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Following the 5th International Endothelin Conference in Kyoto last year, which was focused on basic science, the second `Symposium on Endothelin Antagonism' organized by T. F. Luscher, MD, provided a veritable windfall to clinicians. Throughout its proceedings, the cardiovascular system and the kidney were the two main areas of interest. Here, we will summarize the new observations. In his introduction, Luscher pointed to the multiple areas of interest in which endothelin antagonists Et antagonists; endothelin receptor antagonists to be precise ; appear to be effective. His list included the following disturbances: congestive cardiac failure, coronary artery disease, cardiac arrhythmia, pulmonary hypertension, arteriosclerosis, hypertension essential and renal ; , migraine, Raynaud's phenomenon, ischaemic renal failure, cerebral bleeding, restenosis after angioplasty, cardiac transplantation and many others. Luscher and T. Opgenorth, Abbott Park, showed a list of currently available endothelin antagonists under pre-clinical or clinical study summarized in Figure 1 ; . Most of these agents are non-peptidic, i.e. they are suitable for the oral route of application. In terms of pharmacology, D. Webb, Edinburgh, described the present state of knowledge concerning the endothelin receptors which are termed Et-A receptor and Et-B receptor Figure 2 ; . M. Yanagisawa, Dallas, remarked in the discussion that there is now a third endothelin receptor which has been cloned from birds. He said this work is in press in the Proceedings of the National Academy of Sciences of the USA. The cloned receptor so far had not been identified in humans. ; With respect to the clinical significance of endothelin antagonists possessing different specificity Figure 1 ; , there were two somewhat opposing schools of thought: at this time, it is not clear whether the future will belong to the non-specific Et-A B receptor antagonists or to the A-type receptor antagonists. Webb listed the reasons which would favour the use of Et-A receptor antagonists: i ; to counteract Et-A receptor-mediated vasoconstriction; ii ; to counteract Et-A receptor-mediated venoconstriction; iii ; to counteract Et-A receptor-mediated smooth muscle mitogenesis; and iv ; to counteract Et-A receptor-mediated cardiac dysfunction. Webb gave the following reasons for not wanting to block the Et-B receptor as would occur with non-specific Et-A B antagonists ; : i ; to maintain Et-B receptor-mediated NO PGI release; 2 ii ; to maintain Et-B receptor-mediated ECE Etconverting enzyme ; inhibition; iii ; to maintain Et-Bmediated Et-1 clearance; iv ; to maintain NO-mediated inhibition of Et-1 release; v ; to maintain Et-B receptor-mediated natriuresis and diuresis; and vi ; to maintain Et-B receptor-mediated apoptotic survival. M. Clozel, Basel, and R. Wenzel, Essen, indicated, however, that disease states--such as for instance coronary artery disease in humans--may be associated with a preferential increase in the density of Et-B-type receptor in the cardiovascular system possessing vasoconstrictor properties. If such findings were to be substantiated in additional future studies, then the non-specific Et-A B antagonists would be advantageous over the Et-A-selective antagonists, at least in certain circumstances. Opgenorth reported on A192621, a new highly selective oral Et-B receptor antagonist in clinical development. Systemic application of A-192621 caused blood pressure elevation as well as a marked increase in the plasma concentration of endothelin-1 Et-1 ; in experimental animals. The latter observations were in keeping with new findings in the area of basic science research reported by Yanagisawa. Because of the importance of the Et system in embryonic development, which has caused severe and often lethal malformations in `knockout animals' of individual Et system components, Yanagisawa has now generated `rescued Et componentdeficient mice', e.g. `rescued Et-B receptor-deficient mice'. In the latter, the Et-B receptor-deficient state due to a `knocked-out gene' was limited to one system of the organism, e.g. only to the cardiovascular system and the kidney. There are then no serious malformations interfering with studies of these animals throughout their life. In this way, Yanagisawa found that EtB-deficient rescued mice developed hypertension which was of a volume-dependent type. His findings suggested that the Et-B receptor which is known to be present in a high density in the renal medulla contributes significantly to natriuresis and diuresis. Not surprisingly, amiloride completely corrected the renal and haemodynamic changes in Et-B rescued knock-outs, implying that the renal medullary Et-B receptor exerts major effects on the amiloride-sensitive sodium channel of the collecting duct. In another new application of this type of technique, Yanagisawa discussed the `cardiomyocyte-specific Et-1 knock-out mouse', in which the `knocked-out' state of the Et-1 gene was limited to the cardiomyocytes only. In this model, he has not been able to demonstrate cardiac hypertrophy in.
