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Thalidomide paradox

Herein, we disclose a hypothesis to explain this thalidomide paradox through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent,.. Herein, we disclose a hypothesis to explain this thalidomide paradox through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution Finally, it is discussed the paradox that the «feared» thalidomide drug causing a great human drama affecting about 10,000 infants has led to a formidable contribution to the scientific knowledge, and large range of therapeutic applications The second paradox is that, bearing in mind that 2 to 3% of all babies born have significant birth defects, and that thalidomide consumption was widespread in 1960 to 1961, some mothers who undoubtedly took the drug when pregnan Dr. Frances Oldham Kelsey, who became famous for withholding Food and Drug Administration approval for Thalidomide in the early 1960s, died last week at 101. Notice of her death has been accompanied by retellings of the FDA's early days, and of Kelsey's heroic stand against the morning sickness drug later linked to terrible birth defects in other parts of the world

Understanding the Thalidomide Chirality in Biological

  1. The drug caused severe birth defects, which are referred to as Thalidomide Embryopathy or Thalidomide Syndrome. Thalidomide survivors were born with a range of impairments.1 Most commonly they have missing or short and/or deformed limbs (Phocomelia). Some people have sight or hearing impairments and/or facial disfigurement
  2. The paradox of ENL is that it can be a life-threatening disorder and requires control with immunosuppression which may itself pose life-threatening risks for patients. Treatment with thalidomide provides an effective alternative to steroid therapy, gives better long-term control and avoids the adverse effects of prolonged steroid therapy.
  3. Yet the emotionally charged issue, which split Wichita, Kan., into two armed camps last year and promises to raise the temperature of an increasingly fiery presidential campaign by next fall, was.
  4. The renin-angiotensin-aldosterone system that regulates blood volume presents a paradox in ME/CFS and FM. Renin is the first leg of the renin-angiotensin-aldosterone system (RAAS) that's designed to deliver optimal blood volume levels. If blood volume is low, renin activity should be high
  5. Of course, the disability paradox could be a crock. The people in these studies could be either deluding themselves or deliberately deluding the rest of us. But watching Gault bubble over, gesturing animatedly with his feet as he talks about his beloved wife, his strong faith, and his world travels, it is hard to think he is in denial
  6. Read the Plant Paradox book. Not once but many times. Take notes on info pertaining to your needs. Print the yes list. If the food is not on the list don't eat it. Get all lectin foods out of the house. Get the cooks books and use your pressure cooker. Stay in each phase as long as is necessary to help heal your specific problems

The drug of good and evil. Thalidomide can save a life or upend one. The molecule's unusual mechanism of action is starting to give researchers hints as to why. By Rajendrani Mukhopadhyay. Nov. 1, 2014. Thalidomide is a molecule with a split personality. Notorious as the drug that caused thousands of babies to be born with grotesque. Smithells, Newman structurestobemoreorless symmetrical.This is, broadly, what is observed in practice, not only with thalidomide, but with other terato- genicdrugsandwithdefects ofgenetic origin. However, the extent of the symmetry varies according to the nature ofthe defect, both in the closeness of the match between left and right, andintheproportionofcases whichar Background: Over 60 years ago the biggest drug catastrophe in Germany took place. The drug thalidomide, sold by the German pharmaceutical company Chemie Grünenthal GmbH starting in 1957 under the name Contergan, caused severe birth defects in newborns. Chemie Grünenthal withdraw Contergan in 1961

Thalidomide alone, at the schedule and dose levels used in the cur-rent study, is not a safe and viable therapeutic option for patients with myelodys-plastic syndrome. Limited efficacy and increased toxicity were observed in the for the paradox between the marrow hypercellularity and peripheral blood cytopenias observed in MDS patients. Thalidomide Paradox. However, one question remains regarding the clear biological differences between the thalidomide enantiomers reported in 1979, despite the observed racemization of thalidomide. Why do animal experiments that use (R)-thalidomide not display teratogenicity if the (R)-isomer readily racemizes in vivo? This discrepancy is known.

