bluuebunny/crossref_metadata_2025 huggingface dataset:
“This is the Authority. This Planet is Under Our Protection” — An Exegesis of Superheroes' Interrogations of Law
Authors: Bainbridge Jason
Published: October 2007

This paper examines concepts of authority, law, and justice in the genre of superhero comics. Despite the common view that comic book superheroes do not warrant (and have not received) significant academic attention except as art form (rather than social/legal commentary), they do, in fact, present a locus in which visions of law and its relationship with society are played out with a degree of intellectual and jurisprudential sophistication. This is because superheroes reflect perceptions of failed or deficient law. They are therefore another vehicle for thinking discursively about law because of what they can say about society and its perceptions of the effectiveness of law, in the context of their manifesting a pre-modern, sacralised, view of embodied justice as opposed to modern constructs of law. Using a typology of pre-modern, modern, and postmodern justice, the paper briefly explores the characteristics of justice found in superhero comics. The post-modern superhero is characterized in terms of a relation to rationality (they exist in opposition to it); in relation to law (they supplement its failures); and in terms of action (they are proactive). Finally some ways of relating these accounts of justice are exemplified in the superhero figure of Matt Murdock and Daredevil. Law, Culture and the Humanities 2007; 3: 455—476
The dissemination and uptake of competency frameworks
Authors: Hendry Charles , Lauder William , Roxburgh Michelle
Published: October 2007

Clinical competencies are increasingly being used to structure career and clinical progression in post-registration nursing. Competency framework documents have been proposed as a way of supporting competence development. One major national initiative in this respect is the NHS Education for Scotland (NES) competency frameworks which have seen development of over 26 such frameworks dealing with a wide range of nursing specialties.

Utilising an initial scoping study followed by a stakeholder evaluation the dissemination and uptake of a selected number of competency frameworks was investigated. Participants in the scoping study ( n = 18) and in the main stakeholder survey ( n = 24) from a sample of Health Boards and Higher Education Institutions were recruited. Data were collected by telephone and face-to-face interviews.

Within the NHS and HEI's the specified framework documents have a variable penetration. Documents are used to support CPD at the individual and organisational levels. They also inform, albeit in a very limited way, curricular developments in HEIs. The success of framework documents is linked to their timeliness in relation to local and national developments such as service redesign and to whether or not documents were `championed' by committed practitioners or professional groups.

Competency framework documents are recognised and utilised by clinicians, NHS managers and Education providers. Information providers and users need to co-ordinate their initiatives in order that staff development links with service redesign.
`I'm like you': establishing and protecting a common ground in focus groups with Huntington disease caregivers
Authors: Williams Janet K. , Ayres Lioness
Published: October 2007

Focus group research reflects content contributed by participants and the influence of interactions among participants. Analysis of interactions provides insights into focus group dynamics and the contextual meaning of focus group topics. The aim of this report is to analyse interactions that establish or protect a common ground in focus groups of family members caring for adults with Huntington disease (HD). HD tends to stigmatise persons with the disease, as well as their families. Thus, many of the topics in these groups were sensitive. Establishing a common ground was of paramount importance to group members. Participants used interactional processes that combined validations and challenges across assertions of knowledge or expertise, and disclosure of personally painful or socially sanctioned thoughts or feelings. Participants couched their contributions in ways that established similarity with others and when disagreements arose, group members developed processes to sustain their common ground. These behaviours served to facilitate group solidarity and may have influenced the information provided by group members. Awareness of interactions to facilitate maintenance of a common ground allows leaders to recognise the importance of such interactions for the group's functioning, and provides insights for researchers into meanings of focus group findings.
A different type of appointment: the experiences of parents who have children with intellectual disabilities referred for genetic investigation
Authors: Barr Owen , McConkey Roy
Published: October 2007

