bluuebunny/crossref_metadata_2025 huggingface dataset:
Mindfulness Research Update: 2008
Authors: Greeson Jeffrey M.
Published: January 2009

Objective: To briefly review the effects of mindfulness on the mind, the brain, the body, and behavior. Methods: Selective review of MEDLINE, PsycINFO, and Google Scholar databases (2003—2008) using the terms ``mindfulness,'' ``meditation,'' ``mental health,'' ``physical health,'' ``quality of life,'' and ``stress reduction.'' A total of 52 exemplars of empirical and theoretical work were selected for review. Results: Both basic and clinical research indicate that cultivating a more mindful way of being is associated with less emotional distress, more positive states of mind, and better quality of life. In addition, mindfulness practice can influence the brain, the autonomic nervous system, stress hormones, the immune system, and health behaviors, including eating, sleeping, and substance use, in salutary ways. Conclusion: The application of cutting-edge technology toward understanding mindfulness— an ``inner technology''—is elucidating new ways in which attention, awareness, acceptance, and compassion may promote optimal health—in mind, body, relationships, and spirit.
The Role of Automated External Defibrillators in Athletics
Authors: Rothmier Justin D. , Drezner Jonathan A.
Published: January 2009

Context:

Sudden cardiac arrest is the leading cause of death in young athletes. The purpose of this review is to summarize the role of automated external defibrillators and emergency planning for sudden cardiac arrest in the athletic setting.

Evidence Acquisition:

Relevant studies on automated external defibrillators, early defibrillation, and public-access defibrillation programs were reviewed. Recommendations from consensus guidelines and position statements applicable to automated external defibrillators in athletics were also considered.

Results:

Early defibrillation programs involving access to automated external defibrillators by targeted local responders have demonstrated a survival benefit for sudden cardiac arrest in many public and athletic settings.

Conclusion:

Schools and organizations sponsoring athletic programs should implement automated external defibrillators as part of a comprehensive emergency action plan for sudden cardiac arrest. In a collapsed and unresponsive athlete, sudden cardiac arrest should be suspected and an automated external defibrillator applied as soon as possible, as decreasing the time interval to defibrillation is the most important priority to improve survival in sudden cardiac arrest.
The Use of Eccentrically Biased Resistance Exercise to Mitigate Muscle Impairments Following Anterior Cruciate Ligament Reconstruction: A Short Review
Authors: Gerber J. Parry , Marcus Robin L. , Dibble Leland E. , LaStayo Paul C.
Published: January 2009

Background:

Novel interventions that can safely and effectively overload muscle early following anterior cruciate ligament reconstruction are needed to minimize atrophy and weakness that often becomes longstanding.

Evidence Acquisition:

Eccentrically induced forces can be safely applied during the early stages of rehabilitation following surgery and serve as a potent stimulus for increasing muscle size and strength.

Results:

Compared to a standard rehabilitation program, adding an early 12-week eccentric resistance-training program 3 weeks after anterior cruciate ligament reconstruction induces improvement in quadriceps and gluteus maximus volume at 15 weeks and at 1 year after surgery. Likewise, those who performed an eccentrically biased rehabilitation program also achieved greater improvements in quadriceps strength and hopping ability measured at 15 weeks and at 1 year after surgery.

Clinical Relevance:

There is potential to safely and feasibly perform eccentric contractions as part of a formal rehabilitation program following anterior cruciate ligament reconstruction.
Microstructure and properties of arc sprayed coatings containing Fe based amorphous phase and nanocrystallites
Authors: Fu B.-Y. , He D.-Y. , Zhao L.-D. , Jiang J.-M. , Li X.-Y.
Published: January 2009

An Fe based cored wire was used to deposit wear resistant coatings containing Fe based amorphous phase and nanocrystallites on Q235 steel substrate by arc spraying. The microstructure of the coatings was investigated by scanning electron microscopy and transmission electron microscopy. Electron probe microanalyser and X-ray diffraction analysis were used to study the chemical compositions and phase compositions in the coatings. The microhardness of the coating was determined. The wear behaviour of the coatings was evaluated. The results showed that the coatings contained Fe based amorphous phase and other crystallites such as Fe2B, Cr2B, M23(C,B)6, Fe3O4 and α-(Fe,Cr). Some of the crystallites show grain sizes of <30 nm. The coatings were hard. Compared with the reference sample of commercial 3Cr13 coating, the coatings showed a much higher wear resistance; the relative wear resistance of the amorphous coating was 8 times higher than that of commercial 3Cr13 coating.
Distribution and dissolution of WC particles in surface metal matrix composites produced by plasma melt injection
Authors: Liu A. , Guo M. , Hu H. L.
Published: January 2009

