bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells
Authors: Jin Quanri , Yuan Linda X , Boulbes Delphine , Baek Jong Min , Wang Ying Nai , Gomez-Cabello Daniel , Hawke David H , Yeung Sai Ching , Lee Mong Hong , Hortobagyi Gabriel N , Hung Mien Chie , Esteva Francisco J
Published: January 2011

Introduction

The human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in breast cancer. Heterodimerization of HER2 with other HER family members results in enhanced tyrosine phosphorylation and activation of signal transduction pathways. HER2 overexpression increases the translation of fatty acid synthase (FASN), and FASN overexpression markedly increases HER2 signaling, which results in enhanced cell growth. However, the molecular mechanism and regulation of HER2 and FASN interaction are not well defined. Lapatinib is a small-molecule tyrosine kinase inhibitor that blocks phosphorylation of the epidermal growth factor receptor and HER2 in breast cancer cells, resulting in apoptosis. We hypothesized that FASN is directly phosphorylated by HER2, resulting in enhanced signaling and tumor progression in breast cancer cells.

Methods

Using mass spectrometry, we identified FASN as one of the proteins that is dephosphorylated by lapatinib in SKBR3 breast cancer cells. Immunofluorescence, immunoprecipitation, Western blotting, a kinase assay, a FASN enzymatic activity assay, an invasion assay, a cell viability assay and zymography were used to determine the role of FASN phosphorylation in invasion of SKBR3 and BT474 cells. The FASN inhibitor C75 and small interfering RNA were used to downregulate FASN expression and/or activity.

Results

Our data demonstrated that FASN is phosphorylated when it is in complex with HER2. FASN phosphorylation was induced by heregulin in HER2-overexpressing SKBR3 and BT474 breast cancer cells. Heregulin-induced FASN phosphorylation resulted in increased FASN enzymatic activity, which was inhibited by lapatinib. The FASN inhibitor C75 suppressed FASN activity by directly inhibiting HER2 and FASN phosphorylation. Blocking FASN phosphorylation and activity by lapatinib or C75 suppressed the activity of matrix metallopeptidase 9 and inhibited invasion of SKBR3 and BT474 cells.

Conclusions

FASN phosphorylation by HER2 plays an important role in breast cancer progression and may be a novel therapeutic target in HER2-overexpressing breast cancer cells.
An updated study-level meta-analysis of randomised controlled trials on proning in ARDS and acute lung injury
Authors: Abroug Fekri , Ouanes-Besbes Lamia , Dachraoui Fahmi , Ouanes Islem , Brochard Laurent
Published: January 2011

Introduction

In patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), recent randomised controlled trials (RCTs) showed a consistent trend of mortality reduction with prone ventilation. We updated a meta-analysis on this topic.

Methods

RCTs that compared ventilation of adult patients with ALI/ARDS in prone versus supine position were included in this study-level meta-analysis. Analysis was made by a random-effects model. The effect size on intensive care unit (ICU) mortality was computed in the overall included studies and in two subgroups of studies: those that included all ALI or hypoxemic patients, and those that restricted inclusion to only ARDS patients. A relationship between studies' effect size and daily prone duration was sought with meta-regression. We also computed the effects of prone positioning on major adverse airway complications.

Results

Seven RCTs (including 1,675 adult patients, of whom 862 were ventilated in the prone position) were included. The four most recent trials included only ARDS patients, and also applied the longest proning durations and used lung-protective ventilation. The effects of prone positioning differed according to the type of study. Overall, prone ventilation did not reduce ICU mortality (odds ratio = 0.91, 95% confidence interval = 0.75 to 1.2; P = 0.39), but it significantly reduced the ICU mortality in the four recent studies that enrolled only patients with ARDS (odds ratio = 0.71; 95% confidence interval = 0.5 to 0.99; P = 0.048; number needed to treat = 11). Meta-regression on all studies disclosed only a trend to explain effect variation by prone duration (P = 0.06). Prone positioning was not associated with a statistical increase in major airway complications.

Conclusions

Long duration of ventilation in prone position significantly reduces ICU mortality when only ARDS patients are considered.
Editorial: Can PKCδ be a novel therapeutic target?
Authors: Martins Joilson O
Published: January 2011

Several lines of evidence indicate that PKCδ plays a crucial role in cell growth, migration, differentiation, and cell death, thus being involved in many human disorders, such as cancer, diabetes, and sepsis.
Heat shock proteins and high mobility group box 1 protein lack cytokine function
Authors: Tsan Min-Fu
Published: January 2011

