bluuebunny/crossref_metadata_2025 huggingface dataset:
Newborn Screening for Congenital Adrenal Hyperplasia: Additional Steroid Profile using Liquid Chromatography-Tandem Mass Spectrometry
Authors: Janzen N. , Peter M. , Sander S. , Steuerwald U. , Terhardt M. , Holtkamp U. , Sander J.
Published: April 2007

Background: Neonatal screening programs for congenital adrenal hyperplasia (21-CAH) using an immunoassay for 17α-hydroxyprogesterone (17-OHP) generate a high rate of positive results attributable to physiological reasons and to cross-reactions with steroids other than 17α-OHP, especially in preterm neonates and in critically ill newborns.

Methods: To increase the specificity of the screening process, we applied a liquid chromatography-tandem mass spectrometry method quantifying 17α-OHP, 11-deoxycortisol, 21-deoxycortisol, cortisol, and androstenedione. The steroids were eluted in aqueous solution containing d8-17α-OHP and d2-cortisol and quantified in multiple reaction mode.

Results: Detection limit was below 1 nmol/liter, and recovery ranged from 64% (androstenedione) to 83% (cortisol). Linearity was proven within a range of 5–100 nmol/liter (cortisol, 12.5–200 nmol/liter), and total run time was 6 min. Retrospective analysis of 6151 blood samples and 50 blood samples from newborns with clinically confirmed 21-CAH, as well as prospective analysis of 1609 samples of a total of 242,500 testing positive in our routine 17-OHP immunoassay, allowed clear distinction of affected and nonaffected newborns. High levels of 21-deoxycortisol were only found in children with 21-hydroxylase deficiency. Calculating the ratio of 17α-OHP to 21-deoxycortisol divided by cortisol further increased the sensitivity of the method.

Conclusion: Our liquid chromatography-tandem mass spectrometry procedure as a second-tier test can be used to reduce false-positive results of standard 21-CAH screening. The short total run time of 6 min allows for immediate reanalysis of all immunoassay results above the cutoff.
Serum Estrogen, But Not Testosterone, Levels Differ between Black and White Men in a Nationally Representative Sample of Americans
Authors: Rohrmann Sabine , Nelson William G. , Rifai Nader , Brown Terry R. , Dobs Adrian , Kanarek Norma , Yager James D. , Platz Elizabeth A.
Published: April 2007

Context: Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population.

Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men.

Participants, Design, and Setting: A total of 1413 men aged 20+ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988–1991 were included in this cross-sectional study.

Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays.

Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n = 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n = 674; 5.11 ng/ml; P > 0.05) but were higher in Mexican-Americans (n = 376; 5.48 ng/ml; P < 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P < 0.01) and Mexican-Americans (34.11 pg/ml; P < 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than non-Hispanic whites (34.91 nmol/liter; P < 0.05) and Mexican-Americans (35.04 nmol/liter; P < 0.05).

Conclusions: Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity.
Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice
Authors: Sainsbury Amanda , Lin Shu , McNamara Keely , Slack Katy , Enriquez Ronaldo , Lee Nicola J. , Boey Dana , Smythe George A. , Schwarzer Christoph , Baldock Paul , Karl Tim , Lin En-Ju D. , Couzens Michelle , Herzog Herbert
Published: April 2007

Endogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn−/− mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn−/− mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn−/− as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn−/− mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn−/− mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn−/− mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y1 but not Y2 receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.
Phosphoinositide 3-kinase signalling regulates early development and developmental haemopoiesis
Authors: Bone Heather K. , Welham Melanie J.
Published: April 2007

Phosphoinositide 3-kinase (PI3K)-dependent signalling regulates a wide variety of cellular functions including proliferation and differentiation. Disruption of class IA PI3K isoforms has implicated PI3K-mediated signalling in development of the early embryo and lymphohaemopoietic system. We have used embryonic stem (ES) cells as an in vitro model to study the involvement of PI3K-dependent signalling during early development and haemopoiesis. Both pharmacological inhibition and genetic manipulation of PI3K-dependent signalling demonstrate that PI3K-mediated signals, most likely via 3-phosphoinositide-dependent protein kinase 1 (PDK1), are required for proliferation of cells within developing embryoid bodies (EBs). Surprisingly, the haemopoietic potential of EB-derived cells was not blocked upon PI3K inhibition but rather enhanced, correlating with modest increases in expression of haemopoietic marker genes. By contrast, PDK1-deficient EB-derived progeny failed to generate terminally differentiated haemopoietic lineages. This deficiency appeared to be due to a requirement for PI3K signalling during the proliferative phase of blast-colony-forming cell (BL-CFC) expansion, rather than as a result of effects on differentiation per se. We also demonstrate that PI3K-dependent signalling is required for optimal generation of erythroid and myeloid progenitors and their differentiation into mature haemopoietic colony types. These data demonstrate that PI3K-dependent signals play important roles at different stages of haemopoietic development.
Modelling of the twin-entry turbocharger turbine
Authors: Katrašnik T
Published: April 2007

