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Regulating Ito between the quiescent and proliferating states. First, a posttranslational modification by kinases could regulate K channel activity 26, 42, 63 ; . However, various kinases tyrosine kinases, phosphatidylinositol 3-kinase, and protein kinase A and C ; seem unable to regulate Ito in GH3 cells personal observations, data not shown ; . Second, various auxiliary subunits Kv , KCHaP, and Kchip ; could heteromerize with Kv -subunits, thereby modifying the amplitude, gating, and or expression of K currents 31, 43, 65 ; . The precise nature of the link between K channel activity and cell cycle progression has not yet been elucidated. The main mechanism evoked to account for the role of K channels in the proliferation of nonexcitable cells is the regulation of the membrane potential. Membrane hyperpolarization resulting from increased K channel activity would interfere directly with mitogenic activity by increasing the driving force for electrogenic entry of Ca2 ions, a condition necessary for cell cycle progression 3, 61 ; . Ito is involved in the excitability of myocytes 19 ; and neurons 11 ; , in which it modulates interspike latency and action potential repolarization 22, 28 ; . A modification in cell excitability caused by variations in Ito amplitude could, therefore, constitute a messenger for cell growth 38, 66 ; . Our data show that the electrophysiological parameters, including membrane resting potential, AP frequency, and AP amplitude, were similar, irrespective of the proliferation state of the cells. It is particularly interesting that complete inhibition of Ito by 0.5 mM 4-AP had no significant effect on membrane excitability, because the acceleration of AP firing rate at concentrations 0.5 mM 4-AP probably results from the inhibition of 4-AP-sensitive K currents other than Ito 23 ; . Ito is thus unlikely to play a significant, if any, role in regulating GH3 cell excitability, and the link between Ito expression and cell cycle progression is still open to question. Besides the well-known role of Ito and, more particularly, of Kv1.4 in cell excitability, it has been recently described that this channel could play a role in the proliferation process of glial cells 1, 18 ; . An Ito-like current has been described in differentiated astrocytes but not in glioma cells. The disappearance of this current seems to be an early feature accompanying the transformation of a normal astrocyte into a tumor glial cell 4 ; . The Kv1.4 channel subunit has also been found to be upregulated in oligodendrocytes induced to proliferate after chronic spinal cord injury 18 ; . However, the action mechanism of Kv1.4 in these proliferation processes could not be assessed because no selective pharmacological agents are available. In conclusion, we show here in a pituitary cell model that the expression of the transient outward K current is cell cycle dependent. We found that upregulation of Ito density in quiescent cells was probably due to a selective increase in Kv1.4 channel subunit expression at the protein level. Moreover, we demonstrate that the link between Ito and cell proliferation is apparently not mediated by variations in cell excitability.
INHIBITION OF JNK MAPK ENHANCES INTESTINAL BARRIER PROPERTIES OF T84 CELLS. L.E.M. Willemsen, T. Wijnhoven, S.J.H. van Deventer1 and E.A.F. van Tol. Numico Research B.V., Wageningen; 1Dept. of Exp. Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. J. Physiol. Biochem., 60 2 ; , 182, 2004. Background and aims: Increased intestinal permeability is thought to play an important role in the pathogenesis of Crohn's disease. Inflammatory cytokines that are found to be elevated in Crohn's disease, e.g. IFN- are often studied for their capacities to cause barrier disruption. Little is known about the role of signaling molecules, like mitogen activated protein kinases MAPK ; , in regulation of barrier integrity and particularly the barrier disruption following cytokine stimulation. We investigated the importance of the phosphoinositide-3kinase PI3K ; , MAPK, and protein kinase C PKC ; pathways in regulation of epithelial barrier integrity. Methods: T84 monolayers were incubated with selective inhibitors for PI3K LY294002, 10 M ; , MAPK ERK PD98095, 5 M ; , p38 SB203580, 1 M ; , JNK SP600125, 20 M , and PKC rottlerin, 5 M ; or the flavonol quercetin 25 g ml ; the presence or absence of IFN- 100 U ml ; . Both trans-epithelial resistance TER ; and 4kDa-FITC-dextran FD4 ; fluxes were measured to evaluate barrier integrity. In addition, STAT1 phosphorylation in T84 cells was determined by Western blotting. Results: T84 monolayers developed adequate barrier integrity with high basal resistance and low dextran fluxes. These barrier properties were dramatically affected after incubation with IFN- for 72h, resulting in reduced resistance 1484 86 vs 790 44 ohm.cm2, p 0.002 ; and increased FD4 fluxes 20 11 vs 520 60 pmol cm2 h ; . Inhibition of JNK MAPK, dramatically enhanced basal resistance and reduced permeability caused by IFN- incubation for more than 50% p 0.02 ; . The flavonol quercetin, similar to the PI3K inhibitor ameliorated IFN- mediated barrier disruption and inhibited IFN- induced STAT1 phosphorylation n 3 ; . contrast, PKC inhibition resulted in a marginal reduction of basal resistance and aggravated IFN- mediated barrier disruption. Conclusions: JNK MAPK may play an essential role in the regulation of epithelial barrier function and is an interesting therapeutic target in diseases with underlying intestinal barrier defects. Natural food components such as quercetin, may ameliorate IFN- mediated barrier disruption and diamicron.
