bluuebunny/crossref_metadata_2025 huggingface dataset:
Cinacalcet Decreases Bone Formation Rate in Hypercalcemic Hyperparathyroidism after Kidney Transplantation
Authors: Borchhardt Kyra A. , Diarra Danielle , Sulzbacher Irene , Benesch Thomas , Haas Martin , Sunder-Plassmann Gere
Published: April 2010

Background/Aims: Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. Its effect on bone, however, has not been investigated in this population. Methods: We prospectively examined bone turnover, histomorphometry and density as well as serum bone biomarkers in 10 transplant recipients before and after treatment with cinacalcet. Results: After 18–24 months of treatment with cinacalcet, bone formation decreased in 7, increased in 2, and remained zero in 1 patient (p = 0.11). Trabecular bone volume was maintained. Trabecular number decreased (p = 0.03), but trabecular thickness was unchanged (p = 0.17). Osteoid decreased (p = 0.02) and osteoblast surface increased (p = 0.02). Bone mineral density of the femur remained stable in 1 patient, decreased in 2 patients, but increased in 7 patients (p = 0.153). Serum calcium concentration (p = 0.005), iPTH (p = 0.01) and calcitonin concentration decreased (p = 0.03), while 25(OH) vitamin D3 increased (p = 0.02). No fractures were reported. Graft function remained stable. Conclusion: Whilecinacalcet might decrease bone formation rate, it did not change bone volume, and bone mineral density of the femur increased. Therefore, the use of cinacalcet in hypercalcemic hyperparathyroidism might be safe with regard to the bone disease present after kidney transplantation.
Effect of Flap Removal in Myopic Epi-LASIK Surgery on Visual Rehabilitation and Postoperative Pain: A Prospective Intraindividual Study
Authors: Na Kyung-Sun , Lee Kyung-Min , Park Shin-Hae , Lee Hyun-Soo , Joo Choun-Ki
Published: April 2010

Purpose: A prospective intraindividual study to evaluate the effect of flap removal in myopic epi-LASIK surgery on visual rehabilitation and postoperative pain. Methods: Ninety eyes of 45 patients were treated for myopia with epi-LASIK. In each patient, the epithelial flap was repositioned in one eye after epi-LASIK (group 1) while the flap was removed in the other (group 2). Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), spherical equivalent (SE) refraction, postoperative pain and corneal haze were examined for 6 months after surgery in both groups. Results: Group 2 had a better UCVA at 4 days and BCVA at 1 week after surgery (p = 0.001, p = 0.043) than group 1. No significant differences were observed between the two groups in terms of UCVA, BCVA, or SE refraction at 1 week and 1, 2 and 6 months. Postoperative pain scores were similar for both groups. In group 2, severe pain (pain level ≧6) was relatively less than in group 1 at 2 h and 12 h after surgery. Corneal haze levels in both groups were not different. Conclusions: Epi-LASIK surgery with flap removal was found to significantly promote re-epithelialization and visual recovery during the early postoperative period. It was also found to be more predictable and less painful than epi-LASIK surgery.
Response to Sham and Active Gamma Ventral Capsulotomy in Otherwise Intractable Obsessive-Compulsive Disorder
Authors: Gouvea F. , Lopes A. , Greenberg B. , Canteras M. , Taub A. , Mathis M. , Miguel E.
Published: April 2010

This case regards a 34-year-old woman with severe and refractory obsessive-compulsive disorder, who was enrolled in a double-blind, randomized controlled trial of radiosurgery. She was at first submitted to a sham radiosurgical procedure, and 1 year later to an active intervention. Opposite clinical responses were observed in the follow-up of these different phases. During the sham surgery follow-up, no improvements were observed, but a remarkable amelioration was seen a few months after the active procedure. Detailed descriptions of psychopathological changes and neuroimaging findings as well as a discussion regarding the surgical technique are provided.
Kinetics of FKBP12.6 Binding to Ryanodine Receptors in Permeabilized Cardiac Myocytes and Effects on Ca Sparks
Authors: Guo Tao , Cornea Razvan L. , Huke Sabine , Camors Emmanuel , Yang Yi , Picht Eckard , Fruen Bradley R. , Bers Donald M.
Published: April 2010

Rationale
:

FK506-binding proteins FKBP12.6 and FKBP12 are associated with cardiac ryanodine receptors (RyR2), and cAMP-dependent protein kinase A (PKA)-dependent phosphorylation of RyR2 was proposed to interrupt FKBP12.6-RyR2 association and activate RyR2. However, the function of FKBP12.6/12 and role of PKA phosphorylation in cardiac myocytes are controversial.