Finally, we discuss the paradox that the embryonic molecular pathology induced by thalidomide suggests this drug as a candidate for therapeutic application in idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease characterized by downregulation of Bmp signaling, increased Wnt and Akt activity, and apoptosis resistance The REMS Publication Paradox. July 14, 2009. an interpretation led to an academic organization agreeing not to publicly disclose the results of a study relating to thalidomide (Thalomid).[5,6] Although the results of some voluntary programs conducted with IRB oversight have been published in the scientific literature,[7-10] results from. Thalidomide alone, at the schedule and dose levels used in the current study, is not a safe and viable therapeutic option for patients with myelodysplastic syndrome. 11 These cytokines, by promoting the apoptosis of intramedullary hematopoietic cells, may be responsible in part for the paradox between the marrow hypercellularity and. An EPQ (Extended Project Qualification) allows A-Level students to write either a 5,000 word essay on any question or subject of their choice. Alternatively, students can create an artefact or product, and write a shorter essay explaining it. The EPQ is equivalent to half an A-Level. EPQs are a fantastic way of proving to universities that you.

Evaluation of the Thalidomide Fetal Exposure Prevention Program (Thalidomide Survey) Background. Thalidomide is a drug known to cause serious birth defects if taken during pregnancy. In 1998, FDA approved thalidomide under restricted distribution regulations Disseminated herpes simplex virus (HSV) and varicella zoster virus (VZV) have been reported individually in immunosuppressed adults. We present a case of coinfection with disseminated HSV and VZV infection in a patient taking thalidomide for relapsed multiple myeloma. This is the first report of opportunistic infection associated with thalidomide

Kostenlose Lieferung möglic thalidomide and was isolated as a thalidomide-binding protein from various cell types [1]. CRBN, originally This paradox could be solved by the recently-clarified fact that these drugs directly bound to CRBN promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus. In the late 1950s and early 1960s the drug Thalidomide was given to thousands of pregnant women across the world to relieve morning sickness. The drug caused severe birth defects. Much has been written about the drug, its teratogenic effects, and the nature of the damage it caused. The paradox of normalisation through rehabilitation.

[The thalidomide experience: review of its effects 50

The disability paradox is a psychologists' term to describe the contradiction that while disabled people often who was born with no arms after his mother took Thalidomide while she was. Thalidomide-induced peripheral neuropathy (TIPN) occurs in 25-75% of patients, with dose-dependent prevalence and severity . The risk of neurotoxicity increases in a dose-dependent manner up to a cumulative dose of 20 g. In practice, thalidomide is administered at a maximum dose of 200 mg daily and for a limited treatment duration The paradox of sustainable innovation: The 'Eroom' effect (Moore's law backwards) gradually reducing their risk tolerances to avoid safety disasters such as the drug Thalidomide, the anti-morning sickness treatment for pregnant women that resulted in birth defects. They further note that some corporations have increased their R&D. But thalidomide was distributed in Canada, and there were almost 100 Canadian victims. 9 . Those Canadian victims faced substantial procedural hurdles, much like the British victims, and a young Canadian academic at Professor Rosenberg has described the paradox that the jury's virtues of injecting communit

History. In La Bégueule (1772), Voltaire wrote Le mieux est l'ennemi du bien, which is often translated as The perfect is the enemy of the good (literally: The better is the enemy of the good).. The nirvana fallacy was given its name by economist Harold Demsetz in 1969, who said:. The view that now pervades much public policy economics implicitly presents the relevant choice as between an. Itch Unresponsive to Scratching. In some cases of chronic itch, the normal cross-talk between pain and itch pathways in the spine does not exist. To explain this, it's possible that the peripheral nerves, or the nerves that travel from the spinal cord to the skin and other parts of the body, become more sensitive. 5  Thalidomide (brand names Immunoprin ®, Talidex ®, Talizer ®, Thalomid ®) is chemically defined as RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione. It was initially developed in the early 1960's as a sedative and hypnotic agent [191] , but it quickly became known for its anti-nausea properties and was consequently sold without.

