bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxaliplatin neurotoxicity – no general ion channel surface-charge effect
Authors: Broomand Amir , Jerremalm Elin , Yachnin Jeffrey , Ehrsson Hans , Elinder Fredrik
Published: January 2009

Background

Oxaliplatin is a platinum-based chemotherapeutic drug. Neurotoxicity is the dose-limiting side effect. Previous investigations have reported that acute neurotoxicity could be mediated via voltage-gated ion channels. A possible mechanism for some of the effects is a modification of surface charges around the ion channel, either because of chelation of extracellular Ca2+, or because of binding of a charged biotransformation product of oxaliplatin to the channel. To elucidate the molecular mechanism, we investigated the effects of oxaliplatin and its chloride complex [Pt(dach)oxCl]- on the voltage-gated Shaker K channel expressed in Xenopus oocytes. The recordings were made with the two-electrode and the cut-open oocyte voltage clamp techniques.

Conclusion

To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.
Total fertilization failure and idiopathic subfertility
Authors: Tanahatoe Sandra J , McDonnell Joseph , Goverde Angelique J , Hompes Peter GA , Lambalk Cornelis B
Published: January 2009

Background

To gain more insight in whether failure of intrauterine insemination (IUI) treatment in patients with idiopathic subfertility could be related to diminished fertilization, the aim of this study is to compare the fertilization of an initial IVF procedure after six cycles of IUI and the fertilization of an initial IVF procedure without preceding IUI cycles in couples with idiopathic subfertility.

Methods

We performed a complimentary analysis of a randomized controlled trial, in which the number of total fertilization failure (TFF) in the first IVF procedure after unsuccessful IUI was compared to those of IVF without preceding IUI in patients with idiopathic subfertility. These patients participated in a previous study that assessed the cost effectiveness of IUI versus IVF in idiopathic subfertility and were randomized to either IUI or IVF treatment.

Results

45 patients underwent IVF after 6 cycles of unsuccessful IUI and 58 patients underwent IVF immediately without preceding IUI. In 7 patients the IVF treatment was cancelled before ovum pick. In the IVF after unsuccessful IUI group TFF was seen in 2 of the 39 patients (5%) versus 7 of the 56 patients (13%) in the immediate IVF group. After correction for confounding factors the TFF rate was not significantly different between the two groups (p = 0.08, OR 7.4; 95% CI: 0.5–14.9).

Conclusion

Our data showed that TFF and the fertilization rate in the first IVF treatment were not significantly different between couples with idiopathic subfertility undergoing IVF after failure of IUI versus those couples undergoing IVF immediately without prior IUI treatment. Apparently, impaired fertilization does not play a significant role in the success rate of IUI in patients with idiopathic subfertility.
Microarray and cDNA sequence analysis of transcription during nerve-dependent limb regeneration
Authors: Monaghan James R , Epp Leonard G , Putta Srikrishna , Page Robert B , Walker John A , Beachy Chris K , Zhu Wei , Pao Gerald M , Verma Inder M , Hunter Tony , Bryant Susan V , Gardiner David M , Harkins Tim T , Voss S Randal
Published: January 2009

Background

Microarray analysis and 454 cDNA sequencing were used to investigate a centuries-old problem in regenerative biology: the basis of nerve-dependent limb regeneration in salamanders. Innervated (NR) and denervated (DL) forelimbs of Mexican axolotls were amputated and transcripts were sampled after 0, 5, and 14 days of regeneration.

Results

Considerable similarity was observed between NR and DL transcriptional programs at 5 and 14 days post amputation (dpa). Genes with extracellular functions that are critical to wound healing were upregulated while muscle-specific genes were downregulated. Thus, many processes that are regulated during early limb regeneration do not depend upon nerve-derived factors. The majority of the transcriptional differences between NR and DL limbs were correlated with blastema formation; cell numbers increased in NR limbs after 5 dpa and this yielded distinct transcriptional signatures of cell proliferation in NR limbs at 14 dpa. These transcriptional signatures were not observed in DL limbs. Instead, gene expression changes within DL limbs suggest more diverse and protracted wound-healing responses. 454 cDNA sequencing complemented the microarray analysis by providing deeper sampling of transcriptional programs and associated biological processes. Assembly of new 454 cDNA sequences with existing expressed sequence tag (EST) contigs from the Ambystoma EST database more than doubled (3935 to 9411) the number of non-redundant human-A. mexicanum orthologous sequences.

Conclusion

Many new candidate gene sequences were discovered for the first time and these will greatly enable future studies of wound healing, epigenetics, genome stability, and nerve-dependent blastema formation and outgrowth using the axolotl model.
Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice
Authors: Jacobsen Nicklas Raun , Møller Peter , Jensen Keld Alstrup , Vogel Ulla , Ladefoged Ole , Loft Steffen , Wallin Håkan
Published: January 2009

Background

The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid.