Objective
:

To directly measure in situ binding of FKBP12.6/12 to RyR2 in ventricular myocytes, with simultaneous Ca sparks measurements as a RyR2 functional index.

Methods and Results
:

We used permeabilized rat and mouse ventricular myocytes, and fluorescently-labeled FKBP12.6/12. Both FKBP12.6 and FKBP12 concentrate at Z-lines, consistent with RyR2 and Ca spark initiation sites. However, only FKBP12.6 inhibits resting RyR2 activity. Assessment of fluorescent FKBP binding in myocyte revealed a high FKBP12.6-RyR2 affinity (
K
d
=0.7±0.1 nmol/L) and much lower FKBP12-RyR2 affinity (
K
d
=206±70 nmol/L). Fluorescence recovery after photobleach confirmed this
K
d
difference and showed that it is mediated by
k
off
. RyR2 phosphorylation by PKA did not alter binding kinetics or affinity of FKBP12.6/12 for RyR2. Using quantitative immunoblots, we determined endogenous [FKBP12] in intact myocytes is ≈1 μmol/L (similar to [RyR]), whereas [FKBP12.6] is ≤150 nmol/L.

Conclusions
:

Only 10% to 20% of endogenous myocyte RyR2s have FKBP12.6 associated, but virtually all myocyte FKBP12.6 is RyR2-bound (because of very high affinity). FKBP12.6 but not FKBP12 inhibits basal RyR2 activity. PKA-dependent RyR2 phosphorylation has no significant effect on binding of either FKBP12 or 12.6 to RyR2 in myocytes.
Endovascular Thrombectomy for Acute Ischemic Stroke in Failed Intravenous Tissue Plasminogen Activator Versus Non–Intravenous Tissue Plasminogen Activator Patients
Authors: Shi Zhong-Song , Loh Yince , Walker Gary , Duckwiler Gary R.
Published: April 2010

Background and Purpose—

Intracranial mechanical thrombectomy is a therapeutic option for acute ischemic stroke patients failing intravenous tissue plasminogen activator (IV tPA). We compared patients treated by mechanical embolus removal in cerebral ischemia (MERCI) thrombectomy after failed IV tPA with those treated with thrombectomy alone.

Methods—

We pooled MERCI and Multi MERCI study patients, grouped them either as failed IV tPA or non–IV tPA, and assessed revascularization rates, procedural complications, symptomatic hemorrhage rates, clinical outcomes, and mortality. We also evaluated outcomes stratified by the occlusion site and final revascularization.

Results—

Among 305 patients, 48 failed, and 257 were ineligible for IV tPA. Nonresponders to IV tPA trended toward a higher revascularization rate (73% versus 63%) and less mortality (27.7% versus 40.1%) and had similar rates of symptomatic hemorrhage and procedural complications. Favorable 90-day outcomes were similar in failed and non–IV tPA patients (38% versus 31%), with no difference according to occlusion site. Among patients failing IV tPA, good outcomes tended to occur more frequently in revascularized patients (47.1% versus 15.4%), although this relationship was attributable solely to middle cerebral artery and not internal carotid artery occlusions, with no difference in mortality. Among IV tPA–ineligible patients, revascularization correlated with good outcome (47.4% versus 4.4%) and less mortality (28.5% versus 59.6%).

