors the development of Th2-type responses to some xenobiotic adducts of guanidino compounds. Or maybe other mechanisms could account for the effects, etc. In any case, these are just my opinions. I should mention that covalent adducts/conjugates of drugs to proteins are thought to be a major, if not the major, cause of drug-induced liver injury, and the adducts or conjugates can form by lots of different mechanisms. There are endogenous molecules, such as some geometric isomers, I guess, of bilirubin, that can become covalently bound to proteins and become mildly immunogenic, etc. And protein tyrosine nitration and all sorts of other covalent modifications of proteins can occur normally. But there's likely to be relatively significant immune tolerance to proteins with nitrotyrosine residues, etc. Additionally, some types of drug-protein adducts are much more wildly immunogenic than others. One interesting question is why acetyl esters of endogenous compounds or of, for example, lipid-soluble vitamins don't seem to cause hypersensitivity reactions (apparently not, in my opinion). Maybe the covalent adducts are formed, via O-to-N acyl migration reactions or anomeric shifts of acyl glucuronides or reactions of acyl-CoA thioesters or other transesterification reactions or whatever other chaotic reactions, but are not immunogenic. There may be so many acetylated proteins, formed during protein acylation reactions, etc., or uridylylated RNA molecules or uridylyl or acyl enzyme intermediates that most or all of the possible neoantigens are tolerogenic or not immunogenic. I would guess that a random adduct of a non-xenobiotic would be less immunogenic than a random adduct of a xenobiotic, but that's just my guess. Another point I'd make is that people can be given the impression that drug-induced adverse effects are random, unpredictable, all-or-nothing events that can just be lumped together into a big heap of vagueness and bewilderment, etc. In many cases, the mechanisms underlying some of the potential adverse effects of a drug have been researched in tremendous detail and are reported in chemistry or pharmacology-related journal articles. It's usually possible to get a fairly clear picture of what's going on with a lot of these things, in my view, but that's just my opinion. And these are all just my opinions, obviously.