bluuebunny/crossref_metadata_2025 huggingface dataset:
Employing the evidence-based paradigm for technology-related decision making
Authors: Budgen David , Kitchenham Barbara , Brereton Pearl , Turner Mark , Charters Stuart , Linkman Stephen
Published: June 2008

We report our experiences with adapting the systematic review procedures to help consolidate software engineering knowledge, seen as a step towards being able to employ evidence-based practices to assist with decision making in IT. We describe the different studies performed, and illustrate our procedures through a fuller description of one of our reviews. Our work has demonstrated the value of a study protocol and identified a number of problems. We conclude that it is practical to employ systematic literature reviews in software engineering, but that some cultural changes are required, particularly for reporting of empirical studies.
Does evidence-based policy work? Learning from the UK experience
Authors: Boaz Annette , Grayson Lesley , Levitt Ruth , Solesbury William
Published: June 2008

This article reviews what has happened to put into effect the commitment to more evidencebased policy and practice in the UK, by identifying the opportunities this has offered to the research community and reflecting on the ways in which researchers have responded. It identifies a number of issues that remain unresolved and offers an agenda for those who are committed to advancing the application of evidence to policy and practice in the UK and elsewhere.
Treatment of Citrobacter kosen Infection with Ciprofloxacin and Cefotaxime in a Preterm Infant
Authors: McPherson Christopher , Gal Peter , Ransom J Laurence
Published: June 2008

Objective:

To report a case of successful treatment of Citrobacter koseri infection in a preterm infant as a means of challenging the current treatment recommendations on the basis of pharmacodynamic and pharmacokinetic considerations.

Case Summary:

A premature infant was diagnosed with C. koseri sepsis after 3 weeks in intensive care. Concern for meningitis was based on the propensity for central nervous system (CNS) involvement with Citrobacter infection along with new findings of ventriculomegaly and hydrocephalus shown on cranial ultrasound (CUS). The infant was treated with ciprofloxacin 10–20 mg/day and cefotaxime 100 mg/day for 21 days. After treatment, lumbar puncture was normal, follow-up CUS returned to baseline, and the Infant passed a hearing screen after discharge. A favorable outcome was achieved in this case.

Discussion:

Approximately 76% of neonatal patients Infected with C. koseri develop brain abscesses. The mortality rate for meningitis due to Citrobacter sop is approximately 30%, and of the infants who survive, more than 80% have some degree of mental retardation. Third-generation cephalosporins and aminoglycosides are traditional therapies against this infection. The current antibiotic strategies have failed to prevent the high rates of morbidity and mortality associated with Citrobacter infections. A possible basis for these poor outcomes is failure to apply appropriate pharmacokinetic and pharmacodynamic principles in selecting antibiotics that will achieve adequate concentrations to kill the bacteria in granulocytes within the CNS. Based on favorable sensitivity data, penetration into neutrophils and the CNS, and favorable toxicity profiles, ciprofloxacin and meropenem would appear to be the most appropriate antibiotic treatment options for systemic infection or meningitis caused by C. koseri.

Conclusions:

Ciprofloxacin and meropenem should be considered antibiotic treatment options for systemic infection or meningitis caused by G koseri.
Medication Reconciliation Effect on Prolonged Inpatient Stress Ulcer Prophylaxis
Authors: Zeigler Amy J , McAllen Karen J , Slot Martha G , Barletta Jeffrey F
Published: June 2008

Background:

While medication reconciliation (MR) has been shown to reduce medication errors by limiting errors of transcription, omission, and duplicate therapy, its Impact on the provision of unnecessary prophylaxis is largely unknown.

Objective:

To determine the effect of MR on the incidence of prolonged stress ulcer prophylaxis (SUP) across the continuum of care from hospital admission to discharge as well as evaluate clinical conditions associated with prolonged SUR

Methods:

This retrospective study assessed patients who were admitted to the intensive care unit (ICU) and had SUP initiated. Patients were excluded if they were receiving gastroprotective therapy prior to ICU admission, were being treated for an acute gastrointestinal hemorrhage, or died. The need for SUP was determined using risk factors adapted from evidence-based guidelines developed by the American Society of Health-System Pharmacists. The use of SUP was assessed upon transfer from the ICU to a non-ICU setting and at hospital discharge. Results were compared between pre-MR and post-MR groups.

Results:

Data from 114 (pre-MR, n = 53; post-MR, n = 61) medical and surgical ICU patients were evaluated. There was no significant difference in the use of prolonged SUP upon transfer from the ICU to a non-ICU setting in the pre-MR and post-MR groups, respectively (85% [45/53] vs 79% [48/61), p = 0.393). Similarly, there was no significant difference in the use of prolonged SUP upon hospital discharge In the pre-MR and post-MR groups, respectively (14% [6/44] vs 23% [10743), p = 0.247), There were no clinical conditions for which prolonged SUP use was predominant.

