bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Analytical Tire Model for Cornering Simulation. Part II: Cornering Force and Self-aligning Torque
Authors: Miyashita N. , Kabe K.
Published: July 2006

An analytical tire model for cornering force (CF) and self-aligning torque (SAT) is described on the basis of the Fiala model. CF and SAT come mainly from the shear stress and sliding friction at the tread/road interface. The CF and SAT variations also change the kinetic conditions for their own generations, that is, the contact-pressure distribution, the tire-part deformation, and the relative position of the steering axis within the contact patch. The present model, the CF/SAT system model, which includes these conditional changes through the CF and SAT feedback loops, approximates the slip-angle dependence of CF and SAT with high accuracy. The inverse data analysis, that is, least-squares fittings of the measured data to the model, give some experimental information about the tread friction coefficient (the adhesive and sliding friction coefficient) and the variation in contact-pressure distribution during cornering. The CF/SAT system model, as well as the CP/SATP model in Part I, may be useful for both the tire production at tire makers and the vehicle dynamics simulation at car makers.
Improved Enantioselectivity of Immobilized Chiral Bisoxazolines by Partial Precapping of the Siliceous Mesocellular Foam Support with Trimethylsilyl Groups
Authors: Lee Su Seong , Hadinoto Sukandar , Ying Jackie Y.
Published: July 2006

Siliceous mesocellular foams (MCF) were partially surface‐modified with trimethylsilyl (TMS) groups prior to the immobilization of chiral tert‐butylbisoxazolines. The resulting MCF‐supported bisoxazoline‐Cu(I) catalyst showed superior enantioselectivity (up to 95 % ee) in asymmetric cyclopropanation, compared to that supported on MCF without TMS precapping. This heterogenized catalyst also exhibited excellent recyclability.
Influence of Elevated Temperature and Pressure on the Chromium‐Catalysed Tetramerisation of Ethylene
Authors: Kuhlmann Sven , Dixon John T. , Haumann Marco , Morgan David H. , Ofili Jimmy , Spuhl Oliver , Taccardi Nicola , Wasserscheid Peter
Published: July 2006

A catalyst system comprising a diphenylphosphineamine (PNP) ligand, chromium(III) acetylacetonate and a methylaluminoxane‐based activator was studied for the selective tetramerisation of ethylene. The reaction was investigated over a broad temperature and pressure range and the resulting product mixture was interpreted in the light of the recently published, enlarged metallacycle mechanism. Vapour‐liquid equilibrium (VLE) data were calculated for the binary ethylene‐cyclohexane mixture over the relevant temperature and pressure ranges to deconvolute the influence of ethylene concentration and temperature. Good agreement of the experimental data with the proposed mechanism was found. Enlargement of the metallacycloheptane ring by insertion of ethylene was found to be dependent on the ethylene concentration, albeit to a lesser extent than assumed. The 1‐octene selectivity, which reaches a maximum of 72–74 mass %, thus seems to be primarily dependent on the temperature. The formation of the cyclic side products methyl‐ and methylenecyclopentane was in effect independent of the ethylene concentration. This is in good accordance with the proposed mechanism, since it indicates that the formation of the products occurs via rearrangement of a metallacycle intermediate.
Ruthenium‐Catalyzed Enantioselective Reduction of Electron‐Rich Aryl Alkyl Ketones
Authors: Wettergren Jenny , Bøgevig Anders , Portier Maud , Adolfsson Hans
Published: July 2006

Presented here is the investigation of the transfer hydrogenation of electron‐rich aryl alkyl ketones using ruthenium complexes of dipeptide‐like ligands and 2‐propanol as hydride source. The reduction proceeded with excellent selectivity (up to>99 % ee) and in moderate to high yields (up to 90 %).
Asymmetric Reductive Amination: Convenient Access to Enantioenriched Alkyl‐Alkyl or Aryl‐Alkyl Substituted α‐Chiral Primary Amines
Authors: Nugent Thomas C. , Ghosh Abhijit K. , Wakchaure Vijay N. , Mohanty Rashmi R.
Published: July 2006

A two‐step procedure for producing optically active, high value primary amines has been developed. The first and key step is the asymmetric reductive amination of a prochiral alkyl alkyl (acyclic or cyclic) or aryl alkyl (acyclic or cyclic) ketone with (R)‐ or (S)‐α‐methylbenzylamine (α‐MBA). The normally stepwise excessive procedures of chiral auxiliary approaches are avoided by simultaneously incorporating the auxiliary and a new stereogenic center at the former carbonyl carbon of the ketone during step one. Specifically, step one is the hydrogenation (4–8 bar) of a prochiral ketone substrate in the presence of α‐MBA, a Lewis acid [Ti(O‐i‐Pr)4, B(O‐i‐Pr)3, Al(O‐i‐Pr)3, or Zr(O‐i‐Pr)4], and a heterogeneous hydrogenation catalyst (Raney‐Ni, Pt‐C, Pd‐C, Ru‐C, or Rh‐C), providing the amine diastereomers 2 in good to excellent yield and diastereoselectivity. Depending on the ketone examined (acyclic vs. cyclic, alkyl alkyl vs. aryl alkyl, sterically encumbered vs. unencumbered), the correct combination of heterogeneous hydrogenation catalyst, solvent, and temperature is crucial for allowing high yield and de with practical reaction times (generally 6–20 h). Performing the reaction in the absence of one of the indicated Lewis acids results in the formation of large amounts of alcohol by‐product (>25 %). Step two, hydrogenolysis, allows smooth removal of the chiral auxiliary providing α‐chiral primary amines in good overall yield (5 examples 71–78 %, 1 example 64 %) and in 66–98 % enantiomeric excess. This two‐step strategy is noteworthy because: 1) it is yield and stepwise efficient; 2) all the reagents are inexpensive and already used by the pharmaceutical industry; 3) a broad range of ketone substrates are suitable; 4) either enantiomeric form of the α‐chiral amine product can be produced; 5) the reaction conditions are mild; and 6) the process is amenable to scale‐up.
Heterogeneous Gold‐Catalysed Synthesis of Phenols
Authors: Carrettin Silvio , Blanco M. Carmen , Corma Avelino , Hashmi A. Stephen K.
Published: July 2006