In search of the etiology and pathophysiology for autoimmune and chronic inflammatory diseases, many molecules have been identified as endogenous damage-associated molecules with proinflammatory cytokine functions that may be responsible for the sterile inflammation leading to tissue injuries observed in these disorders. HSPs and HMGB1 are intracellular molecular chaperones for peptides and DNAs, respectively. They are released extracellularly upon cellular injury or activation. In vitro studies revealed that HSPs and HMGB1 were capable of inducing the release of proinflammatory cytokines by monocytes and macrophages and the activation and maturation of DCs. These cytokine effects were reported to be mediated by TLR2 and TLR4 signal transduction pathways. Thus, they were called endogenous ligands of TLR2 and TLR4 and might serve as danger signals, alarmins, or damage-associated molecules to the host immune system. It has been suggested that HSPs provide a link between innate and adaptive immune systems, and HMGB1 functions at the cross-road between innate and adaptive immunity. However, recent evidence suggests that highly purified HSPs and HMGB1, although retaining their biological activities, do not have cytokine effects. Thus, HSPs and HMGB1 do not meet the definition of endogenous ligands of TLRs, danger signals, alarmins, or damage-associated molecules. In contrast, HSPs and HMGB1 are found to bind a number of pathogen-associated molecules, such as LPS and bacterial lipopeptides, and enhance the cytokine effects of these molecules. The significance of these cytokine-enhancing effects of HSPs and HMGB1 needs further investigation.
Estimation of ultrasonic scattering attenuation in partially frozen brines using magnetic resonance images
Authors: Matsushima Jun , Suzuki Makoto , Kato Yoshibumi , Rokugawa Shuichi
Published: January 2011

Seismic attenuation is not due entirely to intrinsic properties; a component due to scattering effects is included. Although different techniques have been used to experimentally investigate the attenuation of seismic waves, not so many laboratory measurements of attenuation have taken into account the effect of scattering attenuation. Herein, partially frozen brine as a solid-liquid coexistence system is used to investigate attenuation phenomena. We obtained a series of 2D apparent diffusion coefficient (ADC) maps of the ice-brine coexisting system using a diffusion-weighted magnetic resonance imaging (DW-MRI) technique at [Formula: see text], and found a strongly heterogeneous spatial distribution of unfrozen brine. From these maps, we constructed a synthetic seismic data set propagating through 2D media, and generated synthetic data with a second-order finite-difference scheme for the 2D acoustic wave equation. We estimated ultrasonic scattering attenuation in such systems by the centroid frequency shift method and by assuming that the quality factor ([Formula: see text]-value) is independent of frequency. The estimated scattering attenuation ranges from 0.015 to 0.05, corresponding to 10% to 30% of the total attenuation measured in laboratory experiments.
Retrieving reflections by source-receiver wavefield interferometry
Authors: Poliannikov Oleg V.
Published: January 2011

Source-receiver wavefield interferometry has been proposed recently as an extension of classical correlation-based interferometry. Under idealized assumptions, it allows the Green’s function between a source and a receiver to be reconstructed from boundary data that are collected using two closed contours of sources and receivers, respectively. An intuitive geometric description of this method, based on ray theory, can be used to design a method for reconstructing virtual-gather events that typically are lost when conventional interferometry is employed. In classical interferometry, events in the Green’s function between two receiver locations are reconstructed by automatically finding a ray that emanates from a stationary source, passes through the virtual source, reflects off the structure, and finally is recorded by the second receiver. The common path to both receivers is then canceled by a suitable crosscorrelation. If illumination of the structure is not ideal, such a ray may not exist and the reflection is not reconstructed. Source-receiver wave interferometry can be given a similar geometric description. The reflection off the structure can be constructed using not one but multiple rays produced simultaneously by two stationary sources. This new redatuming technique proves successful in geometries in which classical interferometry fails. Extensive numerical simulations support these theoretical conclusions.
Autumn Sonata: a film written and directed by Ingmar Bergman
Authors: Almeida Joyce
Published: January 2011

Ingmar Bergman was a Swedish director, writer and producer for film, stage and television. He directed 62 films, most of which he also wrote. Many of his films were set in the landscape of Sweden and he explored the themes of death, illness, cruelty, betrayal, mental illness, religion, and relationships between partners, children and their parents. Known as an auteur, he frequently used his film-making to examine issues from his own childhood.
Timing of menarche and depressive symptoms in adolescent girls from a UK cohort
Authors: Joinson Carol , Heron Jon , Lewis Glyn , Croudace Tim , Araya Ricardo
Published: January 2011

Background

A growing number of studies suggest a link between timing of menarche and risk of depressive symptoms in adolescence, but few have prospectively examined the emergence of depressive symptoms from late childhood into adolescence.

Aims

To examine whether girls who experience earlier menarche than their peers have higher levels of depressive symptoms in adolescence.

Method

The study sample comprised 2184 girls from the Avon Longitudinal Study of Parents and Children. The association between timing of menarche and depressive symptoms at 10.5, 13 and 14 years was examined within a structural equation model.

Results

Girls with early menarche (<11.5 years) had the highest level of depressive symptoms at 13 (P = 0.007) and 14 years (P<0.001) compared with those with normative and late timing of menarche.