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Starting from the release of the document `PRINCIPLES AND CRITERIA FOR FOREST MANAGEMENT 2 IN THE ATLANTIC FOREST' by the Forest Stewardship Council FSC ; - several participants of the Internet Forum discussed the issue of forest sustainability. Following is the transcribed introduction of the FSC document and the participant's comments. The varied colors help to differentiate the authors. It is substantially accepted that forest resources and their related lands should be managed to supply the social, economical, ecological, cultural, and spiritual needs of present and future generations. The public's growing understanding of forest destruction and degradation has led to consumers demanding that their timber purchases, and other forest products, should not contribute to that destruction, but instead can help to ensure the supply of forest resources for the future. In response to these demands, certification programs now proliferate in the timber trade market, either through third parties or self-certification. The Forest FSC Forest Stewardship Council ; , a council for forest management, is an international entity that approves the certifier organizations, in order to guarantee the authenticity of their declarations. The certification process begins as a voluntary initiative of forest operation owners, with the respective forest management body responsible for that area. They request the services of a certifier organization. The FSC's objective is to guarantee that the management of the world's forests will be environmentally appropriate, socially favorable, and economically feasible. This is done through the establishment of a world pattern of Principles of Forest Management, a considerably recognized and respected methodology. Principles and Criteria for the Forest Management in the Atlantic forest - FSC.
Background aim: A protein molecule is a large and complex physical system with many atoms. At the microscopic level, the laws of quantum mechanics can be used to deduce the interactions but the number of degrees of freedom are far too many for the system to be studied in all its detail. When one attempts to look at the problem in a coarse-grained manner with what one hopes are the essential degrees of freedom, it is very hard to determine what the effective potential energies of interaction are. Nevertheless, proteins fold into a limited number of evolutionary conserved structures [1]. The same fold is able to house many different sequences which have that conformation as their native state and is also employed by nature to perform different biological functions, pointing towards the existence of an underlying simplicity at work in proteins. Methods: We introduce a simple physical model [2] which captures in a minimal way the inherent anisotropy of a chain molecule, the geometrical and energetic constraints placed by the hydrogen bonds and sterics, and hydrophobicity. We model a protein as a chain of identical amino acids, represented by their C atoms, lying along the axis of a selfavoiding flexible tube. We carry out numerical Monte Carlo simulations with pivot and crankshaft moves commonly used in stochastic chain dynamics. Results: In the marginally compact phase which emerges between a swollen and a disordered compact phase, the free-energy landscape for an isolated homopolymer chain is characterized by the presence of relatively few minima which correspond to distinct putative native-state structures of proteins, being tertiary assemblies of helices, hairpins and planar sheets. In the presence of more chains, new minima appear in the free-energy landscape which resemble the basic structures associated with amyloid fibrils. Conclusions: The protein energy landscape is presculpted by general considerations of geometry and symmetry that we have utilized as ingredients in our model. The limited number of folds arises from the geometrical constraints imposed by hydrogen bonds and sterics. A superior fit of a given protein or sequence of amino acids to one of the predetermined folds dictates the choice of the topology of its native-state structure.
