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ARTICLE 3 Term and Termination; Remedies 3.1 Term and Termination. This Agreement shall commence on the Effective Date and remain in effect until March 31, [ * ] or until terminated pursuant to this section. 3.2 This Agreement may be terminated upon: a ; mutual written agreement of FHPC and Wholesaler; or b ; breach by FHPC or Wholesaler of any of the terms of this Agreement that is not cured within thirty 30 ; days of written notification thereof by the non-breaching party; or c ; sixty 60 ; days' prior written notice of termination without cause by FHPC or Wholesaler; or d ; the institution whether voluntarily or involuntarily ; of bankruptcy, insolvency, liquidation or similar proceedings by or against FHPC or Wholesaler, or the assignment of FHPC's or Wholesaler's assets for the benefit of creditors. 3.3. Remedies. In the event Wholesaler breaches any of the terms or conditions of this Agreement, Wholesaler shall immediately forfeit to FHPC without a right of setoff, any pending and future rights to purchase Eligible Product pursuant to Section 2.5. The parties agree that the foregoing remedy is fair and equitable, does not constitute an unfair penalty, and is in addition to, and shall not limit, all other rights and remedies available to FHPC. 3.4 Waiver of Damages. Neither party shall be liable to the other party for consequential, incidental, or special damages. ARTICLE 4 Miscellaneous 4.1. Nature of Relationship. The relationship between FHPC and Wholesaler is that of buyer-seller, and no agency, franchise, partnership, joint venture or other relationship shall be construed to exist between the parties. Nothing contained in this Agreement shall be construed as giving Wholesaler any exclusive rights as a wholesaler of Products, whether in any territory or with respect to any class of customers for Products. FHPC reserves the right to appoint additional wholesalers and to sell directly to customers, including without limitation, the U.S. Government including any agencies, departments or services thereof ; , qualifying tax-supported and non-profit institutions, mail service and other retail providers, and such other accounts as FHPC deems appropriate. 4.2. Confidentiality. During the term of this Agreement, each party, its respective agents, employees and representatives collectively, the "Receiving Party" ; may receive or have access to confidential materials and information of the other party the "Disclosing Party" ; . All such materials and information including, but not limited to the terms of this Agreement, Products information, operations, methods, strategies, formulas, price lists, discount programs, incentives, rebates, records of unit movement for Products, shipping and warehousing, and confidential proprietary information from third parties ; , are collectively referred to herein as "Confidential Information" and constitute the property of the Disclosing Party. During the term hereof and for a period of seven 7 ; years thereafter the Receiving Party shall not use or disclose to third persons any such Confidential Information without the Disclosing Party's prior written consent. Wholesaler shall limit disclosure such Confidential Information within Wholesaler's organization to those persons who need to know such information in order to perform the services hereunder except for disclosure to Customers of discounts and other terms as required by applicable federal, state or local laws and regulations ; . Notwithstanding anything to the contrary in this section, the Receiving Party shall have no liability to the Disclosing Party for the use or disclosure of 1 ; such information as required by applicable law or regulation, provided that the Receiving Party shall give the 5.
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SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-K [X] ANNUAL REPORT PURSUANT TO SECTION 13 OR 15 THE SECURITIES EXCHANGE ACT OF 1934 [FEE REQUIRED] FOR THE FISCAL YEAR ENDED DECEMBER 31, 1994 Commission File Number 1-1136 BRISTOL-MYERS SQUIBB COMPANY Exact name of registrant as specified in its charter ; Delaware State or other jurisdiction of incorporation or organization ; 22-079-0350 IRS Employer Identification No.
Methotrexate is a structural analogue of folic acid. Several controlled trials show that given IM 25mg week, it is effective in inducing remission for patients with steroiddependent and steroid-refractory CD. It is also effective in maintaining remission in patients who are initially responsive, and previous failure on azathioprine 6-mercaptopurine does not preclude a successful response to methotrexate. Presently there are no controlled trials that determine the efficacy of oral methotrexate. Low-dose methotrexate is usually well tolerated, with.
In 2003 only 22 true herb-drug interactions identified with substantial evidence from the world's medical literature [ 1 person, not just an animal study, or suggestion].