An original physical model to calculate the fluid dynamics and energy conversion in twin-entry turbocharger turbines for internal combustion engines is presented. The model is to be used as the boundary condition for one-dimensional wave action techniques and is also capable of considering variable gas properties and composition. The model is based on a simple variable-area approach; however, it is capable of adequately modelling complex flows that occur in multi-cylinder turbocharged engines. This is confirmed through the good agreement between calculated and measured turbine and engine parameters.
Automated data processing and metric generation for driveability analysis
Authors: Pickering S G , Brace C J
Published: April 2007

This paper describes automated data-processing and manoeuvre detection techniques developed as part of a suite of tools used for the prediction of longitudinal vehicle driveability. The core task is to identify events of interest in recorded objective driveability time-series data and generate metrics describing these manoeuvres, which can then be correlated with subjective evaluations provided by the vehicle test drivers. The objective events of particular interest are the start of transients and gear-shift events. As a necessary precursor to the generation of the objective metrics, procedures were designed to check data integrity and to automatically replace data that were found to be faulty, ensuring that as few data points and as little testing time were wasted as is possible.

Of 741 tests analysed (average of 12 drivers for each of five vehicles), only 11 per cent of tests needed further manual attention following the automated processing. Of these, 64 per cent proved to be irrecoverable owing to data problems and were rejected. The processing and generation of metrics take approximately 1 s per set of test data, producing a time saving of approximately 95 per cent. This makes it possible to perform real-time processing and metric generation as part of a continuous testing scheme or real-time evaluation.
Effect of front-wheel drive or rear-wheel drive on the limit handling behaviour of passenger vehicles
Authors: Mashadi B , Ebrahimi N , Marzbanrad J
Published: April 2007

A seven-degree-of-freedom four-wheeled vehicle-handling model was developed for the purpose of investigating differences in the behaviours of front-wheel drive (FWD) and rear-wheel drive (RWD) vehicles. The handling treatments of the two cases have been studied on horizontal, sloping, and low-friction roads by applying step steer angle inputs. The difference between the behaviours of two layouts on a horizontal road was found to be small; it became pronounced on low-friction roads and severe on sloping roads. On horizontal roads, both layouts showed understeering behaviours up to the limit lateral accelerations. On sloping roads, however, the RWD vehicle tended to oversteer whereas the FWD vehicle remained in an understeering mode. The variation in the parameters showed that increasing the velocity or slope and decreasing the friction coefficient reveals the differences in the behaviours of the two layouts. A small perturbation technique was also applied to the model and the resulting linearized equations were used to obtain the modal frequencies at different trims. Considerable differences were noticed in the disturbed behaviours of the two cases, including unit step responses.
Driver perception of steering feel
Authors: Newberry A C , Griffin M J , Dowson M
Published: April 2007

Steering feel is optimized at a late stage of vehicle development, using prototype vehicles and expert opinion. An understanding of human perception may assist the development of a good ‘feel’ earlier in the design process. Three psychophysical experiments have been conducted to advance understanding of factors contributing to the feel of steering systems. The first experiment, which investigated the frames of reference for describing the feel (i.e. haptic properties) of a steering wheel, indicated that subjects focused on the steady state force that they applied to the wheel rather than the steady state torque, and on the angle that they turned the wheel rather than the displacement of their hands. In a second experiment, thresholds for detecting changes in both steady state steering-wheel force and steady state steering-wheel angle were determined as about 15 per cent. The rate of growth in the perception of steady state steering-wheel force and steady state steering-wheel angle were determined using magnitude estimation and magnitude production. It was found that, according to Stevens’ power law, the sensation of steady state steering-wheel force increases with a power of 1.39 with increased force, whereas the perception of steady state steering-wheel angle increases with a power of 0.93 with increased steering-wheel angle. The implications for steering systems are discussed.
Ultrasonic characterization of the mechanical properties and polymerization reaction of acrylic-based bone cements
Authors: Dunne N J , Xu Y , Makem J , Orr J
Published: April 2007

In this investigation the pulse-echo technique was validated as a method that could be used to monitor the complete polymerization of acrylic bone cement in a surgical theatre. Currently, orthopaedic surgeons have no objective method to quantify the state of cure of bone cement as it progresses through its polymerization cycle. Clear benefits of the pulse-echo technique are that it is easy to use, non-invasive, and non-destructive. Furthermore, the test results were found to be highly reproducible with minor deviations. Three proprietary cements were used to confirm the validity of the technique; CMW® Endurance, Palacos® R and Simplex P™. The results showed that the acoustic properties of bone cement clearly demonstrated a relationship with the different stages of polymerization, and in particular with the transitions between the waiting, dough, and setting phases. Additionally, the cure time of the poly(methyl methacrylate) cements consistently correlated with the attainment of 75 per cent of the average maximum velocity of sound value. The measured cure times concurred with the ISO and ASTM standards. Moreover, measurements of the final sound velocity and broadband ultrasonic attenuation correlated strongly with the density and mechanical properties of the cured bone cement samples.
A robotic testing facility for the measurement of the mechanics of spinal joints
Authors: de Visser H , Rowe C , Pearcy M
Published: April 2007