Current research endeavours in genetics largely concentrate on developing more effective approaches to genetic investigation and treatment for individuals. By contrast, less attention has been paid to the impact of genetic referral on the parents of children undergoing investigation, in particular which aspects of the referral process that contribute to increased anxiety reported by parents attending a genetics appointment. The overall aim of this project was to gain an understanding of the experience of parents who have a child referred for genetic investigation. This paper reports how parents perceived an appointment with a geneticist as being `different' from appointments with other doctors they had attended. Using an Interpretative Phenomenological Analysis (IPA) design information was obtained using preappointment self-completion questionnaires with 19 parents that they completed in the two weeks prior to their appointment. After the appointment semi-structured interviews with 17 of these parents within three months of the appointment with the geneticist. In addition, a second interview with 10 parents (of the above 17 parents) for whom genetic investigation were continuing was completed approximately nine months following their initial appointment with the geneticist. All parents who agreed to participate in this study were parents of children with intellectual disabilities. Overall, four superordinate themes were identified, these were: seeking information — the wider context; a different type of appointment; interpreting information and experiences and parents' changing perspectives. The findings reinforce the findings of previous studies that have highlighted the desire of parents to receive an explanation of their child's condition, the wider impact of being referred to and attending an appointment with a geneticist and the role that receiving a diagnosis can play in parents' process of adaptation to their child's condition. However, this study provided a new insight into how parents perceive their appointment with a geneticist as being different from other doctors they have attended. The findings of this study highlight the need to recognise the different manner in which parents perceive an appointment with a geneticist in comparison with appointments with other doctors. The illumination of the perceived `differentness' that parents have prior to and during an appointment with a geneticist appointment provides a new insight into why parents may be anxious as a result of the processes involved. In seeking to support the parents of children referred to a geneticist, health professionals should identify parents' understanding and expectations of the appointment and provide timely information and support in order to assist parents prepare for the appointment and make maximum use of this opportunity to raise and understand new information.
Family communication about cystic fibrosis from the mother's perspective: an exploratory study
Authors: Coates Nicola , Gregory Maggie , Skirton Heather , Gaff Clara , Patch Christine , Clarke Angus , Parsons Evelyn
Published: October 2007

With the advent of national newborn screening for cystic fibrosis in the UK, the communication of information within families after a diagnosis is made is important. As cystic fibrosis is a recessive genetic condition, even distant relatives may be carriers and therefore potentially at risk of having an affected child. Eight semi-structured interviews were carried out with mothers of children who were diagnosed with cystic fibrosis at around the time of birth. Thematic analysis was undertaken on interview transcripts. The interview data suggest open communication in these families with respect to first-degree relatives. Although disclosure was more selective with distant relatives, there was evidence that information was filtered to them through other family members. The main reasons for disclosure by mothers appeared to be the need for support and to allow relatives the option of carrier testing. Barriers to disclosure included lack of emotional and geographical closeness to relatives and the desire to protect relatives from unwelcome information. Health professionals may be able to assist the disclosure process by actively discussing disclosure with parents. It may also be helpful to revisit the issue of disclosure with parents after they have had some time to adjust to the diagnosis of cystic fibrosis in their child.
Human Rights and the Triumph of the Individual in World Culture
Authors: Elliott Michael A.
Published: October 2007

Despite ongoing attention to the subject, cultural accounts of the globalization of human rights are surprisingly scarce. Most accounts describe this phenomenon either as a function of evolutionary progress or the rational/strategic action of states and social movement organizations. As a result, they have difficulty explaining both the moral impulse to act on behalf of human rights and the tremendous expansion of the ideology itself. Borrowing insights from global cultural analysis, I argue that the increasing concern for, and elaboration of, human rights points to a world-cultural environment where the individual is increasingly regarded as sacred and inviolable. To demonstrate this, I explore how human rights have developed historically as a `cult of the individual' and present new data on their recent worldwide expansion.
Whose Collection Is It Anyway? An Autoethnographic Account of `Dividing the Spoils' upon Divorce
Authors: Goode Jackie
Published: October 2007

This article examines competing meanings assigned to collections / collected objects when spouses divorce. An approach to material culture that privileges the mundane and sensual qualities of artefacts as well as their symbolic meanings enables the unpicking of the subtle connections with cultural lives and values that are objectified through such forms. The article illustrates both the way meanings assigned to collected objects can be multiple and shifting, and the ways in which they are constitutive of relationships: between collecting practices, collections, and collector; between `things' and `home'; and, as issues of ownership become contested upon divorce, between spouses. It suggests that, in this case at least, collected objects are also constitutive of class and gender relations. Barnard talked of a `his marriage' and a `her marriage'. This is a `herstor y' of the making, and keeping, of three collections, and of their significance in the parting of spouses and the reconstitution of home(s) post-divorce.
Incorporation of Fe3+ in phase-X, A2–xM2Si2O7Hx, a potential high-pressure K-rich hydrous silicate in the mantle
Authors: Bindi L. , Bobrov A. , Litvin Y. A.
Published: October 2007