Conclusions

Early maturing girls are at increased risk of depressive symptoms in adolescence and could be targeted by programmes aimed at early intervention and prevention.
The smoking culture in psychiatry: time for change
Authors: Ratschen Elena , Britton John , McNeill Ann
Published: January 2011

Smoking is closely linked to severe mental illness and has a major detrimental impact on individuals' lives. Despite this and the recent societal ‘de-normalisation’ of smoking, the historic ‘smoking culture’ still prevails within mental health settings. Change is urgently required to prevent a widening of existing health gaps.
Eating disorders, DSM–5 and clinical reality
Authors: Fairburn Christopher G. , Cooper Zafra
Published: January 2011

The DSM–IV scheme for classifying eating disorders is a poor reflection of clinical reality. In adults it recognises two conditions, anorexia nervosa and bulimia nervosa, yet these states are merely two presentations among many. As a consequence, at least half the cases seen in clinical practice are relegated to the residual diagnosis ‘eating disorder not otherwise specified’. The changes proposed for DSM–5 will only partially succeed in correcting this shortcoming. With DSM–6 in mind, it is clear that comprehensive transdiagnostic samples need to be studied with data collected on their current state, course and response to treatment. Only with such data will it be possible to derive an empirically based classificatory scheme that is both rooted in clinical reality and of value to clinicians.
Nidotherapy in the treatment of substance misuse, psychosis and personality disorder: secondary analysis of a controlled trial
Authors: Tyrer Peter , Milošeska Katarina , Whittington Craig , Ranger Maja , Khaleel Ibrahim , Crawford Mike , North Bernard , Barrett Barbara
Published: January 2011

Aims and method

To examine the clinical outcome and bed usage in patients with comorbid substance misuse and psychosis. The patients were randomised to ordinary assertive outreach team care or to enhanced assertive outreach with nidotherapy. Ratings of clinical symptoms, social function, engagement with services, bed usage (primary outcome after 1 year) and economic costs were assessed at baseline and at 6 and 12 months after randomisation.

Results

Patients referred to nidotherapy had similar reduction in symptoms and engagement, with marginal superiority in social function (P= 0.045). There was a 110% reduction in hospital bed use after 1 year compared with control assertive care (P= 0.03). The mean cost savings for each patient allocated to nidotherapy was £14705 per year, mainly as a consequence of reduced psychiatric bed use.

Clinical implications

Nidotherapy shows promise in the treatment of substance misuse and psychosis and may reduce hospital bed usage.
Estrogen-Regulated Prohibitin Is Required for Mouse Uterine Development and Adult Function
Authors: He Bin , Kim Tae Hoon , Kommagani Ramakrishna , Feng Qin , Lanz Rainer B. , Jeong Jae-Wook , DeMayo Francesco J. , Katzenellenbogen Benita S. , Lydon John P. , O'Malley Bert W.
Published: January 2011

Estrogen signaling is pivotal for maintenance of female reproductive function in mammals. The physiological role of estrogen is mediated by estrogen receptors (ERs) and the steroid receptor coactivator family of transcriptional coregulators. Ablation of steroid receptor coactivator and ER coactivators in mice causes impaired female reproductive function. Recently we reported that prohibitin (PHB) can function as a corepressor for ERs in cultured cells. In this study, we demonstrate that PHB is an estrogen-regulated gene in vitro and in vivo, and its expression is induced by estrogen in the uterus, suggesting the existence of feedback regulatory loops. A conditional PHB knockout mouse model was generated by gene targeting to assess its in vivo function. Female mice with selective ablation of the PHB allele in the uterus were sterile, and their uteri were severely hypoplastic, indicating PHB is required for uterine development. Moreover, expression of ER and progesterone receptor target genes was selectively altered in response to hormone treatment. In summary, this study demonstrates that PHB is an estrogen-regulated gene and that PHB is essential for mouse uterine development and adult function and selectively required for estrogen-regulated gene expression.
Leptin-Independent Programming of Adult Body Weight and Adiposity in Mice
Authors: Cottrell Elizabeth C. , Martin-Gronert Malgorzata S. , Fernandez-Twinn Denise S. , Luan Jian'an , Berends Lindsey M. , Ozanne Susan E.
Published: January 2011

Low birth weight and rapid postnatal weight gain are independent and additive risk factors for the subsequent development of metabolic disease. Despite an abundance of evidence for these associations, mechanistic data are lacking. The hormone leptin has received significant interest as a potential programming factor, because differences in the profile of leptin in early life have been associated with altered susceptibility to obesity. Whether leptin alone is a critical factor for programming obesity has, until now, remained unclear. Using the leptin-deficient ob/ob mouse, we show that low birth weight followed by rapid catch-up growth during lactation (recuperated offspring) leads to a persistent increase in body weight in adult life, both in wild-type and ob/ob animals. Furthermore, recuperated offspring are hyperphagic and epididymal fat pad weights are significantly increased, reflecting greater adiposity. These results show definitively that factors other than leptin are crucial in the programming of energy homeostasis in this model and are powerful enough to alter adiposity in a genetically obese strain.
Glutamine Triggers and Potentiates Glucagon-Like Peptide-1 Secretion by Raising Cytosolic Ca2+ and cAMP
Authors: Tolhurst Gwen , Zheng Yue , Parker Helen E. , Habib Abdella M. , Reimann Frank , Gribble Fiona M.
Published: January 2011