AMP and dipyridamole produced an inhibitory effect on platelet aggregation induced by ADP, adrenalin and collagen. When these drugs were given separately in the same doses, they did not induce any effect on platelet aggregation. These data suggest the existence in vivo of a relationship between inhibition of platelet aggregation induced by many drugs and their ability to enhance the intracellular cyclic AMP levels. In a paper by Dr. G. G. Neri Serneri and associates University of Sassari, Sassari, Italy ; entitled "Platelet Function and Turnover in Subjects With Cerebral Vascular Disorders, " the authors studied platelet survival by the use of 32P-DFP, and platelet and fibrinogen turnover together were investigated with the 75Se-seleniomethionine. In subjects with cerebrovascular disorders an increase of platelets was noted and a statistically significant decrease of platelet turnover evaluated by 32P-DFP was observed together with a more rapid catabolism of fibrinogen and a shorter platelet half-life compared with agematched controls. The paper entitled "High Blood Pressure and Platelet Aggregation in the Pathogenesis of Cerebrovascular Disease" was presented by Dr. S. Lentini Rome, Italy ; , who correlated hypertension with increased platelet aggregation in patients with cerebrovascular disease. Dr. G. Kauchtschischvili and colleagues University of Pavia, Pavia, Italy ; , in their paper "Smoking: Cerebrovascular Diseases and Platelet Functions, " showed that in young subjects there was a significant increase of platelet aggregation and platelet adhesiveness, whereas in old patients with cerebrovascular disease platelet response to smoking test was less evident. In a paper by Drs. J. S. Meyer and K. M. A. Welch Baylor College of Medicine, Houston, Texas ; entitled "Contribution of Platelet Aggregation and Serotonin Release to Progressive Cerebral Infarction, " the authors discussed the fact that serotonin release from platelets results in constriction of the collateral cerebral vessels. This in turn may lead to further aggregation of platelets with the "no reflow" phenomenon. Conditions contributing to the "no reflow" phenomenon include intraluminal aggregation of blood elements, swelling of perivascular astrocytes due to edema formation with vascular compression and vasospasm, all of which may be initiated by platelet aggregation. Measurements of cerebral arteriovenous differences for whole blood serotonin in baboons revealed an initial release of serotonin from ischemic brain into cerebral venous blood following bilateral vertebral artery occlusion. However, this was brief and was followed 30 to 60 minutes after release of temporary total cerebral ischemia by a markedly increased positive cerebral arteriovenous difference i.e., uptake of serotonin by the brain ; . The results suggest that after near total arrest of cerebral circulation.
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Sequencing of the genomes of S. mansoni and S. japonicum is nearing completion and there is now a need for full annotation of the genomes. The S. haematobium genome also requires sequencing, and later the genome of Oncomelania the S. japonicum intermediate snail host ; . These tasks plus the sequencing of other schistosome strains such as the Philippine strain of S. japonicum ; will allow studies on comparative genomics. As annotation of the genomes is being carried out, the nomenclature in relation to transcriptome and proteome libraries should be harmonized, and post-genomics tools such as microarrays and proteomics applied to identify stage-specific antigens or pathways that can be targeted for development of vaccines, drugs and diagnostics. Resources, e.g. microarrays representing the complete genome for each schistosome species, and combined host parasite microarrays to study host parasite interactions, should be developed and standardized and made available for the whole schistosomiasis community. Other worthy goals are to identify host alleles that aggravate or reduce infection intensity or morbidity and resistance, and evaluate their mechanisms of action. The genomics and post-genomics tools now available can also be used to study the basic biology of schistosomes and to produce immortalized schistosome cell lines for screening for new vaccine antigens and drug targets and methylcellulose.
