Search

Objective: Molecular monitoring of treatment response in patients with chronic myelogenous leukemia is performed using the Europe Against Cancer (EAC) qPCR assay using the International Scale (IS). The assay amplifies both e13a2 and e14a2 BCR-ABL1 transcript variants. Observing distinct variant-dependent amplification curves during qPCR, we aimed to determine if this affected quantitation of BCR-ABL1. Methods: We investigated the qPCR efficiency at three Danish diagnostic centers (Zealand University Hospital [ZUH], Aarhus University Hospital [AU], and Rigshospitalet [RH]) on cell lines expressing either the e13a2 or e14a2 BCR-ABL1 transcript variants and compared %IS values from 219 chronic myeloid leukemia patients from the centers with either the e13a2 (n = 113) or e14a2 (n = 106) transcript variants obtained by qPCR with absolute quantitation by droplet digital PCR (ddPCR). Results: Although no significant differences were found in amplification efficiencies of the transcript variants, Bland-Altman analysis of qPCR vs ddPCR values for patient samples revealed a significant average difference in the bias between variants (e3a2/e14a2) of 4.6-, 6.5-, and 1.8-fold for ZUH, AU, and RH, respectively. Furthermore, qPCR %IS values of diagnostic patient samples revealed a significant 4.7-fold difference between the e13a2 and e14a2 variants. Conclusion: Our findings suggest that the EAC qPCR assay may underestimate the e14a2 variant compared to the e13a2 variant.

This paper addresses the relationship between accumulated knowledge and U.S. policy dealing with failed states and terrorism. The central thesis is threefold: (1) that more was known about the possible linkages between failing states and terrorism than appears in pre-9/11 U.S. policies; (2) that since 9/11 some important realignment of knowledge and practice has occurred, but it remains partial and incomplete; and (3) that new knowledge, especially about the policies to sustain and promote legitimate governance, needs to be generated in order to support an effective grand strategy for addressing the threats and challenges of the twenty-first century. The paper recommends such a grand strategy and, in addition to the required new knowledge, a significant reorganization of the U.S. national security policy-making apparatus. International studies curricula appear well suited for contributing to that new knowledge and the practitioners we require.

(2000). Deterrence and competitive strategies: A new look at an old concept. Small Wars & Insurgencies: Vol. 11, Deterrence in the 21st Century, pp. 109-123.

Given the challenges posed by failed and failing states, and the likelihood that such failure will continue well into the new millennium, the need for a strategic approach appears evident. Should we respond? If so, how and with what expectations? Answers to such questions require an underlying set of strategic guidelines. This article contributes to developing that strategy by examining common manifestations of state failure and some possible response objectives. It concludes by arguing that careful and tough analysis must guide our choices about where and when to respond, and how ambitiously we set our objectives.

1H NMR spectroscopy-based metabolic phenotyping was used to identify biomarkers in the plasma of patients with rheumatoid arthritis (RA). Forty-seven patients with RA (23 with active disease at baseline and 24 in remission) and 51 healthy subjects were evaluated during a one-year follow-up with assessments of disease activity (DAS-28) and 1H NMR spectroscopy of plasma samples. Discriminant analysis provided evidence that the metabolic profiles predicted disease severity. Cholesterol, lactate, acetylated glycoprotein, and lipid signatures were found to be candidate biomarkers for disease severity. The results also supported the link between RA and coronary artery disease. Repeated assessment using mixed linear models showed that the predictors obtained from metabolic profiles of plasma at baseline from patients with active RA were significantly different from those of patients in remission (P=0.0007). However, after 31 days of optimized therapy, the two patient groups were not significantly different (P=0.91). The metabolic profiles of both groups of RA patients were different from the healthy subjects. 1H NMR-based metabolic phenotyping of plasma samples in patients with RA is well suited for discovery of biomarkers and may be a potential approach for disease monitoring and personalized medication for RA therapy.

This paper examines conformity voting on the U.S. Supreme Court from 1946 to 1975. We compare pairs of votes in which a justice switches from the minority at the original vote on the merits to the majority at the final vote (conformity voting) with pairs of votes in which a justice votes with the minority at both votes. Using PROBIT, we identify eight variables associated with switching. Particularly important are case salience and the size of the majority at the original vote.

The attitudinal model, as applied to the United States Supreme Court, posits that voting by a justice on the Court is determined by his or her policy attitudes and by the location along the policy dimension of the stimulus provided by the case. Howard (1968) maintained that there was extensive fluidity in voting between the original vote on the merits and the final vote, that such fluidity deflated the ideological voting and that, as a consequence, the final vote, used in the attitudinal model, is an unreliable indicator of judicial attitudes. We question whether there is extensive fluidity in voting on the Court and argue that the fluidity in voting that takes place usually moves in the expected ideological direction. Nevertheless, Howard's general argument that the attitudinal model does not capture the reality of Supreme Court decision-making seems to be valid. For not all fluidity votes move in the expected direction and the most frequent type, i.e. the minority-majority votes, is also driven by small-group variables.

