bluuebunny/crossref_metadata_2025 huggingface dataset:
Neighbourhood Measures: Quantifying the Effects of Neighbourhood Externalities*
Authors: JENSEN BEN , HARRIS MARK N.
Published: March 2008

Analyses of neighbourhood externalities have failed to produce consistent findings of their influence on outcomes. We explore variation in estimations of youths’ education expectations between two sets of neighbourhood proxies: one corresponding to the neighbourhood in which students’ schools were located; the other to students’ home neighbourhoods. Estimations including the latter were found to be less likely to suffer from misspecifications. This might help explain variation in previous findings and provides greater confidence in results showing that there are important neighbourhood effects that influence youths’ education.
A Measure of the Efficacy of the Australian Imputation Tax System*
Authors: HANDLEY JOHN C. , MAHESWARAN KRISHNAN
Published: March 2008

We examine the efficacy of the Australian imputation tax system in eliminating the double taxation of dividends. Using Australian Taxation Office data, we find that, on average, 67 per cent of distributed imputation credits were used to reduce personal taxes during 1990–2000, but this has increased to 81 per cent over 2001–2004. Overall, the policy shift to an imputation tax system has resulted in a significant elimination of double taxation. Our results are relevant not only to the ongoing policy debate concerning the efficacy of integration tax systems, but also to equilibrium asset pricing models that require an estimate of the value of imputation credits.
Separability and Subadditivity in Australian Railways*
Authors: WILLS‐JOHNSON NICK
Published: March 2008

Economic reform in the mid‐1990s saw the application of third‐party access to railway infrastructure and, in some cases, the separation of above‐rail and below‐rail services into separate businesses. Reform was based on the notion that the rail track was a natural monopoly, while the above‐rail sector could potentially support competition. This paper examines the likelihood of such competition through an analysis of subadditivity, and also the consequences of vertical separation for rail efficiency. It finds limited evidence for sustainable above‐rail competition, but also limited evidence that vertical separation should have caused efficiency losses.
Protection of Mouse Brain from Aluminum‐induced Damage by Caffeic Acid
Authors: Yang Jun‐Qing , Zhou Qi‐Xin , Liu Bei‐Zhong , He Bai‐Cheng
Published: March 2008

The natural product caffeic acid is a specific inhibitor of 5‐lipoxygenase (5‐LOX); it also possesses antioxidant and antiinflammatory properties. The current study was designed to determine whether the neuroprotective properties of caffeic acid are due to inhibition of 5‐LOX. Cerebral damage was induced in mice by intracerebroventricular microinjection of aluminum (5.0 μg aluminum in 2.0 μL, once a day, for 5 days). Caffeic acid was administered intragastrically at 30 min prior to aluminum and repeated daily for an additional 10 days. The brain injury was determined by observation of behavioral changes in mice, as well as by measuring biochemical and pathological changes in the cerebral tissue. The levels of 5‐LOX proteins and 5‐LOX mRNA expression were measured in brain tissue. Aluminum impaired learning and memory in mice produced neuronal death in hippocampi, elevated brain malondialdehyde levels, increased protein expression of amyloid precursor protein (APP), amyloid beta, and 5‐LOX. It also increased 5‐LOX mRNA expression and decreased choline acetyl transferase (ChAT) protein expression in the brain tissue of mice. Caffeic acid prevented brain damage as well as behavioral and biochemical changes caused by aluminum overload. The results of this study suggest that overexpression of 5‐LOX accompanies the cerebral injury induced by aluminum overload in mice, and that selective inhibitors of 5‐LOX may have potential value in the treatment of aluminum neurotoxicity and conceivably of diseases associated with neuronal injury.
PE2I: A Radiopharmaceutical forIn vivoExploration of the Dopamine Transporter
Authors: Emond Patrick , Guilloteau Denis , Chalon Sylvie
Published: March 2008

The membrane dopamine transporter (DAT) has a pivotal role in the regulation of dopamine (DA) neurotransmission involved in a number of physiological functions and brain disorders. Molecular imaging techniques, such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT), are relevant tools to explore the DAT, and we developed the cocaine derivative N‐(3‐iodopro‐2E‐enyl)‐2β‐carbomethoxy‐3β‐(4′‐methylphenyl) nortropane (PE2I) that has proved to be a very potent radiopharmaceutical to image the DAT by these techniques.

Several methods are available to obtain PE2I labeled with iodine‐123 or ‐125, carbon‐11 and tritium. The pharmacological properties of PE2I have demonstrated that it has good affinity for the DAT (4 nM) and is one of the most selective DAT ligands. [125I]PE2I characterized postmortem in human brains has revealed very intense and selective binding in the basal ganglia.Ex vivoautoradiography in rats has shown that high level of [125I]PE2I accumulates in the striatum and also in the substantia nigra and ventral tegmental area. [125I]PE2I accumulation in the rat striatum is rapid, high, and selective, providing a maximum striatum/cerebellum ratio of 10 during the first 30 min post injection. Using SPECT or PET, rapid, high, and selective accumulation of PE2I was found in the caudate nucleus and putamen in monkeys, whereas rapid wash out from the cerebellum was observed.In vivoinvestigations in healthy humans have demonstrated that PE2I has high striatal uptake, low nonspecific binding, low radiation exposure, and a fairly short scanning time.

