bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell shape and Wnt signaling redundantly control the division axis ofC. elegansepithelial stem cells
Authors: Wildwater Marjolein , Sander Nicholas , de Vreede Geert , van den Heuvel Sander
Published: September 2011

Tissue-specific stem cells combine proliferative and asymmetric divisions to balance self-renewal with differentiation. Tight regulation of the orientation and plane of cell division is crucial in this process. Here, we study the reproducible pattern of anterior-posterior-oriented stem cell-like divisions in the Caenorhabditis elegans seam epithelium. In a genetic screen, we identified an alg-1 Argonaute mutant with additional and abnormally oriented seam cell divisions. ALG-1 is the main subunit of the microRNA-induced silencing complex (miRISC) and was previously shown to regulate the timing of postembryonic development. Time-lapse fluorescence microscopy of developing larvae revealed that reduced alg-1 function successively interferes with Wnt signaling, cell adhesion, cell shape and the orientation and timing of seam cell division. We found that Wnt inactivation, through mig-14 Wntless mutation, disrupts tissue polarity but not anterior-posterior division. However, combined Wnt inhibition and cell shape alteration resulted in disordered orientation of seam cell division, similar to the alg-1 mutant. Our findings reveal additional alg-1-regulated processes, uncover a previously unknown function of Wnt ligands in seam tissue polarity, and show that Wnt signaling and geometric cues redundantly control the seam cell division axis.
Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish
Authors: Zhu Cong , Smith Tom , McNulty Joseph , Rayla Amy L. , Lakshmanan Abirami , Siekmann Arndt F. , Buffardi Matthew , Meng Xiangdong , Shin Jimann , Padmanabhan Arun , Cifuentes Daniel , Giraldez Antonio J. , Look A. Thomas , Epstein Jonathan A. , Lawson Nathan D. , Wolfe Scot A.
Published: September 2011

Zinc-finger nucleases (ZFNs) allow targeted gene inactivation in a wide range of model organisms. However, construction of target-specific ZFNs is technically challenging. Here, we evaluate a straightforward modular assembly-based approach for ZFN construction and gene inactivation in zebrafish. From an archive of 27 different zinc-finger modules, we assembled more than 70 different zinc-finger cassettes and evaluated their specificity using a bacterial one-hybrid assay. In parallel, we constructed ZFNs from these cassettes and tested their ability to induce lesions in zebrafish embryos. We found that the majority of zinc-finger proteins assembled from these modules have favorable specificities and nearly one-third of modular ZFNs generated lesions at their targets in the zebrafish genome. To facilitate the application of ZFNs within the zebrafish community we constructed a public database of sites in the zebrafish genome that can be targeted using this archive. Importantly, we generated new germline mutations in eight different genes, confirming that this is a viable platform for heritable gene inactivation in vertebrates. Characterization of one of these mutants, gata2a, revealed an unexpected role for this transcription factor in vascular development. This work provides a resource to allow targeted germline gene inactivation in zebrafish and highlights the benefit of a definitive reverse genetic strategy to reveal gene function.
June bloom in Maratea
Authors: Parcy François , Lohmann Jan U.
Published: September 2011

The International Workshop on Molecular Mechanisms Controlling Flower Development took place in the secluded southern Italian village of Maratea in June 2011. This meeting, which takes place biennially, gathers researchers in the fields of flowering time and flower and fruit development from both Europe and overseas to enjoy the sun, the sea and, most importantly, the science. As we summarise here, the results presented at this workshop underlined how mechanistic studies of both model and diverse species are deepening our understanding of the cellular processes involved in flowering.
A regulatory program for excretory system regeneration in planarians
Authors: Scimone M. Lucila , Srivastava Mansi , Bell George W. , Reddien Peter W.
Published: September 2011

Planarians can regenerate any missing body part, requiring mechanisms for the production of organ systems in the adult, including their prominent tubule-based filtration excretory system called protonephridia. Here, we identify a set of genes, Six1/2-2, POU2/3, hunchback, Eya and Sall, that encode transcription regulatory proteins that are required for planarian protonephridia regeneration. During regeneration, planarian stem cells are induced to form a cell population in regeneration blastemas expressing Six1/2-2, POU2/3, Eya, Sall and Osr that is required for excretory system formation. POU2/3 and Six1/2-2 are essential for these precursor cells to form. Eya, Six1/2-2, Sall, Osr and POU2/3-related genes are required for vertebrate kidney development. We determined that planarian and vertebrate excretory cells express homologous proteins involved in reabsorption and waste modification. Furthermore, we identified novel nephridia genes. Our results identify a transcriptional program and cellular mechanisms for the regeneration of an excretory organ and suggest that metazoan excretory systems are regulated by genetic programs that share a common evolutionary origin.
The Effects of Focus on Performance: Evidence from California Hospitals
Authors: KC Diwas Singh , Terwiesch Christian
Published: September 2011