Surface metal matrix composites (MMCs) were produced by plasma melt injection of tungsten carbide (WC)–17%Co and crushed WC–8%Co particles. Distribution and dissolution of WC particles in the surface MMCs were investigated with an SEM. The results show that ball shaped WC particles are much easier to be injected into the melt pool, while crushed WC particles stay on top of the MMC layer. In a shallow melt pool of the single pass MMC, the carbides are evenly distributed. The WC particles in the second pass MMC that was produced when the substrate was hot sink downwards. More WC particles dissolve in the second pass MMC than in the single pass, while the crushed WC–8%Co particles dissolve only partially because the WC particles are large and they are on top of the melt pool.
A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML
Authors: Breitenbuecher Frank , Markova Boyka , Kasper Stefan , Carius Birgit , Stauder Torsten , Böhmer Frank D. , Masson Kristina , Rönnstrand Lars , Huber Christoph , Kindler Thomas , Fischer Thomas
Published: January 2009

Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the β-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)–induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs.
How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation
Authors: Liang Raymond
Published: January 2009

Hepatitis B virus (HBV) reactivation is a serious but preventable complication of immunosuppression. Full HBV serologic profile must be obtained from all patients receiving intensive immunosuppressive therapy. In general, preemptive anti-HBV therapy is more effective than giving treatment after development of reactivation. Prompt lamivudine therapy should be given to at-risk patients who are hepatitis B surface antigen (HBsAg)–positive. It is recommended that lamivudine be continued until at least 6 months after the cessation of immunosuppression. Some patients requiring a longer duration of lamivudine therapy are at risk of developing drug resistance. The newer anti-HBV agents are effective in overcoming lamivudine resistance. Early use of these agents may be considered. HBV reactivation was observed in HBsAg-negative patients with occult HBV infection (HBV DNA-positive) who are on heavy immunosuppression. The optimal management of this group of patients is unclear. For patients receiving allogeneic HSC transplants, the HBV status of the donors requires special attention. To minimize the risk of transmission of infection to recipients, HBsAg-positive donors should receive adequate anti-HBV therapy before HSC donation. As the result of adoptive immune transfer, clearance of HBsAg is observed in HBsAg-positive patients receiving HSC transplants from donors who are positive for hepatitis B surface and core antibodies.
CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Authors: Boehme Volkmar , Schmitz Norbert , Zeynalova Samira , Loeffler Markus , Pfreundschuh Michael
Published: January 2009

One thousand two hundred twenty-two patients treated in the Rituximab with CHOP over age 60 years (RICOVER-60) trial were examined for central nervous system (CNS) disease developing during first-line therapy or after a complete or partial remission had been achieved. Patients received 6 or 8 courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) administered every 2 weeks (CHOP-14) with or without rituximab. CNS prophylaxis for patients with involvement of bone marrow, testes, upper neck, or head consisted of intrathecal (i.th.) methotrexate (days 1 and 5 of first 2 courses). Fifty-eight cases of lymphoma in the CNS were observed (36/609 patients in the CHOP-14 and 22/608 patients in the arituximab–CHOP-14 [R-CHOP–14] arm). The estimated 2-year incidence of CNS disease was 6.9% (confidence interval [CI] 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP–14. R-CHOP reduced the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, P = .046). Cox regression analysis identified “involvement of more than 1 extranodal site” and “B-symptoms” as significant risk factors for CNS disease. Patients treated with R-CHOP–14 did not show any benefit from i.th. methotrexate. We conclude that elderly patients with aggressive CD20-positive lymphoma show a significantly lower incidence of CNS disease if treated with R-CHOP–14 instead of CHOP-14. Intrathecal methotrexate has no role in preventing CNS disease for patients treated with combined immunochemotherapy (R-CHOP–14)—with the possible exception of patients with testicular involvement. The original clinical trials are registered on www.clinicaltrials.gov as NCT000052936.
Studies of the immune response in heparin-induced thrombocytopenia
Authors: Warkentin Theodore E. , Sheppard Jo-Ann I. , Moore Jane C. , Cook Richard J. , Kelton John G.
Published: January 2009

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize PF4/heparin complexes. Uncertainties remain regarding HIT immunobiology, including the temporal relation of antibody formation to onset of thrombocytopenia, and whether immunoglobulin class switching occurs. Using serial plasma samples from 2 heparin thromboprophylaxis trials, we determined the time of onset, antibody levels, and immunoglobulin class distributions (IgG, IgA, IgM) for 12 patients with HIT and 36 patients who formed anti-PF4/heparin antibodies, but did not develop HIT (“seropositive non-HIT controls”). In patients with HIT, anti-PF4/heparin antibodies became detectable 4 days (median) after starting heparin; antibody detection preceded the platelet count decline by 2 days (median). Patients with HIT produced higher levels of IgG antibodies, but similar IgA and IgM levels, compared with seropositive non-HIT controls. Among all 48 seroconverting patients, the first day of a positive antibody test (median, day 6) did not differ among the immunoglobulin classes. Thus, the HIT immune response does not exhibit the classic paradigm of IgM class precedence/immunoglobulin class switching; rather, relatively rapid formation of IgG antibodies is observed, sometimes with concomitant IgA and IgM formation. Compared with seropositive non-HIT controls, HIT patients develop significantly higher anti-PF4/heparin IgG levels that are detectable before the onset of thrombocytopenia.
microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification
Authors: Stamatopoulos Basile , Meuleman Nathalie , Haibe-Kains Benjamin , Saussoy Pascale , Van Den Neste Eric , Michaux Lucienne , Heimann Pierre , Martiat Philippe , Bron Dominique , Lagneaux Laurence
Published: January 2009