The Political Economy of Thalidomide - Harvard University

  1. Beyond Thalidomide; birth defects explained. McCredie, Janet. Royal Society of Medicine Pr. 2007 418 pages $69.00 Hardcover RG626 In 1958 the babies without arms or legs started to be born. Some were missing ears or had organ or bone deformities. Doctors thought perhaps dish soap or some other common chemical was to blame
  2. Thalidomide is a sedative that was given to pregnant women. Thalidomide was withdrawn after thousands of mothers gave birth to disabled babies. Let's clarify this misunderstanding up. Pregnant women are not given drugs to induce the birth of transgender children. Children being born transgender is a natural part of the human condition
  3. Thalidomide & the Present Day. Today, when taken by people who aren't pregnant, thalidomide is used to treat — I'm not even joking — leprosy and multiple myeloma. The FDA in 1998 and 2006 approved the drug for those indications. Ironically, Kelsey was still at the FDA when thalidomide was finally approved. Thalidomide & DF
  4. ary results of the Korean Society for Pediatric Neuro-Oncology study
  5. Which factor can be involved in the Latino paradox of healthy babies despite a tendency to avoid prenatal care? strong cultural support for maternity In the 1950s and early 1960s, many women were prescribed thalidomide to prevent morning sickness

A very pronounced enantioselectivity towards (+)-(S)-a-methyl-thalidomide with complete absence of activity of the (-)-@+form was observed in a cell culture model in which thalidomide-induced enhancement of phorbol-ester stimulated release of T N F a by a leukaemia cell line was determined as biological response.1s As for the apparent paradox. This is called the mortality-morbidity paradox, or Health Survival paradox This is explained by an excess of psychological, rather than physical, distress among women, as well as higher smoking rates among men. Androgens also contribute to the male deficit in longevity. Access to Another example of this is the thalidomide epidemic. In the.

The changing health of Thalidomide survivors as they age

  1. BURNS IN FINAL READ.DOC 07/30/03 2:51 PM 2003] WHEN LIFE IS AN INJURY 809 to recognize parents' wrongful birth claims.5 Until 1982, no state su- preme court permitted wrongful life lawsuits at all.6 Currently, no American jurisdiction permits a child to recover general damages fo
  2. ants, and food additives affect.
  3. The paradox between studies of lenalidomide in newly diagnosed and relapsed disease is interesting. Thalidomide (and to a lesser extent, lenalidomide) can cause bradycardia. The concomitant use of these drugs with a β-blocker should be avoided to decrease the risk of syncope. Using angiotensin-converting enzyme inhibitors or angiotensin.

The role of thalidomide in the management of erythema

To: Paradox You have to get TWO doses of it to be fully vaccinated. 11 posted on 04/19/2021 3:04:46 PM PDT by BipolarBob (Jeffrey Epsteins last words I am not committing suicide. The paradox of ENL is that it can be a life-threatening disorder and requires control with immunosuppression which may itself pose life-threatening risks for patients. Treatment with thalidomide provides an effective alternative to steroid therapy, gives better long-term control and avoids the adverse effects of prolonged steroid therapy A randomized double-blind, placebo-controlled study was performed to determine the safety, efficacy, and effect of thalidomide on a variety of immunological and biochemical parameters in asymptomat.. The realm rejoices as Paradox Interactive announces the launch of Crusader Kings III, the latest entry in the publisher's grand strategy role-playing game franchise. it originally refers to children who were born after their mothers took Thalidomide, which resulted in an unusually large number of children with short and mutated arms (see.

Talidomida: 50 años después - ScienceDirec

Thalidomide is also being investigated for treating symptoms of prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet's disease, and Crohn's disease. In a small trial, Australian researchers found thalidomide sparked a doubling of the number of T cells in patients, allowing the patients' own immune system to attack cancer cells I wanted to share my experience going through thiamine paradox and my journey to heal. I am 27 year old girl from. More. Thiamine for Fibromyalgia, CFS/ME, Chronic Lyme, and SIBO-C May 11, 2021 May 11, 2021. Case Stories / Thiamine. The Road to ThiamineIn August 2020, I was at my wits end. I had developed gastroparesis in March 2020, after 10 day

When 'Miss Sherri' Got an Abortion : A 1962 Ordeal Becomes

The earliest drugstores date back to the Middle Ages. The first known drugstore was opened by Arabian pharmacists in Baghdad in 754, and many more soon began operating throughout the medieval Islamic world and eventually medieval Europe. By the 19th century, many of the drug stores in Europe and North America had eventually developed into larger pharmaceutical companies. Key discoveries of the. PaxAmericana. Crusader Kings III Available Now! The realm rejoices as Paradox Interactive announces the launch of Crusader Kings III, the latest entry in the publisher's grand strategy role-playing game franchise. Advisors may now jockey for positions of influence and adversaries should save their schemes for another day, because on this day.