Conclusions:

The strategy of MR alone will not decrease the incidence of prolonged SUP in hospitalized patients. Other techniques should be evaluated to encourage appropriate use of acid-suppressive agents.
From Silence to Silence: The Hidden Story of a Beef Stew in Cape Verde
Authors: Rodrigues Isabel P. B. Fêo
Published: June 2008

This article engages the cultural continuities that bridge a colonial past of famine with a present context of emerging food vulnerabilities in the urban peripheries of Cape Verde. Merging a historical and ethnographic lens, this work interrogates: Is the present silence about food vulnerability different from past silences regarding famine? How do we interpret present discourses surrounding food when these often conceal rather than reveal food vulnerabilities? How can we bridge the past history of famines (which disproportionately affected the rural poor) with emerging food vulnerabilities in the urban areas where the repetition of rice meals accounts for the bulk of survival?
The Trap of Abstract Space: Recomposing Russian-Speaking Immigrants in Post-Soviet Estonia
Authors: Feldman Gregory
Published: June 2008

Focusing on the Estonian government's policy to integrate Soviet-era Russian-speaking immigrants, this article historically examines how public officials have come to constitute Estonian state space as a particular national place through the re-constitution of these immigrants in public policy. Drawing on Lefebvre's The Production of Space , the analysis describes place as a combined result of three types of space mobilized in social practice: spatial practices, representational spaces, and representations of space. Conceived through the third type, successful statecraft produces an abstract space that traps target populations through subject-making. The article's deeper project is two-fold. First, it aims to theorize the spatial interplay between deterritorialization and the state's efforts to reterritorialize the nation through citizenship and integration policy. Second, it aims to compensate for ethnographic tendencies that privilege data obtained through direct sensory experience to better capture how the deployment of spatial abstractions in public policy marginalize immigrants and minority groups.
Producing Diasporas and Globalization: Indian Middle-Class Migrants in Dubai
Authors: Vora Neha
Published: June 2008

Through ethnographic examples, I explore two modes of diasporic subjectivity that I observed among middle-class Indian migrants in Dubai—racial consciousness and consumer citizenship. However, I argue that the alignment of academic and diasporic informants' understandings of mutually exclusive domains such as culture, nation, economy, and state lead to the relative invisibility of this large population in most literature on South Asian diasporas, and I point to a need to theoretically and methodologically begin our anthropological research with how and when domains become distinct for migrant subjects, rather than taking them as a priori forms.
Conquistas vi(r)olentas y vacunas independentistas: Andrés Bello y Manuel José Quintana ante la enfermedad de la colonia
Authors: Pereiro-Otero José Manuel
Published: June 2008

The discovery of the small-pox vaccine at the end of the 18th century helped to eradicate the once globally endemic illness. Given the viciousness of the disease in Spanish-America, the Spanish Crown financed the philanthropic endeavor known as the “Real Expedición Marítima de la Vacuna” (1803-1812) in order to disseminate the cure. Poetic works in America and in Spain such as “A la vacuna” and “Venezuela consolada” by the Venezuelan Andrés Bello, and “A la expedición española” by the Spanish Manuel José Quintana lauded both the vaccine and the Expedition. In these compositions, the coexistence of colonial rule, a debilitating pandemic, and the introduction of its vaccine creates a representational impasse that relates political independence with a literal and symbolic cure. These works provide solutions to this deadlock that are mediated rather unexpectedly by the notion of writing and colonial dominion as both treatment and infection.
Between Agency and Determinism: A Critical Review of Clarín Studies
Authors: Charnon-Deutsch Lou
Published: June 2008

Since its publication in 1884, critics have persistently debated the topic of agency in Leopoldo Alas' novel La Regenta. To some the novel's characters seem incredibly rational and endowed with heroic moral responsibility, while to others they provide evidence of social constructivism, the result of the author's engagement with French nationalism. A review of these debates over time shows patterns that fluctuate according to ideological positions that transcend rather than simply reflect the novel's biases. For the novel to continue to be a forum for debate, however, critics may have to move beyond these debates as they are usually framed and engage in a more theoretical discussion of social agency in order to arrive at a more precise conception of how social identity is attained.
How Does One Escape One's Own Simulacrum?: Subjectivity and the Asceticism of Being in Terenci Moix's Autobiography
Authors: Vilaseca David
Published: June 2008

This article draws on the early work by Gilles Deleuze in order to elucidate some key aspects relating to the representation of subjectivity in Terenci Moix’s three-volume autobiography El peso de la paja. It starts by looking at Deleuze’s notion of the subject as a “simulacrum” of Being and as a mere “impersonal consciousness” (Jean Khalfa). Drawing on Alain Badiou’s and Slavoj _i_ek’s respective readings of Deleuze, it analyzes the philosopher’s notion of thought as an “ascetic” process whereby the individual is “transfixed” by the “impersonal exteriority” that is also considered to be his or her most authentic being. Against this theoretical background, the article then turns to Moix in order to interpret the author’s renunciation of love in favor of literature at the end of his own personal apprenticeship—among other aspects of his autobiography— as a turn toward a domain of virtual transcendence, one which leads Moix to attain “intellectual beatitude” conceived as “the enjoyment of the Impersonal.”
The Chronicler as Streetwalker: Salvador Novo and the Performance of Genre
Authors: Mahieux Viviane
Published: June 2008