Conclusions—

The risks of hemorrhage and procedure-related complications after mechanical thrombectomy do not differ with respect to previous IV tPA administration. Thrombectomy after IV tPA achieves similar rates of good outcomes, a tendency toward lower mortality, and similar revascularization rates when stratified by clot location. Good outcomes correlate with successful revascularization except with internal carotid artery occlusions in tPA-nonresponders.
Differential Effect of Previous Antiplatelet Use on Stroke Severity According to Stroke Mechanism
Authors: Kim Wook-Joo , Ko Youngchai , Yang Mi Hwa , Im Sun-Hye , Park Jung Hyun , Lee JiSung , Lee Juneyoung , Han Moon-Ku , Bae Hee-Joon
Published: April 2010

Background and Purpose—

The effect of previous antiplatelet use on stroke severity is controversial. We assume that this controversy is attributable to its difference according to the stroke mechanism.

Methods—

Using a prospective stroke registry, patients who were hospitalized because of ischemic stroke and had relevant lesions on MRI were selected. Patients who were using anticoagulants or whose stroke subtype was categorized as stroke of other determined etiology or undetermined etiology were excluded. Baseline stroke severity was measured using the National Institutes of Health Stroke Scale scores at presentation and was compared between no previous antiplatelet users and previous antiplatelet users with stratification by stroke subtypes.

Results—

Among the 1622 patients, a total of 490 (30.2%) patients reported use of an antiplatelet within 1 week of stroke onset. The baseline National Institutes of Health Stroke Scale score showed no difference between the nonantiplatelet and antiplatelet groups by crude comparison. However, the interaction between previous antiplatelet use and stroke subtype was significant (
P
=0.023) in a multivariable analysis; when the study subjects were stratified by stroke subtype, the difference in baseline National Institutes of Health Stroke Scale between the nonantiplatelet and platelet groups was significant in the large artery atherothrombosis group but not in those with cardioembolism and small-vessel occlusion before and after adjustments.

Conclusions—

Our study suggests that the reduction of initial stroke severity in the previous antiplatelet users may differ by stroke mechanism.
Toward Synthesizing Artificial Neural Networks that Exhibit Cooperative Intelligent Behavior: Some Open Issues in Artificial Life
Authors: Dyer Michael G.
Published: April 2010

The tasks that animals perform require a high degree of intelligence. Animals forage for food, migrate, navigate, court mates, rear offspring, defend against predators, construct nests, and so on. These tasks commonly require social interaction/cooperation and are accomplished by animal nervous systems, which are the result of billions of years of evolution and complex developmental/learning processes. The Artificial Life (AL) approach to synthesizing intelligent behavior is guided by this biological perspective. In this article we examine some of the numerous open problems in synthesizing intelligent animal behavior (especially cooperative behavior involving communication) that face the field of AL, a discipline still in its infancy.
The Cell Programming Language
Authors: Agarwal Pankaj
Published: April 2010

In developmental biology, modeling and simulation play an important role in understanding cellular behavior. This article includes a review of the general models of development that are based on cellular interaction. Inspired by these models, we suggest a simple language, the Cell Programming Language (CPL), to write computer programs to describe this developmental behavior. These programs are an estimate of the minimal information needed to model realistically such developmental systems. Using these programs, it is possible to simulate and visualize cell behavior. We have employed CPL to model the following: aggregation in cellular slime mold in response to a chemotactic agent, cellular segregation and engulfment due to differential adhesion, and precartilage formation in vertebrate limbs. We believe CPL is a useful tool for developing, understanding, and checking biological models.
Artificial Symbiogenesis
Authors: Bull Lawrence , Fogarty Terence C.
Published: April 2010

Symbiosis is the phenomenon in which organisms of different species live together in close association, resulting in a raised level of fitness for one or more of the organisms. Symbiogenesis is the name given to the process by which symbiotic partners combine and unify—forming endosymbioses and then potentially transferring genetic material—giving rise to new morphologies and physiologies evolutionarily more advanced than their constituents. In this article we begin by using the NKC model of coevolution to examine endosymbiosis and its effect on the evolutionary performance of the partners involved. We are then able to suggest the conditions under which endosymbioses are more likely to occur and why; we find they emerge between organisms within a window of their respective “chaotic gas regimes” and hence that the association represents a more stable state for the partners. The conditions under which gene transfer is more likely to represent an advantage for such endosymbionts are then examined within the same model. We find that, providing a suitable pathway exists, such a process can lead to a more efficient genetic configuration for the symbionts within a window that overlaps that in which endosymbioses occur. Finally, the results are used as grounds for implementing symbiogenesis within artificial evolutionary multiagent systems.
An Implementation of von Neumann's Self-Reproducing Machine
Authors: Pesavento Umberto
Published: April 2010