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The discussion will first examine the results of studies that have investigated the impact of antenatal care on maternal mortality; secondly, hypothesize from the evidence in the review on the role that each procedure can play in reducing the direct and indirect causes of maternal mortality and morbidity; thirdly, examine the role that actually attending antenatal care could play in reducing maternal mortality and morbidity; and finally, look at the scientific evidence surrounding antenatal care and the problems in obtaining it. The impact of antenatal care on maternal mortality Very few scientific studies have examined the role of antenatal care in reducing maternal mortality. The results of studies investigating the impact of antenatal care are mixed. The work from Zaire found diat antenatal care reduced maternal mortality by 17-fold. The main impact had been a reduction in severe anaemia, cases of obstructed labour, and treatment of medical conditions Royal College of Obstetricians and Gynaecologists 1979 ; . In Vietnam antenatal care was found to reduce maternal mortality by improved nutrition and screening for high risk Swenson et al. 1993 ; . A prospective study in The Gambia Greenwood et al. 1987 ; and a retrospective analysis from Tanzania Moller et al. 1989 ; found no relationship between attendance at antenatal care and maternal mortality. Figures from Lesotho show that although 85% of women attend antenatal care, maternal mortality has not reduced in line with this increase in attendance WHO 1993 ; . Other studies found that maternal mortality was lower in villages receiving community-based maternity services which, included antenatal care. The improvement, however, was attributed to the availability of local midwives Lamb et al. 1984; Fauveau et al. 1991 ; and an efficient referral system Fauveau et al. 1991.
J Fransen, D Uebelhart, G Stucki, T Langenegger, M Seitz and B A Michel for the members of the Swiss Clinical Quality Management in Rheumatoid Arthritis SCQM ; . The ICIDH-2 as a framework for the assessment of functioning and disability in rheumatoid arthritis. Annals of the Rheumatic Diseases and grepafloxacin.
Hematologic 8mg PO IV or Granisetron 1mg PO IV FEC Regimen: - Dexamethasone 20mg PO IV 1. If AGC 1.5 x 109 L, or if PLT 100 x 109 L, HOLD chemotherapy for 1 week. Docetaxel Regimen: 1. If AGC 1.5 x 109 L, or if PLT 100 x 109 L, HOLD Docetaxel dose for 1 week. Renal Failure FEC Regimen: 1. If CrCL 0.2mL sec, OMIT Cyclophosphamide dose. Hepatic Dysfunction FEC Regimen: 1. If T.Bili 26-51umol L or AST 60-180 IU L, give 75% Epirubicin dose. 2. If T.Bili 52-85umol L, or AST 180 IU L, give 50% Epirubicin dose. 3. If T.Bili 85umol L, OMIT Epirubicin. Docetaxel Regimen: 1. If AST or ALT 42 IU L, and if Alk Phos 300 IU L, reduce Docetaxel dose to 75mg m2. 2. If AST or ALT 84 IU L, Alk Phos 720 IU L and T.Bili 18umol L , discontinue Docetaxel. SUGGESTED ACTION.