Nanoparticles of gold supported on nanocrystalline CeO2 catalyse the isomerisation of ω‐alkynylfurans to phenols. Initial leaching of gold was observed, which could be minimised by calcining. Subsequent runs showed that once all soluble species had leached, the surface‐bound, cationic gold species is still active and can reach turnover numbers of up to 391. This is the first time that a heterogeneous gold catalyst showed activity in the gold‐catalysed phenol synthesis.
Efficient, Enantioselective Organocatalytic Synthesis of Trichostatin A
Authors: Zhang Shilei , Duan Wenhu , Wang Wei
Published: July 2006

An efficient, highly stereocontrolled total synthesis of trichostatin A (1) has been achieved in 9 steps with 17.4 % overall yield and >99 % optical purity from readily available achiral starting materials. The key features of this synthesis include the L‐proline‐promoted, highly enantioselective cross‐aldol reaction as a crucial step for the construction of the C‐6 chiral center and the minimization of racemization by final step oxidation of the OH group to a ketone at position 7.
MAOA promoter polymorphism and attention deficit hyperactivity disorder (ADHD) in indian children
Authors: Das Manali , Das Bhowmik Aneek , Sinha Swagata , Chattopadhyay Anindita , Chaudhuri Keya , Singh Manoranjan , Mukhopadhyay Kanchan
Published: July 2006

Attention deficit hyperactivity disorder (ADHD) is a highly disabling, early onset childhood neurobehavioral disorder with a higher occurrence in boys as compared to girls. Pharmacological and molecular genetic studies have revealed the influence of dopaminergic and serotonergic systems in the etiology of the disorder. Monoamine oxidase A (MAOA) is a mitochondrial enzyme that regulates the dopaminergic signals in the pre‐synaptic region. Polymorphism in the promoter region of the MAOA gene, which comprises of 30 bp repeats with repeat number varying between 2.5, 3.5, 4.5, and 5.5, has been shown to be associated with various neurobehavioral disorders including ADHD. This is the first study on Indian ADHD cases to validate an association between transmission of MAOA promoter polymorphism and risk of ADHD. We have analyzed the MAOA promoter polymorphism in a group of ADHD probands, their parents and ethnically matched controls by UNPHASED. Our findings indicate significant difference in the frequency of 3.5 repeat allele (P = 0.02) between cases and controls and preferential transmission of the short allele (3.5 repeat) from mothers to male ADHD probands (P = 0.005). We conclude that the short 3.5 repeat allele of the MAOA‐u VNTR is probably associated with ADHD in our population and could be the reason for making boys prone to ADHD as compared to girls. © 2006 Wiley‐Liss, Inc.
Synthesis and properties study of novel ferrocenyl isoxazole derivatives
Authors: Shang Yongjia , Fan Chenli , Li Maoguo , Zheng Caiyun
Published: July 2006

A synthetic procedure based on the 1,3‐dipolar cycloaddition reactions of nitrile oxides and ethynylferrocene derived from ferrocene has been developed to synthesize new ferrocenyl‐isoxazole derivatives. The stable solids were thoroughly characterized by 1H NMR, FT‐IR, and mass spectroscopy. The structure of (η5‐C5H5) Fe (η5‐C5H4) C3HNOC6H4CH3 was determined by single‐crystal X‐ray diffraction. The electrochemical behaviors of the synthesized ferrocenyl‐isoxazole derivatives were also studied. Copyright © 2005 John Wiley & Sons, Ltd.
Formation and structural characterization of a sterically protected silicic acid diester
Authors: Spirk Stefan , Nieger Martin , Rechberger Gerald N. , Pietschnig Rudolf
Published: July 2006

The hydrolytic stability of the sterically protected dichlorosilane (Mes*O)2SiCl2 was investigated. The resulting products have been identified by electrospray mass spectrometry and, in the case of (Mes*O)2Si(OH)2, the crystal structure was obtained. Copyright © 2005 John Wiley & Sons, Ltd.
Structural and affective aspects of music from statistical audio signal analysis
Authors: Dubnov Shlomo , McAdams Stephen , Reynolds Roger
Published: July 2006

Understanding and modeling human experience and emotional response when listening to music are important for better understanding of the stylistic choices in musical composition. In this work, we explore the relation of audio signal structure to human perceptual and emotional reactions. Memory, repetition, and anticipatory structure have been suggested as some of the major factors in music that might influence and possibly shape these responses. The audio analysis was conducted on two recordings of an extended contemporary musical composition by one of the authors. Signal properties were analyzed using statistical analyses of signal similarities over time and information theoretic measures of signal redundancy. They were then compared to Familiarity Rating and Emotional Force profiles, as recorded continually by listeners hearing the two versions of the piece in a live‐concert setting. The analysis shows strong evidence that signal properties and human reactions are related, suggesting applications of these techniques to music understanding and music information‐retrieval systems.
Evolution of the hemiascomycete yeasts: on life styles and the importance of inbreeding
Authors: Knop Michael
Published: July 2006