A robotic testing facility for the measurement of joint mechanics was used to determine the significance of tears in the intervertebral disc on the mechanics of the spinal joint. Ten lumbar joints of sheep were dynamically loaded and manipulated. Comparisons were made between the behaviour of the intervertebral disc in flexion and extension at two test speeds. The influence of the posterior elements and of rim lesions was assessed by testing the joint immediately before and after removal of the posterior elements and after the creation of a 40 N mm × 10 mm rim lesion in the disc. Stiffness of the spinal joint dropped significantly upon removal of the posterior elements, from 0.81 to 0.23 N m/deg for flexion and from 0.65 to 0.40 N m/deg for extension. Maximum moments dropped 37 per cent for flexion and 63 per cent for extension. The rim lesion caused a further significant stiffness reduction to 0.21 and 0.31 N m/deg respectively. Maximum moments reduced a further 12 per cent and 16 per cent respectively. A higher test speed (2 deg/s instead of 0.5 deg/s) usually did not change these results significantly. The novel six-degrees-of-freedom robotic testing facility used in this study was demonstrated to be an effective system for studying the mechanics of complex biological joints.
Distinct reaction pathway promoted by non-divalent-metal cations in a tertiary stabilized hammerhead ribozyme
Authors: Roychowdhury-Saha Manami , Burke Donald H.
Published: April 2007

Divalent ion sensitivity of hammerhead ribozymes is significantly reduced when the RNA structure includes appropriate tertiary stabilization. Therefore, we investigated the activity of the tertiary stabilized “RzB” hammerhead ribozyme in several nondivalent ions. Ribozyme RzB is active in spermidine and Na+ alone, although the cleavage rates are reduced by more than 1,000-fold relative to the rates observed in Mg2+ and in transition metal ions. The trivalent cobalt hexammine (CoHex) ion is often used as an exchange-inert analog of hydrated magnesium ion. Trans-cleavage rates exceeded 8 min−1 in 20 mM CoHex, which promoted cleavage through outersphere interactions. The stimulation of catalysis afforded by the tertiary structural interactions within RzB does not require Mg2+, unlike other extended hammerhead ribozymes. Site-specific interaction with at least one Mg2+ ion is suggested by CoHex competition experiments. In the presence of a constant, low concentration of Mg2+, low concentrations of CoHex decreased the rate by two to three orders of magnitude relative to the rate in Mg2+ alone. Cleavage rates increased as CoHex concentrations were raised further, but the final fraction cleaved was lower than what was observed in CoHex or Mg2+ alone. These observations suggest that Mg2+ and CoHex compete for binding and that they cause misfolded structures when they are together. The results of this study support the existence of an alternate catalytic mechanism used by nondivalent ions (especially CoHex) that is distinct from the one promoted by divalent metal ions, and they imply that divalent metals influence catalysis through a specific nonstructural role.
A case for “StopGo”: Reprogramming translation to augment codon meaning of GGN by promoting unconventional termination (Stop) after addition of glycine and then allowing continued translation (Go)
Authors: Atkins John F. , Wills Norma M. , Loughran Gary , Wu Chih-Yu , Parsawar Krishna , Ryan Martin D. , Wang Chung-Hsiung , Nelson Chad C.
Published: April 2007

When a eukaryotic mRNA sequence specifying an amino acid motif known as 2A is directly followed by a proline codon, two nonoverlapping proteins are synthesized. From earlier work, the second protein is known to start with this proline codon and is not created by proteolysis. Here we identify the C-terminal amino acid of an upstream 2A-encoded product fromPerina nudapicorna-like virus that is glycine specified by the last codon of the 2A-encoding sequence. This is an example of recoding where 2A promotes unconventional termination after decoding of the glycine codon and continued translation beginning with the 3′ adjacent proline codon.
A rapid, quantitative assay for direct detection of microRNAs and other small RNAs using splinted ligation
Authors: Maroney Patricia A. , Chamnongpol Sangpen , Souret Frédéric , Nilsen Timothy W.
Published: April 2007