Aberrant expression of microRNAs has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Although disease evolution can be predicted by several prognostic factors, a better outcome individualization in a given patient is still of utmost interest. Here, we showed that miR-29c and miR-223 expression levels decreased significantly with progression from Binet stage A to C were significantly lower in poor prognostic subgroups (defined by several prognostic factors) and could significantly predict treatment-free survival (TFS) and overall survival (OS). Furthermore, we developed a quantitative real-time polymerase chain reaction (qPCR) score combining miR-29c, miR-223, ZAP70, and LPL (from 0 to 4 poor prognostic markers) to stratify treatment and death risk in a cohort of 110 patients with a median follow-up of 72 months (range, 2-312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of greater than 312, of 129, 80, 36, and 19 months, respectively (hazard ratio, HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 17.00, P < .001). Patients with a score of 0-1/4, 2-3/4, and 4/4 had a median OS of greater than 312, of 183 and 106 months, respectively (HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 13.69, P = .001). This score will help to identify, among the good and poor prognosis subgroups, patients who will need early therapy and thus will require a closer follow-up.
The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents
Authors: Haitina Tatjana , Fredriksson Robert , Foord Steven M , Schiöth Helgi B , Gloriam David E
Published: January 2009

Background

The dog is an important model organism and it is considered to be closer to humans than rodents regarding metabolism and responses to drugs. The close relationship between humans and dogs over many centuries has lead to the diversity of the canine species, important genetic discoveries and an appreciation of the effects of old age in another species. The superfamily of G protein-coupled receptors (GPCRs) is one of the largest gene families in most mammals and the most exploited in terms of drug discovery. An accurate comparison of the GPCR repertoires in dog and human is valuable for the prediction of functional similarities and differences between the species.

Results

We searched the dog genome for non-olfactory GPCRs and obtained 353 full-length GPCR gene sequences, 18 incomplete sequences and 13 pseudogenes. We established relationships between human, dog, rat and mouse GPCRs resolving orthologous pairs and species-specific duplicates. We found that 12 dog GPCR genes are missing in humans while 24 human GPCR genes are not part of the dog GPCR repertoire. There is a higher number of orthologous pairs between dog and human that are conserved as compared with either mouse or rat. In almost all cases the differences observed between the dog and human genomes coincide with other variations in the rodent species. Several GPCR gene expansions characteristic for rodents are not found in dog.

Conclusion

The repertoire of dog non-olfactory GPCRs is more similar to the repertoire in humans as compared with the one in rodents. The comparison of the dog, human and rodent repertoires revealed several examples of species-specific gene duplications and deletions. This information is useful in the selection of model organisms for pharmacological experiments.
The genome sequence of the fish pathogen Aliivibrio salmonicida strain LFI1238 shows extensive evidence of gene decay
Authors: Hjerde Erik , Lorentzen Marit Sjo , Holden Matthew TG , Seeger Kathy , Paulsen Steinar , Bason Nathalie , Churcher Carol , Harris David , Norbertczak Halina , Quail Michael A , Sanders Suzanne , Thurston Scott , Parkhill Julian , Willassen Nils Peder , Thomson Nicholas R
Published: January 2009

Background

The fish pathogen Aliivibrio salmonicida is the causative agent of cold-water vibriosis in marine aquaculture. The Gram-negative bacterium causes tissue degradation, hemolysis and sepsis in vivo.

Results

In total, 4 286 protein coding sequences were identified, and the 4.6 Mb genome of A. salmonicida has a six partite architecture with two chromosomes and four plasmids. Sequence analysis revealed a highly fragmented genome structure caused by the insertion of an extensive number of insertion sequence (IS) elements. The IS elements can be related to important evolutionary events such as gene acquisition, gene loss and chromosomal rearrangements. New A. salmonicida functional capabilities that may have been aquired through horizontal DNA transfer include genes involved in iron-acquisition, and protein secretion and play potential roles in pathogenicity. On the other hand, the degeneration of 370 genes and consequent loss of specific functions suggest that A. salmonicida has a reduced metabolic and physiological capacity in comparison to related Vibrionaceae species.