Phase-X, a potential sink for K in the mantle, is a synthetic hydrous K-rich silicate formed by the breakdown of K-amphibole at high pressure. It has the general formula A2–xM2Si2O7Hx where A = K, Na, Ca, □ (vacancy), and M = Mg, Al, or Cr. No other isomorphic substitutions, either for the A or the M site, were reported for such a synthetic compound. Here we report the crystal structure and chemical composition of a crystal of phase-X containinglarg e amounts of trivalent Fe. This crystal was synthesized in the model system garnet lherzolite–K2CO3 at lower pressure (P = 7 GPa) and higher temperature (T = 1450–1650°C) with respect to the stability range reported in the literature (i.e. P = 9–17 GPa and T = 1150–1400°C). Quantitative analysis led to the following formula: . The lattice parameters (hexagonal setting) are: a = 5.005(1), c = 13.148(2) Å, V = 285.23(9) Å3, and Z = 2. The structure was refined in space group P63cm to R = 5.06% using199 independent reflections and consists of MO6 octahedra layers stacked alongthe c axis and linked together by Si2O7 groups. The Si2O7 groups form pillars in the layer that contains A atoms in the cavities between the pillars. The Raman spectrum in the OH-stretching region indicates the existence of two different OH environments. However, the position of H could not be determined. The substitution of Fe3+ for Mg shortens octahedral bond distances. In addition, the entry of Fe3+ in M induces geometrical changes to the adjacent A site. The crystal-chemical characteristics are compared with published data on synthetic Fe-free phase-X.
Zeolitic alteration in the Tertiary Feres volcano-sedimentary basin, Thrace, NE Greece
Authors: Marantos I. , Markopoulos T. , Christidis G. E.
Published: October 2007

The Tertiary volcano-sedimentary sequence of the Feres basin (Thrace, NE Greece), includes lavas of andesitic–rhyolitic composition as well as volcaniclastic rocks, pyroclastic flows and pyroclastic fall deposits principally of dacitic–rhyodacitic composition. The pyroclastic flow deposits frequently show intense devitrification, vapour-phase crystallization and evidence of fumarolic activity, which involves deposition of scapolite in pore spaces. The Feres basin can be subdivided on the basis of mineral alteration assemblages: (1) the Pefka region; characterized by intense hydrothermal alteration of the volcanic rocks and mineral zoning(silicic, argillic, sericitic and propylitic zones) with polymetallic mineralization, and (2) the remainder of the basin; where the volcaniclastic rocks are characterized by the alteration of volcanic glass to zeolites (clinoptilolite, heulandite, mordenite, analcime), clay minerals (smectite, illite, celadonite, chlorite), SiO2polymorphs (cristobalite, opal-CT, quartz), K-feldspar and calcite. Laumontite is also present as an alteration product of plagioclase, with stilbite sporadically occurringin veinlets. Locally, rhyolites are also altered to zeolites (clinoptilolite and/or mordenite). The zeolitization process has occurred rapidly with the depositional environment, temperature, rate of cooling(of the volcanic rocks), nature and temperature of the mineral-forming fluids and composition of the parent material controllingthe formation of zeolites.
Cesium kupletskite renamed kupletskite-(Cs)
Authors: Bayliss P.
Published: October 2007

Cesium kupletskite has been renamed kupletskite-(Cs) with the approval of the IMA Commission on New Minerals, Nomenclature and Classification, because the name of a mineral species should be a single word and the International Union of Pure and Applied Chemistry spelling is caesium. The presence or absence of parentheses around the suffix chemical-element is discussed. The advantages of the chemical-element suffix nomenclature are stated.
FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia
Authors: Kim Hyung-Gyoon , Kojima Kyoko , Swindle C. Scott , Cotta Claudiu V. , Huo Yongliang , Reddy Vishnu , Klug Christopher A.
Published: October 2007

The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(16) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBFβ-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBFβ-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBFβ-SMMHC/FLT3-ITD–expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFβ-SMMHC–expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBFβ-SMMHC/FLT3-ITD–reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBFβ-SMMHC in an animal model of inv(16)-associated AML.
Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells
Authors: Zeiser Robert , Leveson-Gower Dennis B. , Zambricki Elizabeth A. , Kambham Neeraja , Beilhack Andreas , Loh John , Hou Jing-Zhou , Negrin Robert S.
Published: October 2007