This article analyzes how a young Salvador Novo established himself as a chronicler and public figure 1920’s Mexico City. Through the lens of a polemic that took place between Novo and Ruben M Campos in the weekly El universal ilustrado in 1929, this essay reads Novo’s turn to the chronicle as his response to the debates on the “feminization” of literature which galvanized Mexico’s intellectuals in the aftermath of the revolution. Novo conceives of the chronicle as a genre that performs both the “masculinity” of literature and the “femininity” of mass culture. Doubling as a temptress or a prostitute, the chronicler strips literature of its aura, making it desirable, irresistible, and public. As a chronicler, Salvador Novo works by engaging readers and drawing them in as sexual/textual accomplices to inscribe literary style into the public sphere.
La dimensión ética de la poesía en el exilio: Primavera en Eaton Hastings de Pedro Garfias
Authors: Barriales-Bouche Sandra
Published: June 2008

This paper examines the impact of exile on the literary works of Pedro Garfias, an outstanding Ultraist poet who was forced to flee Spain after the outbreak of the Spanish Civil War. Primavera en Eaton Hastings (1941), the first book of poetry written by Garfias after having left Spain, reflects, both in structure and content, the challenges of writing in exile. Profoundly affected by isolation and the memories of the war, the poems of Pedro Garfias in exile are informed by an urgent sense of responsibility and guilt that questions the limits of the writing itself. Primavera reflects the ethical dimension that Emmanuel Levinas claims as fundamental in the subjectivity. War and exile oblige Garfias to reconsider his identity and to realize that it is not autonomous, but rather dependent on the other. Likewise, he discovers that writing in exile is primordially a responsible act. Having the victims of the Spanish Civil War as its ultimate addressees, Garfias proposes a poetry that talks to —and not about— the Other. The urge to communicate with their addresses without turning them into an object of the poetic voice makes Garfias defy the bucolic conventions and go beyond the limits of aestheticism. Although Garfias had already pursued a more profound and rich encounter with his addresses in the poems he wrote before the Spanish Civil War, it will be in exile when he finally reaches a more satisfactory poetics.
Role of Immunohistochemistry in Staging Diffuse Large B-cell Lymphoma (DLBCL)
Authors: Talaulikar Dipti , Dahlstrom Jane Esther , Shadbolt Bruce , Broomfield Amy , McDonald Anne
Published: June 2008

The use of immunohistochemistry (IHC) in staging bone marrow in non-Hodgkin's lymphoma (NHL) is largely limited to ambiguous cases, particularly those with lymphoid aggregates. Its role in routine clinical practice remains unestablished. This study aimed to determine whether the routine use of IHC in diffuse large B-cell lymphoma (DLBCL) would improve the detection of lymphomatous involvement in the bone marrow. It also sought to determine the impact of IHC on predicting survival compared with routine histological diagnosis using hematoxylin and eosin (H&E), Giemsa, and reticulin staining. The bone marrow trephines of 156 histologically proven DLBCL cases were assessed on routine histology, and IHC using two T-cell markers (CD45RO and CD3), two B-cell markers (CD20 and CD79a), and κ and λ light chains. IHC detected lymphomatous involvement on an additional 11% cases compared with histology alone. Although both routine histology and IHC were good predictors of survival, IHC was better at predicting survival on stepwise multivariate Cox regression analysis. IHC performed routinely on bone marrow trephines has the ability to improve detection of occult lymphoma in experienced hands. Furthermore, it is a better predictor of survival compared with routine histological examination alone.
Use of Protein Biotinylation In Vivo for Immunoelectron Microscopic Localization of a Specific Protein Isoform
Authors: Viens Antoine , Harper Francis , Pichard Evelyne , Comisso Martine , Pierron Gérard , Ogryzko Vasily
Published: June 2008

Tagging of proteins in vivo by covalent attachment of a biotin moiety has emerged as a new prospective tool for protein detection and purification. Previously, we established a strategy for expression of in vivo biotinylated proteins in mammalian cells. It is based on coexpression of the protein of interest fused to a short biotin acceptor peptide and biotin ligase BirA cloned in the same vector. We show here that the in vivo biotinylation can be used for immunogold postembedding labeling in immunoelectron microscopy experiments. We show that immunoelectron microscopy with biotinylated nuclear proteins is compatible with a wide range of postembedding methods, facilitating combination of morphological and localization studies in a single experiment. We also show that the method works in both transient transfection and stable cell line expression protocols and can be used for colocalization studies. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
Radiochemical studies relevant to the no-carrier-added production of 61,64Cu at a cyclotron
Authors: Sadeghi M. , Amiri M. , Roshanfarzad P. , Avila M. , Tenreiro C.
Published: June 2008

Copper-64 (t
½ = 12.7 h) is a promising cancer treatment radiotherapy agent and combines positron emission tomography (PET). It was produced utilizing the 64Ni(p,n) 64Cu nuclear reaction channel. Natural nickel was electroplated successfully, 48 μm thick, onto a gold-coated copper backing slab. Bombardment of nickel plated target was performed with 16 MeV protons at a current of 200 μA. Copper-64 together with copper-61 was separated from Ni and other non-isotopic impurities by ion exchange chromatography. The method of separation of radiocopper has been improved.
A novel [109Pd] palladium labeled porphyrin for possible use in targeted radiotherapy
Authors: Das T. , Chakraborty S. , Sarma H. D. , Banerjee S.
Published: June 2008