This article describes in detail an implementation of John von Neumann's self-reproducing machine. Self-reproduction is achieved as a special case of construction by a universal constructor. The theoretical proof of the existence of such machines was given by John von Neumann in the early 1950s [6], but was first implemented in 1994, by the author in collaboration with R. Nobili. Our implementation relies on an extension of the state-transition rule of von Neumann's original cellular automaton. This extension was introduced to simplify the design of the constructor. The main operations in our constructor can be mapped into operations of von Neumann's machine.
Evolutionary Transitions and Artificial Life
Authors: Stewart John
Published: April 2010

A major challenge for artificial life is to synthesize the evolutionary transitions that have repeatedly formed differentiated higher-level entities from cooperative organizations of lower-level entities, producing the nested hierarchical structure of living processes. This article identifies the key elements and relationships that must be incorporated or synthesized in an artificial life system if these transitions are to emerge. The processes currently included in artificial life systems are unable to provide an adequate basis for the emergence of the complex cooperative organization that is essential to the transitions. A new theory of the evolution of cooperative organization is developed that points to the additional processes that must be included in artificial life systems to underpin the emergence of the transitions.
The Price of Fame: The Impact of Stimulus Familiarity on Proactive Interference Resolution
Authors: Prabhakaran Ranjani , Thompson-Schill Sharon L.
Published: April 2010

Interference from previously learned information, known as proactive interference (PI), limits our memory retrieval abilities. Previous studies of PI resolution have focused on the role of short-term familiarity, or recency, in causing PI. In the present study, we investigated the impact of long-term stimulus familiarity on PI resolution processes. In two behavioral experiments and one event-related fMRI experiment, long-term familiarity was manipulated through the use of famous and nonfamous stimuli, and short-term familiarity was manipulated through the use of recent and nonrecent probe items in an item recognition task. The right middle frontal gyrus demonstrated greater sensitivity to famous stimuli, suggesting that long-term stimulus familiarity plays a role in influencing PI resolution processes. Further examination of the effect of long-term stimulus familiarity on PI resolution revealed a larger behavioral interference effect for famous stimuli, but only under speeded response conditions. Thus, models of memory retrieval—and of the cognitive control mechanisms that guide retrieval processes—should consider the impact of and interactions among sources of familiarity on multiple time scales.
Brain Structure in Young and Old East Asians and Westerners: Comparisons of Structural Volume and Cortical Thickness
Authors: Chee Michael Wei Liang , Zheng Hui , Goh Joshua Oon Soo , Park Denise , Sutton Bradley P.
Published: April 2010

There is an emergent literature suggesting that East Asians and Westerners differ in cognitive processes because of cultural biases to process information holistically (East Asians) or analytically (Westerners). To evaluate the possibility that such differences are accompanied by differences in brain structure, we conducted a large comparative study on cognitively matched young and old adults from two cultural/ethnic groups—Chinese Singaporeans and non-Asian Americans—that involved a total of 140 persons. Young predominantly White American adults were found to have higher cortical thickness in frontal, parietal, and medial-temporal polymodal association areas in both hemispheres. These findings were replicated using voxel-based morphometry applied to the same data set. Differences in cortical thickness observed between young volunteers were not significant in older subjects as a whole. However, group differences were evident when high-performing old were compared. Although the observed differences in gray matter may be rooted in strategic differences in cognition arising from ethnic/cultural differences, alternative explanations involving genetic heritage and environmental factors are also considered.
Random Responding as a Threat to the Validity of Effect Size Estimates in Correlational Research
Authors: Credé Marcus
Published: April 2010