Based on their ability to control T-cell homeostasis, Foxp3+CD4+CD25+ regulatory T cells (Tregs) are being considered for treatment of autoimmune disorders and acute graft-versus-host disease (aGVHD). When combining Tregs with the immunosuppressant rapamycin (RAPA), we observed reduced alloreactive conventional T-cell (Tconv) expansion and aGVHD lethality compared with each treatment alone. This synergistic in vivo protection was paralleled by intact expansion of polyclonal Tregs with conserved high FoxP3 expression. In contrast to Tconv, activation of Tregs with alloantigen and interleukin-2 preferentially led to signal transducer and activator of transcription 5 (STAT5) phosphorylation and not phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activity. Expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR pathway, remained high in Tregs but not Tconv during stimulation. Conversely, targeted deletion of PTEN increased susceptibility of Tregs to mTOR inhibition by RAPA. Differential impact of RAPA as a result of reduced usage of the mTOR pathway in Tregs compared with conventional T cells explains the synergistic effect of RAPA and Tregs in aGVHD protection, which has important implications for clinical trials using Tregs.
Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice
Authors: Guillot Pascale V. , Abass Oyebode , Bassett J. H. Duncan , Shefelbine Sandra J. , Bou-Gharios George , Chan Jerry , Kurata Hitoshi , Williams Graham R. , Polak Julia , Fisk Nicholas M.
Published: October 2007

The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted human first-trimester fetal blood mesenchymal stem cells (MSCs) into homozygous oim mice in utero. This resulted in a two-thirds reduction in long bone fractures (P < .01), with fewer fractures per mouse (median 1, range 0-2 in mice that received transplants vs median 3, range 1-5 in mice that did not receive transplants by 12 weeks, P < .01). Nearly all mice that did not receive transplants had fractures (47 [97.9%] of 48), in contrast to 17 (58.6%) of 29 4- to 12-week-old mice that received transplants (P < .01). Transplantation was associated with increased bone strength (P < .01), thickness (P < .01), and length (P < .01), and normalization/reduction of growth plate height in 4- to 12-week-old oim was reduced in mice that underwent transplantion (P < .001). More donor cells were found in bone tissues compared with other organs (P < .001), with cells clustered in areas of active bone formation and remodeling, and at sites of fracture healing. Donor cells found in the bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSCs markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.
Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
Authors: Rezaï Keyvan , Lokiec François , Grandjean Isabelle , Weill Sophie , de Cremoux Patricia , Bordier Vincent , Ekue Richard , Garcia Mickael , Poupon Marie-France , Decaudin Didier
Published: October 2007

Background

Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy.

Methods

Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection.

Results

Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone.

Conclusion

Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.
Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion
Authors: Austen Belinda , Skowronska Anna , Baker Claire , Powell Judith E. , Gardiner Anne , Oscier David , Majid Aneela , Dyer Martin , Siebert Reiner , Taylor A. Malcolm , Moss Paul A. , Stankovic Tatjana
Published: October 2007

Purpose

The ataxia telangiectasia mutated (ATM) gene is located on chromosome 11q and loss of this region is common in B-cell chronic lymphocytic leukemia (CLL). Our aim was to determine if CLL tumors with a chromosome 11q deletion might be divided into two subgroups based on the status of the remaining ATM allele.

Methods

The sequence of the residual ATM allele was determined in 72 CLLs with an 11q deletion. This was related to the cellular response to irradiation or cytotoxic drug exposure in vitro and clinical outcome.

Results

We show that the residual ATM allele is mutated in 36% of CLLs with an 11q deletion and that these leukemias demonstrate an impaired cellular response to irradiation or cytotoxic drug exposure in vitro. Inactivation of the second ATM allele was associated with a reduction in patient survival beyond that already dictated by the presence of an 11q deletion (P = .0283). Furthermore, we demonstrate that ATM mutations may arise during the evolution of an 11q deleted subclone and are associated with its expansion.

Conclusion

CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.
VCAP-AMP-VECP Compared With Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801
Authors: Tsukasaki Kunihiro , Utsunomiya Atae , Fukuda Haruhiko , Shibata Taro , Fukushima Takuya , Takatsuka Yoshifusa , Ikeda Shuichi , Masuda Masato , Nagoshi Haruhisa , Ueda Ryuzo , Tamura Kazuo , Sano Masayuki , Momita Saburo , Yamaguchi Kazunari , Kawano Fumio , Hanada Shuichi , Tobinai Kensei , Shimoyama Masanori , Hotta Tomomitsu , Tomonaga Masao
Published: October 2007

Purpose

Our previous phase II trial for treating human T-lymphotropic virus type I–associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL.

Patients and Methods

Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis.

Results

A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm.