Conclusion

Most prominent is the loss of several genes involved in the utilisation of the polysaccharide chitin. In particular, the disruption of three extracellular chitinases responsible for enzymatic breakdown of chitin makes A. salmonicida unable to grow on the polymer form of chitin. These, and other losses could restrict the variety of carrier organisms A. salmonicida can attach to, and associate with. Gene acquisition and gene loss may be related to the emergence of A. salmonicida as a fish pathogen.
Microbial nar-GFP cell sensors reveal oxygen limitations in highly agitated and aerated laboratory-scale fermentors
Authors: Garcia Jose R , Cha Hyung J , Rao Govind , Marten Mark R , Bentley William E
Published: January 2009

Background

Small-scale microbial fermentations are often assumed to be homogeneous, and oxygen limitation due to inadequate micromixing is often overlooked as a potential problem. To assess the relative degree of micromixing, and hence propensity for oxygen limitation, a new cellular oxygen sensor has been developed. The oxygen responsive E. coli nitrate reductase (nar) promoter was used to construct an oxygen reporter plasmid (pNar-GFPuv) which allows cell-based reporting of oxygen limitation. Because there are greater than 109 cells in a fermentor, one can outfit a vessel with more than 109 sensors. Our concept was tested in high density, lab-scale (5 L), fed-batch, E. coli fermentations operated with varied mixing efficiency – one verses four impellers.

Results

In both cases, bioreactors were maintained identically at greater than 80% dissolved oxygen (DO) during batch phase and at approximately 20% DO during fed-batch phase. Trends for glucose consumption, biomass and DO showed nearly identical behavior. However, fermentations with only one impeller showed significantly higher GFPuv expression than those with four, indicating a higher degree of fluid segregation sufficient for cellular oxygen deprivation. As the characteristic time for GFPuv expression (approx 90 min.) is much larger than that for mixing (approx 10 s), increased specific fluorescence represents an averaged effect of oxygen limitation over time and by natural extension, over space.

Conclusion

Thus, the pNar-GFPuv plasmid enabled bioreactor-wide oxygen sensing in that bacterial cells served as individual recirculating sensors integrating their responses over space and time. We envision cell-based oxygen sensors may find utility in a wide variety of bioprocessing applications.
Assessing drug distribution in tissues expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters determination
Authors: Fenneteau Frédérique , Turgeon Jacques , Couture Lucie , Michaud Véronique , LI Jun , Nekka Fahima
Published: January 2009

Background

The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate.

Methods

A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a well-stirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation ofin vitromeasurements of drug permeability to thein vivosituation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues.

Results

This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P-gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model.

Conclusion

Being built prior toin vivodata, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters.

The physiological based model is novel and unique and brought effective information on drug transporters.
Are animal models predictive for humans?
Authors: Shanks Niall , Greek Ray , Greek Jean
Published: January 2009

It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics.
CHSMiner: a GUI tool to identify chromosomal homologous segments
Authors: Wang Zhen , Ding Guohui , Yu Zhonghao , Liu Lei , Li Yixue
Published: January 2009

Background

The identification of chromosomal homologous segments (CHS) within and between genomes is essential for comparative genomics. Various processes including insertion/deletion and inversion could cause the degeneration of CHSs.

Results

Here we present a Java software CHSMiner that detects CHSs based on shared gene content alone. It implements fast greedy search algorithm and rigorous statistical validation, and its friendly graphical interface allows interactive visualization of the results. We tested the software on both simulated and biological realistic data and compared its performance with similar existing software and data source.

Conclusion

CHSMiner is characterized by its integrated workflow, fast speed and convenient usage. It will be useful for both experimentalists and bioinformaticians interested in the structure and evolution of genomes.
Understanding the nature and mechanism of foot pain
Authors: Hawke Fiona , Burns Joshua
Published: January 2009

Approximately one‐quarter of the population are affected by foot pain at any given time. It is often disabling and can impair mood, behaviour, self‐care ability and overall quality of life. Currently, the nature and mechanism underlying many types of foot pain is not clearly understood. Here we comprehensively review the literature on foot pain, with specific reference to its definition, prevalence, aetiology and predictors, classification, measurement and impact. We also discuss the complexities of foot pain as a sensory, emotional and psychosocial experience in the context of clinical practice, therapeutic trials and the placebo effect. A deeper understanding of foot pain is needed to identify causal pathways, classify diagnoses, quantify severity, evaluate long term implications and better target clinical intervention.
A circuit supporting concentration-invariant odor perception in Drosophila
Authors: Asahina Kenta , Louis Matthieu , Piccinotti Silvia , Vosshall Leslie B
Published: January 2009

Background

Most odors are perceived to have the same quality over a large concentration range, but the neural mechanisms that permit concentration-invariant olfactory perception are unknown. In larvae of the vinegar fly Drosophila melanogaster, odors are sensed by an array of 25 odorant receptors expressed in 21 olfactory sensory neurons (OSNs). We investigated how subsets of larval OSNs with overlapping but distinct response properties cooperate to mediate perception of a given odorant across a range of concentrations.