The term ‘breeding system’ is used to describe the morphological and behavioural aspects of the sexual life cycle of a species. The yeast breeding system provides three alternatives that enable hapoids to return to the diploid state that is necessary for meiosis: mating of unrelated haploids (amphimixis), mating between spores from the same tetrad (intratetrad mating, automixis) and mother daughter mating upon mating type switching (haplo‐selfing). The frequency of specific mating events affects the level of heterozygosity present in individuals and the genetic diversity of populations. This review discuses the reproductive strategies of yeasts, in particular S. cerevisiae (Bakers' or budding yeast). Emphasis is put on intratetrad mating, its implication for diversity, and how the particular genome structure could have evolved to ensure the preservation of a high degree of heterozygosity in conjunction with frequent intratetrad matings. I also discuss how the ability of yeast to control the number of spores that are formed accounts for high intratetrad mating rates and for enhanced transmission of genomic variation. I extend the discussion to natural genetic variation and propose that a high level of plasticity is inherent in the yeast breeding system, which may allow variation of the breeding behaviour in accordance with the needs imposed by the environment. BioEssays 28: 696–708, 2006. © 2006 Wiley Periodicals, Inc.
The pea aphid, Acyrthosiphon pisum: an emerging genomic model system for ecological, developmental and evolutionary studies
Authors: Brisson Jennifer A. , Stern David L.
Published: July 2006

Aphids display an abundance of adaptations that are not easily studied in existing model systems. Here we review the biology of a new genomic model system, the pea aphid, Acyrthosiphon pisum. We then discuss several phenomena that are particularly accessible to study in the pea aphid: the developmental genetic basis of polyphenisms, aphid–bacterial symbioses, the genetics of adaptation and mechanisms of virus transmission. The pea aphid can be maintained in the laboratory and natural populations can be studied in the field. These properties allow controlled experiments to be performed on problems of direct relevance to natural aphid populations. Combined with new genomic approaches, the pea aphid is poised to become an important model system for understanding the molecular and developmental basis of many ecologically and evolutionarily relevant problems. BioEssays 28: 747–755, 2006. © 2006 Wiley Periodicals, Inc
Rural Chinese children as consumers: consumption experience and information sourcing
Authors: Chan Kara , McNeal James U
Published: July 2006

This study examines how often rural children in Mainland China interact with different types of retail shops, how they learn about new products and services, and their attitudes toward different sources of product information. A survey of 1008 rural children aged from 5 to 13 years, in four Chinese provinces, was conducted in March 2003. Results indicated that rural Chinese children have limited access to various types of retail shops. Rural children perceived personal sources more useful as well as more credible than commercial sources in obtaining information about new products and services. Older children found parents and grandparents less useful and less credible than younger children for new production information. However, older children did not find peers more useful and credible than younger children.

Copyright © 2006 John Wiley & Sons, Ltd.
Protective role of luteolin in 1,2‐dimethylhydrazine induced experimental colon carcinogenesis
Authors: Manju V. , Nalini N.
Published: July 2006

The aim of the present study was to unravel the chemopreventive effect of luteolin on bacterial enzymes such as β‐glucuronidase and mucinase in a colon carcinogenesis model induced by 1, 2–dimethyl hydrazine (DMH). Twenty mg/kg body weight of DMH were administered subcutaneously once a week for the first 15 weeks and then discontinued. Luteolin (0.1, 0.2, or 0.3 mg/kg body weight/everyday (p.o.) was administered in a dose dependent manner at the initiation and also at the post‐initiation stages of carcinogenesis to DMH treated rats. The animals were sacrificed at the end of 30 weeks. Colon cancer incidence and the activities of bacterial enzymes β‐glucuronidase (in the proximal colon, distal colon, intestines, liver and colon contents) and mucinase (colon and fecal contents) were significantly increased in DMH ‐treated rats compared to the control rats. On luteolin administration, colon cancer incidence, number of tumors per rat and the activities of β‐glucuronidase and mucinase, were significantly decreased both in the initiation and post‐initiation stages of colon carcinogenesis dependent on the three different doses given. The increase in β‐glucuronidase activity may augment the hydrolysis of glucuronide conjugates, liberating toxins, while the increase in the mucinase activity may enhance the hydrolysis of the protective mucins in the colon. Thus our results demonstrate for the first time that luteolin, a dietary flavonoid, exerts chemopreventive and anticarcinogenic effects against DMH induced colon cancer. Copyright © 2006 John Wiley & Sons, Ltd.
Distribution of neuropeptide FF‐like immunoreactivity in the brain of the lizard Gekko gecko and its relation to catecholaminergic structures
Authors: Smeets Wilhelmus J.A.J. , López Jesús M. , González Agustín
Published: July 2006