A 51 year-old female, known diabetic and hypertensive, experienced sudden pricking pain over the right eye. This was shortly followed by blurring of vision and central scotoma, accompanied by slight redness of eye and dull aching occipital headache. Review of systems and family history were unremarkable. She denied any intake of drugs except for her diabetic medications, and had a smoking history of 4.5 packyears. External eye examination was essentially normal. Visual acuity was CF at 2ft on the right eye and 20 100 on the left eye not improved by refraction. Amsler's grid was positive for both eyes. Fluorescein angiography showed Optic Disc Edema OD. 11: 20 Bilateral optic disc edema in an otherwise healthy 16 yearold male: A case report Emiliano M. BERNARDO III, MD, Ronald Antonio N. Reyna, MD, Jesus M. Tamesis, Jr., MD.
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Cancer treatment-related cachexia determine the efficacy of megestrol in preventing further weight loss in patients who do not respond to cyproheptadine determine how these drugs affect body protein and fat levels in these patients Study design: Randomized, multicenter phase III study Eligibility: Children, 220 years of age, with newly diagnosed or relapsed cancer of any type, including brain tumors cachexia with weight loss presumed secondary to cancer or cancer-related treatment, defined as one or more of the following: documented weight loss of 5% within 1 month of study entry; drop in growth rate 2 or more percentile ranks on standard growth charts; weight for height 10th percentile no hormonesensitive tumors ie, meningiomas, breast cancer, ovarian cancer, or endometrial cancer ; life expectancy 8 weeks no thromboembolic disease no congestive heart failure no recurrent or persistent hypertension ie, blood pressure values 20% above normal ; no type I or II neurofibromatosis no glaucoma no chronic persistent asthma no gastrointestinal or genitourinary obstruction no peripheral edema no more than 8 weeks since prior chemotherapy or radiotherapy no concurrent corticosteroids concurrent tumor-debulking surgery, limb-sparing surgery, or amputation allowed 3 weeks since prior cyproheptadine or megestrol 3 weeks since prior dronabinol or other appetite-stimulating medications 1 week since prior parenteral nutrition or tube feedings no other concurrent appetite-stimulating medications no concurrent parenteral nutrition or tube feedings no concurrent monoamine oxidase inhibitors concurrent active or palliative therapy allowed Sponsors: Community Clinical Oncology ProgramH. Lee Moffitt Research VOLUME 1, NUMBER 4 and dimenhydrinate.
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No difference in final general improvement rating or general usefulness rating among the three groups.The effectiveness and usefulness in the treatment of atopic eczema were considered similar for the three groups.There was a significant difference in overall safety rating between the 4 mg day and 2 mg day groups.The safety rating was higher in the 2 mg day group than in the 4 mg day group.The overall safety rating showed no significant difference between the 4 mg day and ketotifen groups or the 2 mg day and ketotifen groups This study suggests that hydroxyzine is more effective than cyproheptadine for the management of pruritus associated with atopic eczema in children Loratadine may be tried as an adjuvant therapy in the management of severe and moderate atopic eczema, in patients complaining of pruritus The results of this preliminary study suggest that cetirizine can effectively control pruritus and other cutaneous symptoms in children suffering from atopic eczema without noticeable adverse effects Loratadine demonstrates a significant antipruritic effect in atopic eczema.
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Resulted from a reduction in the affinity of cyproheptadine for the 5-HTapAC receptor i n high ionic strength physiological saline, as we observed occurs with methiothepin and LSD. Thus, a residual increase in cAMP levels that persists with cyproheptadine may have mediated the 5-HT-induced increase in excitability previously seen in the presence of this antagonist Mercer et al. 1991 ; . Consistent with the possibility that cyproheptadine at 200 M is blocking the AC-coupled 5-HT receptor, though only partially, we observed that cyproheptadine was effective in blocking the excitability increase initiated by a five-fold lower concentration of 5-HT than tested in the studies of Mercer et al. 1991 ; Fig. 11A ; . Also consistent with the possibility that 200 M cyproheptadine only partially blocks the AC-coupled 5-HT receptor in physiological saline, we observed that the efficacy of cyproheptadine in blocking 5-HT modulation of SN excitability depended on the precise test conditions Fig. 11A, B ; . Differential inhibition of increased excitability depending o n.