The discovery and characterization of microRNAs (miRNAs) and other families of short RNAs has led to a rapid expansion of research directed at elucidating their expression patterns and regulatory functions. Here, we describe a convenient, sensitive, and straightforward method to detect and quantitate specific miRNA levels in unfractionated total RNA samples. The method, based on splinted ligation, does not require specialized equipment or any amplification step, and is significantly faster and more sensitive than Northern blotting. We demonstrate that the method can be used to detect various classes of small regulatory RNAs from different organisms.
Reducing Truckload Transportation Costs Through Collaboration
Authors: Ergun Ozlem , Kuyzu Gultekin , Savelsbergh Martin
Published: April 2007

In the highly fragmented truckload transportation industry a substantial fraction of truck movements involves empty trucks, i.e., moves that reposition trucks. However, reducing the amount of truck repositioning is difficult because the need for a carrier to reposition its trucks depends on the interactions between the shippers the carrier is serving. Through collaboration, shippers may be able to identify and submit sequences of continuous loaded movements to carriers, reducing the carriers’ need for repositioning, and thus lowering the carriers’ costs. A portion of the carriers’ cost savings may be returned to the shippers in the form of lower prices. We discuss optimization technology that can be used to assist in the identification of repeatable, dedicated truckload continuous move tours with little truck repositioning. Timing considerations are critical to practical viability and a key focus of our efforts. We demonstrate the effectiveness of the algorithms developed on various randomly generated instances as well as on instances derived from data obtained from a strategic sourcing consortium for a $14 billion U.S. industry.
The Berth Allocation Problem: A Strong Formulation Solved by a Lagrangean Approach
Authors: Monaco M. Flavia , Sammarra Marcello
Published: April 2007

The berth allocation problem is one of the most relevant logistics problems arising in the management of container ports. Depending on assumptions made on the berthing location policy, two classes of the berth allocation problem have been considered in literature: the discrete case and the continuous case. In this paper, the properties of the discrete berth allocation problem, formulated as a dynamic scheduling problem, are analyzed. A new formulation of the problem is proposed, which is shown to be more compact and stronger than another one from the literature; a Lagrangean heuristic algorithm is developed; and computational results are presented.
Integration of the Load-Matching and Routing Problem with Equipment Balancing for Small Package Carriers
Authors: Cohn Amy , Root Sarah , Wang Alex , Mohr Douglas
Published: April 2007

Small package delivery is a multibillion dollar industry with complex planning decisions required to efficiently utilize costly resources and meet tight time requirements. The planning process is typically decomposed into sequential subproblems to establish tractability. This decomposition can greatly degrade solution quality. This paper therefore considers the integration of two closely related key subproblems: load matching and routing and equipment balancing. First, we identify critical challenges faced in trying to solve these problems. Then we present a novel modeling approach to address these challenges. Finally, we conclude with computational results from United Parcel Service, the world’s largest package delivery company, demonstrating an improvement of approximately 5% over the company’s existing methods for solving this pair of problems.
Modeling Discrete Choices in the Presence of Inertia and Serial Correlation
Authors: Cantillo Víctor , Ortúzar Juan de Dios , Williams Huw C. W. L.
Published: April 2007

The concept of habit or inertia in the context of (reluctance to) change in travel behavior has an important bearing on transport policy (e.g., how to break car use habits) and has remained an unresolved issue in demand modeling. Another major problem in modeling the response to policy measures is the potential correlation or dependence between the choices made by a given individual over time (i.e., serial correlation). The two phenomena are closely related. This paper discusses the effects of considering inertia and serial correlation on travel choices. We formulate a fairly general discrete choice model that incorporates randomly distributed inertia thresholds and allow for serial correlation. The inertia thresholds may also be a function of an individual’s socioeconomic characteristics and choice conditions. The model can be applied with panel data as well as with mixed revealed and stated preference data. We applied it to real and simulated data, confirming that if these phenomena exist in the population but are not considered, serious errors in model estimation and prediction may arise, especially in the case of large policy impacts.
Real-Time Freeway Traffic State Estimation Based on Extended Kalman Filter: A Case Study
Authors: Wang Yibing , Papageorgiou Markos , Messmer Albert
Published: April 2007

This paper presents a case study of real-time traffic state estimation. The adopted general approach to the design of universal traffic state estimators for freeway stretches is based on stochastic macroscopic traffic flow modeling and extended Kalman filtering, which are outlined in the paper. The reported investigations were conducted by use of eight-hour traffic measurement data collected from a freeway stretch of 4.1 km close to Munich, Germany. Some key issues are carefully investigated, including the tracking capability of the designed traffic state estimator, significance of the online model parameter estimation, sensitivity of the estimator to the initial values of the estimated model parameters as well as to the related noise standard deviation values, and the capability of the estimator to handle biased flow measurements. The achieved results are quite satisfactory.
A Sequential Stochastic Security System Design Problem for Aviation Security
Authors: Nikolaev Alexander G. , Jacobson Sheldon H. , McLay Laura A.
Published: April 2007