Results

Using calcium imaging, we found that ethyl butyrate, an ester perceived by humans as fruity, activated three OSNs with response thresholds that varied across three orders of magnitude. Whereas wild-type larvae were strongly attracted by this odor across a 500-fold range of concentration, individuals with only a single functional OSN showed attraction across a narrower concentration range corresponding to the sensitivity of each ethyl butyrate-tuned OSN. To clarify how the information carried by different OSNs is integrated by the olfactory system, we characterized the response properties of local inhibitory interneurons and projection neurons in the antennal lobe. Local interneurons only responded to high ethyl butyrate concentrations upon summed activation of at least two OSNs. Projection neurons showed a reduced response to odors when summed input from two OSNs impinged on the circuit compared to when there was only a single functional OSN.

Conclusions

Our results show that increasing odor concentrations induce progressive activation of concentration-tuned olfactory sensory neurons and concomitant recruitment of inhibitory local interneurons. We propose that the interplay of combinatorial OSN input and local interneuron activation allows animals to remain sensitive to odors across a large range of stimulus intensities.
A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways
Authors: Kuriyama Sei , Mayor Roberto
Published: January 2009

Syndecan-4 (Syn4) is a heparan sulphate proteoglycan that is able to bind to some growth factors, including FGF, and can control cell migration. Here we describe a new role for Syn4 in neural induction in Xenopus. Syn4 is expressed in dorsal ectoderm and becomes restricted to the neural plate. Knockdown with antisense morpholino oligonucleotides reveals that Syn4 is required for the expression of neural markers in the neural plate and in neuralised animal caps. Injection of Syn4 mRNA induces the cell-autonomous expression of neural, but not mesodermal, markers. We show that two parallel pathways are involved in the neuralising activity of Syn4: FGF/ERK, which is sensitive to dominant-negative FGF receptor and to the inhibitors SU5402 and U0126, and a PKC pathway, which is dependent on the intracellular domain of Syn4. Neural induction by Syn4 through the PKC pathway requires inhibition of PKCδ and activation of PKCα. We show that PKCα inhibits Rac GTPase and that c-Jun is a target of Rac. These findings might account for previous reports implicating PKC in neural induction and allow us to propose a link between FGF and PKC signalling pathways during neural induction.
Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2
Authors: Funato Noriko , Chapman Shelby L. , McKee Marc D. , Funato Hiromasa , Morris Jesse A. , Shelton John M. , Richardson James A. , Yanagisawa Hiromi
Published: January 2009

Members of the basic helix-loop-helix (bHLH) family of transcription factors regulate the specification and differentiation of numerous cell types during embryonic development. Hand1 and Hand2 are expressed by a subset of neural crest cells in the anterior branchial arches and are involved in craniofacial development. However, the precise mechanisms by which Hand proteins mediate biological actions and regulate downstream target genes in branchial arches is largely unknown. Here, we report that Hand2 negatively regulates intramembranous ossification of the mandible by directly inhibiting the transcription factor Runx2, a master regulator of osteoblast differentiation. Hand proteins physically interact with Runx2, suppressing its DNA binding and transcriptional activity. This interaction is mediated by the N-terminal domain of the Hand protein and requires neither dimerization with other bHLH proteins nor DNA binding. We observed partial colocalization of Hand2 and Runx2 in the mandibular primordium of the branchial arch, and downregulation of Hand2 precedes Runx2-driven osteoblast differentiation. Hand2 hypomorphic mutant mice display insufficient mineralization and ectopic bone formation in the mandible due to accelerated osteoblast differentiation, which is associated with the upregulation and ectopic expression of Runx2 in the mandibular arch. Here, we show that Hand2 acts as a novel inhibitor of the Runx2-DNA interaction and thereby regulates osteoblast differentiation in branchial arch development.
Glycosphingolipids control the extracellular gradient of theDrosophilaEGFR ligand Gurken
Authors: Pizette Sandrine , Rabouille Catherine , Cohen Stephen M. , Thérond Pascal
Published: January 2009