We use hospital-level discharge data from cardiac patients in California to estimate the effects of focus on operational performance. We examine focus at three distinct levels of the organization—at the firm level, at the operating unit level, and at the process flow level. We find that focus at each of these levels is associated with improved outcomes, namely, faster services at higher levels of quality, as indicated by lower lengths of stay (LOS) and reduced mortality rates. We then analyze the extent to which the superior operational outcome is driven by focused hospitals truly excelling in their operations or by focused hospitals simply “cherry-picking” easy-to-treat patients. To do this, we use an instrumental variables estimation strategy that effectively randomizes the assignment of patients to hospitals. After controlling for selective patient admissions, the previously observed benefits of firm level focus disappear; focused hospitals no longer demonstrate a statistically significant reduction in LOS or mortality rate. However, at more granular measures of focus within the hospital (e.g., operating unit level), we find that more focus leads to a shorter LOS, even after controlling for selective admission effects.

This paper was accepted by Yossi Aviv, operations management.
Apologies as Signals: With Evidence from a Trust Game
Authors: Ho Benjamin
Published: September 2011

Apologies are part of a social institution designed to restore frayed relationships not only in daily life but also in the domains of corporate governance, medical malpractice litigation, political reputation, organizational culture, etc. The theory shows that in a general class of moral hazard games with imperfect information about agents with two-dimensional type, apologies exhibit regular properties—e.g., apologies are more frequent in long relationships, early in relationships, and between better-matched partners. A variant of the trust game demonstrates that communication matters in a manner consistent with economic theory; specifically, the words “I am sorry” appear to select equilibrium behavior consistent with the theory's main predictions.

This paper was accepted by Brad Barber, Teck Ho, and Terrance Odean, special issue editors.
Clinical and Demographic Factors Associated with Antipyretic Use in Gram-Negative Severe Sepsis and Septic Shock
Authors: Mohr Nicholas M , Fuller Brian M , Skrupky Lee P , Moy Hawnwan , Alunday Robert , Micek Scott T , Fagley Richard E
Published: September 2011

Background:

Antipyretic therapy is commonly prescribed for patients with Infection, but studies of its impact on clinical outcomes have yielded mixed results. No data exist to characterize the use of antipyretic medications in patients with severe sepsis or septic shock.

Objective:

To identify clinical and demographic factors associated with antipyretic medication administration in severe sepsis and septic shock.

Methods:

This single-center, retrospective, cohort study assessed febrile patients [temperature ≥38.3°C) with gram-negative severe sepsis or septic shock at an 1111-bed academic medical center between January 2002 and February 2008, Patients were excluded if they had liver disease, acute brain injury, or allergy to acetaminophen. Generalized estimating equations were used to estimate the effect of clinical factors on treatment of patients with antipyretic medications,

Results:

Although 76% of patients in this febrile cohort (n = 241) were prescribed an antipyretic agent, only 42% received antipyretic therapy; 95% of the doses were acetaminophen. Variables associated with antipyretic treatment were maximum body temperature (OR 2.11, 95% CI 1.53 to 2.89), time after sepsis diagnosis (OR 0.88, 95% CI 0.82 to 0.95), surgery during hospitalization (OR 0.49, 95% CI 0.31 to 0.80), death within 36 hours (OR 0.35, 95% CI 0.15 to 0.85). and mechanical ventilation (OR 0.58, 95% CI 0.34 to 0.98). Severity of illness factors, demographic factors, and patient treatment location did not predict who would receive antipyretic therapy.

Conclusions:

Most febrile episodes in patients with gram-negative severe sepsis or septic shock were not treated with antipyretic medications. Further studies are needed to demonstrate the effect of antipyretics on clinically relevant outcomes in severe sepsis and septic shock.
Current Perceptions and Practices Surrounding the Recognition and Treatment of Delirium in the Intensive Care Unit: A Survey of 250 Critical Care Pharmacists from Eight States
Authors: Devlin John W , Bhat Shubha , Roberts Russel J , Skrobik Yoanna
Published: September 2011

Background:

Pharmacists are key members of the intensive care unit (ICU) team; however, few data exist regarding their clinical role, perceptions, and current practices in recognizing and managing delirium.

Objective:

To describe current practices and perceptions of ICU pharmacists regarding delirium recognition and treatment relative to current recommendations.

Methods:

A self-administered survey was distributed to 457 pharmacists in 8 states who are members of the Society of Critical Care Medicine or the American College of Clinical Pharmacy and who spend 25% or more of their time providing clinical ICU pharmacy services.

Results:

A total of 250 (55%) pharmacists responded. A delirium screening tool was routinely used by few (7%) pharmacists. Lack of time (34%) and the belief that screening is a nursing role (24%) were key barriers to pharmacist screenings. Most (85%) said that delirium should be pharmacologically managed; 66% responded that 2 or more medications should be used. The treatments of first choice included Haloperidol (76%), an atypical antipsychotic (14%), or a benzodiazepine (10%). Frequently used treatments were Haloperidol (87%), quetiapine (59%), and lorazepam (47%). Haloperidol was perceived by many (42%) to have 1 or more randomized trials supporting its use for delirium and Food and Drug Administration approval for this indication (34%). Haloperidol was most often administered on a scheduled basis (62%), intravenously (92%), and al a daily dose of 5–10 mg (58%). While the QTc interval was frequently measured at least once per shift using an electrocardiogram strip (64%), it was not routinely measured in 20% of ICUs, and 60% continued haloperidol when the QTc exceeded 500 msec.