Passenger screening is a critical component of aviation security systems. This paper introduces the sequential stochastic security design problem (SSSDP), which models passenger and carry-on baggage-screening operations in an aviation security system. SSSDP is formulated as a two-stage model, where in the first stage security devices are purchased subject to budget and space constraints, and in the second stage a policy determines how passengers that arrive at a security station are screened. Passengers are assumed to check in sequentially, with passenger risk levels determined by a prescreening system. The objective of SSSDP is to maximize the total security of all passenger-screening decisions over a fixed time period, given passenger risk levels and security device parameters. SSSDP is transformed into a deterministic integer program, and an optimal policy for screening passengers is obtained. Examples are provided to illustrate these results, using data extracted from the Official Airline Guide.
Managing Complex Medication Regimens: Perspectives of Consumers with Osteoarthritis and Healthcare Professionals
Authors: Manias Elizabeth , Claydon-Platt Kate , Mccoll Geoffrey J , Bucknall Tracey K , Brand Caroline A
Published: April 2007

Background:

Managing medications is complex, particularly for consumers with multiple coexisting conditions for whom benefits and adverse effects are unpredictable and health priorities may be variable.

Objective:

To investigate perceptions of and experiences with managing drug regimens from the perspectives of consumers with osteoarthritis and coexisting chronic conditions and of healthcare professionals from diverse backgrounds.

Methods:

Using an exploratory research design, focus groups were formed with 34 consumers and 19 healthcare professionals. Individual interviews were undertaken with 3 community medical practitioners.

Results:

Consumers' management of medications was explored in terms of 3 themes: administration of medications, provision of information, and the perceived role of healthcare professionals. In general, consumers lacked understanding regarding the reason that they were prescribed certain medications. Since all consumer participants had at least 2 chronic conditions, they were taking many drugs to relieve undesirable symptoms. Some consumers were unable to achieve improved pain relief and were reluctant to take analgesics prescribed on an as needed basis. Healthcare professionals discussed the importance of using nonpharmacologic measures to improve symptoms; however, consumers stated that physicians encourage them to continue using medications, often for prolonged periods, even when these agents are not helpful.

Conclusions:

Consumers were dissatisfied about the complexity of their medication regimens and also lacked understanding as to how to take their drugs effectively. Dedicated time should be devoted during medical consultations to facilitate verbal exchange of information about medications. Pharmacists must communicate regularly with physicians about consumers' medication needs to help preempt any problems that may arise. Instructions need to be revised through collaboration between physicians and pharmacists so that “as needed” directions provide more explicit advice about when and how to use such drugs. Future research, using large, generalizable samples, should examine trends related to consumers' experiences of symptomatic relief from chronic conditions and their understandings about medications.
Adverse Effects of Voriconazole: Analysis of the French Pharmacovigilance Database
Authors: Eiden Céline , Peyrière Hélène , Cociglio Marylène , Djezzar Samira , Hansel Sylvie , Blayac Jean-Pierre , Hillaire-Buys Dominique
Published: April 2007

Background:

The most common adverse effects of voriconazole reported during clinical trials were disturbances of vision (30% of pts.), skin rashes (17.3%), and elevations in hepatic enzymes level (~10% of pts.; varying with enzymes). However, postmarketing data concerning safety of voriconazole are limited.

Objective:

To describe voriconazole adverse drug effects (ADEs) after 4 years of the drug's availability in France and determine their occurrence.

Methods:

All cases of ADEs including voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 were analyzed. For each case, the following data were recorded; age, sex, indication, concomitant disease, concomitant medications, and ADE description. Causality link between voriconazole and ADEs was performed using the Naranjo probability scale.

Results:

A total of 227 ADE cases were reported in 178 adults and 9 children (<12 y), with 66% occurring in males. The patients' median age was 49.6 (2–80) years. ADEs included liver function test abnormalities (23%), visual disturbances (18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events (10%), hematologic disorders (8%), and renal disturbances (4%). Other less commonly identified ADEs included headache, nausea, vomiting, and diarrhea. Drug–drug interactions were observed in 7 cases. According to the Naranjo criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful.

Conclusions:

Most AOEs found in this study are well documented in the literature, except for cardiac complications, which are rarely reported. Few ADEs related to drug interactions were observed; however, due to the extensive metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be aware of potential interactions between voriconazole and other drugs metabolized through this pathway.
Providing Patient Care Through Community Pharmacies in the UK: Policy, Practice, and Research
Authors: Noyce Peter R
Published: April 2007

Objective:

To describe the provision of patient services through community pharmacies in the UK, with particular reference to England, and to explore the research evidence and policy developments for enhancing the contribution of community pharmacy to primary care and public health.