Random responding to psychological inventories is a long-standing concern among clinical practitioners and researchers interested in interpreting idiographic data, but it is typically viewed as having only a minor impact on the statistical inferences drawn from nomothetic data. This article explores the impact of random responding on the size and direction of correlations observed between multi-item inventory scores. Random responses to individual items result in nonrandomly distributed inventory-level scores. Therefore, even low base rates of random responding can significantly affect the statistical inferences made from inventory-level data. Study 1 uses simulations to show that even low base rates of random responding can significantly affect observed correlations, especially when the inventories in question assess low or high base rate phenomena. Study 2 uses archival data to illustrate the moderating effect of random responding on observed correlations in two samples.
‘Our Red Soldiers’: The Nationalist Army's Management of its Left-Wing Conscripts in the Spanish Civil War 1936–9
Authors: Matthews James
Published: April 2010

The ragged division of Spain after the 17 July 1936 military uprising ensured that the two sides were not cleanly split between supporters of the government and the rebels. As a result, many men who subsequently fell under Nationalist conscription decrees had been associated with the various left-wing political parties and unions that expanded their membership under the Second Republic. The challenge for the Nationalists was to incorporate effectively as many as possible into their war effort. The Nationalist Army, as may be expected, relied on threats and violence to maintain a good level of compliance among its conscripted soldiers. However, there was another side to the army's relationship with its drafted soldiers. Men who had left-wing pasts were able to shelter within the Nationalist Army on condition that they provided an effective minimum level of service in uniform. A similar strategic policy allowed the Nationalists to incorporate over half of Republican Popular Army prisoners of war into their own army — a process known as ‘recycling’. The Nationalists' ability to mobilize and manage their conscripts with left-wing pasts is an important factor in explaining their military success in the Civil War.
Varieties of capitalism and local outcomes: A Swedish case study
Authors: Rafiqui Pernilla S.
Published: April 2010

Despite the ‘institutional turn’ in economic geography, relatively limited attention has been paid to the comparative political economy literature that investigates the institutional underpinnings of the different versions of capitalism that we observe in the world. In turn, this literature has shown little interest in variety within national models of capitalism, an issue more often tackled by economic geographers. This paper asks if the Varieties of Capitalism (VoC) framework of Hall and Soskice is a useful tool for investigating institutional disparity within national models, and if it can indicate deviation from national or sectoral norms that may provide insights into the success or failure of local clusters. It applies the framework to two Swedish furniture locations — Tibro and Virserum — that together dominated the industry in the mid-1940s. Today, Tibro maintains its leading position whereas Virserum has been wiped off the map in terms of furniture production. The paper finds that applying the framework in this rather unorthodox manner does indeed paint a more nuanced picture of a rather coherent Swedish institutional system, and that there is varying scope for local creativity among the predetermined institutional spheres of VoC. In particular, the paper illustrates how local outcomes of national systems may differ across space, depending on particular configurations of institutional and non-institutional factors at local and sectoral levels playing themselves out against national developments.
Industrial structure, regional productivity and convergence: The case of Norway and Sweden
Authors: Østbye Stein , Westerlund Olle
Published: April 2010

Are less productive regions catching up with more productive regions? In this paper we investigate the importance of regional industry structure for regional productivity convergence. We use county data for the Scandinavian Peninsula. Norway and Sweden are similar in many respects and the Scandinavian Peninsula therefore represents an attractive natural laboratory with one country inside and another outside the European Union. The data cover five-year intervals from 1980 to 2000 for Norway and from 1985 for Sweden. We find strong productivity convergence between Norwegian counties and weak divergence between Swedish ones. The effect of the industry structure on the spatial distribution of productivity appears to be small in magnitude, but it is qualitatively important. Moreover, the role played by the changing composition of production in the process of economic growth seems to differ over time. By implication, considerable caution should be exercised when undertaking convergence studies based on the commonly used one-sector growth model. More complex models allowing for differences in industry structure, and possibly also other potentially important factors such as wealth effects and transitional dynamics, should be considered.
Postoperative Patient Education: A Systematic Review
Authors: Fredericks Suzanne , Guruge Sepali , Sidani Souraya , Wan Teresa
Published: April 2010