Conclusions:

Current practices and perceptions surrounding recognition and treatment of delirium in patients in the ICU by the critical care pharmacists surveyed are heterogeneous. Antipsychotics are frequently recommended by pharmacists for delirium treatment, despite a lack of rigorous evidence to support their use. While pharmacists are ideally suited to lead delirium recognition efforts and provide treatment recommendations in this area, these roles need further elucidation. The optimal pedagogical strategy to support these efforts remains unclear, and the potential impact of pharmacists’ efforts on patients’ outcomes is unknown.
Comparison of Serum Human Epididymis Protein 4 with Cancer Antigen 125 as a Tumor Marker in Patients with Malignant and Nonmalignant Diseases
Authors: Escudero Jose M , Auge Jose M , Filella Xavier , Torne Aureli , Pahisa Jaume , Molina Rafael
Published: September 2011

BACKGROUND

Human epididymis protein 4 (HE4), a precursor of human epididymis protein, has been proposed as a tumor marker for ovarian cancer. We evaluated HE4 in comparison with cancer antigen 125 (CA 125) in healthy individuals and in patients with benign and malignant diseases.

METHODS

CA 125 and HE4 serum concentrations were determined in 101 healthy individuals, 535 patients with benign pathologies (292 with benign gynecologic diseases) and 423 patients with malignant diseases (127 with ovarian cancers). CA 125 and HE4 cutoffs were 35 kU/L and 140 pmol/L, respectively.

RESULTS

HE4 and CA 125 results were abnormal in 1.1% and 9.9% of healthy individuals and in 12.3% and 37% of patients with benign diseases, respectively. Renal failure was the most common cause of increased HE4 in patients with benign disease, who had significantly higher HE4 concentrations (P = 0.001) than patients with other benign diseases. HE4 showed a higher specificity than CA 125 in patients with benign gynecologic diseases, with abnormal concentrations in 1.3% and 33.2% of the patients, respectively. HE-4 concentrations were abnormal primarily in gynecologic cancer and lung cancer. By contrast, CA 125 was increased in many different nonovarian malignancies, including nonepithelial tumors. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 for differentiating benign from malignant diseases (0.755 vs 0.643) and in the differential diagnosis of gynecologic diseases (0.874 vs 0.722).

CONCLUSIONS

HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types.
Altered Profile of Seminal Plasma MicroRNAs in the Molecular Diagnosis of Male Infertility
Authors: Wang Cheng , Yang Cuihua , Chen Xi , Yao Bing , Yang Chen , Zhu Chen , Li Limin , Wang Junjun , Li Xiaojun , Shao Yong , Liu Yang , Ji Jiang , Zhang Junfeng , Zen Ke , Zhang Chen-Yu , Zhang Chunni
Published: September 2011

BACKGROUND

Although microRNAs (miRNAs) play essential roles in spermatogenesis, little is known about seminal plasma miRNAs in infertile men. We investigated the profile of seminal plasma miRNAs in infertile men to identify miRNAs that are altered in infertility; we then evaluated their diagnostic value.

METHODS

Seminal plasma samples were obtained from 289 infertile men and 168 age-matched fertile control individuals. The stability of the miRNAs was first assessed by time-course and freeze–thaw cycle analyses. The Solexa sequencing technology was used for an initial screen of the miRNAs in samples pooled from 45 patients with nonobstructive azoospermia, 58 patients with asthenozoospermia, and 100 fertile controls. A stem–loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification sets to confirm the concentrations of the altered miRNAs in 73 patients with nonobstructive azoospermia, 79 patients with asthenozoospermia, 34 patients with oligospermia, and 68 fertile controls.

RESULTS

The miRNAs in seminal plasma were stable. The Solexa sequencing analysis demonstrated 19 markedly altered miRNAs in the patient groups, compared with the control group. RT-qPCR analysis identified 7 miRNAs (miR-34c-5p, miR-122, miR-146b-5p, miR-181a, miR-374b, miR-509–5p, and miR-513a-5p) as markedly decreased in azoospermia but increased in asthenozoospermia. The area under the ROC curve for these miRNAs ranged from 0.733 to 0.921, markedly higher than for routine biochemical parameters (0.510–0.622). Moreover, the concentrations of some selected miRNAs were also increased in the semen sperm of the asthenozoospermia patients.