Findings:

In the UK, National Health Service (NHS) pharmaceutical services are delivered under contract by privately owned community pharmacies. In England, a new 3 tier structure for pharmaceutical services was introduced in 2005 comprising essential, advanced, and enhanced-level services. All NHS pharmacies must deliver 7 essential pharmaceutical services and provide evidence that they meet the requirements of a comprehensive quality assurance framework. In the first year of the contract, around 40% of pharmacies were accredited to undertake medicine use reviews, the first advanced-level service to be implemented. Meanwhile, up to 25% of pharmacies provide a variety of enhanced-level services; the most common of these is supervised administration of methadone as well as support programs for patients quitting smoking. New legislation is being introduced that will accomplish the following: allow pharmacists to acquire independent prescribing rights, require pharmacy technicians to be licensed, necessitate that both pharmacists and pharmacy technicians periodically demonstrate their continuing qualification to practice, and introduce the concept of the “responsible pharmacist” to the operation of community pharmacies.

Discussion:

Community pharmacy is now being recognized by the government as a mainstream contributor to primary care and public health. The current priority is to integrate services provided through community pharmacies into programs provided by other primary care professionals, through strengthening information technology and contractual arrangements. While major changes to the regulation of the pharmacy workforce are occurring, the quality management of community pharmacy services merits further attention.

Conclusions:

The new NHS pharmacy contract and current legislative changes provide a basis for community pharmacy to become fully integrated into NHS long-term care and public health programs.
Advancement of Nutrition Support in Clinical Pharmacy
Authors: Mirtallo Jay M
Published: April 2007

2006 marked the 40th year of publication for The Annals. Throughout its history, The Annals has provided important contributions to the development of clinical pharmacy. In 2007, we are continuing to publish articles reflecting on the history of clinical pharmacy through the eyes of practitioners, including those pioneering clinical pharmacy, as well as those who have more recently entered the profession and a well-established specialty. In addition, we are presenting articles and editorials from the early history of The Annals that have given direction and shape to the practice of clinical pharmacy (see page 873).
Pre‐bereavement meaning and post‐bereavement distress in mothers of children who underwent haematopoietic stem cell transplantation
Authors: Wu Lisa , Bonanno George , DuHamel Katherine , Redd William H. , Rini Christine , Austin Jane , Nereo Nancy , Ostroff Jamie , Parsons Susan , Martini Richard , Williams Sharon , Mee Laura , Sexson Sandra , Manne Sharon
Published: April 2007

Objectives The purpose of this study was to explore the association of meaning‐making with psychological adjustment to bereavement among mothers of children who had undergone haematopoietic stem cell transplantation (HSCT).

Design A prospective research design was used. Regression analyses were conducted to determine the relations between pre‐bereavement variables (distress, searching for meaning, and finding meaning) and distress post‐bereavement.

Methods Thirty‐five mothers of children who had undergone HSCT were interviewed at the time of their child's HSCT and 3 months post‐bereavement.

Results Mothers who reported searching for meaning at HSCT reported greater post‐bereavement distress, and mothers who reported finding meaning at HSCT reported less post‐bereavement distress. Distress at HSCT and the number of days between the time of death and the post‐bereavement time point were also found to be significant predictors of post‐bereavement distress.

Conclusions This study provides partial support for the role of meaning in adjustment to loss.
Impossible crossings: Gender melancholy in Lola Bilidikid and Auslandstournee
Authors: Klbay Bar
Published: April 2007

This article examines two recent Turkish-German films, Lola Bilidikid (Kutlu Ataman) and Auslandstournee (Aye Polat). Drawing on Butlerian theory of gender melancholy, this article explores the close relationship between transvestism, motherland and national identification.
Reading the films as a revelation of the performative nature of gender and the heterosexual matrix, this article suggests that the ambiguous relationship of drag queens with the mother(land), their fathers and national identity, can be explained by the ungrievable lack that melancholy is built
upon.
Welcome to Reality. Constructions of German identity in Lichter (Schmid, 2003) and Halbe Treppe (Dresen, 2002)
Authors: Mueller Gabriele
Published: April 2007

During the last 15 years, the city of Berlin has dominated German cinema as the metaphoric site of the continued negotiation of a new national identity. This article examines two films, Lichter (Schmid 2003) and Halbe Treppe (Dresen 2002), which are both set in the eastern border town
of Frankfurt (Oder). It is argued that both films try to offer a counter-model to the Berlin discourse by constructing German identity as explicitly European rather than distinctly German, and by attempting to dissociate themselves from myths surrounding Berlin which defy a more objective
perception of reality. The article analyses and compares the use of spatial metaphors and stylistic conventions which connect the films to European realist film traditions. The location of Frankfurt (Oder) sharpens the awareness for social divisions and, at the same time, shifts the focus
from exploring an inner-German identity to the broader perspective of Europe.
Contemporary cinematic work from Finland: The non-place of cinema and identity
Authors: Sundholm John
Published: April 2007

