Twitter Archaeology

Twitter Archaeology.jpg

OMG, in 2514, microchip found with summary of July 2012 JID issue.

Visible light (VL) induces oxygen species and enzymes & sunscreens need 2 block VL to be protective.

2 doses of pachyonchia congenita gene worsens disease +s alopecia.

Pemphigus vul linked with ST18 gene 4 inflammation and cell death.

Stretching fibroblasts increases inflammation in DM.

GTG, if this is TMI, LMK or send me your best twitter of JID.

LAG

Image by Kordite, downloaded from Flickr.

Musings on Mucopolysaccharides, Mechanobiology and Eponyms

Image from wikipedia.jpg

Mucopolysaccharides (MPS; an older term), comprise a heterogeneous group of extracellular molecules, each consisting of a core protein(a proteoglycan) with covalently joined linear carbohydrates(a glycosaminoglycan). These molecules are important biomarkers and probes for exploring disease mechanisms.

At the VIII Dermatology International Congress in Copenhagen of 1930, Heinrich Adolf Gottron reported increased metachromatic staining in Dermatomyositis (DM) skin lesions. Gradually, the clinical literature has come to use Gottron’s papules (GP), red to violet plaques over the metacarpalphalangeal distal, and proximal interphalangeal joints as characteristic findings in DM. Although there are recent discussions of the sensitivity and specificity of GP and DM, the term GP has stood the test of time. Medical students are in awe when they learn that this finding can be a sign of inflammatory muscular disease and underlying internal malignancy. Now, these papules can also be a clue to the mechanisms of DM and its intriguing pathophysiology.

The general concept that “structural” molecules can interact with and modify the interactions of growth factors and other molecules is now well accepted. Those interactions can involve receptors on the cell surface and bridging molecules that may be covalently or non-covalently bound to the structural molecule. Such interactions may modulate inflammatory responses.

With this in mind, I refer you to Kim et al’s JID article reporting detailed studies of the MPS in GP. The glycosaminoglycan in GP is a chondroitin-4- sulfate (C4S). It interacts with both CD44 variant7 and osteopontin. Both of those latter molecules have roles in modulating immune responses, as discussed by Kim et al.

A novel feature of this investigation addressed the question that has intrigued investigators for almost a century: the reason for GP’s localization to the extensor surface over hand joints. The reasons for skin disease location are often discussed but rarely approached experimentally.

The role of the constant mechanical stretching of the extensor skin during ordinary circumstances was approached experimentally. Normal human fibroblasts were cultured on a tissue culture matrix, with a glass bead under their tissue culture matrix and another glass bead underneath the cell and its supporting membrane; pressure was applied above the culture. For me, this experiment recalls the fairytale princess who slept on a pea. The matrix around stretched fibroblasts was compared with non-stretched fibroblasts. The stretched cells produced increased levels of the CD 44 variant7 protein and its mRNA, which could have a role with osteopontin in contributing to inflammation and the increases in C4S.

Cells interact both biochemically and physically with their environment, and the mechanical and physical interactions reported by Kim et al can be considered within the realm of “mechanobiology”. The laboratory techniques and the analyses involved may differ from those used in classical immunology and biochemistry, and no doubt they will be used in more studies of the skin. Given its potential insights, mechanobiology should be a rapidly growing science for skin biology, akin to “plastics” — as recommended to the character Benjamin in “”http://www.imdb.com/title/tt0061722/“>The Graduate”. I discussed the increasing importance of engineering analysis in biology in the 75th anniversary issue of JID.

Your blogger has been afflicted by disease eponyms for several decades, as he has downed obscure names, drowning his neurons with eponyms for clinical syndromes since he was a resident. More recently, I have been concerned that eponyms may divide specialties and establish individual knowledge clubs. The issues related to eponyms are discussed in two articles in the British Medical Journal (Whitworth, 2007; Woywodt and Matteson, 2007).

Some eponyms have been removed or de-emphasized on the basis of an individual’s notariety. Reiter and Wegener are the two most prominent examples; due to their activities related to National Socialism in Germany, The primary names of their eponymous designated diseases have been replaced with “reactive arthritis” and “idiopathic necrotizing vasculitis”, respectively (Strous and Edelman, 2007).