CONCLUSIONS

The measurement of miRNAs in seminal plasma provides a novel, noninvasive approach for diagnosing male infertility.
The tree of irreducible numerical semigroups with fixed Frobenius number
Authors: Blanco Victor , Rosales José Carlos
Published: September 2011

In this paper we present a procedure to build the set of irreducible numerical semigroups with a fixed Frobenius number. The construction gives us a rooted tree structure for this set. Furthermore, by using the notion of Kunz-coordinates vector we translate the problem of finding such a tree into the problem of manipulating vectors with as many component as the Frobenius number.
Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury
Authors: Rathore Khizr I. , Berard Jennifer L. , Redensek Adriana , Chierzi Sabrina , Lopez-Vales Ruben , Santos Manuela , Akira Shizuo , David Samuel
Published: September 2011

Lipocalin 2 (Lcn2) plays an important role in defense against bacterial infection by interfering with bacterial iron acquisition. Although Lcn2 is expressed in a number of aseptic inflammatory conditions, its role in these conditions remains unclear. We examined the expression and role of Lcn2 after spinal cord injury (SCI) in adult mice by using a contusion injury model. Lcn2 expression at the protein level is rapidly increased 12-fold at 1 d after SCI and decreases gradually thereafter, being three times as high as control levels at 21 d after injury. Lcn2 expression is strongly induced after contusion injury in astrocytes, neurons, and neutrophils. The Lcn2 receptor (Lcn2R), which has been shown to influence cell survival, is also expressed after SCI in the same cell types. Lcn2-deficient (Lcn2−/−) mice showed significantly better locomotor recovery after spinal cord contusion injury than wild-type (Lcn2+/+) mice. Histological assessments indicate improved neuronal and tissue survival and greater sparing of myelin inLcn2−/−mice after contusion injury. Flow cytometry showed a decrease in neutrophil influx and a small increase in the monocyte population inLcn2−/−injured spinal cords. This change was accompanied by a reduction in the expression of several pro-inflammatory chemokines and cytokines as well as inducible nitric oxide synthase early after SCI inLcn2−/−mice compared with wild-type animals. Our results, therefore, suggest a role for Lcn2 in regulating inflammation in the injured spinal cord and that lack of Lcn2 reduces secondary damage and improves locomotor recovery after spinal cord contusion injury.
“Overshoot” of O2Is Required to Maintain Baseline Tissue Oxygenation at Locations Distal to Blood Vessels
Authors: Devor Anna , Sakadžić Sava , Saisan Payam A. , Yaseen Mohammad A. , Roussakis Emmanuel , Srinivasan Vivek J. , Vinogradov Sergei A. , Rosen Bruce R. , Buxton Richard B. , Dale Anders M. , Boas David A.
Published: September 2011

In vivoimaging of cerebral tissue oxygenation is important in defining healthy physiology and pathological departures associated with cerebral disease. We used a recently developed two-photon microscopy method, based on a novel phosphorescent nanoprobe, to image tissue oxygenation in the rat primary sensory cortex in response to sensory stimulation. Our measurements showed that a stimulus-evoked increase in tissue pO2depended on the baseline pO2level. In particular, during sustained stimulation, the steady-state pO2at low-baseline locations remained at the baseline, despite large pO2increases elsewhere. In contrast to the steady state, where pO2never decreased below the baseline, transient decreases occurred during the “initial dip” and “poststimulus undershoot.” These results suggest that the increase in blood oxygenation during the hemodynamic response, which has been perceived as a paradox, may serve to prevent a sustained oxygenation drop at tissue locations that are remote from the vascular feeding sources.
Tinnitus with a Normal Audiogram: Physiological Evidence for Hidden Hearing Loss and Computational Model
Authors: Schaette Roland , McAlpine David
Published: September 2011

Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of “hidden hearing loss” that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.
Cav1.2 L-Type Ca2+Channels Mediate Cocaine-Induced GluA1 Trafficking in the Nucleus Accumbens, a Long-Term Adaptation Dependent on Ventral Tegmental Area Cav1.3 Channels
Authors: Schierberl Kathryn , Hao Jin , Tropea Thomas F. , Ra Stephen , Giordano Thomas P. , Xu Qinghao , Garraway Sandra M. , Hofmann Franz , Moosmang Sven , Striessnig Joerg , Inturrisi Charles E. , Rajadhyaksha Anjali M.
Published: September 2011

AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization, we have examined phosphorylation of GluA1 at key residues serine 845 (S845) and S831, as well as GluA1 cell surface levels in the nucleus accumbens (NAc) of cocaine-preexposed mice and the role of brain-specific Cav1.2 and Cav1.3 L-type Ca2+channels (LTCCs), therein. We found higher basal levels of S845 phospho-GluA1 (P-GluA1) and cell surface GluA1 in the NAc following protracted withdrawal from cocaine exposure, changes that occur independently of LTCCs. In contrast, we found that a cocaine challenge that elicits expression of the cocaine-sensitized response increases S831 P-GluA1 that further increases surface GluA1 beyond the higher basal levels. Intra-NAc pharmacological manipulations indicate that the Cav1.2-activated CaM kinase II (CaMKII) mediates cocaine-induced increase in S831 P-GluA1 and that both Cav1.2-activated CaMKII and extracellular signal-regulated kinase 2 (ERK2) mediate the increase in GluA1 cell surface levels specific to the sensitized response. Experiments using adenoassociated viral vectors expressing Cav1.3 and ERK2 siRNA further indicate that recruitment of the Cav1.2 pathway in the NAc is dependent on ventral tegmental area Cav1.3 LTCCs and ERK2. Together, these results identify candidate pathways that mediate cocaine-induced AMPAR plasticity in the NAc and provide a mechanism linking LTCCs and GluA1 plasticity to cocaine-induced persistent behavioral changes.
Focal Adhesion Kinase Promotes Integrin Adhesion Dynamics Necessary for Chemotropic Turning of Nerve Growth Cones
Authors: Myers Jonathan P. , Gomez Timothy M.
Published: September 2011