The article discusses the identity-crisis that has taken place in the institution of cinema during the last years. The changes (in aesthetics, economics and the sociological conditions) are related to both the Finnish institutional strategies adopted since the 1990s and to the prolific
experimental film-makers Eija-Liisa Ahtila and Mika Taanila. It is suggested that Ahtila and Taanila are representatives of a new post-cinematic citizenship in a contemporary European culture of the moving image.
Polymorphisms in the Human Soluble Epoxide Hydrolase GeneEPHX2Linked to Neuronal Survival after Ischemic Injury
Authors: Koerner Ines P. , Jacks Rachel , DeBarber Andrea E. , Koop Dennis , Mao Peizhong , Grant David F. , Alkayed Nabil J.
Published: April 2007

Single nucleotide polymorphisms (SNPs) in the humanEPHX2gene have recently been implicated in susceptibility to cardiovascular disease, including stroke.EPHX2encodes for soluble epoxide hydrolase (sEH), an important enzyme in the metabolic breakdown of arachidonic acid-derived eicosanoids referred to as epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs are protective against ischemic cell death in culture. Therefore, we tested the hypothesis that polymorphisms in the humanEPHX2gene alter sEH enzyme activity and affect neuronal survival after ischemic injuryin vitro. HumanEPHX2mutants were recreated by site-directed mutagenesis and fused downstream of TAT protein transduction domain. Western blot analysis and immunocytochemistry staining revealed high-transduction efficiency of human TAT-sEH variants in rat primary cultured cortical neurons, associated with increased metabolism of 14,15-EET to corresponding 14,15-dihydroxyeicosatrienoic acid. A human variant of sEH with Arg103Cys amino acid substitution, previously demonstrated to increase sEH enzymatic activity, was associated with increased cell death induced in cortical neurons by oxygen-glucose deprivation (OGD) and reoxygenation. In contrast, the Arg287Gln mutation was associated with reduced sEH activity and protection from OGD-induced neuronal cell death. We conclude that sequence variations in the humanEPHX2gene alter susceptibility to ischemic injury and neuronal survival in a manner linked to changes in the hydrolase activity of the enzyme. The findings suggest that humanEPHX2mutations may in part explain the genetic variability in sensitivity to ischemic brain injury and stroke outcome.
CNS Progenitor Cells Promote a Permissive Environment for Neurite Outgrowth via a Matrix Metalloproteinase-2-Dependent Mechanism
Authors: Zhang Yiqin , Klassen Henry J. , Tucker Budd A. , Perez Maria-Thereza R. , Young Michael J.
Published: April 2007

Transplantation of progenitor cells to the CNS has shown promise in neuronal and glial replacement and as a means of rescuing host neurons from apoptosis. Here we examined the effect of progenitor grafts on neurite extension in the degenerating retina ofrd1(retinal degeneration 1) mice. Transplantation of retinal progenitor cells induced increased matrix metalloproteinase-2 (MMP2) secretion, partly from activated glial cells, which was then activated by neuronally expressed MMP14. Active MMP2 resulted in proteolysis of the neurite outgrowth inhibitors CD44 and neurocan in the degenerative retina, allowing significantly increased neurite outgrowth across the border between abutting nondystrophic andrd1retinas. Progenitor-induced enhancement of outgrowth was abrogated by an MMP inhibitor or by coculture with retinal explants fromMMP2−/−mice. This study provides the first identification of an MMP2-dependent mechanism by which exogenous progenitor cells alter the host environment to promote neural regeneration. This suggests a novel therapeutic role for progenitor cells in the treatment of CNS degenerative diseases.
DrosophilaHomer Is Required in a Small Set of Neurons Including the Ellipsoid Body for Normal Ethanol Sensitivity and Tolerance
Authors: Urizar Nancy L. , Yang Zhiyong , Edenberg Howard J. , Davis Ronald L.
Published: April 2007

The molecular mechanisms occurring in the nervous system that underlie behavioral responses to ethanol remain poorly understood. Here, we report that molecular requirements for two of these responses, initial sensitivity and the development of rapid tolerance, comap to the same small set of neurons. We show that nullhomermutant flies exhibit both increased sensitivity to the sedative effects of ethanol and failure to develop normal levels of rapid tolerance. Both the sensitivity and rapid tolerance phenotypes of thehomermutants are rescued by the expression of wild-typehomerin a subset of neurons that include the ellipsoid body. Thus, some of the molecular- and systems-level requirements for these two behavioral responses to ethanol are identical.
Subnanometer Fusion Pores in Spontaneous Exocytosis of Peptidergic Vesicles
Authors: Vardjan Nina , Stenovec Matjaž , Jorgačevski Jernej , Kreft Marko , Zorec Robert
Published: April 2007

Kiss-and-run exocytosis, consisting of reversible fusion between the vesicle membrane and the plasma membrane, is considered to lead to full fusion after stimulation of vesicles containing classical transmitters. However, whether this is also the case in the fusion of peptidergic vesicles is unknown.