The present study provides a detailed description of the distribution of neuropeptide FF (NPFF)‐like immunoreactivity in the brain of the lizard Gekko gecko. NPFF is found to be involved in nociception, cardiovascular regulation, and endocrine function. Because of its known relationship with catecholamines in mammals, double staining with tyrosine hydroxylase (TH) antibodies was used to corroborate this for reptiles. The present study revealed that NPFF‐like‐immunoreactive (NPFF‐ir) cells and fibers were widely distributed throughout the brain. Major NPFF‐ir cell groups were observed in the diagonal band nucleus of Broca, hypothalamus, and dorsal horn of the spinal cord. Additional cells were found in the anterior olfactory nucleus, lateral and dorsal cortices, dorsolateral septum, and diencephalic intergeniculate leaflet formation. Dense plexuses of NPFF‐ir fibers were identified in the diagonal band nucleus of Broca, septum, preoptic and hypothalamic areas, isthmic region, ventrolateral tegmentum, solitary tract nucleus, and dorsolateral funiculus of the spinal cord. Extensive fiber staining also occurred in the nucleus accumbens and the midbrain tectum. Although an intimate relationship between NPFF‐ir and TH‐ir structures was obvious at many places in the brain, colocalization of these two substances was not observed. In conclusion, the distribution of NPFF in the brain of Gekko shares more features with anamniotes in terms of number of cell groups, more elaborate networks of fibers, and lack of colocalization with catecholamines than with mammals, suggesting a decrease in the distribution of this peptide in the latter vertebrate group. J. Comp. Neurol. 498:31–45, 2006. © 2006 Wiley‐Liss, Inc.
Methodology of clinical research: an overview
Authors: Floriani Irene , Torri Valter
Published: July 2006

The goal of clinical research is to establish safety efficacy and effectiveness of treatments or intervention. In order to obtain it, different clinical studies are needed, with a quite definite hierarchy of research objectives, in order to gather all information needed for appraising the clinical role of the intervention being tested. Clinical trials are generally considered as the best tool for learning whether a new treatment is safe and effective in patients. They are conducted in all areas of medicine but represent only a small part of the research for developing a new treatment. In particular, even after providing evidence for the approval of treatment, further research is needed on the implementation of results of clinical research into clinical practice and health policy. This is the place of outcome research that investigates the impact of various influences, especially interventions, on final endpoints that matter to decision makers with special emphasis on the use of patient‐reported outcomes. This article reviews the methodological characteristics of each research phase, with particular emphasis on comparative trials and effectiveness studies. Drug Dev. Res. 67:183–187, 2006. © 2006 Wiley‐Liss, Inc.
An active role for patients in clinical research?
Authors: O'Connell Deirdre , Mosconi Paola
Published: July 2006

In the context of stricter control of clinical research, more informed patients, and a growing number of patient organizations, an active role for patients in clinical research has more than one meaning. Patient involvement in research as subjects is insufficient and can be improved by the information provided by patient groups and by better collaboration between the research community and patient groups. Knowledge about and understanding of clinical trials is central to greater participation. Involvement in the research process provides another role for patients and patient groups and a number of studies have examined such involvement. Patient advocacy groups are involved in training initiatives to enable effective patient involvement in the administration and conduct of clinical research. Various national and European research and regulatory organizations now work with patient representatives, often providing training for them. A third role for patient organizations lies in supporting the research community in lobbying for increased funding, especially for independent clinical research. The area of clinical research outside randomized clinical trials needs also to be carefully considered, in particular the Outcomes Research field. Drug Dev. Res. 67:188–192, 2006. © 2006 Wiley‐Liss, Inc.
Patient‐reported outcomes and health‐related quality of life in effectiveness studies: pros and cons
Authors: Marquis Patrick , Arnould Benoit , Acquadro Catherine , Roberts W. Mark
Published: July 2006

The importance of patient perspectives on disease impact and response to therapy is increasingly recognized. Patient‐reported outcomes (PROs), including health‐related quality of life (HRQL), provide information on the effectiveness of medical interventions that cannot be obtained using objective clinical measures. For drug development, PROs such as symptom questionnaires are accepted by the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in the approval process. HRQL assessments can help to establish the niche for a new product to support marketing efforts. Utilities can also be derived from health outcomes measures for cost‐effectiveness analyses required by health plans for granting drug reimbursement. Because they more closely reflect routine clinical care, effectiveness studies are often a superior setting than traditional randomized controlled trials (RCTs) for conducting comprehensive PRO assessments to determine the real‐world impact of therapy on symptoms and other aspects of everyday life. Screening, quality of care, self‐reported adherence to treatment, and patient monitoring are important potential applications of PROs in effectiveness studies. However, well‐known limitations of effectiveness studies also apply to PROs; these sometimes include a lack of randomization, controls, and blinding. It may be difficult to obtain patient compliance and clinician assistance with PRO assessments in a real‐world setting. PRO data may be biased by nonrandom patient dropout, errors in timing of PRO assessments, and the environment in which questionnaires are administered. Additionally, the drug development schedule often requires outcomes results before effectiveness studies can be conducted. Addressing these difficulties during study design and the use of short and targeted questionnaires will improve the usefulness and feasibility of PRO measures in effectiveness studies. Drug Dev. Res. 67:193–201, 2006. © 2006 Wiley‐Liss, Inc.
Case‐mix/risk adjustment of observational data: it all depends on the purpose of the data collection
Authors: Goldfield Norbert
Published: July 2006