A number of findings in various animal models of Parkinson's disease in rats and monkeys have demonstrated the high efficacy of PE2I for detection of reduction in the density of DAT, thus showing the potential value of PE2I for early diagnosis and evaluation of treatment of this disease. The excellent properties of PE2I are basis for the development of new DAT tracers for use in future PET explorations using fluor‐18.
Redefining Affective Disorders: Relevance for Drug Development
Authors: Targum Steven D , Pollack Mark H , Fava Maurizio
Published: March 2008

The evaluation of new drug entities with specific modes of action may be hampered by rigid diagnostic classification systems and patient selection processes that do not focus on the anticipated symptomatic, behavioral, and functional outcomes to be achieved. Patients enrolled in central nervous system (CNS) clinical trials may present with a heterogeneous group of symptoms representing several syndromes or subtypes, subsumed under the same diagnosis in the DSM‐IV classification system. As a result, enrolled patients may not have the valid illness characteristics of interest to the particular study. We propose that clinical drug development needs to focus on the primary nosological entity likely to be affected by a new drug entity's mode of action. Ideally, a valid patient will have the acute primary symptoms that the novel drug is supposed to influence. In this article, we propose operational criteria to delineate a more symptom‐specific and ecologically valid approach to the identification of the valid patient for clinical trials.
A Haplotype of the DRD1 Gene Is Associated With Alcohol Dependence
Authors: Batel P. , Houchi H. , Daoust M. , Ramoz N. , Naassila M. , Gorwood P.
Published: March 2008

Background:  The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine‐seeking behavior and the acquisition of cocaine‐cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se.

Methods:  We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes.

Results:  The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence (p = 0.0008), with a larger excess for patients with severe dependence (p = 6 × 10−6), and even more for patients with severe complications such as withdrawal seizures (p = 7 × 10−7). A specific haplotype rs686*T‐rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample (p = 5 × 10−6).

Conclusions:  Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association.
Ethanol Induces Apoptotic Death of β‐Endorphin Neurons in the Rat Hypothalamus by a TGF‐β1‐Dependent Mechanism
Authors: Kuhn Peter , Sarkar Dipak K.
Published: March 2008

Background:  We have previously shown that developing β‐endorphin neurons, in the arcuate nucleus of the hypothalamus become increasingly apoptotic when exposed to ethanol. As in the previous study we have observed an involvement in transforming growth factor beta 1 (TGF‐β1) in mediation of the apoptotic process, the present study was conducted to determine the ethanol‐induced changes in this apoptotic regulatory peptide signaling in the arcuate nucleus of the hypothalamus of neonatal rats.

Methods:  Pups were exposed to 11.34% ethanol in a milk‐based diet or control diet on postnatal day (PND) 3 to PND7. Two hours after the last daily feeding, brains were collected and frozen in liquid nitrogen for analysis of various apoptosis regulatory proteins in the arcuate tissue by Western blots. Some animals were fixed in 4% paraformaldehyde and analyzed immunohistochemically.

Results:  Ethanol exposure increased apoptotic death of β‐endorphin neurons in the arcuate nucleus of the hypothalamus. The cell death was associated with an increase in the tissue levels of TGF‐β1 in the mediobasal hypothalamus. This was correlated with a reduction in the arcuate level of retinoblastoma protein (Rb) phosphorylation. The reduced level of Rb phosphorylation was associated with an increased protein level of the cyclin dependent kinase inhibitor p27/kip but with a decreased protein level of cyclin dependent kinase 4 and cyclin D3. In addition, the apoptotic cell death was positively correlated with the level of Bclxs but negatively correlated with the level of the Bcl2.

Conclusions:  These results suggest that ethanol exposure increases TGF‐β1 signaling involving Bcl2 and Rb repression that may lead to apoptotic death of cells including β‐endorphin neurons in the arcuate nucleus of the hypothalamus.
Improving transfusion safety: implementation of a comprehensive computerized bar code–based tracking system for detecting and preventing errors
Authors: Askeland R.W. , McGrane S. , Levitt J.S. , Dane S.K. , Greene D.L. , VandeBerg J.A. , Walker K. , Porcella A. , Herwaldt L.A. , Carmen L.T. , Kemp J.D.
Published: March 2008

BACKGROUND: To transfuse blood products safely, health care workers must accurately identify patients, blood samples, and the blood components. A comprehensive bar code–based computerized tracking system was developed and implemented to identify and prevent transfusion errors.

STUDY DESIGN AND METHODS: A data network, wireless devices, and bar‐coded labels were pilot tested before the system was introduced hospitalwide. The system provided a complete audit trail for all transactions. Data from before and after implementation were analyzed.

RESULTS: Incident reports decreased from a mean of 41.5 reports per month in the 6 months before the system was implemented to a mean of 7.2 reports per month after implementation. The blood sample rejection rate decreased from 1.82 percent to a mean of 0.17 percent after implementation. Errors detected by the new system were sorted into misscans, skipped steps, wrong steps, and prevented identification errors (PIEs). Misscans and skipped steps were the most common errors in the first 10 months after implementation. During the final transfusion step, PIEs occurred at the rate of about one per month and scans were omitted approximately 1 percent of the time. Therefore, it is estimated that mistransfusions could occur about once every 100 months on average with the new system.