“Gottron papules” can be a useful shorthand; instead of GP, I could have described the lesions as “symmetrical, disposed, shiny, well-delimited atrophic purplish papules on the extensor aspects of the digits, usually over joints, etc.” Even when their exact basis is known, there may not be a simple molecular name or shorthand for the overall clinical lesion. Therefore, this eponym enhances communication. But what about the man for whom they are named?
Heinrich Adolf Gottron (1890-1974) was Professor and Chair of Dermatology in Breslau Germany during National Socialism and was “exonerated by the denazification committee in 1945”. He was appointed as professor and chairman in Tübingen in 1946, after Breslau was ceded to Poland after World War II. After the war he “was a notable representative of post-war dermatology”. From a brief review there seems no strong evidence that this eponym is being used inappropriately. Important academic and historical details of Gottron’s career can be found in the History of German Language Dermatology.

In the over 80 years since Gottron’s report, investigative studies of the skin and immune system are increasing in DM, and further studies may lead us to understand its frequent association with muscle disease and internal malignancies.

REFERENCES

  • History of German Language Dermatology edited by A. Scholz, K. Holubar, G. Burg, W. Burgdorf, H Gollnick. Wiley-VCH Verlag, 2009.
  • Strous,RD and Edelman,MC. Eponyms and the Nazi era: time to remember and time for change. IMAJ 9:207-214, 2007
  • Whitworth,JA Should eponyms be abandoned? No. BMJ 335:425, 2007.
  • Woywodt,A and Matteson, E. Should eponyms be abandoned? Yes BMJ 335:424,2007.

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Sticking together–Epidermal Lipids and Research Collaborations

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While a resident at Harvard (Massachusetts General Hospital) in Howard Baden’s lab I was assigned a research project studying human epidermal lipids using X-ray diffraction techniques. Pounds of scale that Howard Baden and Irwin Freedberg had collected from patients with erythroderma were extracted with chloroform and methanol over steam baths, and analyzed for lipids by various techniques. These studies culminated in a presentation to the Society for Investigative Dermatology in Atlantic City and publication in Nature; and the idea that a lifetime in the dermatological sciences would be so much fun was instilled.

I have retained a special interest in epidermal lipids. Recently, Iwai et al published a detailed study in JID using various physical, spectrographic, and imaging techniques to study lipids associated with the barrier. They present a new model of how cholesterol and ceramide sphingoids are arranged in the barrier to support its various functions. I will leave the details of the scientific results to the aficionados and concentrate instead on the organization and internationalization of science exemplified by this project.

The main players come from Northern Europe (Sweden, Norway, and the United Kingdom) and Japan, and there was close collaboration between researchers from Academia and Industry in a project that spanned a decade. Is a project of this long duration, involving individuals from multiple institutions and countries, the public (non-profit) sector and the for-profit sector the new norm? In the 75th Anniversary issue of JID, Bauer and Cohen and Parrish discuss increasing industrial and academic collaborations; these articles are required reading for those thinking about commercializing their scientific findings and collaborating with the for-profit sector. In the same issue, Uitto and Rodeck discuss the globalization of the research enterprise.

All institutions must address for themselves the advantages, disadvantages, and barriers to various collaborations. The role of confidentiality, protection of graduate students, and the role of intellectual property must all be considered. In addition, is there a convergence of interests, with academic institutions concerned about commercialization, spinning off companies, and fostering biotech incubators? Is that the best model and direction for academic institutions? What are the best models: for the academic institution, for the investigator?

Our scientific societies should encourage these discussions. Models should be explored, and the excellent – and disastrous — outcomes discussed. Yes, everyone likes to talk about successful collaborations, but failures require as much if not more consideration, even if the discussion is painful and difficult. Seeking profits and patents may complicate or even prevent frank discussions; is that the kind of environment that scientists in academia ultimately desire? These questions lack easy answers, but if they are never asked they will never be answered and the framework for best practices will not be established. Parrish’s article concludes with an important checklist of the institutional, personnel, and leadership issues to consider when beginning new collaborative endeavors. It deserves attention.

We encourage readers to comment on their experiences in this important interface between the for-profit and not-for-profit worlds.

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Pot, Perspiration, Plant Photobiology and Pelage

With Guest Blogger Julie S. Green, MD, PhD, University of Colorado Denver

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The psychotropic properties of marijuana (MJ), prepared from the Cannabis sativa plant, have been appreciated for thousands of years. Nearly 50 years ago, delta-9-tetrahydrocannabinol (THC) was synthesized in the laboratory and was shown soon thereafter to be the primary active ingredient (Mechoulam et al, 1967; Mechoulam and Gaoni, 1967) in MJ. The relative proportion of THC to other, less active ingredients, determines the “potency” of MJ derived from a particular strain of C. sativa and generally averages a THC content of 2-3%, though some variants specifically bred for recreational use approach 20% (Pijlman, et al, 2005).