Results

Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE-/- mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE-/- mice. Thirdly, we compared effects of instillation in ApoE-/- mice of three carbonaceous particles; CB, fullerenes C60 (C60) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in Il-6, Mip-2 and Mcp-1 mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C60 particles caused much weaker inflammatory responses.

Conclusion

Our data suggest that ApoE-/- model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C60 and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles.
Anorexia nervosa: from purgative behaviour to nephropathy. a case report
Authors: Manzato Emilia , Mazzullo Maria , Gualandi Malvina , Zanetti Tatiana , Scanelli Giovanni
Published: January 2009

Background

Individuals who suffer from Anorexia Nervosa refuse to maintain a minimally normal body weight, are intensely afraid of gaining weight and exhibit a significant disturbance in the perception of the shape and size of their body. Postmenarchal females with this disorder are amenorrohic. In the Binge-Eating/Purging subtype individuals regularly engage in binge eating and purging behaviour (i.e self-induced vomiting or misuse of laxatives, diuretics, or enemas).

Hypokalaemia is often seen in chronic Anorexia Nervosa, especially that of the purging type (ANp), and, as well as electrocardiographic anomalies, this can lead to tubulointerstitial nephritis (hypokalaemic nephropathy) with typical histological characteristics. The physiopathological mechanisms behind this damage are linked to altered stimulation of vasoactive mediators, and to the ammonium-mediated activation of the alternative complement pathway. However, it has not yet been ascertained whether a variant of the pathway specific for ANp [1], exists.

Case presentation

We describe herein a case of hypokalaemic nephropathy in a patient affected by chronic ANp who presented to our Centre for Eating Disorders.

Conclusion

Hypokalaemia can provoke cardiovascular alterations as well as muscular and renal complications, and thus potential renal damage needs to be investigated in patients suffering from long-term purgative anorexia.
Stauffer's syndrome as a prominent manifestation of renal cancer: a case report
Authors: Kranidiotis Georgios P , Voidonikola Paraskevi T , Dimopoulos Meletios K , Anastasiou-Nana Maria I
Published: January 2009

Background

Renal cell carcinoma is associated with a wide spectrum of para-neoplastic syndromes, which may be precursors of primary or recurrent disease. Non-metastatic hepatic dysfunction in patients suffering from renal cell carcinoma is known as Stauffer's syndrome. It is associated with the production of cytokines by the tumour, and several biochemical abnormalities, including elevated serum alkaline phosphatase.

Case presentation

We describe a 36-year-old woman presenting with various non-specific, systemic disease manifestations, and elevated liver enzymes due to cholestasis as the main laboratory abnormality. Imaging studies showed a solid mass in the left kidney, which, after surgical excision, was identified as renal cell carcinoma. No metastasis was found.

Conclusion

Stauffer syndrome may precede other manifestations of renal cell carcinoma. In case of unexplained abnormal liver function, particularly in presence of systemic symptoms, underlying renal cell carcinoma should be excluded by focused investigations.
Fear of Foreigners: HIV‐related restrictions on entry, stay, and residence
Authors: Amon Joseph J , Todrys Katherine Wiltenburg
Published: January 2009

Among the earliest and the most enduring responses to the HIV/AIDS epidemic has been the imposition by governments of entry, stay, and residence restrictions for non‐nationals living with HIV and AIDS. Sixty‐six of the 186 countries in the world for which data are available currently have some form of restriction in place. Although international human rights law allows for discrimination in the face of public health considerations, such discrimination must be the least intrusive measure required to effectively address the public health concern. HIV‐related travel restrictions, by contrast, not only do not protect public health, but result in deleterious effects both at the societal level – negatively impacting HIV prevention and treatment efforts – and at the individual level, affecting, in particular, labor migrants, refugee candidates, students, and short‐term travelers. Governments should repeal these laws and policies, and instead devote legislative attention and national resources to comprehensive HIV prevention, care, and treatment programmes serving citizens and non‐citizens alike.
Impact of the Methotrexate Administration Dose on the Need for Intrathecal Treatment in Children and Adolescents With Anaplastic Large-Cell Lymphoma: Results of a Randomized Trial of the EICNHL Group
Authors: Brugières Laurence , Le Deley Marie-Cécile , Rosolen Angelo , Williams Denise , Horibe Keizo , Wrobel Grazyna , Mann Georg , Zsiros Jozsef , Uyttebroeck Anne , Marky Ildiko , Lamant Laurence , Reiter Alfred
Published: January 2009

Purpose

To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL).

Patients and Methods

This randomized trial for children with ALCL was based on the Non-Hodgkin's Lymphoma–Berlin-Frankfurt-Muenster 90 (NHL-BFM90) study protocol and compared six courses of methotrexate 1 g/m2 over 24 hours and an intrathecal injection (IT) followed by folinic acid rescue at 42 hours (MTX1 arm) with six courses of methotrexate 3 g/m2 over 3 hours followed by folinic acid rescue at 24 hours without IT (MTX3 arm). This trial involved most European pediatric/lymphoma study groups and a Japanese group.

