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IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 1993; 260: 180810. Neumann C, Zehentmaier G, Danhauser-Riedl S, Emmerich B, Hallek M. Interleukin-6 induces tyrosine phosphorylation of the Ras activating protein Shc, and its complex formation with Grb2 in the human multiple myeloma cell line LP-1. Eur J Immunol 1996; 26: 37984. Guschin D, Rogers N, Briscoe J et al. A major role for the protein tyrosine kinase JAK1 in the JAK STAT signal transduction pathway in response to interleukin-6. EMBO J 1995; 14: 14219. Kantor TV, Friberg D, Medsger TA Jr, Buckingham RB, Whiteside TL. Cytokine production and serum levels in systemic sclerosis. Clin Immunol Immunopathol 1992; 65: 27885. Ito A, Shimokawa H, Kadokami T et al. Tyrosine kinase inhibitor suppresses coronary arteriosclerotic changes and vasospastic responses induced by chronic treatment with interleukin-1 beta in pigs in vivo. J Clin Invest 1995; 96: 128894. White CR, Haidekker MA, Stevens HY, Frangos JA. Extracellular signal-regulated kinase activation and endothelin-1 production in human endothelial cells exposed to vibration. J Physiol Lond ; 2004; 555: 56572. Freedman RR, Girgis R, Mayes MD. Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma. J Rheumatol 1999; 26: 23868. Ihn H, Sato S, Fujimoto M, Takehara K, Tamaki K. Increased serum levels of soluble vascular cell adhesion molecule-1 and E-selectin in patients with systemic sclerosis. Br J Rheumatol 1998; 37: 118892. Andersen GN, Caidahl K, Kazzam E et al. Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Arthritis Rheum 2000; 43: 108593. Kahaleh MB. Vascular disease in scleroderma. Endothelial T lymphocyte-fibroblast interactions. Rheum Dis Clin North 1990; 16: 5373. Simonini G, Pignone A, Generini S et al. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology 2000; 155: 115. Ringqvist A, Jonason T, Leppert J, Ringqvist I. Non-invasive investigation of endothelium-dependent dilatation of the brachial artery in women with primary Raynaud's phenomenon. Clin Sci Colch ; 1998; 94: 23943. Smyth AE, Bell AL, Bruce IN, McGrann S, Allen JA. Digital vascular responses and serum endothelin-1 concentrations in primary and secondary Raynaud's phenomenon. Ann Rheum Dis 2000; 59: 8704, for instance, metformin. 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New information on adverse events - Updated information on specific safety aspects: use during pregnancy and lactation Changes made to SPC sections: 4.2 4.4 4.8 Posology & method of administration; Warnings & precautions; Adverse effects; Pharmacodynamic properties; Pharmacokinetic properties 6.3 Shelf life. DAVID NEUBAUER, MD: Well, I think what she described of her pattern of going to bed so early and then getting up so late in the morning certainly raised a lot of questions about her ability to sleep all that time. We find that oftentimes when people have so much concern about their insomnia, they end up spending way too much time in bed, to the point where they're really undermining their ability to get better. They're setting themselves up for failure because they're going to be spending a lot of the sleepless and frustrating time in bed. Now while she may not have been sleeping too well during that time, she must have been getting some sleep. Yet during the daytime, she felt very fatigued and frequently would be "resting." It's sort of hard to know what to make of that when we hear that report from patients, because they may or may not fully perceive the extent to which they are getting some sleep during the daytime. Of course, while napping in the daytime isn't necessarily a problem for some people, for those who have lots of trouble with their sleep at nighttime that certainly can be a major factor that can continue to perpetuate the symptoms. CHRISTOPHER EARLEY, MD: One of the points in the history I sort of focused on was this issue of fatigue. I think it's a common point of differentiation for a physician. When is fatigue tiredness versus fatigue sleepiness? A point brought up in your case is that even though she tries to rest in the afternoon, she actually rarely falls asleep, so raising some issues about the fatigue tiredness situation as opposed to strictly a profound sleepiness. Any thoughts in terms of that, sort of the fatigue sleepiness issue in this patient or in any patient? DAVID NEUBAUER, MD: Sure. That's often a challenge, and it's a really important issue to address. So often patients come in complaining of being so tired. Of course, there are a lot of things that can do that. We do try to differentiate the degree to which is it fatigue as opposed to sleepiness, and so exploring those questions about how sleepy people feel, how much they may feel that they're falling asleep during activities perhaps reading or watching television. That's certainly a clue about the sleepiness end of the spectrum. On the other hand, some people simply may be fatigued and "tired" because of anemia, for instance, some other medical issues that may be occurring, chronic fatigue syndrome, for instance. CHRISTOPHER EARLEY, MD: I mean, you noted in the history that she has mild anemia, so that's sort of one of my thoughts was about the fatigue, maybe an element of fatigue was related to the issue of the anemia. Rafael, any comments about your impression on this case? RAFAEL PELAYO, MD: This is not an uncommon situation. This lady is 72-years-old. She's been sleeping poorly for about 20 years, so perhaps the onset of her sleep difficulties was around the time of menopause, when women typically will have difficulty sleeping. Once the poor sleep develops around that time in their life, if they don't address their sleep issues, they tend to gradually snowball. Then Dr. Neubauer mentioned that her sleep got worse around five years ago. She would have been at that point around 67. I was wondering what changed in her life at that time? Did she retire? Did she lose some of her social contacts? She's a widow, so what point did she become a widow? Is it a recent event? Are there any anniversaries coming up within this context? Definitely, there are more things going on with her. But I agree also with what David said. She is now spending about 12 hours a day trying to sleep plus taking some naps. Patients like this ought to sometimes take a step back and say, "Well, at what point were you satisfied with your sleep and what was your sleep schedule then." You can use that as a baseline to figure out where she's at and certainly any kind of chronic conditions that might be affecting this. Is she a widow? Is she a sleeping alone? Or does she have a partner or other people that she lives with? If she lives alone, fear of Alzheimer's would definitely disturb her sleep. She would be worried about losing further her independence. There are a lot of things to get into her history to discuss. But not sleeping well within this context would make sense for her and loratadine and glucovance, because glucovancee prescribing information. 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