The preferential accumulation of porphyrins in malignant tumor cells has been adequately documented. Hence, porphyrin derivatives radiolabeled with a suitable therapeutic radionuclide could be envisaged as potential agents for targeted tumor radiotherapy. Working in this direction, we have radiolabeled a porphyrin derivative, namely, 5,10,15,20-tetrakis[3,4-bis(carboethoxymethyleneoxy)phenyl]-porphyrin, synthesized in-house, with 109Pd [E
β(max)=1.12 MeV, E
γ=88 keV 3.6(%), T
1/2 = 13.7 h]. The envisaged rationale towards designing of this agent is based on the assumption that 109Pd would complex with the tetrapyrrole donor array constituting the porphyrin core, thereby providing a highly stable chelated complex, and the peripheral ester groups would impart optimum lipophilicity needed for sufficiently high tumor accumulation and retention therein. 109Pd was produced with a specific activity of ∼1.85 GBq/mg and radionuclidic purity of 100% by the thermal neutron bombardment of enriched (98% in 108Pd) metallic Pd target at a flux of 3×1013 n/cm2s1 for 3 d. The porphyrin derivative was synthesized by a multi-step reaction and characterized by normal spectroscopic techniques. 109Pd complex of the synthesized porphyrin derivative was prepared with excellent radiochemical purity (>98%) and the complex was observed to be stable upto 24 h at room temperature. Biodistribution studies carried out in Swiss mice bearing fibrosarcoma tumors revealed good tumor uptake [(5.28±1.46)% injected activity (IA)/g] within 30 min post-injection (p.i.). The complex exhibited favorable tumor/blood and tumor/muscle ratios [1.69±0.23 and 5.00±1.54, respectively at 3 h p.i.], albeit with high liver uptake throughout the time of study (>20% IA).
Dissolution of uranium oxides and electrochemical behavior of U(VI) in task specific ionic liquid
Authors: Rao Ch. Jagadeeswara , Venkatesan K. A. , Nagarajan K. , Srinivasan T. G.
Published: June 2008

A task-specific ionic liquid, protonated 1-carboxy-N,N,N-trimethylmethanaminium bis(trifluoromethylsulfonyl)imide trivially known as protonated betaine bis(trifluoromethylsulfonyl)-imide ([Hbet][NTf2]) was prepared and the dissolution of uranium oxides, UO3, UO2 and U3O8 in it was studied. Dissolution of UO3 in [Hbet][NTf2] was very rapid and the saturation solubility of uranium was found to be 15 wt. % at 373 K. In contrast, dissolution of UO2 was sluggish and it was facilitated only by the oxidation of UO2 to UO2
2+. U3O8 was insoluble up to 453 K. A new procedure was developed for the individual separation of uranium oxides using [Hbet][NTf2] based on differences in solubilities. The electrochemical behavior of U(VI) in the resultant solution was investigated by cyclic voltammetry at glassy carbon working electrode at 373 K. A surge in the cathodic peak current at -0.48 V (vs . Fc/Fc+) was due to the reduction of U(VI) to U(V) and the corresponding anodic peak current was observed at a potential of 0.64 V. Increasing the potential sweeping rate increases the peak current and shifts the peak potential negatively indicating the irreversible electroreduction of U(VI) in [Hbet][NTf2]. The diffusion coefficient of U(VI) in [Hbet][NTf2] was determined to be of the order of ∼10−8 cm2/s.
Appraisal in Bonobo-Human Culture
Authors: Knight Naomi K.
Published: June 2008

Instances of linguistic interactions with the bonobo apes (pan paniscus) Kanzi and Panbanisha have demonstrated that symbolic meaning is negotiated by bonobo and caregiver through discourse semantic systems in the English language (Benson & Greaves 2005: 33--34), developing a unique bonobo-human culture based on shared linguistic communication. In this paper, I will exhibit that caregivers and bonobos co-construe a higher order of social behavioural values and activities in bonobo-human culture through the employment of the linguistic semantic system of Appraisal, negotiating rules and boundaries and social expectations specific to their environment. In redesigning the Appraisal systems of JUDGEMENT and APPRECIATION and their subcategories, as well as restating lexical realizations to suit this unique culture, humans and bonobos can be seen to clearly express and comprehend evaluations of the full Appraisal system. I propose that through language, the four essential values of safety, open and growing communication, cooperation, and positive encouragement are built and maintained in evaluative meanings. This illustration of the use of the full system of Appraisal by Kanzi and Panbanisha suggest that the bonobos have achieved metasemiotic development into the English language beyond its affectual beginnings (Painter 2003).
A Critical Analysis of the Image of Immigrants in Multimodal Texts
Authors: Lirola María Martínez
Published: June 2008