Decades of research have associated the intake of THC (for example, via smoking MJ) with increased risk of anxiety and psychosis, the development of dependence and addiction, and appetite enhancement. THC produces these effects by binding two types of receptors found within the central nervous system and various peripheral tissues (including eccrine sweat glands). These receptors, designated CB1 and CB2, can be activated by THC, but they are also activated by endocannabinoids (ECS), compounds that are chemically related to THC but are naturally produced by the body.

ECS are related to arachidonic acid, and they bind to CB1 or CB2 to modulate a number of physiological processes such as appetite, mood, and memory, so that the body does not need exogenous MJ (or ganja, mary jane, weed, or stuff ) for stimulation. An active area of current research involves studying the effects of stimulating or inhibiting the activity of these receptors. Both CB1 and CB2 receptors are present in eccrine sweat glands. Using a viral-transformed eccrine cell line Czifra et al recently studied the effect of ECS, which suppressed proliferation and increased apoptosis of sweat cells. Interestingly, the effect was not mediated by G proteins, which usually mediate CB2 receptor responses, but were mediated by the MAP Kinase pathway, which is active in some epidermal diseases.

An unanswered question is whether there are influences, short or long-term, on eccrine sweating induced by exogenous THC in MJ users. This deserves at least taking detailed histories in dormitory rooms and coffee houses, and even direct measurement of eccrine sweat function in MJ users. Studies involving MJ administration would require institutional review board approval and approval by the US Drug Enforcement Agency (DEA).

MJ plants (Cannabis sativa) synthesize cannabinoids and produce more active THC when exposed to increased levels of UVB (Lydon et al, 1987). That is why so many UVB light bulbs are used not for tanning but for C. sativa cultivation — and why C. sativa is often grown at high elevations. The US Department of Agriculture has carefully studied the UV effects, and Lydon et al. describe detailed techniques for growing C. sativa plants. Such information suggests ambivalence on the part of the US government towards MJ — or the misperception that plant growers do not use Pubmed and Google.

The Sativa plant that produces MJ is a cultivar closely related to the sativa that produces hemp, a rather dull but commercially important product; plants in that family produce seeds that are an important oil and protein source (Pate, 1994). (The Journal of the Industrial Hemp Association, in which this report was published, had a brief life span, but discussions of the life and death of research journals is a topic for another day). While only this particular group of plants produce THC, it is unlikely that the plants use these chemicals for a high; nonetheless, the role of THC in plant ecology is uncertain. Insects do not have CB receptors, but THC may play a role in controlling competing plants, fungi and other parasites, and herbivores. THC also provides a modest sun protection factor, but sun protection is not a likely role for THC in sativa.

Many are interested in knowing whether individuals are using — or have recently used — MJ. When I enter my local Lowe’s to buy tools for my silver workshop I always notice the sign announcing that drug testing is required for employees; that assures me the employee will lead me to the correct aisle to find an odd-sized file or drill bit. And this is where hair enters to story (Huestis, 2007).

MJ is converted to polar and nonpolar metabolites, many of which enter growing hairs. There are sensitive analytical techniques for detecting THC, and hair is an archeological record of past MJ use. Incorporated THC cannot be removed by ordinary techniques available in the home or smoke-shop laboratory. Hair must be washed with lipid solvents to remove any environmental MJ contamination from the sample. There is always the possibility of sampling pubic hair to decrease the likelihood of contamination by ambient MJ, but that seems a bit intrusive. Plucked anagen hairs would allow a more timely analysis of recent MJ usage and would be a good research project for skin biologists.

Since C. sativa and THC have been interacting with humans for millennia, studying ecology and the interface between plants and humankind is a legitimate reason to be growing sativa . . . register with the DEA, get permission to grow the plants, develop testable hypotheses, publish your results, and earn credibility as a sativa ecologist. You may make lots of friends in the process.

REFERENCES
Huestis, MA Cannabinoid Concentration in Hair from documented Cannabis users. Forensic Sci Int 169:129-136, 2007.

Lydon J et al UV-B radiation effects … Photochemistry and Photobiology 46:201-206,1987.

Pate, DW Chemical ecology of Cannabis. J International Hemp Assoc 2:29,32-37,1994.

Pijlman FT, Rigter SM, Hoek J, Goldschmidt HM, Niesink RJ. Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol 10: 171-180, 2005.

Mechoulam R and Gaoni Y. The absolute configuration of delta-1-tetrahydrocannabinol, the major active constituent of hashish. Tetrahedron Lett 12, 1109-1111, 1967.

Mechoulam R, Braun P, and Gaoni Y. A stereospecific synthesis of (-)-delta 1- and (-)-delta 1(6)-tetrahydrocannabinols. J Am Chem Soc 89: 4552-4554, 1967.

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