CONCLUSIONS: The bar code–based computerized tracking system detected and prevented identification and matching errors, thereby reducing the proportion of blood samples rejected and increasing patient safety.
The effect of double‐ and triple‐apheresis platelet product donation on apheresis donor platelet and white blood cell counts
Authors: Richa Elie , Krueger Paul , Burgstaler Edwin A. , Bryant Sandra C. , Winters Jeffrey L.
Published: March 2008

BACKGROUND: Concerned about the effect of multiple platelet (PLT) product donation on donor health, in 2005 the FDA proposed restrictions limiting the number of PLT products donated in 12 months. This was based on limited published evidence. To provide information on the effect of PLT donation on PLT and lymphocyte (LYM) count, hematologic variables were examined in a group of multiple PLT product donors.

STUDY DESIGN AND METHODS: Donors with at least two apheresis PLT donations, one of which was a double‐ or triple‐PLT product, were examined. Donor demographics, number of blood donations, and number of apheresis PLT products donated were determined. Hematologic variables were evaluated at the first and last donation.

RESULTS: A total of 471 donors (median age, 48.8 years; 55% male; median time between first and last donations, 72 weeks) were studied. The median number of PLT donations was 4 (range, 1‐34) with the median number of PLT products donated being 7 (range, 2‐65). The median PLT count demonstrated a significant increase (14 × 109/L, p = 0.0001) while both white blood cell and LYM counts showed significant decreases (−0.2 × 109/L, p = 0.0052; and −0.06 × 109/L, p = 0.0001, respectively). After adjusting for sex and whole‐blood donations, LYM count demonstrated a significant decline associated with both number of donations (−0.01 × 109/L, p = 0.01) and number of products donated (−0.005 × 109/L, p = 0.02). PLT count demonstrated a significant increase associated with number of products donated (0.42 × 109/L, p = 0.03).

CONCLUSION: Significant but small LYM decrease and PLT increase were seen. Limitations on the number of apheresis PLT products donated within 12 months do not seem warranted due to PLT or LYM count changes.
A comparison of hemolysis and red cell mechanical fragility in blood collected with different cell salvage suction devices
Authors: Yazer Mark H. , Waters Jonathan H. , Elkin Kyle R. , Rohrbaugh Max E. , Kameneva Marina V.
Published: March 2008

BACKGROUND: Suction pressure is one variable that can affect the efficiency of red blood cell (RBC) recovery for intraoperative autotransfusion. This study compared a constant‐suction‐pressure system with a device that is expected to minimize hemolysis by automatically varying the suction pressure.

STUDY DESIGN AND METHODS: Twenty‐two 50‐mL reconstituted whole‐blood samples were collected from a flat surface with either a constant‐pressure suction device (BRAT 2 autologous blood recovery system, COBE Cardiovascular) set to a pressure of −200 mmHg or a variable‐pressure suction device (SmartSuction Harmony surgical suction pump, Haemonetics, Inc.). Time of blood collection was recorded and plasma free hemoglobin (PFHb) was spectroscopically measured in the aspirated blood. Postcollection blood was subjected to RBC mechanical fragility test to characterize potential sublethal blood trauma. Relative hemolysis and the mean fragility index (MFI) were calculated.

RESULTS: Hemolysis was significantly reduced with the variable‐pressure suction compared to the constant‐pressure suction (2.17% vs. 3.20%, respectively; p < 0.001). There was no significant difference between both suction devices in either the MFI of RBCs (0.632 vs. 0.673, respectively; p > 0.05) or the collection time at −200 mmHg (54.2 seconds vs. 52.8 seconds, respectively; p > 0.05).

CONCLUSIONS: Although the variable‐pressure device produced a significant reduction in hemolysis during one‐pass blood collection, the clinical significance of this reduction is not clear. In relative terms, the variable‐pressure device would recover an extra 10 mL of RBCs for every liter of salvaged RBCs, which is negligible compared to the blood loss in major surgery.
Risk factors for hepatitis C virus infection among blood donors in Beijing and implications for improving the pretesting donor screening process
Authors: Qiu Yan , Shi Ling , Wang Yi , Zhang Gui , Zheng Jing , Gong Xiaoyan , Xia Hongying , Zhang Ping , Ness Paul , Shan Hua
Published: March 2008

BACKGROUND: The objective was to determine risk factors of hepatitis C virus (HCV) infection in blood donors in Beijing.

STUDY DESIGN AND METHODS: A cross‐sectional study was conducted in a total of 112 volunteer blood donors at Beijing Red Cross Blood Center (BRCBC) who were identified between January 2002 and December 2003 due to isolated HCV antibody reactivity at a donor screening procedure. The donors were recalled and interviewed about possible risk factor history. Additional blood samples were tested in repeated enzyme immunoassay, recombinant immunoblot assay, and nested reverse transcription–polymerase chain reaction. Chi‐square test, analysis of variance, and multivariate logistic regression analysis were conducted to examine associations between HCV serostatus and potential risk factors.