The ability of extending axons to navigate using combinations of extracellular cues is essential for proper neural network formation. One intracellular signaling molecule that integrates convergent signals from both extracellular matrix (ECM) proteins and growth factors is focal adhesion kinase (FAK). Analysis of FAK function shows that it influences a variety of cellular activities, including cell motility, proliferation, and differentiation. Recent work in developing neurons has shown that FAK and Src function downstream of both attractive and repulsive growth factors, but little is known about the effectors or cellular mechanisms that FAK controls in growth cones on ECM proteins. We report that FAK functions downstream of brain-derived neurotrophic factor (BDNF) and laminin in the modulation of point contact dynamics, phosphotyrosine signaling at filopodial tips, and lamellipodial protrusion. BDNF stimulation accelerates paxillin-containing point contact turnover and formation. Knockdown of FAK function either with a FAK antisense morpholino or by expression of FRNK, a dominant-negative FAK isoform, blocks all aspects of the response to BDNF, including the acceleration of point contact dynamics. On the other hand, expression of specific FAK point mutants can selectively disrupt distinct aspects of the response to BDNF. We also show that growth cone turning depends on both signaling cascades tested here. Finally, we provide the first evidence that growth cone point contacts are asymmetrically regulated during turning to an attractive guidance cue.
Supramodal Representation of Emotions
Authors: Klasen Martin , Kenworthy Charles A. , Mathiak Krystyna A. , Kircher Tilo T. J. , Mathiak Klaus
Published: September 2011

Supramodal representation of emotion and its neural substrates have recently attracted attention as a marker of social cognition. However, the question whether perceptual integration of facial and vocal emotions takes place in primary sensory areas, multimodal cortices, or in affective structures remains unanswered yet. Using novel computer-generated stimuli, we combined emotional faces and voices in congruent and incongruent ways and assessed functional brain data (fMRI) during an emotional classification task. Both congruent and incongruent audiovisual stimuli evoked larger responses in thalamus and superior temporal regions compared with unimodal conditions. Congruent emotions were characterized by activation in amygdala, insula, ventral posterior cingulate (vPCC), temporo-occipital, and auditory cortices; incongruent emotions activated a frontoparietal network and bilateral caudate nucleus, indicating a greater processing load in working memory and emotion-encoding areas. The vPCC alone exhibited differential reactions to congruency and incongruency for all emotion categories and can thus be considered a central structure for supramodal representation of complex emotional information. Moreover, the left amygdala reflected supramodal representation of happy stimuli. These findings document that emotional information does not merge at the perceptual audiovisual integration level in unimodal or multimodal areas, but in vPCC and amygdala.
Bond-valence Based Computational Design of High Performance Lithium Ion Battery Cathode Materials
Authors: Adams Stefan
Published: September 2011

Linking the bond valence mismatch to the absolute energy scale, a generally applicable Morse-type force-field is developed and applied to study ion conduction in mixed conducting solids using both an energy landscape approach and molecular dynamics (MD) simulations. Exploring strategies to enhance the power performance of safe low cost lithium ion battery cathode materials, amblygonite-type “high voltage” cathode materials LiVPO4F and LiFeSO4F are used as examples. The amblygonite-type structure exhibits channels for low-energy migration in combination with moderate energy thresholds for "back-up" pathways in perpendicular directions mitigating the effects of channel blocking in mixed conductors with strictly one-dimensional Li+ motion.
Familial Pediatric Endocrine Tumors
Authors: Millar Sarinda , Bradley Lisa , Donnelly Deirdre E. , Carson Dennis , Morrison Patrick J.
Published: September 2011

Learning Objectives

After completing this course, the reader will be able to: Explain the contribution of genetics to heritable aspects of pediatric cancer.Describe the applications of presymptomatic gene testing in family members with familial pediatric cancers to the early detection, prevention, and management of tumors in patients and their family members.