Results

Overall, 352 patients (96% ALK positive) were recruited between 1999 and 2005; 175 were randomly assigned to the MTX1 arm, and 177 were assigned to the MTX3 arm. Ninety-two percent of patients received protocol treatment. Median follow-up time is 3.7 years. Event-free survival (EFS) curves were superimposed with 2-year EFS rates (73.6% and 74.5% in the MTX1 and MTX3 arms, respectively; hazard ratio = 0.98; 91.76% CI, 0.69 to 1.38). Two-year overall survival rates were 90.1% and 94.9% in MTX1 and MTX3, respectively. Only two CNS relapses occurred (both in the MTX1 arm). Toxicity was assessed after 2,050 courses and included grade 4 hematologic toxicity after 79% and 64% of MTX1 and MTX3 courses, respectively (P < .0001); infection after 50% and 32% of courses, respectively (P < .0001); and grade 3 to 4 stomatitis after 21% and 6% of courses, respectively (P < .0001).

Conclusion

The results of the NHL-BFM90 study were reproduced in this large international trial. The methotrexate schedule of the NHL-BFM90 protocol including IT therapy can be safely replaced by a less toxic schedule of methotrexate 3 g/m2 in a 3-hour infusion without IT therapy.
Sequential Testing Approach As an Efficient and Easier Alternative for the Validation of New Predictive Technologies in the Clinic
Authors: Beam Craig A. , Gao Weihua , Macias Virgilia , Liang Weimin , Kajdacsy Balla André
Published: January 2009

Purpose

When clinicians contemplate the use of a new predictive technology in their practice, such as a nomogram, there is always a question of whether the new test is beneficial to their own clinical population. Unfortunately, traditional validation methods require a large number of subjects for validation testing and delay the decision-making process. We present an efficient and easy-to-use method based on the concept of sequential data analysis.

Patients and Methods

We illustrate with an example determining the validity of a technology for predicting Gleason score upgrading from biopsy to postprostatectomy (the Chun nomogram) in a clinical population different from the one used to initially validate the technology. Clinical data required by the Chun nomogram were available from 201 patients from the Cooperative Prostate Cancer Tissue Resource.

Results

Of 124 patients predicted by the Chun nomogram to have an upgrading event, 47 actually did. The positive predictive value (PPV) of the model was therefore 38% and significantly (P < .05) less than the value of 80% which we considered to be the smallest clinically useful PPV in this situation. Had the sequential methods introduced in this article been employed prospectively in this cohort, the same conclusion would have been reached using data from only the first 15 patients.

Conclusion

In-clinic validation of predictive technologies will help the clinician adopt truly beneficial technologies and avoid the adoption of technologies which provide no significant benefit to their local patient population. For this task, sequential methods offer clear advantages.
Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients Who Have Advanced Hepatocellular Carcinoma
Authors: Thomas Melanie B. , Morris Jeffrey S. , Chadha Romil , Iwasaki Michiko , Kaur Harmeet , Lin Elinor , Kaseb Ahmed , Glover Katrina , Davila Marta , Abbruzzese James
Published: January 2009

Purpose

The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity.

Patients and Methods

Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated.

Results

The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each).

Conclusion

The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.
Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA
Authors: Rajasekharan Sathyanath , Baker K. Adam , Horn Katherine E. , Jarjour Andrew A. , Antel Jack P. , Kennedy Timothy E.
Published: January 2009

The molecular mechanisms underlying the elaboration of branched processes during the later stages of oligodendrocyte maturation are not well understood. Here we describe a novel role for the chemotropic guidance cue netrin 1 and its receptor deleted in colorectal carcinoma (Dcc) in the remodeling of oligodendrocyte processes. Postmigratory, premyelinating oligodendrocytes express Dcc but not netrin 1, whereas mature myelinating oligodendrocytes express both. We demonstrate that netrin 1 promotes process extension by premyelinating oligodendrocytes in vitro and in vivo. Addition of netrin 1 to mature oligodendrocytes in vitro evoked a Dcc-dependent increase in process branching. Furthermore, expression of netrin 1 and Dcc by mature oligodendrocytes was required for the elaboration of myelin-like membrane sheets. Maturation of oligodendrocyte processes requires intracellular signaling mechanisms involving Fyn, focal adhesion kinase (FAK), neuronal Wiscott-Aldrich syndrome protein (N-WASP) and RhoA; however, the extracellular cues upstream of these proteins in oligodendrocytes are poorly defined. We identify a requirement for Src family kinase activity downstream of netrin-1-dependent process extension and branching. Using oligodendrocytes derived from Fyn knockout mice, we demonstrate that Fyn is essential for netrin-1-induced increases in process branching. Netrin 1 binding to Dcc on mature oligodendrocytes recruits Fyn to a complex with the Dcc intracellular domain that includes FAK and N-WASP, resulting in the inhibition of RhoA and inducing process remodeling. These findings support a novel role for netrin 1 in promoting oligodendrocyte process branching and myelin-like membrane sheet formation. These essential steps in oligodendroglial maturation facilitate the detection of target axons, a key step towards myelination.
Embryonic hair follicle fate change by augmented β-catenin through Shh and Bmp signaling
Authors: Suzuki Kentaro , Yamaguchi Yuji , Villacorte Mylah , Mihara Kenichiro , Akiyama Masashi , Shimizu Hiroshi , Taketo Makoto M. , Nakagata Naomi , Tsukiyama Tadasuke , Yamaguchi Terry P. , Birchmeier Walter , Kato Shigeaki , Yamada Gen
Published: January 2009