Each year finds dramatic new developments in the pharmacological treatment of diseases. With the availability of numerous interventions for most diseases, the impact of a medication on the course of a disease is critically dependent on the case mix of the patients under study. This article focuses on the different methods, in broad terms, available for case‐mix adjustment of populations of patients. After addressing definitional concerns, this report highlights the different types of case‐mix adjustments available for each type of health care encounter, ranging from ambulatory visits to population‐based measures to long‐term care. There is little or no crossover in the use of different case‐mix systems across different types of health care encounters. This article concludes with evolving trends in case mix and a case example in an effort to highlight the challenges and opportunities present in this ever‐changing field. Drug Dev. Res. 67:202‐207, 2006. © 2006 Wiley‐Liss, Inc.
Propensity score for the analysis of observational data: an introduction and an illustrative example
Authors: Cavuto S. , Bravi F. , Grassi M.C. , Apolone G.
Published: July 2006

The principal aim of analysis of any sample of data is to draw causal inferences about the effects of different exposures, such as decisions, actions, medical treatments, or other interventions on relevant outcomes. Data may be the result of several kinds of study designs and approaches, either experimental or observational. In experimental, comparative intervention studies, randomization of patients guarantees that the groups are comparable before the exposure to the treatments and random assignment assures that the choice for a given treatment is not due to the decision by treating physicians and also allows a correct application of statistical tests. In observational studies when randomization is not used for practical or ethical reasons, treatments are decided by physicians (or by patients, or by both) in the context of the best clinical practice and, thus, groups are not comparable and differences in outcomes may reflect either effects caused by the treatment choices or differences in prognosis before treatment. When differences between groups are observed or expected, different kinds of adjustments are used to statistically adjust for the unbalance, using variables describing the condition of patients before treatment. Usually, potential predictive and/or prognostic variables are used together to adjust for confounding by constructing multivariable models. This approach is most of the time able to reduce the effect of confounders or effect modifiers on relevant outcomes, but it makes it difficult for investigators and for final users of the results to assess the adequacy of the approach, the role and impact of each class of variables, and, eventually, the clinical meaning of the results. In 1983, Rosenbaum and Rubin proposed a new method, named Propensity Score, to balance the variables related to the choice of the exposure (treatments) in order to reconstruct a situation similar to random assignment. Since then, there has been an explosion of examples of the use of this approach in the literature. This report introduces the method, uses an empirical example to illustrate its use, and eventually discusses the pros and cons of the method using the authors' experience and some hints extracted from recent commentaries. Drug Dev. Res. 67:208‐216, 2006. © 2006 Wiley‐Liss, Inc.
Medication effectiveness studies in the United States Veterans Administration health care system: a model for large integrated delivery systems
Authors: Kazis Lewis E. , Nethercot Victoria A. , Ren Xinhua S. , Lee Austin , Selim Alfredo , Miller Donald R.
Published: July 2006

The Veterans Administration health care system (VA) is one of the largest integrated delivery systems in the United States. The VA provides a rich central data base repository that includes detailed medication data, historical information about patient morbidities, clinical data, and inpatient and outpatient utilization information from claims data and health status information derived directly from the patient. The Veterans Health Study (VHS), a large‐scale prospective study following patient's health outcomes for up to six years, derived and validated a number of patient questionnaires for wide‐scale use in the VA as part of its quality monitoring and research programs. Chief among these assessments are the Veterans Rand 36 item and 12 item health surveys (VR‐36 and VR‐12); other assessments include measures of illness and their associated severity, health‐related quality of life, and utilization of health care services. This report reviews the methodologies developed in the VHS and their subsequent applications in the VA system for conducting medication effectiveness studies based upon non‐randomized prospective quasi‐experimental designs that approximate real world clinical conditions. Study cohorts are described that link the patient questionnaire data with administrative, clinical, and pharmacy data to address questions about medication effectiveness. Statistical models include comprehensive risk adjustments in order to better understand the association between medications that are being compared and their associated patient outcomes. Applications of this approach are presented for medication studies in those diagnosed with hypertension, osteoarthritis, low back pain, depression, and schizophrenia. Future implications of this work are described for purposes of quality improvement. Drug Dev. Res. 67:217–226, 2006. © 2006 Wiley‐Liss, Inc.
Artificial intelligence and outcome research
Authors: Grossi Enzo , Buscema Massimo
Published: July 2006

The coupling of computer science and theoretical bases like non‐linear dynamics and chaos, quite new for medicine theory, allows the creation of “intelligent” agents (Artificial Adaptive Systems [AAS]) able to adapt themselves dynamically to problems of high complexity. ASS are able to reproduce the dynamical interaction of multiple factors simultaneously, allowing the study of complexity; they can also draw conclusions on an individual basis and not as average trends. These tools can offer specific advantages within the outcome research arena, helping to answer some open issues like enhancing the internal validity of observational studies, transferring evidence derived from clinical research to a single patient level, and performing “virtual” clinical trials as a guide for more efficient clinical development. A remarkable contribution to this individual approach comes from Fuzzy Logic, according to which there are no sharp limits between opposite things, like wealth and disease. This approach allows for partially escaping from the probability theory trap in situations where it is fundamental to express a judgement based on a single case and favour a novel humanism directed to the management of the patient as an individual subject. Some examples of original applications in the authors' experience are described. Drug Dev. Res. 67:227–244, 2006. © 2006 Wiley‐Liss, Inc.
The contribution of information technology: towards a better clinical data management
Authors: Clivio Luca , Tinazzi Angelo , Mangano Simone , Santoro Eugenio
Published: July 2006