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

Pediatric endocrine tumors are rare but have fairly characteristic presentations. We describe an approach to diagnosis and management of five of the most common presentations including gonadoblastoma, paraganglioma, medullary thyroid cancer, adrenal cancer, and pituitary adenoma. Genetic testing can aid in the early detection and prevention and management of tumors in patients and in other family members.
An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions
Authors: Lowery Maeve A. , Kelsen David P. , Stadler Zsofia K. , Yu Kenneth H. , Janjigian Yelena Y. , Ludwig Emmy , D'Adamo David R. , Salo-Mullen Erin , Robson Mark E. , Allen Peter J. , Kurtz Robert C. , O'Reilly Eileen M.
Published: September 2011

Learning Objectives

After completing this course, the reader will be able to: Describe the genetic syndromes associated with pancreas adenocarcinoma.Explain the potential role of platinum-based therapy and PARP inhibitors in BRCA-mutated pancreas adenocarcinoma.

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

Background.

BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported.

Methods.

Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center.

Results.

Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response.

Conclusion.

BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.
Responses of Gut Microbiota and Glucose and Lipid Metabolism to Prebiotics in Genetic Obese and Diet-Induced Leptin-Resistant Mice
Authors: Everard Amandine , Lazarevic Vladimir , Derrien Muriel , Girard Myriam , Muccioli Giulio G. , Neyrinck Audrey M. , Possemiers Sam , Van Holle Ann , François Patrice , de Vos Willem M. , Delzenne Nathalie M. , Schrenzel Jacques , Cani Patrice D.
Published: September 2011

OBJECTIVE

To investigate deep and comprehensive analysis of gut microbial communities and biological parameters after prebiotic administration in obese and diabetic mice.

RESEARCH DESIGN AND METHODS

Genetic (ob/ob) or diet-induced obese and diabetic mice were chronically fed with prebiotic-enriched diet or with a control diet. Extensive gut microbiota analyses, including quantitative PCR, pyrosequencing of the 16S rRNA, and phylogenetic microarrays, were performed in ob/ob mice. The impact of gut microbiota modulation on leptin sensitivity was investigated in diet-induced leptin-resistant mice. Metabolic parameters, gene expression, glucose homeostasis, and enteroendocrine-related L-cell function were documented in both models.

RESULTS

In ob/ob mice, prebiotic feeding decreased Firmicutes and increased Bacteroidetes phyla, but also changed 102 distinct taxa, 16 of which displayed a >10-fold change in abundance. In addition, prebiotics improved glucose tolerance, increased L-cell number and associated parameters (intestinal proglucagon mRNA expression and plasma glucagon-like peptide-1 levels), and reduced fat-mass development, oxidative stress, and low-grade inflammation. In high fat–fed mice, prebiotic treatment improved leptin sensitivity as well as metabolic parameters.

CONCLUSIONS

We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.
FoxO Feedback Control of Basal IRS-2 Expression in Pancreatic β-Cells Is Distinct From That in Hepatocytes
Authors: Tsunekawa Shin , Demozay Damien , Briaud Isabelle , McCuaig Jill , Accili Domenico , Stein Roland , Rhodes Christopher J.
Published: September 2011

OBJECTIVE

Appropriate regulation of insulin receptor substrate 2 (IRS-2) expression in pancreatic β-cells is essential to adequately compensate for insulin resistance. In liver, basal IRS-2 expression is controlled via a temporal negative feedback of sterol regulatory element–binding protein 1 (SREBP-1) to antagonize transcription factors forkhead box class O (FoxO)1/FoxO3a at an insulin response element (IRE) on the IRS-2 promoter. The purpose of the study was to examine if a similar mechanism controlled IRS-2 expression in β-cells.

RESEARCH DESIGN AND METHODS

IRS-2 mRNA and protein expression, as well as IRS-2 gene promoter activity, were examined in isolated rat islets. Specific transcription factor association with the IRE on the IRS-2 promoter was examined by chromatin immunoprecipitation (ChIP) assay, and their nuclear translocation was examined by immunofluorescence. A direct in vivo effect of insulin on control of IRS-2 expression in liver and pancreatic islets was also investigated.

RESULTS

In IRS-2 promoter-reporter assays conducted in isolated islets, removal of the IRE decreased basal IRS-2 promoter activity in β-cells up to 80%. Activation of IRS signaling in isolated rat islets by insulin/IGF-I (used as an experimental in vitro tool) or downstream constitutive activation of protein kinase B (PKB) significantly decreased IRS-2 expression. In contrast, inhibition of phosphatidylinositol 3-kinase (PI3K) or PKB significantly increased IRS-2 levels in β-cells. ChIP assays indicated that transcription factors FoxO1 and FoxO3a associated with the IRE on the IRS-2 promoter in β-cells in a PI3K/PKB–dependent manner, whereas others, such as SREBP-1, the transcription factor binding to immunoglobulin heavy chain enhancer 3′, and the aryl hydrocarbon receptor nuclear translocator (ARNT), did not. However, only FoxO3a, not FoxO1, was capable of driving IRS-2 promoter activity via the IRE in β-cells. In vivo studies showed insulin was able to suppress IRS-2 expression via activation of SREBP-1 in the liver, but this mechanism was not apparent in pancreatic islets from the same animal.