RESULTS: Among donors identified with isolated HCV antibody reactivity at donor screening, the prevalence of confirmed HCV infection was 31.3 percent (95% confidence interval [CI], 22.0%‐39.2%) and indeterminate HCV infection was 22.3 percent (95% CI, 14.7%‐30.3%), and the negative prevalence was 46.4 percent (95% CI, 37.5%‐56.1%). The confirmed HCV cases were more likely than the indeterminate HCV cases to have the histories of previous transfusion, plasma donation, and hepatitis infection or elevated alanine aminotransferase (ALT), whereas the HCV‐negative subjects were least likely to have the above histories (p  < 0.05).

CONCLUSION: Histories of blood transfusion before 1995, plasma donation, previous hepatitis infection, or elevated ALT were risk factors for HCV infection among blood donors in Beijing.
Teaching the Mediterranean Diet in Italy
Authors: Willows Noreen D. , Strawson‐Fawcett Cynthia , Downs Shauna M.
Published: March 2008

ABSTRACT: Problem‐based learning (PBL) can provide an enhanced appreciation of the relationship between culture and food for students who aspire to become dietitians or nutrition educators; however, large university classes often inhibit the use of PBL. A professor who specializes in research documenting the relationships among food and culture took 17 Canadian university students, many of whom were studying nutrition and food science, to southern Italy where they learned about Mediterranean diets and Italian food culture. PBL was implemented by encouraging students to work together to solve problems, and by the completion of assignments that promoted observation of and interaction with the local culture. Students evaluated the experience positively with majority agreement that the quality of course content was excellent, that knowledge of the subject areas increased, and that the courses challenged students to critically think about issues. Despite a focused effort on PBL in the courses, not all students agreed that the courses helped them to develop the ability to solve real problems in this field. This may have been due to unawareness of dietetic competencies by some students. Many of the assignments used in Italy could be adopted for use in food culture classes in North America, or by postsecondary instructors planning travel study programs in Italy.
Delivering Food Safety Education to Middle School Students Using a Web‐Based, Interactive, Multimedia, Computer Program
Authors: Lynch Rebecca A. , Dale Steen M. , Pritchard Todd J. , Buzzell Paul R. , Pintauro Stephen J.
Published: March 2008

ABSTRACT:  More than 76 million persons become ill from foodborne pathogens in the United States each year. To reduce these numbers, food safety education efforts need to be targeted at not only adults, but school children as well. The middle school grades are ideal for integrating food safety education into the curriculum while simultaneously contributing to national and state education standards in science, technology, and family and consumer sciences. For this project, a multimedia, self‐paced online resource for delivering a food safety curriculum to middle school children was developed. Animated characters were used to deliver the lesson content. The application also included video segments, quiz feedback, and interactive games and activities. The effectiveness of the Web site was evaluated using validated cognitive and attitudinal assessment tools, and by comparing student cognitive gains to individual student learning styles. Participants were recruited from 6 middle schools in 5 states, totaling 217 students (20 sixth graders, 157 seventh graders, and 40 eighth graders). The results show that students had statistically significant modest gains in pretest to posttest knowledge and enjoyed using the Web site. The 6th grade students had significantly lower pretest to posttest improvement compared to 7th and 8th grade students, suggesting that this program may not be appropriate for this grade level. Furthermore, the results indicate that this Web‐based computer application meets the needs of varying individual student learning styles.
Distribution of chemo‐ and mechanoreceptors on the antennae and maxillae of Busseola fusca larvae
Authors: Juma Gerald , Chimtawi Mathayo , Ahuya Peter O. , Njagi Peter G. N. , Le Rü Bruno , Magoma Gabriel , Silvain Jean‐François , Calatayud Paul‐André
Published: March 2008

The stem borer Busseola fusca (Fuller) (Lepidoptera: Noctuidae) is a major pest of maize, Zea mays L., and sorghum, Sorghum bicolor (L.) Moench (both Poaceae), in sub‐Saharan Africa. Like in many other lepidopteran insects, the success of B. fusca in recognizing and colonizing a limited variety of plants is based on the interaction between its sensory systems and the physicochemical characteristics of its immediate environment. The sensilla on the maxillary galeae of B. fusca larvae are typical of Lepidoptera and comprise two uniporous styloconic sensilla, which are contact chemoreceptors, three basiconic sensilla, and two aporous sensilla chaetica. The maxillary palp is two‐segmented and has eight small basiconic sensilla at the tip, which were also found to be gustatory. The antennae of B. fusca larvae are short and simple. The sensilla of the antenna are composed of two aporous sensilla chaetica, three multiporous cone‐shaped basiconic sensilla, three small basiconic sensilla, and one aporous styloconic sensillum. The basiconic sensillum located on the third antennal segment displayed a contact chemoreception response. The other basiconic sensilla did not show any action potential activity in tip‐recording tests. The significant and positive dose–response curve obtained for the antennal basiconic sensillum with sucrose indicated for the first time the presence of gustatory chemoreceptors on the antennae of a lepidopteran larva.
Efficacy of entomopathogenic fungi against soil‐dwelling life stages of western flower thrips, Frankliniella occidentalis, in plant‐growing media
Authors: Ansari M. A. , Brownbridge M. , Shah F. A. , Butt T. M.
Published: March 2008