Clinical data management is a vital vehicle in medical research to ensure the integrity and quality of data used to take medical decisions. When applied to clinical trials or observational studies it must comply with several regulations and guidelines developed in recent years; these include general purpose national and international legislation for data privacy and data protection, good clinical practice (GCPs) for medical interventions, and specific guidelines for electronic data submission to regulatory agencies. The aim of this article is to briefly illustrate the above‐mentioned guidelines and legislation from the data‐acquisition perspective and to describe how this process can be improved through a proper and prudent application of current information technology. Furthermore, a practical application using the current state of the art and, in particular, the web‐based technology, will be presented with two real case studies. Drug Dev. Res. 67:245‐250, 2006. © 2006 Wiley‐Liss, Inc.
Outcome research in gastroenterology: the case of gastroesophageal reflux disease (GERD)
Authors: Pace Fabio , Molteni Paola , Wiklund Ingela
Published: July 2006

Gastroesophageal reflux disease (GERD) is a common, chronic disorder. The main symptom of GERD is heartburn, although a diverse range of symptoms can be associated with the disease including acid regurgitation and epigastric pain. GERD is also a risk factor for Barrett's oesophagus and esophageal adenocarcinoma. The impact of GERD symptoms on patients' lives can be profound and is unrelated to the presence or absence of esophagitis. The impact of GERD can be measured by assessing the patient perspective using Patient Reported Outcomes (PROs). A number of studies have demonstrated that health‐related quality of life (HRQoL) in reflux disease patients is significantly impaired in comparison to the general population, regardless of the endoscopic findings. Furthermore, this impairment is comparable to or greater than that observed in other chronic conditions, such as diabetes, arthritis, or congestive heart failure. Impaired HRQoL in GERD patients is a result of features such as disturbed sleep, reduced vitality, generalized body pain, an impaired sex life, and anxiety about the underlying cause of the symptoms. The burden of illness imposed by reflux disease on HRQoL also has an impact on productivity, both at and outside work. The impact of reflux disease on productivity is significant and comparable to that caused by headache or back pain. Effective treatment is available for reflux disease, and there is evidence that this can quickly restore HRQoL to levels observed in the general population. Drug Dev. Res. 67:251–259, 2006. © 2006 Wiley‐Liss, Inc.
Outcome research in obesity: lessons from the QUOVADIS study
Authors: Marchesini Giulio , Marzocchi Rebecca , Grave Riccardo Dalle
Published: July 2006

Outcome research in obesity is aimed at the identification of clinically meaningful goals. Over the years, the focus has moved from surrogate health markers to cardiovascular risk and survival. The 7–10% weight loss recommended by guidelines is a target easily attained with any treatment, but does not guarantee physical and psychological benefits unless it is accompanied by weight loss maintenance, a target very difficult to achieve with either behavior treatment or pharmacological intervention. A reduced cardiovascular risk profile is associated with weight loss, irrespective of the treatment program. In contrast, no controlled studies have so far documented an increased survival, but evidence has been provided by epidemiological surveys. Also bariatric surgery, promoting a larger weight loss and good weight loss maintenance, has failed to demonstrate an improved survival. Health‐related quality of life is an additional significant outcome, approved by international agencies. Concern regarding a possible detrimental effect of dieting on mood and depression is not substantiated by the results of controlled studies. The high prevalence of obesity and its consequences pose a serious and unresolved challenge to the medical community and the definition of outcome measures is a key issue for the assessment of results. Drug Dev. Res. 67:260–270, 2006. © 2006 Wiley‐Liss, Inc.
Combined counseling and bupropion therapy for smoking cessation: identification of outcome predictors
Authors: Grassi Maria Caterina , Enea Domenico , Marchetti Rosanna , Caricati Alessio Maria , Nencini Paolo
Published: July 2006

Because some smoking‐induced pathologies improve upon discontinuation, strategies have been developed to help smokers quit. The aim of this study was to measure the rate of smokers still abstinent one year after one cycle of a six‐week group counseling given alone or in combination with a seven‐week period of daily administration of bupropion. We also evaluated the predictor validity of nicotine dependence intensity at enrollment, administering both the Fageström Tolerance Questionnaire (FTQ) and the Severity of Dependence Scale (SDS). Visual Analogue Scale (VAS), to measure the intensity of “smoke craving,” was also administered. Two hundred twenty‐nine subjects trying to quit smoking were enrolled. Bupropion therapy was accepted by 110 subjects, but only 50 completed the 7‐week cycle of therapy. Abstinence rates at one year were 68.0 and 56.6%, respectively, in the group that used bupropion for the scheduled 7 weeks and in the group that discontinued bupropion, and 35.3% in the group with counseling therapy alone. SDS (but not FTQ) scores at enrollment, VAS values for craving at the end of the program, and bupropion therapy were the variables selected by Linear Discriminant Analysis to assign subjects to the Smoker or Non‐smoker group, with a global correctness of 70.9%. In conclusion, the efficacy of bupropion largely depends upon its interaction with psychological factors, such as the level of nicotine dependence, craving for nicotine, and the subject's commitment to quit smoking. Drug Dev. Res. 67:271–279, 2006. © 2006 Wiley‐Liss, Inc.
Outcome research in diabetes: from theory to practice. Results of the QuED study
Authors: Nicolucci Antonio , De Berardis Giorgia , Franciosi Monica , Pellegrini Fabio
Published: July 2006