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Conclusions: We described an evidence-based process of decision making applied to the organisational level of a health intervention. The model produced by this process needs now to be evaluated and monitored in its final phase: the impact on population health. P-161 THE XELOX-EL REGIMEN IS EFFECTIVE AND SAFE REGIMEN IN METASTATIC COLORECTAL CANCER IN ELDERLY PATIENTS 70 YEARS ; : A SINGLE CENTER PHASE II TRIAL Geurs F1, Ponette S1, Ponette J1, Kempeneers I1, Itterbeek P1, Vandenhove J1, Vandesteen O2 & Simmilon A1 1 Sint Mariaziekenhuis, Halle, Belgium; 2Sanofi-aventis, Belgium Introduction: The combination of oxaliplatin and capecitabin chemotherapy regimen XELOX ; , is one of the most active regimens in metastatic colorectal cancer, which does not produce significant neutropenia. This makes it an ideal regimen for elderly patients, especially if, by co-administration of neuroprotective agents like Ca and Mg, the cumulative neuropathy can be avoided. Study design: From Aug 2004 to Feb 2006, 21 patients over 70 years of age with metastatic colorectal cancer were studied in a prospective, phase II single institution trial. 20 21 were first line. Patients received oxaliplatin 100 mg m2 d 1, followed by capecitabin 2g m2 bid for 13 days q3w. In addition, 1g of CaC03 + 1gMgS04 were administered before and after oxaliplatin. `XELOX-EL' ; Granisetron and steroids were given as antiemetics. Treatment was given for a maximum of ten cycles or until disease progression. Restaging was performed after 4, 7 and 10 courses RECIST ; . Results: A total of 21 patients have been enrolled so far: 10 male and 11 female, median age 78 range 70-86 ; . A total of 136 doses have been administered median 7; range and guaifenesin
Some states and localities allow submission of the FPCA by email. Voters must be sure their jurisdiction accepts emailed FPCAs before sending. A by email. Voters must be ForSome states and localities allow submission of the FPCA fillable Portable Document sure mat PDF ; of the acceptsis available online OFPCA ; at fvap.gov. their jurisdiction FPCA emailed FPCAs before sending. A fillable Portable Document ForWhere allowed by state is available online OFPCA ; at fvap.gov. from the local elecmat PDF ; of the FPCA law, the blank absentee ballot will be emailed tion official to the individual's email address as indicated on the absentee ballot request FPCA ; . The citizen should follow all instructions provided by the local election official in marking, executing and returning the ballot. Where allowed by state law, the blank absentee ballot will be emailed from the local elecIf the citizen to the individual's email addresstimeindicated on the absentee ballotthe state tion official determines there is not sufficient as to return the ballot by mail and request allows receiptcitizen should followemail, the voted provided by the local electionemail. The FPCA ; . The of a voted ballot by all instructions ballot may be transmitted via official in State or local election official cannot ballot. an emailed voted ballot unless allowed by state marking, executing and returning the accept law. The citizen should follow the instructions provided by the local election official in marking and executing the ballot.
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Normally, the circulating neutrophil series consists only of band neutrophils and segmented neutrophils, the latter being the most mature type. In stress situations i.e., the "acute phase reaction" ; , earlier forms usually no earlier than myelocytes ; can be seen in the blood. This picture is called a "left shift." The band count has been used as an indicator of acute stress. In practice, band counts tend to be less than reliable due to tremendous interobserver variability, even among seasoned medical technologists, in discriminating bands from segs by microscopy. Other morphologic clues to acute stress may be more helpful: In the acute phase reaction, any of the neutrophil forms may develop deep blue cytoplasmic granules, vacuoles, and vague blue cytoplasmic inclusions called Dhle bodies, which consist of aggregates of ribosomes and endoplasmic reticulum. All of these features are easily seen except possibly the Dhle bodies ; , even by neophytes. The normal range for neutrophil band + seg ; count is 1160 8300 L for blacks, and 1700 8100 L for other groups. Keeping in mind the lower expected low-end value for blacks will save you much time and patients much expense and pain ; over the course of your career. Obesity and cigarette smoking are associated an increased neutrophil count. It is said that for each pack per day of cigarettes smoked, the granulocyte count may be expected to rise by 1000 L. B. Monocytes These large cells are actually more closely related to neutrophils than are the other "granulocytes, " the basophil and eosinophil. Monocytes and neutrophils share the same stem cell. Monocytes are to histiocytes or macrophages ; what Bruce Wayne is to Batman. They are produced by the marrow, circulate for five to eight days, and then enter the tissues where they are mysteriously transformed into histiocytes. Here they serve as the welcome wagon for any outside invaders and are capable of "processing" foreign antigens and "presenting"9 them to the immunocompetent lymphocytes. They are also capable of the more brutal activity of phagocytosis. Unlike neutrophils, histiocytes can usually survive the phagocytosis of microbes. What they trade off is killing power. For instance, mycobacteria can live in histiocytes following phagocytosis ; for years. The normal range for the monocyte count is 200 950 L and guanethidine.