L-glutamine stimulates glucagon-like peptide 1 (GLP-1) secretion in human subjects and cell lines. As recent advances have enabled the study of primary GLP-1–releasing L cells, this study aimed to characterize glutamine-sensing pathways in native murine L cells. L cells were identified using transgenic mice with cell-specific expression of fluorescent markers. Cells were studied in primary colonic cultures from adult mice, or purified by flow cytometry for expression analysis. Intracellular Ca2+ was monitored in cultures loaded with Fura2, and cAMP was studied using Förster resonance energy transfer sensors expressed in GLUTag cells. Asparagine, phenylalanine, and glutamine (10 mm) triggered GLP-1 release from primary cultures, but glutamine was the most efficacious, increasing secretion 1.9-fold with an EC50 of 0.19 mm. Several amino acids triggered Ca2+ changes in L cells, comparable in magnitude to that induced by glutamine. Glutamine-induced Ca2+ responses were abolished in low Na+ solution and attenuated in Ca2+ free solution, suggesting a role for Na+ dependent uptake and Ca2+ influx. The greater effectiveness of glutamine as a secretagogue was paralleled by its ability to increase cAMP in GLUTag cells. Glutamine elevated intracellular cAMP to 36% of that produced by a maximal stimulus, whereas asparagine only increased intracellular cAMP by 24% and phenylalanine was without effect. Glutamine elevates both cytosolic Ca2+ and cAMP in L cells, which may account for the effectiveness of glutamine as a GLP-1 secretagogue. Therapeutic agents like glutamine that target synergistic pathways in L cells might play a future role in the treatment of type 2 diabetes.
Leptin Signaling Modulates the Activity of Urocortin 1 Neurons in the Mouse Nonpreganglionic Edinger-Westphal Nucleus
Authors: Xu Lu , Scheenen Wim J. J. M. , Leshan Rebecca L. , Patterson Christa M. , Elias Carol F. , Bouwhuis Sanne , Roubos Eric Willem , Myers Martin G. , Kozicz Tamás
Published: January 2011

A recent study systematically characterized the distribution of the long form of the leptin receptor (LepRb) in the mouse brain and showed substantial LepRb mRNA expression in the nonpreganglionic Edinger-Westphal nucleus (npEW) in the rostroventral part of the midbrain. This nucleus hosts the majority of urocortin 1 (Ucn1) neurons in the rodent brain, and because Ucn1 is a potent satiety hormone and electrical lesioning of the npEW strongly decreases food intake, we have hypothesized a role of npEW-Ucn1 neurons in leptin-controlled food intake. Here, we show by immunohistochemistry that npEW-Ucn1 neurons in the mouse contain LepRb and respond to leptin administration with induction of the Janus kinase 2-signal transducer and activator of transcription 3 pathway, both in vivo and in vitro. Furthermore, systemic leptin administration increases the Ucn1 content of the npEW significantly, whereas in mice that lack LepRb (db/db mice), the npEW contains considerably reduced amount of Ucn1. Finally, we reveal by patch clamping of midbrain Ucn1 neurons that leptin administration reduces the electrical firing activity of the Ucn1 neurons. In conclusion, we provide ample evidence for leptin actions that go beyond leptin's well-known targets in the hypothalamus and propose that leptin can directly influence the activity of the midbrain Ucn1 neurons.
Comparison between Surrogate Indexes of Insulin Sensitivity/Resistance and Hyperinsulinemic Euglycemic Glucose Clamps in Rhesus Monkeys
Authors: Lee Ho-Won , Muniyappa Ranganath , Yan Xu , Yue Lilly Q. , Linden Ellen H. , Chen Hui , Hansen Barbara C. , Quon Michael J.
Published: January 2011