The paradox is that the longer people live with their myeloma, the more likely that such other problems may require attention. That is a good thing! Please note: Dr. Greipp's advice is for consumer educational purposes only and should not be considered or used as a substitute for medical, nursing or other professional health care advice. Unseen Passage for Class 8 CBSE With Answers. September 11, 2020 by Prasanna. Type -1. Read the passage given below and write the answer you consider the most appropriate in your answer sheet. This grammar section explains English Grammar in a clear and simple way. There are example sentences to show how the language is used

The Paradox in Chronic Fatigue Syndrome (ME/CFS) and POTS

  1. Thalidomide was a drug given to pregnant women for nausea. It caused devastating birth defects, from stunted limbs to spina bifida, and many babies died. Thalidomide was widely available in Europe and produced thousands of cases of birth defects there. American Abundance and the Paradox of Poverty..
  2. Thalidomide Thalidomide is a drug with immunomodulatory properties through the inhibition of TNF-α. creating a paradox between the hypotheses and the evidence, further complicated by the.
  3. There is a big push by trump and Republicans to bring a Covid to market quickly. Remember the Thalidomide Disaster, The Morning Call, May 12, 2020. Thalidomide. In the rush to find a vaccine or treatment for the coronavirus, let's not forget the bitter lesson learned in the 1950s and '60s when thalidomide was prescribed to pregnant women for morning sickness
  4. Although thalidomide led to adverse effects in clinical trials in children, more research is needed on the less-toxic thalidomide analog IMiD3 in adults. creating a paradox between the.
  5. g Pools Were The Best, The MSM has NFI what the U.S. Constitution is, Secret Election News, Drink Cheap/Bake Well /Look Epic, How Gnarly Astrology will undo the faux Kamala Harris & Joe Biden Love Affair, MANK & THE CROWN previews, Why.
  6. Autism is a spectrum or range of disorders and no exact cause is known. There are several interacting causes that may lead to Autism Spectrum Disorders (ASD). In most cases there is a combination.
  7. Immunomodulatory drugs (IMiDs) are key components of treatment of a number of hematological malignancies. 1 The first drug in this class, thalidomide, became infamous for its teratogenic effects. Early mechanism of action studies implicated multiple potential, but no definitive drug activities, that explained this teratogenicity. 2,3 Recently, however, Ito et al described that cereblon (CRBN.

The Disability Paradox Common Reade

When Helping Hurts (Ep. 295) Well-intentioned social programs go back to the Depression era. A study of their effectiveness came decades later. (Photo: Jack Delano / Farm Security Administration / Flickr) Our latest Freakonomics Radio episode is called When Helping Hurts. (You can subscribe to the podcast at Apple Podcasts or elsewhere. Horror films offer a psychological thrill ride. October 24, 2018. (photo: Getty Images) There's a lot of thought behind a good scare. So says Jason Middleton, an associate professor of English and the director of the Film and Media Studies Program. A scholar and experimental filmmaker, he studies both documentary and horror films

References. Answer. Erythema nodosum leprosum (ENL), also known as lepra type 2 reaction, is a complication of lepromatous leprosy. It is characterized by the development of inflamed subcutaneous. No products in the cart. 0. Car Because thalidomide interferes with the formation of new blood vessels (angiogenesis) it is now used to treat cancer, and leprosy, and a few other things as well. Cancers need their own blood supply to grow, and if you stop them triggering new blood vessel growth and development the shrivel up and die Here we have a paradox. The drug more than doubled HDL and lowered LDL levels by as much as many statins, but had no effect on cardiac events, said Steve Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. These findings illustrate the importance of performing large, high-quality outcome trials