Glycosphingolipids (GSLs) are present in all eukaryotic membranes and are implicated in neuropathologies and tumor progression in humans. Nevertheless,their in vivo functions remain poorly understood in vertebrates, partly owing to redundancy in the enzymes elongating their sugar chains. In Drosophila, a single GSL biosynthetic pathway is present that relies on the activity of the Egghead and Brainiac glycosyltransferases. Mutations in these two enzymes abolish GSL elongation and yield oogenesis defects,providing a unique model system in which to study GSL roles in signaling in vivo. Here, we use egghead and brainiac mutants to show that GSLs are necessary for full activation of the EGFR pathway during oogenesis in a time-dependent manner. In contrast to results from in vitro studies, we find that GSLs are required in cells producing the TGFα-like ligand Gurken,but not in EGFR-expressing cells. Strikingly, we find that GSLs are not essential for Gurken trafficking and secretion. However, we characterize for the first time the extracellular Gurken gradient and show that GSLs affect its formation by controlling Gurken planar transport in the extracellular space. This work presents the first in vivo evidence that GSLs act in trans to regulate the EGFR pathway and shows that extracellular EGFR ligand distribution is tightly controlled by GSLs. Our study assigns a novel role for GSLs in morphogen diffusion, possibly through regulation of their conformation.
Steroid Profiles in Ovarian Follicular Fluid from Regularly Menstruating Women and Women after Ovarian Stimulation
Authors: Kushnir Mark M , Naessen Tord , Kirilovas Dmitrijus , Chaika Andrey , Nosenko Jelena , Mogilevkina Iryna , Rockwood Alan L , Carlström Kjell , Bergquist Jonas
Published: January 2009

Background: Information on the concentrations of steroids in ovarian follicular fluid (FF) from regularly menstruating (RM) women has been limited because of the absence of methods for the simultaneous quantification of multiple steroids in small volumes of FF. We studied steroid profiles in FF during the early follicular phase of the menstrual cycle and after ovarian stimulation for in vitro fertilization (IVF), and compared concentrations with published values obtained by immunoassay (IA).

Methods: We used liquid chromatography–tandem mass spectrometry (LC-MS/MS) to measure 13 steroids in 40-μL aliquots of FF samples from 21 RM women and from 5 women after ovarian stimulation for IVF. Relationships between concentrations of steroids and their ratios (representations of the enzyme activities) were evaluated within and between subgroups.

Results: The concentrations of testosterone (Te), androstenedione (A4), and estradiol (E2) measured by LC-MS/MS were lower than those previously reported in studies with IAs. In RM women, androgens were the most abundant class of steroids, with A4 being the major constituent. The concentrations of 17-hydroxyprogesterone (17OHP), total androgens, and estrogens were 200- to 1000-fold greater in FF than in serum. Compared with RM women, FF samples from women undergoing ovarian stimulation had significantly higher concentrations of E2 (P = 0.021), pregnenolone (P = 0.0022), 17OHP (P = 0.0007), and cortisol (F) (P = 0.0016), and significantly higher ratios of F to cortisone (P = 0.0006), E2 to estrone (P = 0.0008), and E2 to Te (P = 0.0013).

Conclusions: The data provide the first MS-based concentration values for 13 steroids in ovarian FF from RM women, from estrogen- and androgen-dominant follicles, and from women after ovarian stimulation for IVF.
Specific Determination of β-Galactocerebrosidase Activity via Competitive Inhibition of β-Galactosidase
Authors: Martino Sabata , Tiribuzi Roberto , Tortori Andrea , Conti Daniele , Visigalli Ilaria , Lattanzi Annalisa , Biffi Alessandra , Gritti Angela , Orlacchio Aldo
Published: January 2009

Background: The determination of cellular β-galactocerebrosidase activity is an established procedure to diagnose Krabbe disease and monitor the efficacy of gene/stem cell-based therapeutic approaches aimed at restoring defective enzymatic activity in patients or disease models. Current biochemical assays for β-galactocerebrosidase show high specificity but generally require large protein amounts from scanty sources such as hematopoietic or neural stem cells. We developed a novel assay based on the hypothesis that specific measurements of β-galactocerebrosidase activity can be performed following complete inhibition of β-galactosidase activity.

Methods: We performed the assay using 2–7.5 μg of sample proteins with the artificial fluorogenic substrate 4-methylumbelliferone-β-galactopyranoside (1.5 mmol/L) resuspended in 0.1/0.2 mol/L citrate/phosphate buffer, pH 4.0, and AgNO3. Reactions were incubated for 30 min at 37 °C. Fluorescence of liberated 4-methylumbelliferone was measured on a spectrofluorometer (λex 360 nm, λem 446 nm).

Results: AgNO3 was a competitive inhibitor of β-galactosidase [inhibition constant (Ki) = 0.12 μmol/L] and completely inhibited β-galactosidase activity when used at a concentration of 11 μmol/L. Under this condition, the β-galactocerebrosidase activity was preserved and could be specifically and accurately measured. The assay can detect β-galactocerebrosidase activity in as little as 2 μg cell protein extract or 7.5 μg tissue. Assay validation was performed using (a) brain tissues from wild-type and twitcher mice and (b) murine GALC−/− hematopoietic stem cells and neural precursor cells transduced by GALC-lentiviral vectors.