1. Meyers, P.A., Heller, G., Healey, J., Huvos, A., Lane, J., Marcove, R., Applewhite, A., Vlamis, V. and Rosen, G. 1992 ; Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial SloanKettering experience. J. Clin. Oncol., 10, 515. 2. Bramwell, V.H, Burgers, M., Sneath, R. et al. 1992 ; A comparision of two short intensive adjuvant chemotherapy regimens in operable osteosarcima of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J. Clin. Oncol., 10, 15791591. 3. Patel, S.J., Lynch, J.W. Jr, Jhonson, T., Carroll, R.R., Schumacher, C., Spanier, S. and Scarborough, M. 2002 ; Dose-intense ifosfamide doxorubicin cisplatin based chemotherapy for osteosarcoma in adults. Am. J. Clin. Oncol., 25, 489495. 4. Zalupski, M.M., Rankin, C., Ryan, J.R., Lucas, D.R., Muler, J., Lanier, K.S., Budd, G.T., Biermann, J.S., Meyers, F.J. and Antman, K. 2004 ; Adjuvant therapy of osteosarcoma- A phase a trial: Southwest Oncology Group study 9139. Cancer, 100, 818825. 5. Marina, N.M., Pratt, C.B., Rao, B.N., Shema, S.J. and Meyer, W.H. 1992 ; Improved prognosis of children with osteosarcoma metastatic to the lung s ; at the time of diagnosis. Cancer, 70, 27222727. 6. Voute, P.A., Souhami, R.L., Nooij, M. et al. 1999 ; A phase a study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma. European Osteosarcoma Intergroup EOI ; . Ann. Oncol., 10, 12111218. 7. Ozaki, T., Flege, S., Kevric, M. et al. 2003 ; Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J. Clin. Oncol., 21, 334341. 8. Bacci, G., Briccoli, A., Rocca, M. et al. 2003 ; Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann. Oncol., 14, 11261134. 9. Patel, S.R., Papadopolous, N., Raymond, A.K., Donato, M., Seong, C.M., Yasko, A.W., Lewis, V.O., Lin, P.P., Champlin, R. and Benjamin, R.S. 2004 ; A phase a study of cisplatin, doxorubicin and ifosfamide with peripheral blood stem cell support in patients with skeletal osteosarcoma and variant bone tumors with a poor prognosis. Cancer, 101, 156163. 10. Walczak, H., Miller, R.E., Ariail, K. et al. 1999 ; Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med., 5, 157163. 11. Ashkenazi, A., Pai, R.C., Fong, S. et al. 1999 ; Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest., 104, 155162. 12. Pan, G., Ni, J., Wei, Y.F., Yu, G., Gentz, R. and Dixit, V.M. 1997 ; An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science, 277, 815818. 13. Sheridan, J.P., Marsters, S.A., Pitti, R.M. et al. 1997 ; Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science, 277, 818821. 14. Wu, G.S., Burns, T.F., McDonald, E.R. III et al. 1997 ; KILLER DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat. Genet., 17, 141143. 15. LeBlanc, H.N. and Ashkenazi, A. 2003 ; Apo2L TRAIL and its death and decoy receptors. Cell Death Differ., 10, 6675. 16. Wu, G.S., Burns, T.F., McDonald, E.R. III, Meng, R.D., Kao, G., Muschel, R., Yen, T. and El-Deiry, W.S. 1999 ; Induction of the TRAIL receptor KILLER DR5 in p53-dependent apoptosis but not growth arrest. Oncogene, 18, 64116418. 17. Takimoto, R. and El-Deiry, W.S. 2000 ; Wild-type p53 transactivates the KILLER DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene, 19, 17351743. 18. Wang, S. and El-Deiry, W.S. 2004 ; Inducible silencing of KILLER DR5 in vivopromotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res, 64, 66666672. 19. Zhang, Y., Talalay, P., Cho, C.G. and Posner, G.H. 1992 ; A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc. Natl Acad. Sci. USA, 89, 23992403. 20. Zhang, Y., Kensler, T.W., Cho, C.G., Posner, G.H. and Talalay, P. 1994 ; Anticarcinogenic activities of sulforaphane and structurally related syn-thetic norbornyl isothiocyanates. Proc. Natl Acad. Sci. USA, 91, 31473150. 21. Fahey, J.W., Zhang, Y. and Talalay, P. 1997 ; Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl Acad. Sci. USA., 94, 1036710372.