In this article I will explore the main strategies used to make meaning in different multimodal texts related to immigration. I will pay attention to the way in which each semiotic resource has evolved to be used with other semiotic resources, which has implications in the ideational function of language, and in the way readers create meaning. My corpus of examples belongs to a local newspaper in Alicante, the city with the third highest number of immigrants in Spain. I will explore the reasons why the journalist chooses some linguistic and visual forms instead of others, and the influence of these forms in the creation of meaning. I will also observe how the written text in each article supports the construction of a particular image of immigrants, and will compare the texts for the visual and linguistic construction of immigrants. Through a visual grammar and linguistic analysis I will demonstrate how readers are positioned to have a negative view of immigrants that is supported through linguistic choices in the multimodal texts. In this way, I will point out some of the ways in which Halliday’s metafunctions are interlinked and impact on each other.
Impact of an Institution‐Specific Hospital‐Acquired Pneumonia Protocol on the Appropriateness of Antibiotic Therapy and Patient Outcomes
Authors: Lancaster Jason W. , Lawrence Kenneth R. , Fong Jeffrey J. , Doron Shira I. , Garpestad Erik , Nasraway Stan A. , Devlin John W.
Published: June 2008

Study Objective. To evaluate the impact of a hospital‐acquired pneumonia (HAP) protocol on appropriateness of empiric antibiotic therapy, antibiotic deescalation, antibiotic duration, patient mortality, and length of stay.

Design. Before‐ and after‐study of protocol implementation.

Setting. A 450‐bed, academic medical center.

Patients. One hundred consecutive patients with proven or suspected HAP.

Intervention. Implementation of an HAP protocol that was based on the 2005 American Thoracic Society‐Infectious Diseases Society of America guidelines and included extensive education of clinicians and monitoring by pharmacists.

Measurements and Main Results. Before protocol implementation, 50 patients with HAP were evaluated against protocol criteria. After protocol implementation, a second cohort of 50 patients with HAP was evaluated. Compared with the preprotocol group, implementation of the protocol led to an increase in both the proportion of patients who received appropriate empiric antibiotic coverage (17 [34%] vs 31 [62%] patients, p=0.005) and appropriate antibiotic deescalation (21 [42%] vs 36 [72%] patients, p=0.002) according to protocol recommendations but did not affect the appropriateness of empiric antibiotic therapy based on final lung culture data (34 [68%] vs 41 [82%] patients, p=0.11). Compared with the preprotocol group, use of the protocol decreased the duration of intravenous antibiotic therapy (median [range] 9 [2–21] vs 7 [1–16] days, p=0.024), was associated with a trend for a shorter duration of stay in the intensive care unit (median [range] 19 [2–57] vs 11 [3–76] days, p=0.065), and did not significantly affect mortality (5 [10%] vs 8 [16%] patients, p=0.37). Pharmacists performed 59 interventions to support the protocol in 29 patients in the postprotocol group, of which 48% were accepted.

Conclusions. Implementation of an HAP protocol improved appropriate empiric antibiotic use and decreased the duration of antibiotic therapy without adversely affecting patient outcomes.
Comparison of Intranasal Administration of Haloperidol with Intravenous and Intramuscular Administration: A Pilot Pharmacokinetic Study
Authors: Miller Jodi L. , Ashford J. Wesson , Archer Sanford M. , Rudy Anita C. , Wermeling Daniel P.
Published: June 2008

Study Objective. To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration.

Design. Randomized, open‐label, three‐way crossover study.

Setting. Academic medical center.

Subjects. Four healthy volunteers (two men, two women; aged 24–37 yrs).

Intervention. Each subject received in a randomized order the following three treatments, with a 2‐week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1‐ml spray into a single naris).

Measurements and Main Results. Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse‐effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild‐to‐moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild‐to‐moderate nasal irritation after the intranasal doses.

Conclusion. Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short‐lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.
Lack of Effect of P‐glycoprotein Inhibition on Renal Clearance of Dicloxacillin in Patients with Cystic Fibrosis
Authors: Beringer Paul M. , Kriengkauykiat Jane , Zhang Xiyun , Hidayat Levita , Liu Shanshan , Louie Stan , Synold Tim , Burckart Gilbert J. , Rao Purush A. , Shapiro Bertrand , Gill Mark
Published: June 2008

Study Objective. To determine whether upregulation of P‐glycoprotein is responsible for the enhanced renal clearance of dicloxacillin in patients with cystic fibrosis.

Design. Single‐center, prospective, open‐label, randomized, three‐part crossover pharmacokinetic study.

Setting. General clinical research center.

Subjects. Eleven patients with cystic fibrosis and 11 age‐matched healthy volunteers.

Intervention. All subjects received a single oral dose of dicloxacillin 500 mg alone, dicloxacillin 500 mg plus probenecid (an organic anion transport inhibitor) 1 g, and dicloxacillin 500 mg plus cyclosporine (a P‐glycoprotein inhibitor) 5 mg/kg; each treatment was separated by a washout period of 48 hours. A bolus dose of iothalamate meglumine 456 mg was administered on each study day as a marker of glomerular filtration.