Conclusions: The procedure is straightforward, rapid, and reproducible. Within a clinical context, our method unequivocally discriminated cells from healthy subjects and Krabbe patients and is therefore suitable for diagnostic applications.
Heightening Levels of Activity and J. S. Bach's Parallel-Section Constructions
Authors: Lester Joel
Published: January 2009

Three constructive principles underlie the large-scale thematic and organizational aspects of J. S. Bach's compositions: (1) the opening of a piece states a core of material that is worked with throughout the composition; (2) recurrences of material almost invariably exhibit a heightening level of activity in some or all musical elements; and (3) movements quite frequently subdivide into roughly parallel sections within which these heightened recurrences appear. The interaction of these three principles, all pertinent to contemporaneous theoretical perspectives, provides a unified perspective on Bach's creations in all genres. This essay explores interactions of the latter principles with the more familiar first one.
An Exotic Enemy: Anti-Japanese Musical Propaganda in World War II Hollywood
Authors: Sheppard W. Anthony
Published: January 2009

The cinema was the most effective medium for anti-Japanese propaganda in the United States during World War II and was the site of music's most important wartime role. From shortly after Pearl Harbor to the end of the U.S. occupation of Japan in 1952, Hollywood produced a large number of films offering negative depictions of the Japanese. Music assumed multiple roles in these anti-Japanese feature films and U.S. government documentaries. Never had Orientalist and racial politics been more clearly evident in music heard by so many as in these productions. These films marshaled preexistent European music, stereotypical Orientalist signs, and traditional Japanese music against the exotic enemy. This essay analyzes some sophisticated examples of musical propaganda that offer new perspectives for the study of cross-cultural musical encounters. For many in the United States, Hollywood film music continues to shape their impressions of Japan and their perceptions of Japanese music.
Schoenberg, Boulez, and Twelve-Tone Composition as “Ideal Type”
Authors: Ashby Arved
Published: January 2009

Twelve-tone music is often defined empirically, in generalized terms of compositional practice. I contend that historians and theorists have neglected a heuristic perspective of twelve-tone composition. One heuristic model proves particularly helpful: the “ideal type,” first described by social scientist Max Weber in “Objectivity' in Social Science and Social Policy” (1904). Weber's ideal type can help to move the discussion away from scientistic ideas of problem solving and overly abstract invocations of “the twelve-tone idea,” and toward what Weber would call the “cultural significance” of twelve-tone methodologies (a move in line with influential revisions to the historiography of scientific “problem solving” proposed by Thomas Kuhn and Imre Lakatos).

Differences of perspective between Arnold Schoenberg and the young Pierre Boulez, at about the time the latter first arrived at Darmstadt, highlight the difficulty in establishing a coherent history of twelve-tone compositional practice (as opposed to a heuristic “ideal type”). The anonymous typescript “Komposition mit zwöölf Töönen,” linked with Schoenberg's Viennese circle of the early 1920s, reveals how the early twelve-tone “discovery” described by Schoenberg is, no less than the later descriptions by Boulez, an a posteriori construct—or, as Kuhn and Lakatos might say, an ideological colonization of past practice.
“Imitar col canto chi parla”: Monteverdi and the Creation of a Language for Musical Theater
Authors: Calcagno Mauro
Published: January 2009

Conventional views of text/music relationships in early Italian opera focus on the imitation of affections. But by dealing exclusively with the referential meanings of texts (e.g., emotions, images, and concepts) these views overlook an important aspect of music's interaction with language. In opera, music also imitates language's contextual and communicative functions—i.e., discourse, as studied today by the subfield of linguistics called pragmatics. In his operas Monteverdi fully realized Peri's ideal of “imitating in song a person speaking” (“imitar col canto chi parla”) by musically emphasizing those context-dependent meanings that emerge especially in ordinary language and that are prominent in dramatic texts, as opposed to poetry and prose. Such meanings are manifest whenever words such as “I,” “here,” and “now” appear— words called “deictics”—with the function of situating the speaker/singer's utterances in a specific time and place. Monteverdi highlights deictics through melodic and rhythmic emphases, repetition, shifts of meter, style, and harmony, as part of a strategy to create a musical language suited to opera as a genre and to singers as actors. In Il ritorno d'Ulisse in patria and L'incoronazione di Poppea, this strategy serves large-scale dramaturgical aims with respect to the relationships among space, time, and character identity, highlighting issues also discussed within the contemporary intellectual context.
Stravinsky's Music in Hitler's Germany
Authors: Evans Joan
Published: January 2009

This investigation of the reception in Nazi Germany of the work (and person) of Igor Stravinsky offers new insights into the issue of modern music in Hitler's Germany. As the most prominent modernist composer of the period, Stravinsky was the chief beneficiary of Germany's desire, after the xenophobic early Nazi years, to rejoin the European cultural community. Thanks to the determination of his supporters, and aided by the greater accessibility of his 1930s works, Stravinsky's music achieved a significant position in the musical life of the New Germany, which it maintained until the outbreak of war. Modern-minded critics articulated the ideological basis for his “rehabilitation”: although rooted in a foreign musical tradition, Stravinsky was an “Aryan” composer with acceptable political views, whose tonally based music revealed suitably “national” qualities.