The euglycemic glucose clamp is the reference method for assessing insulin sensitivity in humans and animals. However, clamps are ill-suited for large studies because of extensive requirements for cost, time, labor, and technical expertise. Simple surrogate indexes of insulin sensitivity/resistance including quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) have been developed and validated in humans. However, validation studies of QUICKI and HOMA in both rats and mice suggest that differences in metabolic physiology between rodents and humans limit their value in rodents. Rhesus monkeys are a species more similar to humans than rodents. Therefore, in the present study, we evaluated data from 199 glucose clamp studies obtained from a large cohort of 86 monkeys with a broad range of insulin sensitivity. Data were used to evaluate simple surrogate indexes of insulin sensitivity/resistance (QUICKI, HOMA, Log HOMA, 1/HOMA, and 1/Fasting insulin) with respect to linear regression, predictive accuracy using a calibration model, and diagnostic performance using receiver operating characteristic. Most surrogates had modest linear correlations with SIClamp (r ≈ 0.4–0.64) with comparable correlation coefficients. Predictive accuracy determined by calibration model analysis demonstrated better predictive accuracy of QUICKI than HOMA and Log HOMA. Receiver operating characteristic analysis showed equivalent sensitivity and specificity of most surrogate indexes to detect insulin resistance. Thus, unlike in rodents but similar to humans, surrogate indexes of insulin sensitivity/resistance including QUICKI and log HOMA may be reasonable to use in large studies of rhesus monkeys where it may be impractical to conduct glucose clamp studies.
Independent and Combined Effects of Calcium-Vitamin D3 and Exercise on Bone Structure and Strength in Older Men: An 18-Month Factorial Design Randomized Controlled Trial
Authors: Kukuljan Sonja , Nowson Caryl A. , Sanders Kerrie M. , Nicholson Geoff C. , Seibel Markus J. , Salmon Jo , Daly Robin M.
Published: January 2011

Context:

Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis, but their combined effects on bone strength and its determinants remain uncertain.

Objective:

To assess whether calcium-vitamin D3 fortified milk could enhance the effects of exercise on bone strength, structure, and mineral density in middle-aged and older men.

Design, Setting, Participants:

An 18-month factorial design randomized controlled trial in which 180 men aged 50–79 years were randomized to the following: exercise + fortified milk; exercise; fortified milk; or controls. Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week. Men assigned to fortified milk consumed 400 ml/d of 1% fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D3.

Main Outcome Measures:

Changes in bone mineral density (BMD), bone structure, and strength at the lumbar spine (LS), proximal femur, mid-femur, and mid-tibia measured by dual energy x-ray absorptiometry and/or quantitative computed tomography.

Results:

There were no exercise-by-fortified milk interactions at any skeletal site. Main effect analysis showed that exercise led to a 2.1% (95% confidence interval, 0.5–3.6) net gain in femoral neck section modulus, which was associated with an approximately 1.9% gain in areal BMD and cross-sectional area. Exercise also improved LS trabecular BMD [net gain 2.2% (95% confidence interval, 0.2–4.1)], but had no effect on mid-femur or mid-tibia BMD, structure, or strength. There were no main effects of the fortified milk at any skeletal site.

Conclusion:

A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men, but providing additional calcium-vitamin D3 to these replete men did not enhance the osteogenic response.
GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide
Authors: Hegedüs Laszlo , Moses Alan C. , Zdravkovic Milan , Le Thi Tu , Daniels Gilbert H.
Published: January 2011

Background:

Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations.

Aim:

The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects.

Methods:

Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy.

Results:

Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups.

Conclusions:

These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.
The Strong Law of Large Numbers for Extended Negatively Dependent Random Variables
Authors: Chen Yiqing , Chen Anyue , Ng Kai W.
Published: January 2011

A sequence of random variables is said to be extended negatively dependent (END) if the tails of its finite-dimensional distributions in the lower-left and upper-right corners are dominated by a multiple of the tails of the corresponding finite-dimensional distributions of a sequence of independent random variables with the same marginal distributions. The goal of this paper is to establish the strong law of large numbers for a sequence of END and identically distributed random variables. In doing so we derive some new inequalities of large deviation type for the sums of END and identically distributed random variables being suitably truncated. We also show applications of our main result to risk theory and renewal theory.
A Simple Model for Random Oscillations
Authors: Papangelou F.
Published: January 2011

A simple model for a randomly oscillating variable is suggested, which is a variant of the two-state random velocity model. As in the latter model, the variable keeps rising or falling with constant velocity for some time before randomly reversing its direction. In contrast however, its propensity to reverse depends on its current value and it is for this desirable feature that the model is proposed here. This feature has two implications: (a) neither the changing variable nor its velocity is Markovian, although the joint process is, and (b) the linear differential equations arising in the case of our model do not have constant coefficients. The results given in this paper are meant to illustrate the straightforward nature of some of the calculations involved and to highlight the relationship with one-dimensional diffusions.
Probabilistic Analysis of the Efficacy of Periodic Testing of Employees
Authors: Berman Simeon M.
Published: January 2011

Some major companies have the policy of annually giving numerical scores to their employees according to their performance, firing those whose performance scores are below a given percentile of the scores of all employees, and then recruiting new employees to replace those who were fired. We introduce a probabilistic model to describe how this practice affects the quality of employee performance as measured over time by the annual scores. Let n be the number of years that the policy has been in effect, and let Fn(x) be the distribution function of the evaluation scores in year n. We show, under certain technical assumptions, that the sequence (Fn(x)) satisfies a particular nonlinear difference equation, and furnish estimates of the solution of the equation and expressions for the quantiles of Fn. The mathematical tools that are used include convex functions, difference equations, and extreme value theory for independent and identically distributed random variables.
Wnt/PCP signaling controls intracellular position of MTOCs during gastrulation convergence and extension movements
Authors: Sepich Diane S. , Usmani Mohsinah , Pawlicki Staci , Solnica-Krezel Lila
Published: January 2011