β-catenin signaling is one of the key factors regulating the fate of hair follicles (HFs). To elucidate the regulatory mechanism of embryonic HF fate determination during epidermal development/differentiation, we analyzed conditional mutant mice with keratinocytes expressing constitutively activeβ-catenin (K5-Cre Catnb(ex3)fl/+). The mutant mice developed scaly skin with a thickened epidermis and showed impaired epidermal stratification. The hair shaft keratins were broadly expressed in the epidermis but there was no expression of the terminal differentiation markers K1 and loricrin. Hair placode markers (Bmp2 and Shh) and follicular dermal condensate markers (noggin, patched 1 and Pdgfra)were expressed throughout the epidermis and the upper dermis, respectively. These results indicate that the embryonic epidermal keratinocytes have switched extensively to the HF fate. A series of genetic studies demonstrated that the epidermal switching to HF fate was suppressed by introducing the conditional mutation K5-Cre Catnb(ex3)fl/+Shhfl/- (with additional mutation of Shh signaling) or K5-Cre Catnb(ex3)fl/+BmprIAfl/fl (with additional mutation of Bmp signaling). These results demonstrate that Wnt/β-catenin signaling relayed through Shh and Bmp signals is the principal regulatory mechanism underlying the HF cell fate change. Assessment of Bmp2 promoter activities suggested a putative regulation by β-catenin signaling relayed by Shh signaling towards Bmp2. We also found that Shh protein expression was increased and expanded in the epidermis of K5-Cre Catnb(ex3)fl/+BmprIAfl/fl mice. These results indicate the presence of growth factor signal cross-talk involving β-catenin signaling, which regulates the HF fate.
Tinkering with the inductive mesenchyme: Sostdc1 uncovers the role of dental mesenchyme in limiting tooth induction
Authors: Munne Pauliina M. , Tummers Mark , Järvinen Elina , Thesleff Irma , Jernvall Jukka
Published: January 2009

Like epithelial organs in general, tooth development involves inductive crosstalk between the epithelium and the mesenchyme. Classically, the inductive potential for tooth formation is considered to reside in the mesenchyme during the visible morphogenesis of teeth, and dental mesenchyme can induce tooth formation even when combined with non-dental epithelium. Here, we have investigated induction of mouse incisors using Sostdc1(ectodin), a putative antagonist of BMP signaling in the mesenchymal induction of teeth. Deletion of Sostdc1 leads to the full development of single extra incisors adjacent to the main incisors. We show that initially, Sostdc1 expression is limited to the mesenchyme, suggesting that dental mesenchyme may limit supernumerary tooth induction. We test this in wild-type incisors by minimizing the amount of mesenchymal tissue surrounding the incisor tooth germs prior to culture in vitro. The cultured teeth phenocopy the extra incisors phenotype of the Sostdc1-deficient mice. Furthermore, we show that minimizing the amount of dental mesenchyme in cultured Sostdc1-deficient incisors causes the formation of additional de novo incisors that resemble the successional incisor development that results from activated Wnt signaling. Finally, Noggin and Dkk1 prevent individually the formation of extra incisors, and we therefore suggest that inhibition of both BMP and Wnt signaling contributes to the inhibitory role of the dental mesenchyme. Considering the role of mesenchyme in tooth induction and the design of tissue engineering protocols, our work may have uncovered how delicate control of tissue quantities alone influences the outcome between induction and inhibition.
Fasciclin 2, theDrosophilaorthologue of neural cell-adhesion molecule, inhibits EGF receptor signalling
Authors: Mao Yanlan , Freeman Matthew
Published: January 2009