Measurements and Main Results. Blood and urine samples were taken serially up to 6 hours after each dose. Pharmacokinetics of dicloxacillin and iothalamate were determined by using compartmental and noncompartmental methods. Quantitative polymerase chain reaction was performed on peripheral blood mononuclear cells to measure expression of multidrug resistance 1 (MDR1) messenger RNA (mRNA). Genotyping for ABCB1 was performed to determine the presence of single nucleotide polymorphisms (exons 21 and 26). In both healthy subjects and patients with cystic fibrosis, compared with dicloxacillin alone, coadministration with probenecid produced a significantly lower renal clearance of dicloxacillin, whereas coadministration with cyclosporine resulted in no significant change; renal clearance was not significantly different between the two study groups. No correlation was found between MDR1 mRNA expression and renal clearance of dicloxacillin. The renal excretion of dicloxacillin was significantly greater in subjects with the ABCB1 exon 26 TT polymorphism when compared with subjects with the CT genotype.

Conclusion. We found no significant difference in the pharmacokinetics of dicloxacillin between patients with cystic fibrosis and healthy volunteers. Renal clearance of dicloxacillin was significantly reduced in the presence of probenecid but not with cyclosporine, suggesting that the rate‐limiting step in tubular secretion of dicloxacillin is uptake mediated by the organic anion transporter, and not P‐glycoprotein inhibition.
Diversity of Antimicrobial Use and Resistance in 42 Hospitals in the United States
Authors: Pakyz Amy , Powell J. Patrick , Harpe Spencer E. , Johnson Chris , Edmond Michael , Polk Ron E.
Published: June 2008

Study Objective. To measure diversity (or heterogeneity) of antibiotic use in a sample of hospitals in the United States and to assess an association with bacterial resistance.

Design. Observational cross‐sectional study.

Setting. Forty‐two general medical‐surgical hospitals, mostly in the Eastern United States.

Data Source. Administrative claims data and hospital antibiograms during 2003.

Measurements and Main Results. Antibiotic use was measured by defined daily dose (DDD), and diversity was assessed by using Simpson's Index and the Shannon‐Weiner Index. Aggregated antibiograms (from 17 hospitals) were used to assess resistance. There were a total of 3,655,579 patient‐days during 2003, with a mean ± SD of 87,037 ± 62,679 patient‐days/hospital. Mean ± SD antibiotic use was 704 ± 244 DDD/1000 patient‐days/hospital, and fluoroquinolones represented the largest single class. Mean ± SD diversity by Simpson's Index was 0.861 ± 0.022/hospital, and a strong correlation was noted between the two diversity measures. Multivariate analysis found no significant relationship between diversity and the proportion of resistant pathogens.

Conclusion. Diversity of aggregate antibiotic use can be measured, but additional investigations are needed to determine if it is a useful strategy to contain resistance.
Safety and Efficacy of Simvastatin for the Treatment of Dyslipidemia in Human Immunodeficiency Virus‐Infected Patients Receiving Efavirenz‐Based Highly Active Antiretroviral Therapy
Authors: Rahman Anita P. , Eaton Susan A. , Nguyen Sean T. , Bain Amy M. , Payne Kenna D. , Bedimo Roger , Busti Anthony J.
Published: June 2008

Study Objectives.To evaluate the safety and efficacy of simvastatin for treatment of dyslipidemia in patients with the human immunodeficiency virus (HIV) who were receiving efavirenz‐based highly active antiretroviral therapy (HAART), and to evaluate the effect of simvastatin when added to efavirenz on CD4+count, HIV viral load, and frequency of attainment of patient‐specific National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III lipid goals.

Design.Retrospective medical record review.

Setting.Veterans Affairs health care system in Dallas, Texas.

Patients.Thirteen HIV‐infected men who received a stable efavirenz‐based HAART regimen concurrently with simvastatin 20 mg/day, and 19 HIV‐negative men who received simvastatin 20 mg/day (controls).

Measurements and Main Results.Demographic, clinical, and laboratory data were collected before and after starting simvastatin. Reductions in lipid profile values in the HIV‐infected group versus HIV‐negative group were as follows: total cholesterol −20% versus −28% (p=0.15), low‐density lipoprotein cholesterol (LDL) −36% versus −41% (p=0.06), non‐high‐density lipoprotein cholesterol (non‐HDL) −22% versus −33% (p=0.212), and total cholesterol:HDL ratio −33% versus −30% (p=0.26). These effects were seen without any documented adverse drug reactions or changes in viral and immunologic control. However, 28% fewer HIV‐infected patients were able to achieve NCEP ATP III LDL goals compared with HIV‐negative subjects.

Conclusion.These preliminary comparative data suggest that simvastatin can be safely and effectively used to treat dyslipidemia in HIV‐infected patients receiving efavirenz‐based HAART without compromising viral or immunologic control. However, our results are suggestive of slight lessening of the LDL‐lowering effects, which might be explained by the known reduction in simvastatin levels with efavirenz. Furthermore, fewer HIV‐infected patients were able to meet their NCEP ATP III goals compared with HIV‐negative controls, highlighting the difficulty in treating this population to current standards of care.
Possible Antiretroviral Therapy‐Warfarin Drug Interaction
Authors: Fulco Patricia Pecora , Zingone Michelle M. , Higginson Robert T.
Published: June 2008