Conclusion

The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.
Prediction of human pharmacokinetics — renal metabolic and excretion clearance
Authors: Fagerholm Urban
Published: October 2007

The kidneys have the capability to both excrete and metabolise drugs. An understanding of mechanisms that determine these processes is required for the prediction of pharmacokinetics, exposures, doses and interactions of candidate drugs. This is particularly important for compounds predicted to have low or negligible non-renal clearance (CL). Clinically significant interactions in drug transport occur mostly in the kidneys. The main objective was to evaluate methods for prediction of excretion and metabolic renal CL (CLR) in humans. CLR is difficult to predict because of the involvement of bi-directional passive and active tubular transport, differences in uptake capacity, pH and residence time on luminal and blood sides of tubular cells, and limited knowledge about regional tubular residence time, permeability (Pe) and metabolic capacity. Allometry provides poor predictions of excretion CLR because of species differences in unbound fraction, urine pH and active transport. The correlation between fraction excreted unchanged in urine (fe) in humans and animals is also poor, except for compounds with high passive Pe (extensive/complete tubular reabsorption; zero/negligible fe) and/or high non-renal CL. Physiologically based in-vitro/in-vivo methods could potentially be useful for predicting CLR. Filtration could easily be predicted. Prediction of tubular secretion CL requires an in-vitro transport model and establishment of an in-vitro/in-vivo relationship, and does not appear to have been attempted. The relationship between passive Pe and tubular fraction reabsorbed (freabs) for compounds with and without apparent secretion has recently been established and useful equations and limits for prediction were developed. The suggestion that reabsorption has a lipophilicity cut-off does not seem to hold. Instead, compounds with passive Pe that is less than or equal to that of atenolol are expected to have negligible passive freabs. Compounds with passive Pe that is equal to or higher than that of carbamazepine are expected to have complete freabs. For compounds with intermediate Pe the relationship is irregular and freabs is difficult to predict. Tubular cells are comparably impermeable (for passive diffusion), and show regional differences in enzymatic and transporter activities. This limits the usefulness of microsome data and makes microsome-based predictions of metabolic CLR questionable. Renal concentrations and activities of CYP450s are comparably low, suggesting that CYP450 substrates have negligible metabolic CLR. The metabolic CLR of high-Pe UDP-glucuronyltransferase substrates could contribute to the total CL.
Laser-ablated nanofunctional polymers for the formulation of slow-release powders for dry powder inhalers: physicochemical characterization and slow-release characteristics
Authors: Coowanitwong Intira , Arya Vikram , Patel Gina , Kim Won-Seok , Craciun Valentin , Rocca James R , Singh Rajiv , Hochhaus Günther
Published: October 2007

Recently, dry powder inhalation (DPI) powders coated with nanometre-thin layers of biodegradable polymers, prepared using pulse laser deposition (PLD), have been evaluated as a slow-release formulation for DPI use, with the goal of improving pulmonary selectivity. This paper describes evaluation of the chemical stability of one potential polymer, poly lactic acid (PLA), during the ablation process, the resulting respirable properties and potential cytotoxicity of coated glucocorticoid powders, and the resulting sustained-release characteristics of PLA-coated glucocorticoids creating using PLD. Triamcinolone acetonide (TA) and budesonide (BUD) were used as two model glucocorticoids to determine pulmonary targeting (PT) in-vivo.

The chemical stability of PLA was determined at various laser energy densities. The respirable fraction and the cytotoxicity of the micronized particles of TA and BUD, coated using optimum laser energy density, were determined. In-vitro dissolution profiles were generated for the coated/uncoated formulations and an ex-vivo receptor binding assay was used to determine PT in rats.

Increasing laser energy density led to decreases in molecular weight and film density, and increases in degradation products, roughness and thickness of the film. The mean dissolution time of coated formulations of BUD was longer (4 h) than with the less lipophilic TA (2 h). This correlated well with a more pronounced pulmonary selectivity observed for coated BUD ex-vivo.