Adhesion proteins not only control the degree to which cells adhere to each other but are increasingly recognised as regulators of intercellular signalling. Using genetic screening in Drosophila, we have identified Fasciclin 2 (Fas2), the Drosophila orthologue of neural cell adhesion molecule (NCAM), as a physiologically significant and specific inhibitor of epidermal growth factor receptor (EGFR) signalling in development. We find that loss of fas2 genetically interacts with multiple genetic conditions that perturb EGFR signalling. Fas2 is expressed in dynamic patterns during imaginal disc development, and in the eye we have shown that this depends on EGFR activity, implying participation in a negative-feedback loop. Loss of fas2 causes characteristic EGFR hyperactivity phenotypes in the eye, notum and wing, and also leads to downregulation of Yan, a transcriptional repressor targeted for degradation by EGFR activity. No significant genetic interactions were detected with the Notch, Wingless,Hedgehog or Dpp pathways, nor did Fas2 inhibit the FGF receptor or Torso,indicating specificity in the inhibitory role of Fas2 in EGFR signalling. Our results introduce a new regulatory interaction between an adhesion protein and a Drosophila signalling pathway and highlight the extent to which the EGFR pathway must be regulated at multiple levels.
Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice
Authors: Zhou Hong , Mak Wendy , Kalak Robert , Street Janine , Fong-Yee Colette , Zheng Yu , Dunstan Colin R. , Seibel Markus J.
Published: January 2009

Glucocorticoids are important regulators of bone cell differentiation and mesenchymal lineage commitment. Using a cell-specific approach of osteoblast-targeted transgenic disruption of intracellular glucocorticoid signaling, we discovered a novel molecular pathway by which glucocorticoids,mainly through the mature osteoblast, regulate the cellular mechanisms that govern cranial skeleton development. Embryonic and neonatal transgenic mice revealed a distinct phenotype characterized by hypoplasia and osteopenia of the cranial skeleton; disorganized frontal, parietal and interparietal bones;increased suture patency; ectopic differentiation of cartilage in the sagittal suture; and disturbed postnatal removal of parietal cartilage. Concurrently,expression of Mmp14, an enzyme essential for calvarial cartilage removal, was markedly reduced in parietal bone and cartilage of transgenic animals. Expression of Wnt9a and Wnt10b was significantly reduced in osteoblasts with disrupted glucocorticoid signaling, and accumulation of β-catenin, the upstream regulator of Mmp14 expression, was decreased in osteoblasts,chondrocytes and mesenchymal progenitors of transgenic mice. Supracalvarial injection of Wnt3a protein rescued the transgenic cranial phenotype. These results define novel roles for glucocorticoids in skeletal development and delineate how osteoblasts - under steroid hormone control - orchestrate the intricate process of intramembranous bone formation by directing mesenchymal cell commitment towards osteoblastic differentiation while simultaneously initiating and controlling cartilage dissolution in the postnatal mouse.
EHD3 regulates early-endosome-to-Golgi transport and preserves Golgi morphology
Authors: Naslavsky Naava , McKenzie Jenna , Altan-Bonnet Nihal , Sheff David , Caplan Steve
Published: January 2009

Depletion of EHD3 affects sorting in endosomes by altering the kinetics and route of receptor recycling to the plasma membrane. Here we demonstrate that siRNA knockdown of EHD3, or its interaction partner rabenosyn-5, causes redistribution of sorting nexin 1 (SNX1) to enlarged early endosomes and disrupts transport of internalized Shiga toxin B subunit (STxB) to the Golgi. Moreover, under these conditions, Golgi morphology appears as a series of highly dispersed and fragmented stacks that maintain characteristics of cis-, medial- and trans-Golgi membranes. Although Arf1 still assembled onto these dispersed Golgi membranes, the level of AP-1 γ-adaptin recruited to the Golgi was diminished. Whereas VSV-G-secretion from the dispersed Golgi remained largely unaffected, the distribution of mannose 6-phosphate receptor (M6PR) was altered: it remained in peripheral endosomes and did not return to the Golgi. Cathepsin D, a hydrolase that is normally transported to lysosomes via an M6PR-dependent pathway, remained trapped at the Golgi. Our findings support a role for EHD3 in regulating endosome-to-Golgi transport, and as a consequence, lysosomal biosynthetic, but not secretory, transport pathways are also affected. These data also suggest that impaired endosome-to-Golgi transport and the resulting lack of recruitment of AP-1 γ-adaptin to Golgi membranes affect Golgi morphology.
Preparation and Electrochemical Performance of Ni–Al LDH Doped with Co and La
Authors: Yang Jianfeng , Zhou Zhentao
Published: January 2009

Ni–Al LDH doped with Co and La was prepared by coprecipitation. The sample obtained consisted of loose pellets which were further reunited with masses of smaller particles. Its BET surface area reached 132.5 m2/g and was much larger than that of a sample doped only with Co. The electrode fabricated from it exhibited better electrochemical reversibility, and the proton diffusion coefficient is also much higher.
Visible and Near-infrared Laser Desorption Ionization Mass Spectrometry Using Single Wall Carbon Nanotubes
Authors: Nanjo Daisuke , Shibamoto Kohei , Korenaga Takashi
Published: January 2009

We demonstrated detection of PEG 1000 on a surface of single wall carbon nanotubes (SWCNTs) for surface-assisted laser desorption ionization mass spectrometry (SALDI-MS) by irradiating laser pulses with wavelengths of 532 and 1064 nm. We succeeded in observation of molecule-related ion of a coronene with no fragmentation in visible SALDI-MS measurements.
Fluorescence Enhancement Due to Gap Mode of Gold Colloids Immobilized on a Hydrophilic Amino-terminated Glass Substrate
Authors: Ishida Akito , Kumagai Keisuke
Published: January 2009