During vertebrate gastrulation, convergence and extension cell movements are coordinated with the anteroposterior and mediolateral embryonic axes. Wnt planar cell polarity (Wnt/PCP) signaling polarizes the motile behaviors of cells with respect to the anteroposterior embryonic axis. Understanding how Wnt/PCP signaling mediates convergence and extension (C&E) movements requires analysis of the mechanisms employed to alter cell morphology and behavior with respect to embryonic polarity. Here, we examine the interactions between the microtubule cytoskeleton and Wnt/PCP signaling during zebrafish gastrulation. First, we assessed the location of the centrosome/microtubule organizing center (MTOC) relative to the cell nucleus and the body axes, as a marker of cell polarity. The intracellular position of MTOCs was polarized, perpendicular to the plane of the germ layers, independently of Wnt/PCP signaling. In addition, this position became biased posteriorly and medially within the plane of the germ layers at the transition from mid- to late gastrulation and from slow to fast C&E movements. This depends on intact Wnt/PCP signaling through Knypek (Glypican4/6) and Dishevelled components. Second, we tested whether microtubules are required for planar cell polarization. Once the planar cell polarity is established, microtubules are not required for accumulation of Prickle at the anterior cell edge. However, microtubules are needed for cell-cell contacts and initiation of its anterior localization. Reciprocal interactions occur between Wnt/PCP signaling and microtubule cytoskeleton during C&E gastrulation movements. Wnt/PCP signaling influences the polarity of the microtubule cytoskeleton and, conversely, microtubules are required for the asymmetric distribution of Wnt/PCP pathway components.
Combinatorial cell-specific regulation of GSK3 directs cell differentiation and polarity in Dictyostelium
Authors: Kim Leung , Brzostowski Joseph , Majithia Amit , Lee Nam-Sihk , McMains Vanessa , Kimmel Alan R.
Published: January 2011

In Dictyostelium, the interaction of secreted cAMP with specific cell surface receptors regulates the activation/de-activation of GSK3, which mediates developmental cell patterning. In addition, Dictyostelium cells polarize in response to extracellular cAMP, although a potential role for GSK3 in this pathway has not been investigated. Previously, we had shown that ZAK1 was an activating tyrosine kinase for GSK3 function in Dictyostelium and we now identify ZAK2 as the other tyrosine kinase in the cAMP-activation pathway for GSK3; no additional family members exist. We also now show that tyrosine phosphorylation/activation of GSK3 by ZAK2 and ZAK1 separately regulate GSK3 in distinct differentiated cell populations, and that ZAK2 acts in both autonomous and non-autonomous pathways to regulate these cell-type differentiations. Finally, we demonstrate that efficient polarization of Dictyostelium towards cAMP depends on ZAK1-mediated tyrosine phosphorylation of GSK3. Combinatorial regulation of GSK3 by ZAK kinases in Dictyostelium guides cell polarity, directional cell migration and cell differentiation, pathways that extend the complexity of GSK3 signaling throughout the development of Dictyostelium.
Genetic inducible fate mapping in larval zebrafish reveals origins of adult insulin-producing β-cells
Authors: Wang Yiyun , Rovira Meritxell , Yusuff Shamila , Parsons Michael J.
Published: January 2011

The Notch-signaling pathway is known to be fundamental in controlling pancreas differentiation. We now report on using Cre-based fate mapping to indelibly label pancreatic Notch-responsive cells (PNCs) at larval stages and follow their fate in the adult pancreas. We show that the PNCs represent a population of progenitors that can differentiate to multiple lineages, including adult ductal cells, centroacinar cells (CACs) and endocrine cells. These endocrine cells include the insulin-producing β-cells. CACs are a functional component of the exocrine pancreas; however, our fate-mapping results indicate that CACs are more closely related to endocrine cells by lineage as they share a common progenitor. The majority of the exocrine pancreas consists of the secretory acinar cells; however, we only detect a very limited contribution of PNCs to acinar cells. To explain this observation we re-examined early events in pancreas formation. The pancreatic anlage that gives rise to the exocrine pancreas is located in the ventral gut endoderm (called the ventral bud). Ptf1a is a gene required for exocrine pancreas development and is first expressed as the ventral bud forms. We used transgenic marker lines to observe both the domain of cells expressing ptf1a and cells responding to Notch signaling. We do not detect any overlap in expression and demonstrate that the ventral bud consists of two cell populations: a ptf1-expressing domain and a Notch-responsive progenitor core. As pancreas organogenesis continues, the ventral bud derived PNCs align along the duct, remain multipotent and later in development differentiate to form secondary islets, ducts and CACs.
Role of Tbx2 in defining the territory of the pronephric nephron
Authors: Cho Gun-Sik , Choi Sun-Cheol , Park Edmond Changkyun , Han Jin-Kwan
Published: January 2011