Member of an ethnic group with a higher than normal rate of type 2 diabetes Glycosuria at the first prenatal visit Polycystic ovary syndrome A family history of diabetes, especially in first degree relatives Prepregnancy weight 110 percent of ideal body weight or significant weight gain in early adulthood Age greater than 25 years Previous delivery of a baby greater than 9 pounds 4.1 kg ; Personal history of abnormal glucose tolerance Previous unexplained perinatal loss or birth of a malformed child Maternal birth weight greater than 9 pounds 4.1 kg ; or less than 6 pounds 2.7 kg ; Current use of glucocorticoids Personal birth weight of over 9 lbs and enalapril.
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CYMBALTA cyotic. 53 cyproheptadine.hcl CYSTADANE CYSTAGON cysteamine.bitartrate CYSTOSPAZ * . See.hyoscyamine, e.hyospaz CYTADREN cytarabine . cytarabine.liposome CYTOMEL CYTOSAR-U * . See.cytarabine . CYTOTEC * . See soprostol . CYTOVENE CYTOVENE * . See.ganciclovir p . CYTOXAN * . See.cyclophosphamide cytra-2 . cytra-3 . cytra-k . cytra.k.crystals and estradiol.
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1. Bullingham RES, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429 Lipsky JJ. Mycophenolate mofetil. Lancet 1996; 348: 13579. Shaw LM, Nicholls A, Hale M, Armstrong VW, Oellerich M, Yatscoff R, et al. Therapeutic monitoring of mycophenolic acid: a consensus panel report. Clin Biochem 1998; 5: 31722. Shipkova M, Armstrong VW, Wieland E, Niedmann PD, Schutz E, Brenner-Weiss G, et al. Identification of glucoside and carboxyllinked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Br J Pharmacol 1999; 126: 1075 Shipkova M, Wieland E, Braun F, Grone H-J, Schutz E, Armstrong VW, et al. Extrahepatic glucuronidation of mycophenolic acid in human gut and kidney [Abstract]. Ther Drug Monit 1999; 21: 441. Schutz E, Shipkova M, Armstrong VW, Wieland E, Oellerich M. Identification of a pharmacologically active metabolite of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Clin Chem 1999; 45: 419 Wieland E, Shipkova M, Schutz E, Wiese C, Bonitz U, Niedmann PD, et al. The acyl glucuronide of the immunosuppressant mycophenolic acid induces release of proinflammatory cytokines and TNF-alpha mRNA expression [Abstract]. Clin Chem 1999; 45 Suppl 6 ; : A127. 8. Spahn-Langguth H, Benet LZ. Acyl glucuronides revised: is the glucuronidation process a toxification as well as a detoxification? Drug Metab Rev 1992; 24: 5 Faed EM. Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drug. Drug Metab Rev 1984; 15: 1213 Shipkova M, Niedmann PD, Armstrong VW, Schutz E, Wieland E, Oellerich M. Simultaneous determination of mycophenolic acid and its glucuronide in human plasma using a simple high.
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As noted in our last newsletter, we were disappointed by this year's Annual Report of the House Appropriations Committee, because it included only 1 of the 9 requests of the Fragile X community: support for "promoting early intervention through developmental screening, " "developing a Fragile X public health program to expand surveillance and epidemiological study of Fragile X, " and providing "patient and provider outreach on Fragile X." We wanted this, of course, but we were disappointed that our 8 basic research requests which were agreed upon and urged by FRAXA, the National Fragile X Foundation, and Conquer Fragile X were ignored by the House Subcommittee. The good news is that the Senate Appropriations Committee Report included all 9 of our requests directing the Department of Health and Human Services which includes the Health Resources and Services Administration, the National Institutes of Health, and the Center for Disease Control and Prevention ; . Unless specifically overruled by the Conference Committee Report which won't happen ; , the Senate language will govern next year's allocations. Fragile X was mentioned in the Senate Report 34 times a record! Our champions in the Senate as has been the case since 1999 were Senators Chuck Hagel and John Edwards. Their bipartisan "Dear Colleague" letter persuaded 22 of their fellow.
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