The potential of several entomopathogenic fungi to control soil‐dwelling stages of western flower thrips, Frankliniella occidentalis Pergande (Thysanoptera: Thripidae), was evaluated in various growing media. Two Metarhizium anisopliae (Metsch) Sorokin strains, V275 and ERL700, were the most effective, causing 85–96% mortality of thrips larvae and pupae (as measured by relative adult emergence rates), 11 days after inoculation. Mortality in other M. anisopliae‐treated media ranged from 51–84%; Beauveria bassiana (Balsamo) Vuillemin strains caused 54–84% mortality, and Paecilomyces fumosoroseus (Wize) 63–75% mortality. In contrast, mortality from the insecticide treatment (fipronil 1 g l−1 medium) was only 15–54%. Metarhizium anisopliae V275 was selected for more in‐depth evaluation under greenhouse conditions. There was no significant difference in M. anisopliae efficacy in growing media whether it was applied as drench (84–93%) or premixed into the medium as dry conidia (85–92%). The use of M. anisopliae with reduced rates of either fipronil or imidacloprid did not significantly improve control. Overall, our study shows that M. anisopliae V275 is robust and offers much promise for the control of soil‐dwelling stages of thrips as part of an integrated pest‐management programme.
Tetracycline suppresses ATPγS‐induced CXCL8 and CXCL1 production by the human dermal microvascular endothelial cell‐1 (HMEC‐1) cell line and primary human dermal microvascular endothelial cells
Authors: Bender Anna , Zapolanski Tamar , Watkins Shannon , Khosraviani Ava , Seiffert Kristina , Ding Wanhong , Wagner John A. , Granstein Richard D.
Published: March 2008

Abstract:  Tetracyclines (TCN) have powerful anti‐inflammatory properties in addition to their anti‐microbial effects. These anti‐inflammatory effects are thought to play a role in inhibiting cutaneous inflammation in patients with rosacea and acne; however, the mechanism(s) of this action remains poorly understood. We have previously shown that adenosine‐5′‐triphosphate (ATP)γS, a hydrolysis‐resistant ATP analogue, augments secretion of pro‐inflammatory messengers by a human dermal microvascular endothelial cell line (HMEC‐1). ATP released by the sympathetic nerves during stress may stimulate release of pro‐inflammatory chemokines by dermal vessel endothelial cells, resulting in recruitment of inflammatory cells and exacerbation of inflammatory skin disease. Here we demonstrate that TCN inhibits ATPγS‐induced release of pro‐inflammatory mediators by HMEC‐1 cells and primary human dermal microvascular endothelial cells. TCN dose‐dependently inhibited ATPγS‐induced augmentation of CXCL8 (interleukin‐8) and CXCL1 (growth‐regulated oncogene‐α) production by HMEC‐1 cells and primary human dermal endothelial cells in vitro. TCN and ATPγS did not affect HMEC‐1 cell viability as determined by trypan‐blue exclusion and cell counts. Inhibition of production of inflammatory mediators by endothelial cells may be one mechanism by which TCN improves inflammatory skin diseases. The ability to inhibit release of inflammatory mediators induced in HMEC‐1 cells by purinergic agonists may be a useful way to screen for potential therapeutic agents for cutaneous inflammation.
Anti‐inflammatory and immune‐regulatory mechanisms prevent contact hypersensitivity to Arnica montana L.
Authors: Lass Christian , Vocanson Marc , Wagner Steffen , Schempp Christoph M. , Nicolas Jean‐Francois , Merfort Irmgard , Martin Stefan F.
Published: March 2008

Abstract:  Sesquiterpene lactones (SL), secondary plant metabolites from flowerheads of Arnica, exert anti‐inflammatory effects mainly by preventing nuclear factor (NF)‐κB activation because of alkylation of the p65 subunit. Despite its known immunosuppressive action, Arnica has been classified as a plant with strong potency to induce allergic contact dermatitis. Here we examined the dual role of SL as anti‐inflammatory compounds and contact allergens in vitro and in vivo. We tested the anti‐inflammatory and allergenic potential of SL in the mouse contact hypersensitivity model. We also used dendritic cells to study the activation of NF‐κB and the secretion of interleukin (IL)‐12 in the presence of different doses of SL in vitro. Arnica tinctures and SL potently suppressed NF‐κB activation and IL‐12 production in dendritic cells at high concentrations, but had immunostimulatory effects at low concentrations. Contact hypersensitivity could not be induced in the mouse model, even when Arnica tinctures or SL were applied undiluted to inflamed skin. In contrast, Arnica tinctures suppressed contact hypersensitivity to the strong contact sensitizer trinitrochlorobenzene and activation of dendritic cells. However, contact hypersensitivity to Arnica tincture could be induced in acutely CD4‐depleted MHC II knockout mice. These results suggest that induction of contact hypersensitivity by Arnica is prevented by its anti‐inflammatory effect and immunosuppression as a result of immune regulation in immunocompetent mice.
Biomarkers for lysosomal storage disorders: identification and application as exemplified by chitotriosidase in Gaucher disease
Authors: Aerts Johannes M , Van Breemen Marielle J , Bussink Anton P , Ghauharali Karen , Sprenger Richard , Boot Rolf G , Groener Johanna E , Hollak Carla E , Maas Mario , Smit Suzanne , Hoefsloot Huub C , Smilde Age K , Vissers Johannes PC , De Jong Sheryas , Speijer Dave , De Koster Chris G
Published: March 2008

A biomarker is an analyte that indicates the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing determinations of disease activity. In the case of lysosomal storage disorders (LSDs), metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Potential clinical applications of biomarkers are found in improved diagnosis, monitoring of disease progression and assessment of therapeutic correction. These applications are illustrated by reviewing the use of plasma chitotriosidase in the clinical management of patients with Gaucher disease, the most common LSD. The ongoing debate on the value of biomarkers in patient management is addressed. Novel analytical methods have revolutionized the identification and measurement of biomarkers at the protein and metabolite level. Recent developments in biomarker discovery by proteomics are described and the future for biomarkers of LSDs is discussed.