Global warming is an international environmental issue, and the Law Concerning the Promotion of Measures to Cope with Global Warming, the Revised Law Concerning the Rational Use of Energy and other regulations concerning greenhouse gases have been strengthened. In 1993, Shionogi instituted an energy conservation promotion committee in its Manufacturing Division, which uses a large amount of energy. In 1995, energy-saving activities began on a company-wide basis. We consider global warming to be an important issue for Group companies as well, and are working to curb greenhouse gas emissions.
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Participants were seen at least semiannually for blood pressure measurements, treatment dispensing, and end point surveillance. On-site data verification was performed at least annually by the contract research organization. An independent data and safety monitoring board met semiannually to review accumulating data. Confidence intervals CIs ; based on the Lan-DeMets version9 of the O'Brien-Fleming group sequential boundaries were used as guidelines for early termination.10 The data and safety monitoring board met 8 times and recommended continuation of the trial after each meeting. All analyses were performed independently of the sponsor by the statistical center at the Division of Biostatistics at the University of Minnesota. All study investigators and the study sponsor were blinded to all betweentreatment comparisons until completion of end point data collection and review. The sponsor closed the study 2 years earlier than originally planned for commercial reasons. A common calendar date of December 31, 2000, was chosen through which all participants would be followed up. Clinical sites were asked to verify the end point status primary end point and survival status ; of each participant as of this date. In addition, in the United States, vital and guanfacine.
The prophylaxis of postoperative nausea and vomiting. Br J Anaesth 1996; 76: 83540 Liu K, Hsu CC, Chia YY. Effect of dexamethasone on postoperative emesis and pain. Br J Anaesth 1998; 80: 856 Koivuranta MK, Laara E, Ryhanen PT. Antiemetic efficacy of prophylactic ondansetron in laparoscopic cholecystectomy. Anaesthesia 1996; 51: 525 Thune A, Appelgren L, Haglind E. Prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. Eur J Surg 1995; 161: 2658 Mraovic B, Jurioic T, Kogler-Majeric V, Sustic A. Intraperitoneal bupivacaine for analgesia after laparoscopic cholecystectomy. Acta Anaesthesiol Scand 1997; 41: 1936 Naguib M, Bakry AKEI, Khoshim MHB, et al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo. Can J Anaesth 1996; 43: 22631 Fredman B, Jedeikin R, Olsfanger D, Flor P, Gruzman A. Residual pneumoperitoneum: a cause of postoperative pain after laparoscopic cholecystectomy. Anesth Analg 1994; 79: 1524 NIH Consensus Development Panel on Gallstones and Laparoscopic Cholecystectomy. Gallstones and laparoscopic cholecystectomy. JAMA 1993; 269: 101824 Begos DG, Modlin IM. Laparoscopic cholecystectomy: from gimmick to gold standard. J Clin Gastroenterol 1994; 19: 32530.
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[21] 2, 360, 894 [13] A1 [51] Int.Cl. 7C07D 401 06 00 7A61K 31 445 [25] EN [54] ; PIPERIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME [54] DERIVES DE 1-PHENACY-3PHENYL-3PIPERIDYLETHYL ; PIPERIDINE, PROCEDE POUR LEUR OBTENTION ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT [72] DUCOUX, JEAN PHILIPPE, FR [72] EMONDS-ALT, XAVIER, FR [72] PROIETTO, VINCENZO, FR [72] GUEULE, PATRICK, FR [71] SANOFI-SYNTHELABO, FR [85] 2001-07-18 [86] 2000-02-08 PCT FR00 00284 ; [87] 2000-08-17 WO00 47572 ; [30] FR 99 01593 ; 1999-02-10 [30] FR 99 04429 ; 1999-04-07.
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