Stability and the physical properties of the film correlated with the laser energy density. We observed a direct relationship between the dissolution rate of the uncoated and coated formulation and the degree of PT; however, physiochemical properties of the drug (e.g. lipophilicity) may also contribute to the improved PT.
Determination of calcium salt solubility with changes in pH and PCO2, simulating varying gastrointestinal environments
Authors: Goss Sandra L , Lemons Karen A , Kerstetter Jane E , Bogner Robin H
Published: October 2007

The amount of calcium available for absorption is dependent, in part, on its sustained solubility in the gastrointestinal (GI) tract. Many calcium salts, which are the calcium sources in supplements and food, have pH-dependent solubility and may have limited availability in the small intestine, the major site of absorption. The equilibrium solubility of four calcium salts (calcium oxalate hydrate, calcium citrate tetrahydrate, calcium phosphate, calcium glycerophosphate) were determined at controlled pH values (7.5, 6.0, 4.5 and ≤ 3.0) and in distilled water. The solubility of calcium carbonate was also measured at pH 7.5, 6.0 and 4.5 with two CO2 environments (0.3 and 152 mmHg) above the solution. The precipitation profile of CaCO3 was calculated using in-vivo data for bicarbonate and pH from literature and equilibrium calculations. As pH increased, the solubility of each calcium salt increased. However, in distilled water each salt produced a different pH, affecting its solubility value. Although calcium citrate does have a higher solubility than CaCO3 in water, there is little difference when the pH is controlled at pH 7.5. The partial pressure of CO2 also played a role in calcium carbonate solubility, depressing the solubility at pH 7.5. The calculations of soluble calcium resulted in profiles of available calcium, which agreed with previously published in-vivo data on absorbed calcium. The experimental data illustrate the impact of pH and CO2 on the solubility of many calcium salts in the presence of bicarbonate secretions in the intestine. Calculated profiles using in-vivo calcium and bicarbonate concentrations demonstrate that large calcium doses may not further increase intestinal calcium absorption once the calcium carbonate solubility product has been reached.
Citric acid as a solid-state plasticizer for Eudragit RS PO
Authors: Schilling Sandra U , Shah Navnit H , Malick A Waseem , Infeld Martin H , McGinity James W
Published: October 2007

The use of solid-state plasticizers for the hot-melt extrusion of pharmaceutical dosage forms has been shown to be beneficial compared with liquid plasticizers. The purpose of this study was to determine the suitability of citric acid (CA) as a solid plasticizer for the preparation of Eudragit RS PO extended-release matrix systems by a melt extrusion technique. The influence of increasing levels of CA monohydrate (CA MH) or anhydrous CA in the powder blend on the extrusion process parameters (screw speed and motor load) was determined as a function of temperature. The solubility of CA MH in extruded tablets was studied by means of modulated differential scanning calorimetry (MDSC) and powder X-ray diffraction (PXRD). Films were cast from organic solutions to demonstrate the plasticizing effect of CA MH as a change in physico-mechanical properties (tensile strength, elastic modulus and elongation). The CA release from extruded tablets was studied over 12 h. The monohydrate form was found to distinctly facilitate the extrusion of Eudragit RS PO, whereas the addition of anhydrous CA to the polymer powder was less effective. This divergent behaviour in plasticization of Eudragit RS PO was attributed to the higher solubility of the monohy-drate in the acrylic polymer. The plasticizing effect of the CA MH reached a plateau at 25% during hot-melt extrusion, which coincided with the solubility limit of the organic acid in the polymer as shown by MDSC and PXRD results. The CA MH increased the flexibility of Eudragit RS PO films, as demonstrated by a decrease in tensile strength and elastic modulus and an increase in elongation as a function of CA MH concentration. The dissolution of CA from the matrix tablets followed an extended-release profile, with CA MH exhibiting a faster dissolution rate than the anhydrous form. In conclusion, CA MH was found to be an effective plasticizer for Eudragit RS PO that facilitates the production of controlled-release matrix systems by hot-melt extrusion.
Hydrogen peroxide overproduced in breast cancer cells can serve as an anticancer prodrug generating apoptosis-stimulating hydroxyl radicals under the effect of tamoxifen-ferrocene conjugate
Authors: Wlassoff Wjatschesslaw A , Albright Craig D , Sivashinski Michael S , Ivanova Anastasia , Appelbaum Jacob G , Salganik Rudolph I
Published: October 2007

A new approach to the treatment of cancer is suggested, based on the innate overproduction of hydrogen peroxide in cancer cells. Hydrogen peroxide serves as a prodrug in the presence of transition metal ions, such as iron delivered by ferrocene. Under the effect of ferrocene, hydrogen peroxide is split into hydroxyl anions and highly reactive hydroxyl radicals. The latter cause oxidative DNA damage, which induces apoptosis, leading to elimination of cancer cells. Tamoxifen, a drug that interacts with oestrogen receptors, was used as a carrier to deliver ferrocene to breast cancer cells. For this aim tamoxifen conjugated to ferrocene (Tam-Fer) was synthesized. We have shown that the frequency of apoptotic events in MCF-7 breast cancer cells treated with Tam-Fer is significantly higher than in cells treated with tamoxifen or ferrocene separately. The increase of apoptosis correlates well with the rise in generation of reactive oxygen species in cancer cells. These results show that the hydrogen peroxide overproduced in tumour cells can serve as a prodrug for the treatment of cancer.
Milton, the Gunpowder Plot, and the Mythography of Terror
Authors: Appelbaum Robert
Published: October 2007