Despite the fact that several pharmacological and educational interventions have been proven to improve diabetes outcomes in the context of randomized clinical trials, the transferability of these results to clinical practice can encounter obstacles represented by physicians' knowledge and beliefs, structural and organizational constraints, and patients' clinical and socio‐economical characteristics. Outcomes research represents a fundamental tool to investigate the extent to which trials results can be reproduced under routine clinical conditions, to evaluate clinical behavior in areas of uncertainty, and to ascertain which features of diabetes care are more important to improve clinical outcomes and quality of life. This report will discuss some of the results of the QuED (Quality of Care and Outcomes in Type 2 Diabetes) study, to exemplify the yield of an outcomes research approach to a complex, chronic disease. The QuED Study is a nation‐wide initiative aimed at assessing the relationship between the quality of care delivered to subjects with type 2 diabetes and outcomes. The study involved 101 outpatient diabetes clinics and 103 General Practitioners (GPs) in Italy. Overall, 3,437 patients have been enrolled and followed up for 5 years at 6‐month intervals. Quality of life was evaluated through questionnaires filled in by the patients at 6‐month intervals for 3 years. A physicians' survey was also conducted to investigate physician's beliefs regarding metabolic control, blood pressure, and lipid control. Given the multiplicity of the sources of information, the study allowed for matching physicians' beliefs and practices with intermediate and long‐term clinical and humanistic outcomes. Drug Dev. Res. 67:280–286, 2006. © 2006 Wiley‐Liss, Inc.
Chiral Half‐Sandwich Ruthenium(II) Complexes as Catalysts in 1,3‐Dipolar Cycloaddition Reactions of Nitrones with Methacrolein
Authors: Carmona Daniel , Lamata M. Pilar , Viguri Fernando , Ferrer Joaquina , García Néstor , Lahoz Fernando J. , Martín M. Luisa , Oro Luis A.
Published: July 2006

Ruthenium complexes of formula [(η6‐arene)Ru(LL*)(H2O)][SbF6]2 (arene = C6H6, p‐MeC6H4iPr, C6Me6; LL* = bidentate chelate chiral ligand with PN, PP or NN donor atoms) have been tested as catalyst precursors for the asymmetric 1,3‐dipolar cycloaddition of nitrones to methacrolein. The reaction occurs quantitatively with perfect endo selectivity and moderate enantioselectivity (up to 74 % ee). The ruthenium aqua complexes can be prepared from the corresponding chlorides, [(η6‐arene)RuCl(LL*)][SbF6]. Dipolarophile intermediates [(η6‐arene)Ru(PNiPr)(methacrolein)][SbF6]2 {PNiPr = (4S)‐2‐(2‐diphenylphosphanylphenyl)‐4‐isopropyl‐1,3‐oxazoline} as well as nitrone‐containing complexes [(p‐MeC6H4iPr)Ru(PNiPr)(nitrone)][SbF6]2 (nitrone = N‐benzylidenephenylamine N‐oxide, N‐benzylidenemethylamine N‐oxide, 3,4‐dihydroisoquinoline N‐oxide) have been also isolated and characterised. The crystal structures of the chlorides (RRu)‐[(η6‐C6Me6)RuCl(PNiPr)][SbF6], (RRu)‐[(η6‐C6H6)RuCl(PNInd)][SbF6] {PNInd = (3aR,8aS)‐2‐[2‐(diphenylphosphanyl)phenyl]‐3a,8a‐dihydroindane[1,2‐d]oxazole} and those of the aqua solvates (RRu)‐[(η6‐arene)Ru(PNiPr)(H2O)][SbF6]2 (arene = C6H6, C6Me6) were determined by X‐ray diffraction methods. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
New Facile Synthesis of 3,5‐Dihydro‐6H‐imidazo[1,2‐b]‐1,2,4‐triazol‐6‐ones by an Iminophosphorane‐Mediated Annulation
Authors: Yuan Ju‐Zhen , Fu Bo‐Qiao , Ding Ming‐Wu , Yang Guang‐Fu
Published: July 2006

Iminophosphorane 1 reacted with an aromatic isocyanate to unexpectedly give a mixture of carbodiimides 2, 3 and 4 through both the normal and the abnormal aza‐Wittig reactions. 3‐Aminoimidazolone 10 was obtained from the reaction of hydrazine hydrate with carbodiimide 2. Reaction of 10 with triphenyphosphane, hexachloroethane and triethylamine produced iminophosphorane 11 in good yield. A tandem aza‐Wittig reaction of iminophosphorane 11 with isocyanate or CS2 generated 3,5‐dihydro‐6H‐imidazo[1,2‐b]‐1,2,4‐triazol‐6‐ones 13 or 15 in satisfactory yield. Carbodiimides 18, obtained from normal aza‐Wittig reactions of vinyl iminophosphorane 17 with aromatic isocyanates, reacted with hydrazine to give 2‐arylamino‐3‐amino‐4H‐imidazol‐4‐ones 20. One‐pot reactions of 2‐arylamino‐3‐amino‐4H‐imidazol‐4‐ones 20 with isocyanates (or acyl chlorides), triphenyphosphane, hexachloroethane and triethylamine produced 3,5‐dihydro‐6H‐imidazo[1,2‐b]‐1,2,4‐triazol‐6‐ones 22 (or 23) in good yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Anion‐selective exhaustive injection‐sweeping microemulsion electrokinetic chromatography
Authors: Huang Hsi‐Ya , Lien Wei‐Chih , Huang I‐Yun
Published: July 2006