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has resulted in significant morbidity and mortality reductions. Lifelong antiretroviral therapy must be incorporated into each patient's medical regimen. Patients with HIV may also have simultaneous chronic medical conditions, resulting in the possibility of complex drug‐drug interactions. We report a possible drug‐drug interaction between HAART and warfarin in two patients, as assessed by the Naranjo adverse drug reaction probability scale and the Drug Interaction probability scale. Both patients' pharmacotherapy regimens included a nonnucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavirritonavir, and two nucleoside analogs. In both patients, high warfarin doses were required to maintain therapeutic international normalized ratios (INRs). Warfarin has two enantiomers, R‐and S‐warfarin, which are substrates primarily of cytochrome P450 (CYP) 3A4 (R‐warfarin), CYP1A2 (R‐warfarin), and CYP2C9 (S‐warfarin). Protease inhibitors and NNRTIs have variable effects on CYP: induction, inhibition, or mixed. The increased warfarin doses required in these two patients may have been caused by induction of CYP3A4 by nevirapine, CYP2C9 by nelfinavir, or CYP2C9 by lopinavir‐ritonavir. Thus, practitioners should prudently monitor INRs in patients receiving warfarin with concomitant HAART that includes either a protease inhibitor or an NNRTI.
Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels around the time of conception
Authors: James William H
Published: June 2008

An attempt is made to summarize the evidence that the offspring sex ratios (proportions male at birth) of mammals (including man) are causally related to the hormone levels of both parents around the time of conception. Almost all of the cited studies were reported by non-endocrinologists. This being so, it would seem desirable to have comments of endocrinologists on this topic. The purpose of this article is to elicit such comment. Readers are requested to read the accompanying editorial (Clark & Davis 2008) to gain a better perspective of this hypothesis article.
Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes
Authors: Weise Sebastian , Kralisch Susan , Sommer Grit , Lossner Ulrike , Bluher Matthias , Stumvoll Michael , Fasshauer Mathias
Published: June 2008

The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1β on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1β. Thus, IL-1β induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1β relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1β in a dose-dependent fashion with 2.5-fold induction seen at IL-1β concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1β treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1β-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1β, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.
Adenovirus vectors differentially modulate proliferation of pituitary lactotrophs in primary culture in a mitogen and infection time-dependent manner
Authors: Wang Zhenhua , Mitsui Tetsuo , Ishida Maho , Arita Jun
Published: June 2008

Adenoviruses are powerful, widely utilized vectors for gene transfer. Limitations to their application, however, have not been well described. We used rat pituitary lactotrophs in primary culture as a model for studying how adenovirus vector infection modulates mitogen-induced proliferation and the activities of mitogen signaling pathways. Infection with adenovirus vectors expressing β-galactosidase (βgal) raised basal proliferative levels and blocked fetal bovine serum (FBS)-induced proliferation of lactotrophs, but did not influence the changes in proliferation induced by forskolin, IGF-I, and bromocriptine. The βgal-expressing adenoviruses did not alter the inhibitory action of 17β-estradiol (E2) in the presence of IGF-I; however, they blocked the stimulatory action of E2 in the presence of dextran-coated charcoal-striped serum or forskolin. An adenovirus expressing no protein failed to block FBS-induced proliferation, but was effective in modulating basal proliferative levels and the stimulatory actions of E2. The increased basal proliferative level and the blockade of FBS-induced proliferation were transient, and lost 5 days after infection while the blockade of the stimulatory action of E2 in the presence of forskolin persisted. Adenovirus infection raised basal protein levels of the phosphorylated forms of cAMP response element-binding protein (pCREB) and ERK1/2 and increased the proportion of pCREB-immunoreactive lactotrophs. Adenoviruses also altered estrogen-induced responses in mRNA expression of several estrogen-responsive genes in a gene-specific manner. The results demonstrate that an adenovirus vector differentially interferes with lactotroph proliferation in response to various mitogens. Our results suggest that the effects of the adenovirus that are independent of the genes transferred must be considered when performing adenoviral gene transfer in the primary cultures of normal cells.
The calcium-sensing receptor and insulin secretion: a role outside systemic control 15 years on
Authors: Hodgkin M N , Hills C E , Squires P E
Published: June 2008

In the 15 years since the identification and characterisation of the extracellular calcium-sensing receptor (CaR), it has become increasingly apparent that this cationic binding receptor is found in many tissues, not associated with the control of plasma calcium. One of these tissues is the pancreatic islet where insulin secretion provides the basis of energy regulation. It seems inherently unlikely that the islet responds to alterations in systemic calcium and a more plausible and intriguing possibility is that the CaR mediates cell-to-cell communication through local increases in the concentration of extracellular Ca2+, co-released with insulin. This short article explores this possibility and suggests that this novel mechanism of cell communication, along with direct coupling via gap junctions and other local paracrine regulators helps explain why the glucose responsiveness of the intact islet is greater than the sum of the composite parts in isolation.
Collateral Geochemical Impacts of Agricultural Nitrogen Enrichment from 1963 to 1985: A Southern Wisconsin Ground Water Depth Profile
Authors: Browne Bryant A. , Kraft George J. , Bowling Juliane M. , DeVita William M. , Mechenich David J.
Published: June 2008