Conclusion: Besides direct applications for biomarkers in patient management, biomarker searches are likely to render new insights into pathophysiological mechanisms and metabolic adaptations, and may provide new targets for therapeutic intervention.
Methods for assessing neurodevelopment in lysosomal storage diseases and related disorders: a multidisciplinary perspective
Authors: Martin Holly R , Poe Michele D , Reinhartsen Debra , Pretzel Rebecca E , Roush Jackson , Rosenberg Angela , Dusing Stacey C , Escolar Maria L
Published: March 2008

Lysosomal storage diseases and related disorders (LSRDs) are a heterogeneous group of rare diseases caused by genetic mutations that result in deficiencies of specific lysosomal enzymes. Some of these enzymes are necessary for normal development of the central and peripheral nervous systems. Because of the heterogeneity in clinical presentation and complexity of these disorders, evaluation of disease progression poses unique challenges. In recent years, recombinant enzyme replacement therapy and haematopoietic stem cell transplantation have been developed to treat some of these diseases. With the development of specific therapies and screening programmes, there is a need to systematically follow the natural course and effects of treatment in these disorders with standardized and validated tools. This review describes the limitations of currently available neurobehavioural tools in longitudinally tracking disease outcomes in patients with neurodegenerative LSRDs. A multidisciplinary team reviewed over 750 evaluations in 274 patients. These patients were found to have neurological, sensory and somatic problems that considerably influence the results of neurobehavioural testing.

Conclusion: Treatment effects in patients with neurodegenerative LSRDs are best evaluated by repeated measures and longitudinal analysis of each domain of function.
Newborn screening for lysosomal storage disorders
Authors: Matern Dietrich
Published: March 2008

Newborn screening is a public health programme aimed at identifying treatable conditions in pre‐symptomatic newborns to avoid premature mortality, morbidity and disabilities. With the advent of successful treatment options for an increasing number of lysosomal storage disorders (LSDs), such as enzyme replacement or bone marrow transplantation, inclusion of these disorders into newborn screening programmes seems reasonable. However, the success of these programmes depends on the availability of testing methods that are suitable for population screening, have high sensitivity and a low false‐positive rate. In recent years, two methods have been proposed for newborn screening of LSDs, which enable assessment of more than one LSD from a single blood spot sample. One applies tandem mass spectrometry, the other microbead array technology. Now, prospective studies are needed to determine the most effective approach to newborn screening that will identify those patients who require treatment.

Conclusion: With the advent of high‐throughput assays for the detection of LSDs, newborn screening for these disorders may soon become a reality. However, careful prospective studies are required to optimize this process before it is used on a larger scale.
Gaucher disease: unmet treatment needs
Authors: Mehta Atul
Published: March 2008

Gaucher disease is a multisystemic metabolic disorder arising from a deficiency of lysosomal glucocerebrosidase. The predominant clinical manifestations of the disease are hepatosplenomegaly, peripheral blood cytopenias and skeletal disease. Treatment with enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) has been shown to be effective in improving organ volume, anaemia, thrombocytopenia, bone markers and biomarkers in patients with Gaucher disease. However, some patient needs remain unmet because of the limited availability of treatment, the inaccessibility of certain disease sites and emerging disease manifestations. An increase in haematological, lymphoreticular and immune system malignancies has been observed in patients with Gaucher disease, but mechanisms underlying the development of these are not fully understood. Mild neurological manifestations may also affect patients with type 1 Gaucher disease, but treatment with ERT or SRT does not improve neurological function. Potential new treatments for Gaucher disease include small molecules, which may penetrate tissues that are not accessible by ERT.

Conclusion: ERT currently remains the most effective treatment for Gaucher disease. New treatments are emerging, but deficiencies in understanding basic pathophysiological mechanisms hinder progress.
Apoptotic abnormalities in differential gene expression in peripheral blood mononuclear cells from children with Fabry disease
Authors: Moore David F , Goldin Ehud , Gelderman Monique P , Robinson Chevalia , Baer Jessica , Ries Markus , Elkahloun Abdel , Brady Roscoe O , Schiffmann Raphael
Published: March 2008

Aim: This study was designed to examine the effect of enzyme replacement therapy (ERT) on differential gene expression in peripheral blood mononuclear cells (PBMCs) of children with Fabry disease who had not previously been exposed to ERT.

Methods: Thirteen children with Fabry disease (age range, 6.5–17.0 years) were studied as part of a 6‐month, open‐label study of ERT with agalsidase alfa. Paired blood samples were taken at the start of the study and after 6 months of ERT. Further blood samples were also taken from 16 age‐matched control subjects. PBMCs were isolated and, following RNA extraction, differential gene expression analysis was performed using the Human Genome U133 Plus 2.0 microarray.