The United States does not have a clearly defined national security strategy for the 21st century. This problem has its roots in a failure, which precedes 9/11, to come to grips with the fundamentally different nature of the global strategic environment. Stating that we are “at war with terrorism” may be correct at some levels, but it fails to identify an underlying strategic imperative around which we can build a comprehensive organizing framework to protect and promote our security both at home and abroad. Terrorism and other critical threats emerge from a failure and weakness of legitimate governance. A grand strategy focused on the promotion of legitimate governance and the expansion of the global community of legitimately governed states would provide the organizing framework for managing national security.

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.

A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency relative to acyclovir. In a single-dose mouse model of infection, one of the most potent derivatives in vitro, 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarbo xamide (97), displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple-dose regimen, however, 97 was 2-fold less potent. In mice dosed orally with 97, sustained plasma drug levels were evident that may account for the high efficacy observed. The molecular mechanism of action of these agents is not known; however, based on in vitro studies with acyclovir resistant mutants, it is likely that the mechanism differs from that of acyclovir. In vitro plaque-reduction potency was not generally predictive of oral efficacy in mice. An X-ray crystal structure of 97 corroborated the assignment of structure and provided useful insights as to the effect of conformation on plaque-reduction potency.

This article presents a model of decision making and introduces a new theoretical variable to the literature, namely, the modes of decision making. The theoretical focus is on the face-to-face group, and the article also develops an innovative methodology for studying this type of decision-making behavior. Variation in the decision modes is explained as a function of the strategic considerations of individual decision makers. These considerations are affected by a set of four independent variables: structure of the decision group, substance of the conflict, context of the conflict, and the decision process. The data, drawn from observations of decision-making groups in Switzerland, are tested with discriminant analysis and a simulation. In both cases total correct classifications exceed 55 percent, indicating that there is a meaningful structure relating variation in the decision modes to the theoretical framework.

There is a large body of research about decision cases in Western democracies. Unfortunately, the individual case studies are widely scattered so that the research has little cumulative effect. We present an effort to construct a data bank for which existing case studies are coded according to a uniform scheme. This presentation is done at a relatively early stage so that changes can still be made in response to unanticipated problems or different theoretical perspectives. The article gives the rationale for the data bank, addresses the problem of the units of analysis, enumerates the variables contained in the data bank, and illustrates for what theoretical questions the data can be used.

Rudolf Wildenmann (1967: 5) hat schon fruh auf die Bedeutung des politischen EntScheidungsprozesses als theoretische Variable hingewiesen, wenn er argumentierte, es sei „eines der wesentlichen Probleme politisch-wissenschaftlichen Denkens, die einer Demokratie angemessenen Bedingungen fur eine konstitutionelle Regierungsweise zu ermitteln“. Welches ist die einer Demokratie angemessene Regierungsweise? Wie sollen die politischen Entscheidungsprozesse in einem demokratisch verfasten Staat ablaufen? Beim jetzigen Stand der wissenschaftlichen Diskussion ist die Antwort alles andere als offenkundig. Soll sich beispielsweise das Verhaltnis unter den grosen politischen Parteien eines Landes eher durch Konkurrenz oder eher durch Kooperation kennzeichnen? Mussen die politischen Parteien im politischen Entscheidungsprozes notwendigerweise die zentralen Akteure sein, oder kann diese Rolle unter Umstanden auch von wirtschaftlichen Interessengruppen ubernommen werden? Soll sich die staatliche Burokratie auf die Ausfuhrung politischer Entscheide beschranken, oder soll sie auch an ihrer Ausgestaltung mitwirken? Zu welchem Zeitpunkt, in welchen Formen und mit welcher Intensitat sollen sich die Burger am politischen Entscheidungsprozes beteiligen?

It is relatively easy to characterize the institutional structure of a country as consociational or federal. The task is much more difficult if we turn from structure to the decision process. Within a given structure, there may be a great deal of variation with regard to the decision process. Data for such variation are given for the decision process in Switzerland for which the following four types are distinguished: (1) consociational and federal, (2) consociational and unitary, (3) competitive and federal, and (4) competitive and unitary. Difficulties are discussed in aggregating from such a variation to a measure for the prevailing decision process in a country as a whole. It is suggested that the problem be disaggregated and that decision processes be compared for particular issues. This can be done both across and within countries.