In this study, we used chlorofluorocarbon (CFC) age‐dating to investigate the geochemistry of N enrichment within a bedrock aquifer depth profile beneath a south central Wisconsin agricultural landscape. Measurement of N2O and excess N2allowed us to reconstruct the total NO3−and total nitrogen (TN) leached to ground water and was essential for tracing the separate influences of soil nitrification and ground water denitrification in the collateral geochemical chronology. We identify four geochemical impacts due to a steady ground water N enrichment trajectory (39 ± 2.2 μmol L−1yr−1,r2= 0.96) over two decades (1963–1985) of rapidly escalating N use. First, as a by‐product of soil nitrification, N2O entered ground water at a stable (r2= 0.99) mole ratio of 0.24 ± 0.007 mole% (N2O–N/NO3–N). The gathering of excess N2O in ground water is a potential concern relative to greenhouse gas emissions and stratospheric ozone depletion after it discharges to surface water. Second, excess N2measurements revealed that NO3−was a prominent, mobile, labile electron acceptor comparable in importance to O2.Denitrification transformed 36 ± 15 mole% (mol mol−1× 100) of the total N within the profile to N2gas, delaying exceedance of the NO3−drinking water standard by approximately 6 yr. Third, soil acids produced from nitrification substantially increased the concentrations of major, dolomitic ions (Ca, Mg, HCO3−) in ground water relative to pre‐enrichment conditions. By 1985, concentrations approximately doubled; by 2006, CFC age‐date projections suggest concentrations may have tripled. Finally, the nitrification induced mobilization of Ca may have caused a co‐release of P from Ca‐rich soil surfaces. Dissolved P increased from an approximate background value of 0.02 mg L−1in 1963 to 0.07 mg L−1in 1985. The CFC age‐date projections suggest the concentration could have reached 0.11 mg L−1in ground water recharge by 2006. These results highlight an intersection of the N and P cycles potentially important for managing the quality of ground water discharged to surface water.
Humic Acid Formation in Artificial Soils Amended with Compost at Different Stages of Organic Matter Evolution
Authors: Adani Fabrizio , Spagnol M.
Published: June 2008

A composting process was conducted under optimal conditions for 150 d, obtaining three biomasses at different levels of maturity: raw material (RM), fresh compost obtained after 11 d of composting (FC), and evolved compost (EC) obtained after 150 d of composting. During the composting process, HAs were extracted and fully characterized by mass balance, DRIFT, and 1H and 13C‐nuclear magnetic resonance spectroscopy. Each compost sample was incubated for 180 d in an artificial soil, after which HA extraction was repeated and characterized. To compare composts containing different amounts of labile organic matter (OM), an equal amount of unhydrolyzable OM was added to the soils. Our results indicated that compost HAs consist of a biologically and chemically stable fraction (i.e., the unhydrolyzable HA [U‐HA]) and a labile fraction, whose relative contents depended on the composting duration. Humic acid from more EC contained a higher amount of recalcitrant fraction (aromatic carbon) and a lesser amount of labile fraction (aliphatic carbon) than HA from RM and FC. These results suggest that the humification process during composting preserves the more recalcitrant fraction of the compost‐alkali soluble/acid insoluble fraction (HA‐fraction). Incubation of composts in soil showed that due to the higher labile fraction content, HAs from raw material were more degraded than those from EC. The abundance of labile carbon of soil amended with less‐evolved compost (RM and FC) allowed the more recalcitrant fractions of U‐HA to be more preserved than in EC. These results suggest that less‐evolved compost could contribute more than well evolved compost to the stable soil OM.
The Effect of River Pulsing on Sedimentation and Nutrients in Created Riparian Wetlands
Authors: Nahlik Amanda M. , Mitsch William J.
Published: June 2008

Sedimentation under pulsed and steady‐flow conditions was investigated in two created flow‐through riparian wetlands in central Ohio over 2 yr. Hydrologic pulses of river water lasting for 6 to 8 d were imposed on each wetland from January through June during 2004. Mean inflow rates during pulses averaged 52 and 7 cm d−1 between pulses. In 2005, the wetlands received a steady‐flow regime of 11 cm d−1 with no major hydrologic fluctuations. Thirty‐two sediment traps were deployed and sampled once per month in April, May, June, and July for two consecutive years in each wetland. January through March were not sampled in either year due to frozen water surfaces in the wetlands. Gross sedimentation (sedimentation without normalizing for differences between years) was significantly greater in the pulsing study period (90 kg m−2) than in the steady‐flow study period (64 kg m−2). When normalized for different hydrologic and total suspended solid inputs between years, sedimentation for April through July was not significantly different between pulsing and steady‐flow study periods. Sedimentation for the 3 mo that received hydrologic pulses (April, May, and June) was significantly lower during pulsing months than in the corresponding steady‐flow months. Large fractions of inorganic matter in collected sediments indicated that allochthonous inputs were the main contributor to sedimentation in these wetlands. Organic matter fractions of collected sediments were consistently greater in the steady‐flow study period (1.8 g kg−1) than in the pulsed study period (1.5 g kg−1), consistent with greater primary productivity in the water column during steady‐flow conditions.