CONCLUSIONS

The molecular mechanism for feedback control of IRS signaling to decrease IRS-2 expression in liver and β-cells is quite distinct, with a predominant role played by FoxO3a in β-cells.
Influence of Familial Risk on Diabetes Risk–Reducing Behaviors Among U.S. Adults Without Diabetes
Authors: Chang Man-huei , Valdez Rodolfo , Ned Renée M. , Liu Tiebin , Yang Quanhe , Yesupriya Ajay , Dowling Nicole F. , Meigs James B. , Bowen Michael S. , Khoury Muin J.
Published: September 2011

OBJECTIVE

To test the association of family history of diabetes with the adoption of diabetes risk–reducing behaviors and whether this association is strengthened by physician advice or commonly known factors associated with diabetes risk.

RESEARCH DESIGN AND METHODS

We used cross-sectional data from the 2005–2008 National Health and Nutrition Examination Survey (NHANES) to examine the effects of family history of diabetes on the adoption of selected risk-reducing behaviors in 8,598 adults (aged ≥20 years) without diabetes. We used multiple logistic regression to model three risk reduction behaviors (controlling or losing weight, increasing physical activity, and reducing the amount of dietary fat or calories) with family history of diabetes.

RESULTS

Overall, 36.2% of U.S. adults without diabetes had a family history of diabetes. Among them, ~39.8% reported receiving advice from a physician during the past year regarding any of the three selected behaviors compared with 29.2% of participants with no family history (P < 0.01). In univariate analysis, adults with a family history of diabetes were more likely to perform these risk-reducing behaviors compared with adults without a family history. Physician advice was strongly associated with each of the behavioral changes (P < 0.01), and this did not differ by family history of diabetes.

CONCLUSIONS

Familial risk for diabetes and physician advice both independently influence the adoption of diabetes risk–reducing behaviors. However, fewer than half of participants with familial risk reported receiving physician advice for adopting these behaviors.
What is wrong with unarticulated constituents?
Authors: Zouhar Marián
Published: September 2011

It is quite popular nowadays to postulate various kinds of unarticulated constituents that have essential bearing on truth conditions of utterances. F. Recanati champions an elaborated version of contextualism according to which one has to distinguish two kinds of unarticulated constituents: those that are articulated at the level of the logical form of a given sentence and those that are truly unarticulated. Recanati offers a theory which explains the manner of incorporating truly unarticulated constituents into the propositions expressed. This theory invokes variadic functions. The present paper shows that variadic functions are unnecessary because no constituents are truly unarticulated in the sense assumed by Recanati. An alternative explanation is offered according to which all propositional constituents are either explicitly or implicitly represented at the syntactic level.
The Is-Ought Problem, the Open Question Argument, and the new science of morality
Authors: Bělohrad Radim
Published: September 2011

The article deals with a recent attack by Sam Harris on two famous arguments that purport to establish a gap between factual and evaluative statements—Hume’s Is-Ought Problem and Moore’s Open Question Argument. I present the arguments, analyze the relationship between them and critically assess Harris’ attempt to refute them. I conclude that Harris’ attempt fails.
Is Rorty a linguistic idealist?
Authors: Marvan Tomáš
Published: September 2011

The paper addresses the recurrent charge that Richard Rorty is a “linguistic idealist”. I show what the charge consists of and try to explain that there is a charitable reading of Rorty’s works, according to which he is not guilty of linguistic idealism. This reading draws on Putnam’s well-known conception of “internal realism” and accounts for the causal independence of the world on our linguistic practices. I also show how we can reconcile this causal independence of things and the sense of our discourse being guided by them with our autonomy with regard to the construction of various “vocabularies” with which we describe, or cope with, reality. In the final part, I address in some detail Rorty’s animadversions concerning the idea of the intrinsic nature of reality. I show them to be only partly successful.
The linguistic-pragmatic turn in the history of philosophy
Authors: Ralston Shane
Published: September 2011

Did the pragmatic turn encompass the linguistic turn in the history of philosophy? Or was the linguistic turn a turn away from pragmatism? Some commentators identify the so-called “eclipse” of pragmatism by analytic philosophy, especially during the Cold War era, as a turn away from pragmatist thinking. However, the historical evidence suggests that this narrative is little more than a myth. Pragmatism persisted, transforming into a more analytic variety under the influence of Quine and Putnam and, more recently, a continental version in the hands of Richard Rorty and Cornel West. In this paper, I argue that proof of the linguistic turn’s presence as a moment in a broader pragmatic turn in philosophy can be garnered from close examination of a single article, W. V. O. Quine’s “Two Dogmas of Empiricism,” and a single issue: whether the analytic-synthetic distinction is philosophically defensible.
Local disposition to environmental protection, poverty alleviation and other issues in the sustainable development agenda in Ondo State, Nigeria
Authors: Olumekun Victor , Ige Emmanuel
Published: September 2011