Many foreign composers, including the antifascist Béla Bartók, shared Stravinsky's desire for German performances. Whether they allowed this to temper their modernist tendencies is difficult to determine. What is certain is that their tonally based music allowed many (racially and politically acceptable) foreign composers to find an audience in Nazi Germany. It also made feasible Germany's desire to reconnect with the larger musical world.
Britten's Dubious Trysts
Authors: Whitesell Lloyd
Published: January 2009

One hypothesis pursued in contemporary queer musicology argues that music provides an arena for reflection on a composer's experience of a marginal sexual identity. The music of Benjamin Britten has furnished material for a recent outpouring of such criticism. Much of this work, however, addresses covert meanings constrained by censorship and directed toward a minority audience of initiates or sympathizers; its impact on Britten reception in general remains unclear. I propose that Britten's music dramatizes a deviant perspective in fundamental ways, resulting in a queer aesthetic whose import extends to all listeners. Britten composes dramas of psychological reorientation from the following elements: the appearance of a stranger, a figure of worldly or spiritual initiation, in opposition to the familiar protagonist; and the setting in a limbo between worlds, making possible uncanny meetings whose vocal exchanges convey erotic knowledge. The confrontation of different perspectives casts the protagonist into disorientation and leads to bonds of identification across incompatible positions. Through the protagonist's perspective, such effects of deviant perception and cross-identification extend to the audience. Britten's queer aesthetic is not so much defiant or antagonistic as Socratic—based on a logic of persuasion and transformative dialogue.
Exploring the Generality of Recruitment Hypotheses for Largemouth Bass along a Latitudinal Gradient of Florida Lakes
Authors: Rogers Mark W. , Allen Micheal S.
Published: January 2009

Latitudinal influences on growing season length and winter severity cause variation in prerecruitment life history across species distributions. We evaluated two recruitment hypotheses for a broadly distributed species, largemouth bass Micropterus salmoides, at the southern extent of their natural range. We tested (1) whether early hatching provided a growth and survival advantage relative to later hatching through their first summer and (2) whether overwinter size‐selective mortality strongly influenced recruitment to age 1 across Florida's latitudinal gradient. We sampled the 2003 and 2004 year‐classes at six Florida lakes that spanned latitudes from 27°0′N to 30°5′N. Our results did not fully conform to our hypotheses or the results frequently reported from more northerly latitudes because largemouth bass that hatched early did not exhibit a growth and survival advantage at all lakes and we did not detect strong size‐selective overwinter mortality. Early hatching at south Florida lakes resulted in slow growth for three of four lake and year combinations and early‐hatched fish never exhibited a survival advantage relative to later‐hatched fish, which was probably due to cool water temperatures soon after hatching. Environmental variability influenced the interactions between hatching period, growth, and survival for Florida's largemouth bass populations, which has implications for understanding fish recruitment across broad spatial scales.
Evolutionary Relationships among Sympatric Life History Forms of Dolly Varden Inhabiting the Landlocked Kronotsky Lake, Kamchatka, and a Neighboring Anadromous Population
Authors: Ostberg C. O. , Pavlov S. D. , Hauser L.
Published: January 2009

We investigated the evolutionary relationships among five sympatric morphs of Dolly VardenSalvelinus malma(white, Schmidti, longhead, river, and dwarf) inhabiting landlocked Kronotsky Lake on the Kamchatka Peninsula, Russia, and an anadromous population below the barrier waterfall on the outflowing Kronotsky River. Morphological analyses indicated phenotypic differentiation corresponding to preferred habitat, the longhead (a limnetic piscivorous morph) having a fusiform body, long jaw, and short fins and the Schmidti (a benthic morph) having a robust body, small jaw, and long fins. Analysis of molecular variance among the Kronotsky Lake morphs indicated that contemporary gene flow is restricted both among morphs within locations and among locations within morphs. Gene flow from Kronotsky Lake into the anadromous population also appears to be restricted. Our findings indicate that there are two divergent evolutionary lineages, one consisting of the white, Schmidti, river, and dwarf morphs and the other of the longhead morph and the anadromous population, which suggests that Kronotsky Lake was subject to separate waves of immigration. The Kronotsky Lake Dolly Varden morphs may represent an example of ecological speciation in progress, and we present a working hypothesis for the diversification of morphs within Kronotsky Lake.
Untangling the Complexities of Depression Diagnosis in Older Cancer Patients
Authors: Weinberger Mark I. , Roth Andrew J. , Nelson Christian J.
Published: January 2009

Learning Objectives

Identify the two “gateway” symptoms of depression. Describe and differentiate symptoms of depression in cancer patients. Analyze the most common symptoms of depression in geriatric cancer patients in order to determine best care management.

This article is available for continuing medical education credit at CME.TheOncologist.com.