Results: Twenty‐one genes were determined to be differentially expressed in PBMCs of ERT‐naïve children with Fabry disease compared with healthy controls; neuronal apoptosis inhibitory protein ranked as the most significantly differentially expressed gene. Comparison of gene expression in children with Fabry disease prior to and after ERT showed that two genes were significantly differentially expressed (p ≤ 0.05) following treatment; the expressed sequence tag (probe set ID, 243259_at) was downregulated, while expression of apoptosis‐inducing factor was increased, possibly as an antioxidant counter‐regulatory response.

Conclusion: This study identifies a number of genes that are differentially expressed in a small cohort of children with Fabry disease relative to healthy controls. These genes may relate to the underlying biological abnormalities in Fabry disease.
Fabry disease during childhood: clinical manifestations and treatment with agalsidase alfa
Authors: Ramaswami Uma
Published: March 2008

Fabry disease is a rare X‐linked disorder that leads to widespread and progressive disease manifestations, with patients at risk of premature mortality as a result of renal, cardiovascular or cerebrovascular complications. In recent years there has been a growing awareness that the first signs and symptoms of Fabry disease may begin during childhood. Studies show that clinical manifestations such as pain, hypohidrosis, gastrointestinal disturbances, angiokeratomas, cornea verticillata and acroparaesthesiae may be common in childhood and that such manifestations may become apparent during the first few years of life. Despite the early onset of these signs and symptoms, however, diagnosis is often delayed. Interest is now focused on whether enzyme replacement therapy can slow or prevent the onset of these disease manifestations. Preliminary data from two studies suggest that treatment with agalsidase alfa is well tolerated in children and that it may have beneficial clinical effects; however, further research is needed to determine whether enzyme replacement therapy can prevent the development of disease manifestations.

Conclusion: The manifestations of Fabry disease first become apparent during childhood. It is well known that disease‐associated manifestations are progressive; however, it has yet to be determined whether specific treatment with enzyme replacement therapy can prevent the development of the associated severe and life‐threatening complications.
CNS‐directed gene therapy for lysosomal storage diseases
Authors: Sands Mark S , Haskins Mark E
Published: March 2008

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders usually caused by deficient activity of a single lysosomal enzyme. As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems, including the central nervous system (CNS). At least 75% of all LSDs have a significant CNS component. Approaches such as bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) can effectively treat the systemic disease associated with LSDs in some patients. However, CNS disease remains a major challenge. Gene therapy represents a promising approach for the treatment of CNS disease as it has the potential to provide a permanent source of the deficient enzyme. Direct intracranial injection of viral gene transfer vectors has resulted in reduced lysosomal storage and functional improvement in certain small (rodent) and large (canine and feline) animal models of LSDs. The addition of protein transduction domains (PTDs) to the recombinant enzymes increased the distribution of enzyme and the extent of correction. Therapeutic levels of lysosomal enzymes can also be delivered to distant sites in the brain by anterograde and retrograde axonal transport. Finally, combining disparate approaches such as BMT and CNS‐directed gene therapy can increase treatment efficacy in LSDs with severe CNS disease that are refractory to more conventional approaches.

Conclusion: The development of gene transfer vectors that mediate persistent expression in vivo, the addition of PTDs, a better understanding of lysosomal enzyme trafficking and combining different therapies provide hope that the CNS component of LSDs can be effectively treated.
Hypoxia‐driven proliferation of embryonic neural stem/progenitor cells – role of hypoxia‐inducible transcription factor‐1α
Authors: Zhao Tong , Zhang Cui‐ping , Liu Zhao‐hui , Wu Li‐ying , Huang Xin , Wu Hai‐tong , Xiong Lei , Wang Xuan , Wang Xiao‐min , Zhu Ling‐ling , Fan Ming
Published: March 2008

We recently reported that intermittent hypoxia facilitated the proliferation of neural stem/progenitor cells (NPCs) in the subventricule zone and hippocampus in vivo. Here, we demonstrate that hypoxia promoted the proliferation of NPCs in vitro and that hypoxia‐inducible factor (HIF)‐1α, which is one of the key molecules in the response to hypoxia, was critical in this process. NPCs were isolated from the rat embryonic mesencephalon (E13.5), and exposed to different oxygen concentrations (20% O2, 10% O2, and 3% O2) for 3 days. The results showed that hypoxia, especially 10% O2, promoted the proliferation of NPCs as assayed by bromodeoxyuridine incorporation, neurosphere formation, and proliferation index. The level of HIF‐1α mRNA and protein expression detected by RT‐PCR and western blot significantly increased in NPCs subjected to 10% O2. To further elucidate the potential role of HIF‐1α in the proliferation of NPCs induced by hypoxia, an adenovirus construct was used to overexpress HIF‐1α, and the pSilencer 1.0‐U6 plasmid as RNA interference vector targeting HIF‐1α mRNA was used to knock down HIF‐1α. We found that overexpression of HIF‐1α caused the same proliferative effect on NPCs under 20% O2 as under 10% O2. In contrast, knockdown of HIF‐1α inhibited NPC proliferation induced by 10% O2. These results demonstrated that moderate hypoxia was more beneficial to NPC proliferation and that HIF‐1α was critical in this process.
Structural modeling and mutational analysis of yeast eukaryotic translation initiation factor 5A reveal new critical residues and reinforce its involvement in protein synthesis
Authors: Dias Camila A. O. , Cano Veridiana S. P. , Rangel Suzana M. , Apponi Luciano H. , Frigieri Mariana C. , Muniz João R. C. , Garcia Wanius , Park Myung H. , Garratt Richard C. , Zanelli Cleslei F. , Valentini Sandro R.
Published: March 2008