The preparation and characterization of a novel plasmonic substrate that exhibits remarkable fluorescence enhancement due to the presence of gap mode and hydrophilicity have been studied.
Silica Capillary with Thin Metal (Pd and Pt) Inner Wall: Application to Continuous Decomposition of Hydrogen Peroxide
Authors: Javaid Rahat , Tanaka David A Pacheco , Kawanami Hajime , Suzuki Toshishige M
Published: January 2009

Thin metallic (Pd and Pt) layer was coated over inner wall of silica capillary tube (i.d. φ 0.33mm×100cm) by electroless plating. Rapid and continuous decomposition of hydrogen peroxide (H2O2) was achieved at room temperature simply by passing the solution through the capillary.
Application of FITC-labeled Ternatin on Its Cellular Localization in 3T3-L1 Murine Preadipocytes
Authors: Shimokawa Kenichiro , Ohno Osamu , Yamada Kaoru , Oba Yuichi , Uemura Daisuke
Published: January 2009

The cellular localization of a potent fat-accumulation inhibitor (−)-ternatin was investigated. FITC-labeled ternatin, a chemical probe for current study, was synthesized from a highly bioactive ternatin analogue using Click Chemistry, which was found to be bioactive. The treatment of 3T3-L1 murine preadipocytes with synthetic probe revealed that (−)-ternatin is localized in a specific organelle of 3T3-L1 cells.
Association of Uranyl Ions with Amino Functional Groups
Authors: Kozai Naofumi , Ohnuki Toshihiko
Published: January 2009

We investigated the adsorption of uranyl ions (UO22+) on amino functional groups at various pH values using amino group-modified silica particles. We found that uranyl ions were associated with the amino groups by forming 1:2 uranyl amino group complexes.
Porcinein vitroandin vivomodels to assess the virulence ofSalmonella entericaserovar Typhimurium for pigs
Authors: Boyen F , Pasmans F , Van Immerseel F , Donné E , Morgan E , Ducatelle R , Haesebrouck F
Published: January 2009

Salmonella Typhimurium infections in pigs pose an important human health hazard. One promising control measure is the development of live attenuated vaccine strains using defined knockout mutants. Preferably, screening of candidate knockout vaccine strains for attenuation should first be done in models allowing testing of a large number of strains. Thereafter, a limited number of selected strains should be further characterized in an experimental infection model in pigs. The aim of the present study was to develop such models. The invasive and proliferative characteristics of S. Typhimurium were assessed in both a non-polarized and a polarized porcine intestinal epithelial cell line. Neutrophils obtained from porcine blood were used to study the capacity of Salmonella to withstand killing by these phagocytes. The ability to induce an intestinal inflammatory response was investigated in a terminal intestinal loop model. The systemic phase of infection was mimicked by studying the uptake and intracellular survival of S. Typhimurium in porcine pulmonary alveolar macrophages and peripheral blood monocytes. These models should allow screening for attenuated strains. For further characterization, an experimental infection model was established, providing extensive data on the course of an oral infection and the optimal time points for colonization (day 5 postinoculation [pi]) and persistency (days 21–28 pi) in pigs. In conclusion, screening for virulence of S. Typhimurium strains with subsequent confirmation for a subset of strains in a well-defined experimental infection model would significantly reduce the number of experimental pigs required.
Dynamic contrast-enhanced and T2-weighted magnetic resonance imaging study of the correlation between tumour angiogenesis and growth kinetics
Authors: Sathy B N , Chou Y H , Li H J , Chang C , Chow K P N
Published: January 2009

Accumulating evidence indicates that tumour growth is angiogenesis-dependent. Non-invasive assessment of the relationship between tumour growth and associated angiogenesis is essential for diagnosis and for therapeutic interventions. We utilized a combination of high-resolution T2-weighted and dynamic contrast-enhanced magnetic resonance imaging to investigate the dynamics of angiogenesis during tumour growth in a mouse tumour model expressing Epstein-Barr virus-encoded latent membrane protein 1 isolated from a nasopharyngeal carcinoma in Taiwan. Serial imaging acquisitions were performed starting on the third day after subcutaneous implantation of tumours, through day 28. We observed a progressive increase in tumour volume until day 14, followed by rapid and exponential growth. The volume transfer constant, Ktrans, also increased significantly on day 14, and then gradually decreased, suggesting that the angiogenic switching occurs prior to significant tumour growth. At the initial stage, the Ktrans values were significantly higher in the tumour peripheral region than in the tumour core, but, during tumour growth, the Ktrans values in the region between the tumour periphery and core gradually increased, becoming larger than those of the periphery. These results demonstrate that the ability to perform repeated measurements assessing the correlation between tumour growth kinetics and tumour angiogenesis makes it possible to determine the critical time of angiogenic switching prior to rapid tumour growth, as well as suggesting the timing of therapy.
Analysis of breeding and pathology helps refine management practices of a large-scale N′-ethyl-N′-nitrosourea mouse mutagenesis programme
Authors: Smith A P L , Polley S , Wells S , Stewart M , Vizor L , Humphreys J , Warren M V , Dear N , Cheeseman M T
Published: January 2009