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Of their hospital's reputation were measured using a 5-point evaluation rating scale poor, fair, good, very good, excellent ; questionnaire, on which discharged patients gave a score for each of 33 items relevant to specific aspects of their care while in hospital. When compared with normal distribution, the distribution of values from the scales is highly acceptable, as confirmed by Ross et al., although the scale distribution was slightly skewed toward the positive [24]. According to Ware and Hays, this scale format yields a mean score closer to the midpoint of the scale's range i.e. a lower score ; , together with a greater variability of responses, than a 6choice scale [17]. The 33 items were analyzed individually to identify specific aspects of patient satisfaction that affect overall satisfaction relative to different LOS. To reduce recall bias and blank responses as much as possible, we used an ordinal scale to determine LOS. A number of studies on patient satisfaction have been conducted in North America and Europe, where the average LOS is 1 week [1]. Average LOS in Japanese hospitals, excluding departments of psychiatry and other special chronic care units, is reported in official government statistics to be 32.8 days [16]. Therefore, to make our study more useful for OECD cross-country comparisons, we divided our respondents into three groups on the basis of LOS: group 1 comprised respondents who had been hospital in-patients for 1 week; group 2 respondents who had been hospitalized for between 1 week and 1 month; and group 3 respondents who had been hospitalized for 1 month.
Methotrexate as anticancer
Basal levels. In the other pancreatic tumor cell line PANC-1 ; , the cell surface es-NT content increased by a factor of 1.6 over basal levels when the cells were pretreated with 30 M 5-FU but was unaffected by raltitrexed pretreatment Table 2 ; . When pretreated with 100 M 5-FU, the PANC-1 cells did exhibit increased cell kill as compared with gemcitabine monotherapy but did not show a significant increase in cell surface es-NT. All of these increases, although small in magnitude, were found to be statistically significant P 0.05, t test ; when compared with basal levels. These concentrations of 5-FU and raltitrexed were analyzed for increased es-NT content because the cytotoxic effects seen during their use in combination studies showed increased cell kill over single-agent gemcitabine administration. This evidence lends support to our hypothesis that an increase in cell surface es-NTs can positively modulate the in vitro cytotoxicity to gemcitabine in the pancreatic tumor cell lines tested. From the viewpoint of gemcitabine resistance, these findings also lend support to the assumption that decreased amounts of cell surface es-NTs lead to increased resistance to the cytotoxic effects of gemcitabine. The relevance of NT to cancer treatment is an area that is rapidly expanding. There exist two aspects of nucleoside transport as it relates to chemotherapy: a ; reduced transporter expression may be associated with resistance to treatment with nucleoside analogue agents such as 1 D-arabinofuranosylcytosine, 2-chlorodeoxyadenosine, and gemcitabine; and b ; increased cellular salvage capacity for preformed nucleosides from the extracellular fluid is believed to confer resistance to drugs of the antimetabolite class such as methotrexate and 5-FU, which inhibit the de novo process of DNA synthesis. This second aspect can be exploited by combining TS inhibitors with nucleoside analogues. We have shown that gemcitabine cytotox and methysergide.
Product sales for the year ended June 30, 2005 decreased as compared to the prior year primarily due to the expected decline in sales of our distributed version of Ciprofloxacin, as discussed in detail below. Partially offsetting the decrease in Ciprofloxacin sales was a significant increase in sales of our proprietary products.
This work was supported by U.S. Public Health Service Grants DA 09094 to K.A.B. and S.M. ; and GM 58652 to W.P.C and metolazone.
There are many ideas for the further extension and application of the WANDA Workbench. Primary we are envisaging its usage in forensic case work. We expect a huge potential for research and development in the field of forensic handwriting analysis and writer identification. Particularly, the distributed client server architecture allows for joining and sharing collected handwriting data, domain-specific knowledge, and implemented software routines. In the near future, we foresee adaptations and extensions of the data model and its corresponding modeling language WandaXML according to reviews by forensic handwriting experts as well as by new demands arising with upcoming investigation and analysis objectives. It is understood that those objectives will also result in the integration of further client and server plug-ins. Besides representing existing practices in forensic data analysis in a standard way, WANDA can facilitate experimenting with new ideas. The framework and data format will be particularly useful for research and development since it will allow researchers to parse and annotate large bodies of data, partially manually, partially automatically. Such data will lend themselves to statistical data analysis to automate writer identification, extract new features of interest, infer new correlation between handwriting attributes, and improve handwriting recognition. The existence of publicly available data formatted in a standard way will stimulate research for forensic applications. We foresee the possibility of organizing benchmarks based on such data. A standard data format also facilitates and stimulates data exchange. We anticipate that their will be a growing body of data incorporating contributions of many institutions. Moreover, we are thinking of further improvements of the WANDA Workbench itself, as for example providing easy-to-use administration tools with graphical user interfaces and wizards. Another point is extending the workbench to customizable central views. It should be possible that developers can implement and integrate their own central views. This is the final step for allowing such called domain theme were the WANDA workbench can be set up to an application domain by using a dedicated data viewer e.g. video player with corresponding client and server plug-ins as for example for video processing.