Despite extensive study of the development of the nephron, which is the functional unit of the kidney, the molecular mechanisms underlying the determination of nephron size remain largely unknown. Using the Xenopus pronephros, we demonstrate here that Tbx2, a T-box transcriptional repressor, functions to demarcate the territory of the pronephric nephron. Tbx2 is specifically expressed around three distinct components of the pronephric nephron: the tubule, duct and glomus. Gain of function of Tbx2 inhibits nephric mesoderm formation. Conversely, Tbx2 loss of function expands the boundary of each component of the pronephric nephron, resulting in an enlarged pronephros. BMP signals induce Tbx2 in the non-nephric mesoderm, which inhibits the expression of the nephric markers Hey1 and Gremlin. Importantly, these pronephric molecules repress Tbx2 expression by antagonizing BMP signals in the nephric mesoderm. These results suggest that the negative regulatory loops between BMP/Tbx2 and Gremlin or Hey1 are responsible for defining the territory of the pronephric nephron.
Menstruation, Sanitary Products, and School Attendance: Evidence from a Randomized Evaluation
Authors: Oster Emily , Thornton Rebecca
Published: January 2011

Policy-makers have cited menstruation and lack of sanitary products as barriers to girls' schooling. We evaluate these claims using a randomized evaluation of sanitary products provision to girls in Nepal. We report two findings. First, menstruation has a very small impact on school attendance. We estimate that girls miss a total of 0.4 days in a 180 day school year. Second, improved sanitary technology has no effect on reducing this (small) gap. Girls who randomly received sanitary products were no less likely to miss school during their period. We can reject (at the 1 percent level) the claim that better menstruation products close the attendance gap. (JEL I21, J13, J16, O12)
Simple Analytics of the Government Expenditure Multiplier
Authors: Woodford Michael
Published: January 2011

This paper explains the key factors that determine the output multiplier of government purchases in New Keynesian models, through a series of simple examples that can be solved analytically. Sticky prices or wages allow for larger multipliers than in a neoclassical model, though the size of the multiplier depends crucially on the monetary policy response. A multiplier well in excess of one is possible when monetary policy is constrained by the zero lower bound, and in this case welfare increases if government purchases expand to partially fill the output gap that arises from the inability to lower interest rates. (JEL E12, E23, E32, E62, H20, H50)
Worker Heterogeneity and Endogenous Separations in a Matching Model of Unemployment Fluctuations
Authors: Bils Mark , Chang Yongsung , Kim Sun-Bin
Published: January 2011

We model worker heterogeneity in the rents from being employed in a Diamond-Mortensen-Pissarides model of matching and unemployment. We show that heterogeneity, reflecting differences in match quality and worker assets, reduces the extent of fluctuations in separations and unemployment. We find that the model faces a trade-off— it cannot produce both realistic dispersion in wage growth across workers and realistic cyclical fluctuations in unemployment. (JEL D31, E24, E32, J41, J63)
Housing Bubbles
Authors: Arce Óscar , López-Salido David
Published: January 2011

We use the notion of a housing bubble as an equilibrium in which some investors hold houses for resale purposes only and not with the expectation of receiving a dividend, either in the form of rent or utility. We show that an economy with looser collateral constraints is less prone to bubbles, which, in turn, have smaller size, but are more fragile in the face of credit-crunch shocks. Our environment also allows for the existence of pure bubbles on unproductive assets. We find that multiple equilibria, in which the economy moves endogenously from a pure bubble to a housing bubble and vice versa, are possible. (JEL G12, R21, R31)
Industry Evidence on the Effects of Government Spending
Authors: Nekarda Christopher J , Ramey Valerie A
Published: January 2011

This paper investigates the effects of government purchases at the industry level in order to shed light on the transmission mechanism for government spending on the aggregate economy. We create a new panel dataset that matches output and labor variables to industry-specific shifts in government demand. An increase in government demand raises output and hours, lowers real product wages and labor productivity, and has no effect on the markup. The estimates also imply approximately constant returns to scale. The findings are more consistent with the effects of government spending in the neoclassical model than the textbook New Keynesian model. (JEL E12, E23, E62, H50)
Diabetic Neuropathy: Lacosamide
Authors: Generali Joyce A. , Cada Dennis J.
Published: January 2011

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@kumc.edu .
Experimental and Numerical Study of the Effect of an Oversize Particle on the Shear Strength of Mined-Rock Pile Material
Authors: Fakhimi Ali , Hosseinpour Hooman
Published: January 2011