In this study, anion‐selective exhaustive injection‐sweeping (ASEI‐sweeping) technique, which is a selective on‐line sample concentration technique, was first proposed in microemulsion electrokinetic chromatography (MEEKC) for analyses of eight acidic phenolic compounds. In contrast to a capillary that is typically filled with nonmicellar background solution in conventional ASEI‐sweeping MEKC method, in the proposed ASEI‐sweeping MEEKC method, a capillary is filled with a low pH microemulsion solution (pH 2.0), and then with a short acid plug (pH 2.0, 1.9 cm) before field‐amplified sample injection. This proposed design has two functions. First, the microemulsion solution that is present at the front of capillary column is able to avoid phase separation of microemulsion solution during MEEKC separation. Second, the presence of the short acid plug would effectively limit the partition behavior of acid analytes with the oil droplets in the microemulsion during field‐amplified sample injection; otherwise, the stacking effect of acid analytes would be markedly reduced. This optimal ASEI‐sweeping MEEKC method afforded about 96 000‐fold to 238 000‐fold increases in detection sensitivity in terms of peak areas without any separation efficiency loss when compared to normal MEEKC separation. Furthermore, trace levels (about 3 ng/g) of gallic acid and catechin in foods were also detected successfully by the proposed ASEI‐sweeping MEEKC technique.
Homopolymerization and copolymerization of isocyanatoethyl methacrylate
Authors: Lam O. A. , Hervaud Y. , Boutevin B.
Published: July 2006

This article describes the homopolymerization of isocyanatoethyl methacrylate (IEM) and its copolymerization with methyl methacrylate (MMA) in acetonitrile in the presence of 2,2′‐azobisisobutyronitrile. The constant characteristic of IEM polymerizability (kp2/kte = 128 × 10−3 L mol−1 s−1, where kp is the propagation constant and kte is the termination constant) was determined. The study of IEM reactivity toward MMA gave ratios of 0.88 and 1.20 for IEM and MMA, respectively. The physicochemical properties of the IEM homopolymer and IEM/MMA copolymers were also studied. The glass‐transition temperature of poly(isocyanatoethyl methacrylate) was found to be 47 °C. From the thermogravimetric analysis of the weight‐loss percentage corresponding to the first wave of the thermogram, it was shown that the degradation mechanism of the IEM/MMA copolymers started from the isocyanate group. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4762–4768, 2006
Isomeric effect of the Et(H4Ind)2Zr(CH3)2 catalyst on the copolymerization of ethylene and styrene: A computational study
Authors: Martínez Sonia , Ramos Javier , Cruz Víctor L. , Martínez‐Salazar Javier
Published: July 2006

A density functional theory (B3LYP) computational study of the ethylene–styrene copolymerization process using meso‐Et(H4Ind)2Zr(CH3)2 as the catalyst is presented. The monomer insertion barriers in meso species are evaluated and compared with previously obtained barriers in rac diastereoisomers. Differences related to ethylene homopolymerization and ethylene–styrene copolymerization activities as well as styrene incorporation into the copolymer are found between the meso and rac diastereoisomers. Nevertheless, a migratory insertion mechanism seems to hold for both diastereoisomeric species. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4752–4761, 2006
High‐molar‐mass polypropene with tunable elastic properties by hafnocene/borate catalysts
Authors: Seraidaris Tanja , Puranen Arto , Karesoja Mikko , Löfgren Barbro , Repo Timo , Leskelä Markku , Seppälä Jukka
Published: July 2006

Elastic polypropene has gained growing industrial and academic interest as a thermoplastic elastomer. In this study, “rac”‐ and “meso”‐dimethylsilyl(3‐benzylindenyl)(2‐methylindenyl)hafnium dichloride complexes (Hfr and Hfm, respectively), activated with [NHMe2Ph][B(C6F5)4]/triisobutyl aluminum, were used in propene polymerization. Using these catalyst systems, we obtained polymers with high molar masses, up to 550 kg/mol, and moderate isotacticities between 34 and 52%. By varying the polymerization conditions, we could modify the polymer microstructure and molar mass. 13C NMR was used to calculate the polymer pentad sequence distributions. The crystalline parts of the polymers were analyzed with the differential scanning calorimetry successive self‐nucleation and annealing (SSA) technique. The SSA thermograms revealed that Hfr produced polypropene with a more uniform lamellar structure than Hfm. The mechanical properties were tested with dynamic mechanical analysis creep‐recovery tests. In the series, the polymers with the lowest isotacticities and therefore lowest crystallinities showed the best elastic properties. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4743–4751, 2006
Acrylic polymer/silica organic–inorganic hybrid emulsions for coating materials: Role of the silane coupling agent
Authors: Watanabe Mitsuru , Tamai Toshiyuki
Published: July 2006

Acrylic polymer/silica organic–inorganic hybrid emulsions were synthesized by a simple method, that is, a conventional emulsion polymerization and subsequent sol–gel process, to provide water‐based coating materials. The acrylic polymer emulsions contained a silane coupling agent monomer, such as methacryloxypropyltriethoxysilane, to form highly solvent‐resistant hybrid films. On the other hand, the hybrid films from the surface‐modified polymer emulsions, in which the silane coupling agent was located only on the surface of the polymer particles and the particle core was not crosslinked, did not exhibit high solvent resistance. A honeycomblike array structure, which was derived from the polymer particles (diameter ≈ 50 nm) and the silica domain, on the hybrid film surfaces was observed by atomic force microscopy. The crosslinked core part and silane coupling agent containing the shell part of the polymer particles played important roles in attaining high solvent resistance. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 4736–4742, 2006