N′-ethyl- N′-nitrosourea (ENU) is a powerful germline mutagen used in conjunction with phenotype-driven screens to generate novel mouse mutants. ENU also induces genetic lesions in somatic cells and dosage requires optimization between maximum germline mutation rate versus induced sterility and tumourigenesis that compromise the welfare and fecundity of the ENU-treated males. Here, we present our experience with BALB/cAnNCrl and C57BL/6J mice in terms of the pathology induced by ENU and its impact on breeding. In both mouse strains, morbidity and mortality rises with ENU dose. In more than 75% of C57BL/6J males, morbidity and mortality were attributable to the development of malignant T-lymphoblastic lymphoma. Approximately 50% of ENU-treated BALB/cAnNCrl males develop early malignant T-lymphoblastic lymphoma, but the cohort that survives develops late-onset lung carcinoma. Within strains, the latency of these clinically important tumour(s) was not dosage-dependent, but the proportion of mice developing tumours and consequently removed from the breeding programme increased with ENU dosage. The median number of offspring per ENU-treated C57BL/6J male in standard matings with C3H/HeH females decreased with increasing dosage. The two most important underlying causes for lower male fecundity were increased infertility in the highest dosage group and reduced numbers of litters born to the remaining fertile C57BL/6J males due to a higher incidence of morbidity. These findings have allowed us to refine breeding strategy. To maximize the number of offspring from each ENU-treated male, we now rotate productive males between two cages to expose them to more females. This optimizes the number of mutation carrying offspring while reducing the number of ENU-treated males that must be generated.
Effects of bedding material and running wheel surface on paw wounds in male and female Syrian hamsters
Authors: Beaulieu A , Reebs S G
Published: January 2009

The present study investigated the effects of bedding material (pine shavings versus beta chip) and running wheel surfaces (standard metal bars versus metal bars covered with a plastic mesh) on the occurrence of wounds on the paws of male and female Syrian (golden) hamsters, Mesocricetus auratus. Four groups of 10 males and 10 females were each assigned to one of the following treatments: pine/no mesh, pine/mesh, chips/no mesh and chips/mesh. Each hamster paw was observed at 1–3-day intervals for 60 days. A total of 1–3 wounds, separate in time, developed on the paws (mostly the hind ones) of almost all animals. Wounds appeared as small pinpricks, cuts or scabs, mostly on the palms. Females ran 15% less than males, yet their front paws were more commonly affected and their wounds tended to last longer. Hamsters with plastic mesh inside their wheels took longer to develop wounds but once they appeared, the wounds were larger and lasted longer. Hamsters on pine shavings developed fewer wounds and had more wound-free days. Hamsters kept running at high levels and many wounds did not heal during the study, suggesting a need for veterinary intervention.
Automated analysis of postoperative behaviour: assessment of HomeCageScan as a novel method to rapidly identify pain and analgesic effects in mice
Authors: Roughan J V , Wright-Williams S L , Flecknell P A
Published: January 2009

This study evaluated whether the automated behaviour recognition software ‘HomeCageScan’ (HCS) could detect behaviour changes and any positive analgesic effects in two mouse strains undergoing vasectomy (C3H/HeNCrl and C57BL/6). Another objective was to test the effectiveness of HCS in differentiating between the effects of each treatment relative to conventional manual analysis. Each control (unoperated) group consisted of four mice of each strain. They were either untreated mice, mice given meloxicam alone (10 mg/kg) or mice given either saline or meloxicam (10 mg/kg) 30 min prior to isoflurane anaesthesia. The vasectomized mice received either saline or meloxicam at 5, 10 or 20 mg/kg, again, 30 min prior to isoflurane anaesthesia. Filming began one hour following surgery. Each mouse was filmed for 6 min for the manual analysis and then for a further 20 min for analysis with HCS. In a time-matched test, HCS and the manual analysis produced activity data that generated identical conclusions regarding treatment effects and strain differences. Both HCS and the manual analysis found the C57BL/6 controls were overall more active, but not following vasectomy, when both types of analysis detected markedly reduced activity. Low-dose meloxicam (5 mg/kg) had a positive effect on postoperative mobility in the C3H/HeNCrl mice; however, increasing the dose rate progressively reduced this. These effects were also detected with the manual analysis. Overall, HCS provided a sufficiently accurate and rapid method of analysing mouse behaviour encouraging more prolonged assessments in the future. This capability and the possibility of training the software to recognize a greater range of behaviours, including pain-specific indicators, should be of considerable value for assessing postoperative behaviour in both mice and rats. This would allow analgesic requirements to be investigated in a greater range of rodent models than is currently feasible with conventional analysis methods.
Ventral recumbency is crucial for fast and safe orotracheal intubation in laboratory swine
Authors: Theisen M M , Maas M , Hartlage M A Grosse , Ploner F , Niehues S M , Van Aken H K , Weber T P , Unger J K
Published: January 2009