Thalidomide potentiated the effect of cyclophosphamide only when This paradox may be resolved by the concept of 'normalization' of the tumor vasculature: the judicious application of the anti-angiogenic drug prunes the immature and inefficient blood vessels, leaving th Thalidomide ultimately caused birth defects in over 10,000 infants in 46 countries, but only 17 of those infants were in the Donne finds power in a paradox. Catag the forms of death's impotence, he ends by triumphantly pointing out that death itself, rather than the speaker-poet, is the on There is an apparent paradox here: ifthe male body in patriarchy becomes the norm, the standard against which one measures otherness - and thus creates the enigma ofwoman - one might expect the male Thalidomide. Introduced as a sedative in 1956 and most frequently prescribed for pregnant women, it affected the growth ofthe foetus

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The apparent paradox of a vascular disruption causing such focal manifestations can be understood either by supposing a zone of vascular vulnerability with the fetal brainstem 80 or by invoking transient focal ischemia resulting from an embolic The specific timing of thalidomide embryopathy 79 may be largely linked to embryonic scaffold. The disability paradox 18 November 2020, 22:40. I watched this program on BBC4 and found it enlightening. The one highlight for me was the idea that most of the medical professionals focus on what we have lost and try to find a solution rather than focusing on what we can achieve with our disability. The guy with no arms due to thalidomide. The sleight of hand that resolves the paradox is that no one is ever required to define what comes after the Elites are toppled. Suggested reading The media has acted as cheerleader for a long history of failed medicines (think Thalidomide, Vioxx, etc. etc.), immoral and illegal coups in foreign countries, and yesgovernment conspiracies.. John Richard Pilger (/ ˈ p ɪ l dʒ ər /; born 9 October 1939) is an Australian journalist, writer, and documentary filmmaker. He has been mainly based in Britain since 1962. Pilger is a strong critic of American, Australian, and British foreign policy, which he considers to be driven by an imperialist and colonialist agenda. Pilger has also criticised his native country's treatment of. Homochirality is a uniformity of chirality, or handedness. Objects are chiral when they cannot be superposed on their mirror images. For example, the left and right hands of a human are approximately mirror images of each other but are not their own mirror images, so they are chiral. In biology, 19 of the 20 natural amino acids are homochiral.

IG Farben was founded in December 1925 as a merger of six companies: BASF (27.4 percent of equity capital); Bayer (27.4 percent); Hoechst, including Cassella and Chemische Fabrik Kalle (27.4 percent); Agfa (9 percent); Chemische Fabrik Griesheim-Elektron (6.9 percent); and Chemische Fabrik vorm. Weiler Ter Meer (1.9 percent). The supervisory board members became widely known as, and were said. We designed our new Special Pedals in cooperation with Georg Busch from the company Ergodynamik Busch. They are much more adjustable to individual needs than other models: for starters, they fit an impressive range of shoe sizes, from US kids' 1/UK kids' 13 / EU 32 to US men's 16 /UK 15.5 / EU 52. And the angle to the direction of travel can. This reversal is known as the obesity paradox and supports the view in oncology that overweight patients are at lower Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α.

Thalidomide research breakthrough. Researchers at the University of Aberdeen, in Scotland, have discovered why limb defects occur in babies born to mothers who have taken thalidomide. Dr Neil Vargesson, who led the research, said: We have put to rest a 50-year puzzle, in finally deducing how thalidomide triggers limb defects and why it appears. 13th March 2021 I am particularly interested in the whole concept of being 'anti-' or a 'denier', or a sceptic. I think in great part this is due to constant attacks I have had to put up with because of my views of cholesterol and statins. I am often called a statin 'denier'. I hav Solving the Hiring Paradox: A Method to Address Bias in the Hiring Process Within the Law by Jad Salem, Swati Gupta, and Deven Desai, discussion by Pauline Kim: With widespread use of automated methods in applicant screening, there is growing concern over fairness and growing need for legal analysis of relevant algorithmic techniques The thalidomide catastrophe of the 1950s clearly demonstrated that potential harms of medications in pregnancy are genuine. 1 However, this was a lesson badly learned, as it arose precisely in the wake of enormous harms arising from ill-advised research exclusion: widespread rollout and clinical use of thalidomide in pregnancy without ever. The obesity paradox is a curious phenomenon in HF. anti-TNF-alpha therapy and appetite stimulants. 12 A research of thalidomide to treat cardiac cachexia is ongoing because of its potential to reduce the secretion of TNF-alpha and to relieve the symptoms of wasting. 7,12 Studies of megestrol and testosterone in therapy to improve appetite.