Previously, we have observed that spontaneous neuropeptide discharge from a single vesicle is slower than stimulated release, because of the kinetic constraints of fusion pore opening. To explore whether slow spontaneous release also reflects a relatively narrow fusion pore, we analyzed the permeation of FM 4-64 dye and HEPES molecules through spontaneously forming fusion pores in lactotroph vesicles expressing synaptopHluorin, a pH-dependent fluorescent fusion marker. Confocal imaging showed that half of the spontaneous exocytotic events exhibited fusion pore openings associated with a change in synaptopHluorin fluorescence but were impermeable to FM 4-64 and HEPES. Together with membrane capacitance measurements, these findings indicate an open fusion pore diameter <0.5 nm, much smaller than the neuropeptides. In stimulated cells, >70% of exocytotic events exhibited a larger, FM 4-64-permeable pore (>1 nm). Interestingly, capacitance measurements showed that the majority of exocytotic events in spontaneous and stimulated conditions were transient. Stimulation increased the frequency of transient events and the fusion pore dwell time but decreased the fraction of events with lowest measurable fusion pore.

Kiss-and-run is the predominant mode of exocytosis in resting and in stimulated peptidergic vesicles. Stimulation prolongs the effective opening of the fusion pore and expands its primary subnanometer diameter to enable hormone secretion without full fusion.
Inactivation ofArx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation
Authors: Colombo Elena , Collombat Patrick , Colasante Gaia , Bianchi Marta , Long Jason , Mansouri Ahmed , Rubenstein John L. R. , Broccoli Vania
Published: April 2007

ARXloss-of-function mutations cause X-linked lissencephaly with ambiguous genitalia (XLAG), a severe neurological condition that results in profound brain malformations, including microcephaly, absence of corpus callosum, and impairment of the basal ganglia. Despite such dramatic defects, their nature and origin remain largely unknown. Here, we usedArxmutant mice as a model to characterize the cellular and molecular mechanisms underlying the basal ganglia alterations. In these animals, the early differentiation of this tissue appeared normal, whereas subsequent differentiation was impaired, leading to the periventricular accumulation of immature neurons in both the lateral ganglionic eminence and medial ganglionic eminence (MGE). Both tangential migration toward the cortex and striatum and radial migration to the globus pallidus and striatum were greatly reduced in the mutants, causing a periventricular accumulation of NPY+ or calretinin+ neurons in the MGE.Arxmutant neurons retained their differentiation potentialin vitrobut exhibited deficits in morphology and migration ability. These findings imply that cell-autonomous defects in migration underlie the neuronal localization defects. Furthermore, Arx mutants lacked a large fraction of cholinergic neurons and displayed a strong impairment of thalamocortical projections, in which major axon fiber tracts failed to traverse the basal ganglia. Altogether, these results highlight the critical functions ofArxin promoting neural migration and regulating basal ganglia differentiation in mice, consistent with the phenotype of XLAG patients.
Specificity of Human Cortical Areas for Reaches and Saccades
Authors: Levy Ifat , Schluppeck Denis , Heeger David J. , Glimcher Paul W.
Published: April 2007

Electrophysiological studies in monkeys have identified effector-related regions in the posterior parietal cortex (PPC). The lateral intraparietal area, for example, responds preferentially for saccades, whereas the parietal reach region responds preferentially for arm movements. However, the degree of effector selectivity actually observed is limited; each area contains neurons selective for the nonpreferred effector, and many neurons in both areas respond for both effectors. We used functional magnetic resonance imaging to assess the degree of effector preference at the population level, focusing on topographically organized regions in the human PPC [visual area V7, intraparietal sulcus 1 (IPS1), and IPS2]. An event-related design adapted from monkey experiments was used. In each trial, an effector cue preceded the appearance of a spatial target, after which a Go signal instructed subjects to produce the specified movement with the specified effector. Our results show that the degree of effector specificity is limited in many cortical areas and transitions gradually from saccade to reach preference as one moves through the hierarchy of areas in the occipital, parietal, and frontal cortices. Saccade preference was observed in visual cortex, including early areas and V7. IPS1 exhibited balanced activation to saccades and reaches, whereas IPS2 showed a weak but significant preference for reaches. In frontal cortex, areas near the central sulcus showed a clear and absolute preference for reaches, whereas the frontal eye field showed little or no effector selectivity. Although these results contradict many theoretical conclusions about effector specificity, they are compatible with the complex picture arising from electrophysiological studies and also with previous imaging studies that reported mostly overlapping saccade- and arm-related activation. The results are also compatible with theories of efficient coding in cortex.