During in situ direct shear testing on the Questa mined-rock pile material, oversize rock fragments were encountered in the shear box. To study the effect of an oversize particle on the measured friction angles and cohesions, both laboratory and numerical direct shear tests were conducted on unsaturated samples of the rock pile material. In the numerical simulation, a hybrid discrete-finite element method was implemented in which the rock pile material was modeled with discrete particles while the shear box was modeled with finite elements. Both the numerical and physical tests suggest an increase in the measured shear strength of the material due to the presence of an oversize particle in the box. More specifically, the presence of an oversize particle causes an increase in friction angle while cohesion in most situations decreases. The location of the oversize particle along the shear plane was found to be important, as it can modify the failure mechanism.
Association Between Sexually Transmitted Diseases and Young Adults' Self-reported Abstinence
Authors: DiClemente Ralph J. , Sales Jessica McDermott , Danner Fred , Crosby Richard A.
Published: January 2011

OBJECTIVE:

Self-reported behavior has been the cornerstone of sexual health research and clinical practice, yet advances in sexually transmitted disease (STD) screening provide researchers with the opportunity to objectively quantify sexual risk behaviors. However, the extent to which young adults' laboratory-confirmed STD results and self-reported sexual behaviors are consistent has not been assessed in a nationally representative sample.

PATIENTS AND METHODS:

Data are derived from participants who completed wave 3 in the National Longitudinal Study of Adolescent Health. Young adults (N = 14 012) completed an audio computer-assisted self-interviewing survey and provided a urine specimen to detect the presence of Chlamydia trachomatis and Neisseria gonorrhoeae, and a polymerase chain reaction assay to detect Trichomonas vaginalis.

RESULTS:

More than 10% of young adults with a laboratory-confirmed positive STD result reported abstaining from sexual intercourse in the 12 months before assessment and STD testing. After controlling for several sociodemographic factors, self-reported sex (versus those who reported abstinence) in the previous 12 months was significantly associated with testing positive, but the odds of testing positive were only slightly more than twofold (adjusted odds ratio: 2.11 [95% confidence interval: 2.097–2.122]).

CONCLUSIONS:

Findings indicate discrepancy between young adults' positive STD status and self-reported sexual behavior. No significant correlates of discrepant reporting were identified. From a clinical standpoint, the discrepancies between STD positivity and self-reported sexual behavior observed in this nationally representative sample suggest that routine STD screening may be beneficial and necessary to reduce STD morbidity among young adults.
Varicella-Related Hospitalizations in the United States, 2000–2006: The 1-Dose Varicella Vaccination Era
Authors: Lopez Adriana S. , Zhang John , Brown Cedric , Bialek Stephanie
Published: January 2011

OBJECTIVE:

To describe the effect of the mature 1-dose varicella vaccination program on varicella morbidity, we analyzed 2 national databases for varicella-related hospitalizations in the United States since implementation of the varicella vaccination program in 1995.

PATIENTS AND METHODS:

Data from the National Hospital Discharge Survey and Nationwide Inpatient Sample were analyzed to describe trends in varicella-related hospitalizations during the 1-dose vaccination era (2000–2006) compared with those in the prevaccination era (1988–1995). Varicella-related hospitalizations were defined by using International Classification of Diseases, Ninth Revision codes. Results were extrapolated to represent national estimates.

RESULTS:

Using National Hospital Discharge Survey data, 24 488 varicella-related hospitalizations were estimated to occur in the United States during the 1-dose vaccination era. The varicella-related hospitalization rate was 0.12 per 10 000 population during the 1-dose vaccination era versus 0.42 per 10 000 population in the prevaccination era (P < .01). During the 1-dose vaccination era, the estimated annual average number of varicella-related hospitalizations was significantly lower and decreased by ≥65% in all age groups compared with those in the prevaccination era (P < .001 in all age groups). The varicella-related hospitalization rate during the 1-dose vaccination era estimated from the Nationwide Inpatient Sample was 0.09 per 10 000 population.

CONCLUSIONS:

Varicella-related hospitalization numbers and rates declined significantly during the 1-dose varicella vaccination era. Assuming declines in varicella-related hospitalizations are due, mainly, to the routine childhood varicella vaccination program, these data suggest that varicella vaccination prevented ∼50 000 varicella-related hospitalizations in the United States from 2000 to 2006.
The Impact of Pediatric Vision Disorders in Adulthood
Authors: Davidson Stefanie , Quinn Graham E.
Published: January 2011

In addition to refractive errors such as myopia and astigmatism, ocular disorders that occur in infants, toddlers, and children may present lifelong problems for the child. Conditions such as strabismus, amblyopia, and retinopathy of prematurity may require adaptations in adulthood. In addition, vision disorders that occur in childhood may manifest as problems well into adulthood. When visual impairment is present, there may be further effects on overall health, self-perception, educational attainment, job choices, and a number of other social factors.
Why Should There Be an NICHD?
Authors: Alexander Duane F.
Published: January 2011

In its nearly 5 decades of existence, the Eunice Kennedy Shriver National Institute of Child Health and Human Development has expended $23 billion in conducting and supporting research and translating discoveries to practice. The resulting dramatic impact on peoples' lives and improved health for children and families, chronicled herein, are a testament to the benefits of having this institute at the National Institutes of Health.