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310 ; Seror P. Frequency of neurogenic thoracic outlet syndrome in patients with definite carpal tunnel syndrome: an electrophysiological evaluation in 100 women. Clin.Neurophysiol. 2005 Feb; 116 2 ; : 259-63. 311 ; Sesto ME, Radwin RG, Salvi FJ. Functional deficits in carpal tunnel syndrome. Am.J.Ind.Med. 2003 Aug; 44 2 ; : 133-40. 312 ; Sevim S, Dogu O, Camdeviren H, Kaleagasi H, Aral M, Arslan E, Milcan A. Long-term effectiveness of steroid injections and splinting in mild and moderate carpal tunnel syndrome. Neurol i. 2004 Jun; 25 2 ; : 48-52. 313 ; Seyfert S, Boegner F, Hamm B, Kleindienst A, Klatt C. The value of magnetic resonance imaging in carpal tunnel syndrome. J.Neurol. 1994 Dec; 242 1 ; : 41-6. 314 ; Sharma KR, Rotta F, Romano J, Ayyar DR. Early diagnosis of carpal tunnel syndrome: comparison of digit 1 with wrist and distoproximal ratio. Neurol.Clin.Neurophysiol. 2001; 2 ; : 2-10. 315 ; Sharma V, Wilder-Smith EP. Self-administered hand symptom diagram for carpal tunnel syndrome diagnosis. J.Hand Surg.[Br.] 2004 Dec; 29 6 ; : 571-4. 316 ; Sheean GL, Houser MK, Murray NM. Lumbrical-interosseous latency comparison in the diagnosis of carpal tunnel syndrome. 1995 Dec; 97 6 ; : 285-9. 317 ; Shih YC. Effect of a splint on measures of sustained grip exertion under different forearm and wrist postures. Appl.Ergon. 2005 May; 36 3 ; : 293-9. 318 ; Shivde AJ, Dreizin I, Fisher MA. The carpal tunnel syndrome. A clinical electrodiagnostic analysis. Electromyogr.Clin.Neurophysiol. 1981 Feb; 21 23 ; : 143-53. 319 ; Shurr DG, Blair WF, Bassett G. Electromyographic changes after carpal tunnel release. J.Hand Surg.[Am.] 1986 Nov; 11 6 ; : 876-80. 320 ; Simovic D, Weinberg DH. The median nerve terminal latency index in carpal tunnel syndrome: a clinical case selection study. Muscle Nerve 1999 May; 22 5 ; : 573-7. 321 ; Singh I, Khoo KM, Krishnamoorthy S. The carpal tunnel syndrome: clinical evaluation and results of surgical decompression. Ann.Acad.Med.Singapore 1994 Jan; 23 1 ; : 94-7. 322 ; Singh R, Gamble G, Cundy T. Lifetime risk of symptomatic carpal tunnel syndrome in Type 1 diabetes. Diabet.Med. 2005 May; 22 5 ; : 625-30. 323 ; Slattery PG. Endoscopic carpal tunnel release. Use of the modified Chow technique in 215 cases. Med.J.Aust. 1994 Feb 7; 160 3 ; : 104-7 and micafungin.
To answer this question, scientists found and analysed 2 high quality studies testing 100 people who had scleroderma. People received either injections or pills of methotrexate or a placebo or sugar pill and were monitored for 6 months or a year. These studies provide the best evidence we have today.
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