Thalidomide (N-α-phthalimidoglutarimid) is an old drug with immunomodulatory and anti-inflammatory effects that are used in the treatment of diseases with TNF-α involvement . One of the main effects of thalidomide in cirrhosis is mediated by the reduction of hepatic fibro- inflammation Thalidomide therapy in adult patients with myelodysplastic syndrome. Cancer, 2006. Alvaro Moreno-aspiti The use of thalidomide and pentoxifylline have been shown to reduce the levels of TNF in vivo in subjects whose ENL has shown clinical improvement [42, 43]. However, a recent study by Haslett et al. has demonstrated low TNF levels in individuals with milder ENL reactions, and paradoxically these levels increased during therapy with thalidomide The innovation paradox is that longer research programs lead to lesser rewards for innovation. In cases like Paraplatin, the paradox may be acceptable. In theory, the company had two choices with respect to its product: a surrogate endpoint and limited indication early, or a clinical endpoint and full indication later This has created an apparent paradox between the mobilising regimens effect on the cellular content of the autograft and its impact on patient outcomes. Thalidomide monotherapy or combined.

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It does to the brain what the drug thalidomide did to the fetus that emerged from the womb without arms. Blumenfeld's reasoning is largely correct, but highly misleading: E. W. Dolch was a professor of education in the early 1920s who composed a list of the most frequently used words in English Editorial: The precautionary paradox and Zika. Sarah JL Edwards. Research Ethics 2016 12: 4, 178-181 (since Thalidomide) is to run a randomized controlled trial of a new drug against best available care, which implies restrictions - if not on access to the trial, then on access to the investigational drug by virtue of the randomization. Doctors figured out that thalidomide, a drug used in sleeping pills, cough syrups, and other over-the counter medications sold in West Germany and England was the cause of these deformations. The drug also caused many brain-damaged babies, miscarriages, stillbirths, and early infant deaths. Freedom and Paradox,. Welcome to the Molecule of the Month page! This is one of the longest running chemistry webpages on the internet. Each month since January 1996 a new molecule has been added to the list on this page, which makes this one of the longest running Chemical websites on the internet! The links will take you to a page at one of the Web sites at a University Chemistry Department or commercial site in.

The drug of good and evi

One solution to the Fermi paradox not generally considered is contained in esoteric science, and was likely one of the secrets of the Mystery schools. The subjective realm in each person, which Jung called the collective unconscious, is a vast realm that's currently poorly understood. The classic example is thalidomide. If they had waited. Other treatments using thalidomide or lenalidomide may also be effective, but these drugs have been shown to exacerbate cardiac failure in a percentage of patients . Despite the advancement in hematological treatment, mortality in patients with severe heart failure is still high . Moreover, worsening of cardiac function may occur during the.

In extreme cases, however, the nerve damage may be permanent. Some of the drugs that may cause peripheral neuropathy include: Anti-alcohol drugs (Disulfiram) Anticonvulsants: Phenytoin (Dilantin®) Cancer medications (Cisplatin) Vincristine. Heart or blood pressure medications (Amiodarone) Hydralazine. Perhexiline L-methamphetamine is a fine example of how molecules that vary only in their chirality can have very different biological effects. Chiral molecules have non-superimposable mirror images. L. By the way, Thalidomide was a morning sickness medication given to pregnant women in the early 1960's. This happened before modern medicine developed tests to find out this probably wasn't a good plan and it was banned in 1963 The Ark of the Covenant is one of the holiest artifacts of the Hebrew Bible. So holy that looking at or touching it could be deadly. But what actually is it,.. Thalidomide. Because cytokines have an important role in the pathogenesis of LCH, it has been thought that targeting the chemokine-receptor axis may provide new therapeutic targets, and this has been the theoretical basis for studies of TNF-α inhibition. Eosinophilic granuloma of the orbit: understanding the paradox of aggressive.