Eukaryotic translation initiation factor 5A (eIF5A) is a protein that is highly conserved and essential for cell viability. This factor is the only protein known to contain the unique and essential amino acid residue hypusine. This work focused on the structural and functional characterization of Saccharomyces cerevisiae eIF5A. The tertiary structure of yeast eIF5A was modeled based on the structure of its Leishmania mexicana homologue and this model was used to predict the structural localization of new site‐directed and randomly generated mutations. Most of the 40 new mutants exhibited phenotypes that resulted from eIF‐5A protein‐folding defects. Our data provided evidence that the C‐terminal α‐helix present in yeast eIF5A is an essential structural element, whereas the eIF5A N‐terminal 10 amino acid extension not present in archaeal eIF5A homologs, is not. Moreover, the mutants containing substitutions at or in the vicinity of the hypusine modification site displayed nonviable or temperature‐sensitive phenotypes and were defective in hypusine modification. Interestingly, two of the temperature‐sensitive strains produced stable mutant eIF5A proteins – eIF5AK56A and eIF5AQ22H,L93F– and showed defects in protein synthesis at the restrictive temperature. Our data revealed important structural features of eIF5A that are required for its vital role in cell viability and underscored an essential function of eIF5A in the translation step of gene expression.
Distinct signaling pathways of microtubule inhibitors – vinblastine and Taxol induce JNK‐dependent cell death but through AP‐1‐dependent and AP‐1‐independent mechanisms, respectively
Authors: Kolomeichuk Sergey N. , Terrano David T. , Lyle Christopher S. , Sabapathy Kanaga , Chambers Timothy C.
Published: March 2008

Vinblastine and paclitaxel (Taxol) are widely used chemotherapeutic drugs that inhibit the normal function of microtubules causing mitotic arrest and cell death. Despite these similarities, the signaling pathways that mediate and regulate cell death induced by these agents remain incompletely understood. The purpose of this study was to directly compare the two drugs in terms of their ability to activate components of the c‐Jun N‐terminal protein kinase (JNK) pathway, and to establish the importance of these signaling events in apoptosis induced by these agents. We show that both drugs induce mitotic arrest and subsequent apoptotic cell death with highly similar kinetics and that both activate JNK and induce c‐Jun protein and c‐jun mRNA expression. Surprisingly, vinblastine induced c‐Jun phosphorylation and c‐jun transcriptional activation, although Taxol failed to do so. However, inhibition of JNK or an absence of JNK protected against both vinblastine‐ and Taxol‐induced cell death. These results suggest that although JNK activation plays an important role in cell death induced by both agents, vinblastine and Taxol differ markedly with respect to signaling downstream of JNK, with AP‐1‐dependent and ‐independent mechanisms, respectively. In addition, these results show, contrary to popular belief, that JNK activation is not necessarily accompanied by c‐Jun activation, and thus c‐Jun is not an obligate substrate of JNK.
Effects of Perinatal, Combined Exposure to 1,4‐Dichlorobenzene and 1,1‐Dichloro‐2,2‐bis(p‐chlorophenyl)ethylene on Rat Female Reproductive System
Authors: Makita Yuji
Published: March 2008

Abstract:  Prenatal or early postnatal exposure to some synthetic chemicals may affect the later reproductive system of the offspring. 1,4‐Dichlorobenzene (DCB) is used as an air freshener and a moth repellent and 1,1‐dichloro‐2,2‐bis(p‐chlorophenyl) ethylene (p,p′‐DDE) is a persistent metabolite of 1,1,1‐trichloro‐2,2‐bis(p‐chlorophenyl)ethane that was used as a pesticide before. DCB concentrations of residential air and oral p,p′‐DDE intake through marine products are demonstrated to be rather high in Japan. Such situations lead to high body burden of these pollutants in pregnant women. Consequently, foetuses and neonates will be exposed much more to DCB and p,p′‐DDE via the mother. Therefore, the effects of the perinatal, combined exposure to DCB and p,p′‐DDE on the female reproductive system have been investigated in mature rat female offspring of dams ingesting 25 p.p.m. DCB (approximately 2 mg/kg) and 125 p.p.m. p,p′‐DDE (approximately 10 mg/kg) during the gestational and lactational period. Sexual maturation was fully developed in the rat female offspring perinatally exposed to DCB and/or p,p′‐DDE through maternal exposure. The combined effect of DCB and p,p′‐DDE was observed, and the ovarian weight was seen to decrease to approximately 80% of the control rat in matured female offspring following perinatal exposure to DCB and p,p′‐DDE. This alteration might lead to reproductive dysfunction in matured female offspring. However, biological relevance of the alteration in the ovary remained uncertain in the present study. Further investigations concerning the reproductive function and mechanistic implication are required for elucidating the combined effects of perinatal exposure to DCB and p,p′‐DDE on the later female reproductive system entirely.