The aim of this study was to find the fastest, easiest and safest method of achieving orotracheal intubation for general anaesthesia in laboratory pigs. Twenty-one Yorkshire × Landrace crossbreed male castrated pigs (32.9 ± 4.8 kg) were investigated. Dorsal and ventral recumbency are the alternatives most frequently described for animal positioning during intubation procedures. Based on standardized induction of general anaesthesia using pentobarbital and remifentanil, the dorsoventral and ventrodorsal positions were compared with regard to the time needed, changes in oxygenation and circulatory response. Positioning was found to be crucial for fast orotracheal intubation. The time required for safe intubation is significantly shorter with the ventrodorsal position (17.3 s) in comparison with the dorsoventral position (58.4 s; P < 0.001). Hypoxia did not occur in either group. A significant drop in systolic blood pressure was observed in both groups. Diastolic and mean arterial pressures were not influenced by intubation. A significant increase in heart rate was observed in pigs intubated in ventral recumbency, but not after intubation in the dorsal position. Preoxygenation before intubation is vitally important for preventing hypoxia. With regard to clinical practice, the haemodynamic changes observed in this investigation do not appear to be relevant, as the mean arterial pressure was not altered and heart rates only increased moderately. It may be concluded that the ventrodorsal position can be recommended for orotracheal intubation in pigs as the first choice for providing a smooth and fast airway.
Do Innovations Really Pay Off? Total Stock Market Returns to Innovation
Authors: Sood Ashish , Tellis Gerard J.
Published: January 2009

Critics often decry an earnings-focused short-term orientation of management that eschews spending on risky, long-term projects such as innovation to boost a firm's stock price. Such critics assume that stock markets react positively to announcements of immediate earnings but negatively to announcements of investments in innovation that have an uncertain long-term pay off. Contrary to this position, we argue that the market's true appreciation of innovation can be estimated by assessing the total market returns to the entire innovation project. We demonstrate this approach via the Fama-French 3-factor model (including Carhart's momentum factor) on 5,481 announcements from 69 firms in five markets and 19 technologies between 1977 and 2006.

The total market returns to an innovation project are $643 million, more than 13 times the $49 million from an average innovation event. Returns to negative events are higher in absolute value than those to positive events. Returns to initiation occur 4.7 years ahead of launch. Returns to development activities are the highest and those to commercialization the lowest of all activities. Returns to new product launch are the lowest among all eight events tracked. Returns are higher for smaller firms than larger firms. Returns to the announcing firm are substantially greater than those to competitors across all stages. We discuss the implications of these results.
Research Note—Impact of Customer Knowledge Heterogeneity on Bundling Strategy
Authors: Basu Amiya , Vitharana Padmal
Published: January 2009

We consider a marketer of components who can select one of three alternative pricing strategies: (1) a pure component strategy (i.e., the customer can only buy the components individually), (2) a pure bundling strategy (i.e., the components must be purchased together), or (3) a mixed bundling strategy (i.e., the customer may buy a component individually, or buy the bundle). We consider a market where customer knowledge of components varies and propose that a high-knowledge customer can determine with greater certainty whether a given component is useful to her. Consequently, more knowledgeable customers have higher variability in their reservation price of a component. Using an analytical model, we identify the conditions under which each of the three pricing strategies maximizes profit and show that three factors determine the optimal strategy: marginal costs of components, distribution of knowledge over the customer population, and relative sizes of customer segments where each segment is interested in the same subset of components. Managerial implications and directions for future research are discussed.
Optimal Product Line Design When Consumers Exhibit Choice Set-Dependent Preferences
Authors: Orhun A. Yeşim
Published: January 2009

In a market of consumers with varying willingness to pay, using product line as a discrimination tool may extract higher profits than serving all consumers with a single product. Local context effects, however, point to yet another consideration in designing product lines: how the appeal of a product changes with the context provided by other products in the choice set.

I present a model of product line design that incorporates both discrimination and context management goals and offers recommendations for the variety and positioning of products. To this end, the model makes use of a framework that allows preferences to be choice set dependent. Given this framework, I study how the firm manages externalities between products created by such dependencies. The firm creates distortions above and beyond those resulting from discrimination motives alone. For example, in a vertically differentiated market for quality, quality distortions exist even for the consumers with the highest valuations. The range of quality provisions, given the number of products, is compressed as the relative importance of unfavorable comparisons among products increases. Surprisingly, this compression may even lead the firm to forego discrimination among consumers regardless of the cost of offering distinct products.