Robert Appelbaum is senior lecturer in Renaissance studies at Lancaster University. He is author, most recently, of Aguecheek's Beef, Belch's Hiccup, and Other Gastronomic Interjections: Literature, Culture, and Food among the Early Moderns (2006). A Leverhulme fellow for 2007-8, he is working on a new book, tentatively titled Terrorism before the Letter.
Photoisomerization of 2-(2-Hydroxyphenyl)benzothiazole Derivatives as an Adequate Model to Reveal Photochromism of Schiff Bases in the Solid State
Authors: Taneda Masatsugu , Kodama Yoshinori , Eda Yusaku , Koyama Hiroyuki , Kawato Toshio
Published: October 2007

Photochromic behavior of 2-(2-hydroxyphenyl)benzothiazole derivatives, whose photoinduced deformation was restricted by the cyclic structure, was first observed to suggest the existence of a cis-keto form as a certain structure for the photochrome of N-salicylideneanilines in the crystal state.
Unusual Demethylation of O,O′-Dimethyl Chlorothiophosphate with Aryllithiums
Authors: Ribeiro Nigel , Maeda Jin , Ishida Yasuhiro , Kobayashi Yuka , Saigo Kazuhiko
Published: October 2007

The reaction of O,O′-dimethyl chlorothiophosphate with aryllithiums took place easily to afford the corresponding methylated aryl compounds in place of expected O,O′-dimethyl aryl(thiophosphonate)s.
The sheep as a knee osteoarthritis model: early cartilage changes after meniscus injury and repair
Authors: Burger C , Mueller M , Wlodarczyk P , Goost H , Tolba R H , Rangger C , Kabir K , Weber O
Published: October 2007

The purpose of this study was to analyse cartilage changes after traumatic meniscal lesions and to provide a detailed description of the model used with a view to reducing the number of animals used in future studies. The sheep's knee was chosen, as ovine biomechanics are similar to that of humans. In two groups of 10 animals each, a radial tear in the medial meniscus was either sutured with polydioxanone (PDS) or left untreated (sham-operated). Half of the animals in each group were sacrificed after six months, the other half after one year. The time periods to achieve weight bearing, meniscus healing, joint effusion (magnetic resonance imaging scan) and knee cartilage in the medial, lateral and patellofemoral compartments were evaluated in comparison to the opposite knee (control). Osteoarthritis (OA) was assessed by a modified Outerbridge classification and confirmed by scanning electron microscopy. Only one sutured meniscus remained completely adapted. In all other meniscus lesions, the rupture healed with a scar. In the PDS and sham-operated groups, OA was significantly higher in the medial knee compartment than in the lateral compartment and in controls ( P < 0.001). In the operated groups, joint effusion was higher in the right hindlimb knee than in the normal left hindlimb knee (control) after six and 12 months ( P < 0.001). Non-treated, displaced and even adapted sutured radial ovine meniscus tears produced intense OA within less than six months. Therefore, this animal model is suitable for assessment of new therapeutic regimens in meniscal surgery.
Refinement of a transplantation project in the non-human primate by the use of a humane endpoint
Authors: Fante F , Boldrin M , Polito L , Ravarotto L , Castagnaro M , Hutabba S , Cozzi E , Ancona E
Published: October 2007

An assessment scheme was developed to establish a humane endpoint in a pig-to-primate renal xenotransplantation project, with a view to minimizing and controlling any pain or suffering conditions in the animals involved while still achieving the scientific objective. In particular, the assessment criteria for identifying the earliest endpoint are described, bearing in mind both the researcher's need to obtain top-quality data and the ethical need to safeguard the animals. The scheme should also be applicable to other experiments involving non-human primates (e.g. allotransplantation, survival after major surgery, pharmacological safety tests) because it considers reproducible general parameters together with aspects specific to each experimental model.
Ophthalmology: the good, the bad and the ugly
Authors: Scott Robert A H
Published: October 2007