Sustainable development is the global agenda designed to ensure that the world’s climate is not irretrievably damaged and future generations have equal access to the world’s resources for their own development. The institutionalisation of measures to promote sustainable development has however not had unanimous cooperation. This study therefore investigated the attitude of officials at the local government level to topical issues in the sustainable development agenda in Ondo State, Nigeria, as a pointer to entrenched attitudes in the Third World. Prioritisation of issues varied between localities but premium was placed on poverty alleviation more than on climate change or power generation. People were more concerned with the improvement of their general well-being including health. Respondents indicated that most of the topical issues on the sustainable development agenda could be addressed at the local level thereby lending support for the notion that local action can contribute to global action. However, inclusive measures to promote positive action need to be institutionalised.
Luminescence dating of young coastal deposits from New Zealand using feldspar
Authors: Madsen Anni , Buylaert Jan-Pieter , Murray Andrew
Published: September 2011

A new measurement protocol has been tested on K-feldspars from Whanganui Inlet and Parengarenga Harbour, New Zealand. A Single Aliquot Regenerative (SAR) dose protocol, using two successive infrared (IR) stimulations (post-IR IR SAR protocol) is setup for these young (<1000 years) coastal sediments. Significant anomalous fading (g2days=7 %/decade) is observed using the conventional IR signal measured at 50°C. In contrast, the fading rate of the IR signal measured at elevated temperature (150°C) after the IR stimulation at 50°C (a post-IR IR signal) is not significant (g2days≤ 1 %/decade). Surprisingly low residual infrared stimulated luminescence (IRSL) signals were observed for a surface sample, suggesting that accurate ages as young as ∼50 years can be obtained for these recent deposits. IRSL ages ranging between 48±6 years and 1050±50 years are obtained from six samples, indicating that sediment accumulation has occurred at the two sites during the last millennia, despite a falling trend in relative sea-level in Whanganui Inlet and a stable relative sea-level at Parengarenga Harbour.
IRSL and post-IR IRSL residual doses recorded in modern dust samples from the Chinese Loess Plateau
Authors: Buylaert Jan-Pieter , Thiel Christine , Murray Andrew , Vandenberghe Dimitri , Yi Shuangwen , Lu Huayu
Published: September 2011

Using a set of modern/young (0 to about 200 years old) dust samples collected from the Chinese Loess Plateau the bleachability of IRSL measured at 50°C (IR50) and post-IR50 elevated temperature IRSL (measured at 225°C and at 290°C) is investigated by measuring the apparent (residual) doses recorded by these signals. Doses recorded by quartz OSL are used as a reference. Allowing for differences in dose rates it seems that both IRSL and post-IR IRSL signals yield residual doses that are significantly larger than the doses measured in quartz. These residual doses can be largely explained by thermal transfer caused by preheating. Nevertheless, we advise against the use of a low temperature preheat (<200°C) with IR50 to date loess samples because, as has been reported before, the signal appears to be thermally unstable. In general, we conclude that it may not be advisable to apply post-IR IRSL dating to Chinese loess samples where residuals of up to ∼20 Gy are a significant fraction of the total dose. However, these residuals quickly become unimportant when dating older samples, and this is the age range in which post-IR IRSL dating is likely to be most useful.
Determination of the pore size of woven structures through image analysis
Authors: Angelova R.
Published: September 2011

The paper presents an experimental procedure developed for determination of the pore size, shape and distribution in a single layer woven fabric, for the construction of a virtual model to be incorporated in a future CFD software package. The procedure is based on non-destructive observation and analysis of woven samples. 14 different samples of gray fabrics of 100 % cotton in plain and twill weaves are investigated. The results obtained allow the creation of reality more realistic virtual model of the woven structure, and theoretical investigation of its porosity and permeability through computer simulation.
Where Have All the Good Men Gone?: Afflicted Fathers and Endangered Daughters in Russell Banks's The Sweet Hereafter
Authors: Baiada Christa
Published: September 2011

This article explores a recurrent theme in postwar American culture, a perceived crisis of manhood/masculinity, through Russell Banks's novel The Sweet Hereafter. On one level, Banks establishes a sense of anxiety and threat with roots in confused and devalued masculine roles. Linked in the narrative to the deaths of multiple children of a small town and especially to fathers' failure to protect their daughters, Banks implies that America's future is imperiled by the degradation of fatherhood. But on a deeper level, the novel suggests that at the core of America's postwar anxiety about families and fathers is not a loss but a lack. The idealized masculine roles whose loss we mourn, Banks tells us, may never really have existed at all.
Gatsby's Mentors: Queer Relations between Love and Money in the Great Gatsby
Authors: Froehlich Maggie Gordon
Published: September 2011

This essay examines relationships between men and the role patriarchal capitalism plays in the construction of sexuality in F. Scott Fitzgerald's The Great Gatsby (1925), a novel written during a critical period in the history of sexuality, as well as of gay and lesbian history. The ambivalence about male bonds—in particular the simultaneously loving and abusive dynamics of mentoring—depicted in this canonical work of American literature reveals the author's unease about his relationship with Catholic priest and teacher Sigourney Fay and provides insight into the author's well-known lifelong anxiety about his gender and sexuality.