This article describes procedures and common complications relating to some aspects of eye surgery. Most ophthalmic claims divide into three groups: the first, where the surgery and general care of the patient is not at fault but the patient is dissatisfied with the result or simply dislikes the surgeon; the second is where substandard care and clinical negligence has occurred and the patient has had a bad result; and the third is where a surgical disaster has occurred. Medicolegal issues in cataract surgery often concern the preoperative consenting and counselling process, when an individual claims not to have been warned about a particular complication when the result is not as good as the patient expects. Vitreoretinal procedures for retinal detachments and macular disease do not attain the same excellent surgical outcomes as cataract surgery, though patient expectation is often as high. Common cases in this group involve chronic retinal detachments that have blinded an eye over several months and not been diagnosed by an optician. Another recurring theme is the negligent use of intraocular gas where an unintended expansile volume is injected into the eye or if the patient is not warned about high altitudes or the effect of anaesthetic gases that make the bubble expand in the eye to cause a very high pressure with excrutiating pain and blindness from occlusion of the central retinal artery. Ocular trauma cases often centre on inadequacies of ocular protection, the lack of prophylactic antibiotic cover and not warning patients about sympathetic ophthalmia after penetrating ocular injuries.
Cardiac surgery: the medicolegal issues
Authors: Hamilton J R L
Published: October 2007

This article provides the lawyer and other uninitiated readers with an introduction to the principles and practice of cardiac surgery. Medicolegal problems relating to consent, professional competence, supervision of trainees and peri-operative care are outlined. Liability issues in three cardiac operations valve surgery, aortic surgery and coronary artery bypass grafts are discussed.
Book Reviews
Authors: Lev Benjamin
Published: October 2007

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. However, we do not review software. To submit a book for review, please send it to me at the above address. Although we cannot review all books because of space limitations, we do list all books that we receive.

We commission all book reviews and do not accept unsolicited reviews. To become a reviewer, please send me your name, address, and specific areas of expertise. We encourage readers to suggest books for review or to ask publishers to send copies of such books.

The authors or editors of books we review in this issue are Antonio Conejo, Enrique Castillo, Roberto Minguez, Raquel Garcia-Bertrand, Randolph W. Hall, Thomas L. Saaty, Luis G. Vargas, Antony Unwin, Martin Theus, and Heike Hofmann.
A Periodic-Review Modeling Approach for Guaranteed Service Supply Chains
Authors: Bossert John M. , Willems Sean P.
Published: October 2007

We extend the guaranteed service, supply chain modeling framework to allow for an arbitrary, integer review period or ordering frequency at each stage. We define a notation for the cyclic inventory dynamics that review periods introduce and generalize inventory-balance equations to accommodate three different periodic-review operating policies—constant base stock, constant safety stock, and adaptive base stock. As a form of validation, we apply the model to the Celanese acetic acid supply chain and show that inventory metrics of the new model differ by more than 30 percent from those derived through the simpler modeling approach of aggregating a review period into lead time.
Warranty Inventory Optimization for Hitachi Global Storage Technologies, Inc.
Authors: Khawam John , Hausman Warren H. , Cheng Dinah W.
Published: October 2007

Warranty inventory management is a challenge that many companies must confront. Customers return allegedly defective units to a company for replacement or credit. The company can then economically recover the unit through either a testing or remanufacturing process; it can use recovered units to fulfill future warranty requests. The company also has the option of purchasing a new product from the production line. In high-volume situations, warranty inventory management involves many complexities such as stochastic demand rates, probabilistic requests for credit instead of replacement, probabilistic repairs, multiple sources of supply, and tight customer-service constraints. Companies may also have to consider the complexities that a batch remanufacturing process causes.

In this paper, we formulate several related models of such warranty inventory systems. In these models, we study a periodic, single-location, inventory system that is dedicated to warranty returns. We find near-optimal policies for each system using well-developed heuristics. The models include the following complexities: random warranty claims, random requests for replacement or credit, three sources of supply (testing, remanufacturing, and new product), random flows of returned products into testing and remanufacturing, random yields from testing and remanufacturing, different lead times for each resupply process, remanufacturing lead time variability, and random batching of remanufacturing. The results of the models provide near-optimal inventory-control policies in this complex environment and demonstrate the payoffs that result from reducing production lead times and batching in remanufacturing.

Hitachi GST has gained a great deal from this modeling process. In addition to the direct benefit from the model's calculations, additional sensitivity analyses have shed light on the quantitative importance of various factors, including demand volatility, the percentage of credit requests, the percentage of units successfully remanufactured, and batching effects in remanufacturing.