Introduction: Knowledge of the effects of the specific approach, mode of delivery, and dose of educational interventions is essential to develop and implement effective postoperative educational interventions. Understanding the relationships of patient characteristics to outcomes is important for educational interventions. Purpose and method: The purpose of this systematic review was to examine who would most benefit from postoperative education, given in what type of approach and mode, and at what dose? The sample included 58 studies involving 5,271 participants. Major results: Findings indicate that delivery of postoperative patient education through the individualization of content, use of combined media for delivery, provision of education on a one-on-one basis, and in multiple sessions is associated with improvement in educational/health outcomes. Samples that contained individuals younger than 50 years and higher percentages of males showed benefits in outcomes of moderate magnitude. Application: The results highlight the importance of attending to the characteristics of both the elements of postoperative educational interventions and the individual patients in the design and delivery of patient education.
Ras and Rap Signaling in Synaptic Plasticity and Mental Disorders
Authors: Stornetta Ruth L. , Zhu J. Julius
Published: April 2010

The Ras family GTPases (Ras, Rap1, and Rap2) and their downstream mitogen-activated protein kinases (ERK, JNK, and p38MAPK) and PI3K signaling cascades control various physiological processes. In neuronal cells, recent studies have shown that these parallel cascades signal distinct forms of AMPA-sensitive glutamate receptor trafficking during experience-dependent synaptic plasticity and adaptive behavior. Interestingly, both hypo- and hyperactivation of Ras/ Rap signaling impair the capacity of synaptic plasticity, underscoring the importance of a “happy-medium” dynamic regulation of the signaling. Moreover, accumulating reports have linked various genetic defects that either up- or down-regulate Ras/Rap signaling with several mental disorders associated with learning disability (e.g., Alzheimer’s disease, Angelman syndrome, autism, cardio-facio-cutaneous syndrome, Coffin-Lowry syndrome, Costello syndrome, Cowden and Bannayan-Riley-Ruvalcaba syndromes, fragile X syndrome, neurofibromatosis type 1, Noonan syndrome, schizophrenia, tuberous sclerosis, and X-linked mental retardation), highlighting the necessity of happy-medium dynamic regulation of Ras/Rap signaling in learning behavior. Thus, the recent advances in understanding of neuronal Ras/Rap signaling provide a useful guide for developing novel treatments for mental diseases.
Lateral Hip Pain in an Athletic Population: Differential Diagnosis and Treatment Options
Authors: Grumet Robert C. , Frank Rachel M. , Slabaugh Mark A. , Virkus Walter W. , Bush-Joseph Charles A. , Nho Shane J.
Published: April 2010

Context:

Historically, the term greater trochanteric pain syndrome has been used to describe a spectrum of conditions that cause lateral-sided hip pain, including greater trochanteric bursitis, snapping iliotibial band, and/or strains or tendinopathy of the abductor mechanism. Diagnosis of these conditions may be difficult because clinical presentations are variable and sometimes inconclusive. Especially difficult is differentiating intrinsic pain from pain referred to the greater trochanteric region. The purposes of this article are to review the relevant anatomy and pathophysiology of the lateral hip.

Evidence Acquisition:

Data were collected through a thorough review of the literature conducted through a MEDLINE search of all relevant papers between 1980 and January 2010.

Results:

Recent advances in imaging and an improved understanding of pathomechanics have helped to guide the evaluation, diagnosis, and appropriate treatment for patients presenting with lateral hip pain.

Conclusion:

Various diagnostic tools and treatment modalities can be used to effectively manage the athletic patient presenting with lateral hip pain.
The Effects of Health Literacy on Asthma Self-management
Authors: Thai Aileen L. , George Maureen
Published: April 2010

The purpose of this inquiry was to explore, analyze, and synthesize the current research findings regarding the role of low health literacy in asthma self-management. The authors obtained relevant articles by conducting a search in the following databases: Cumulative Index of Nursing and Allied Health (CINAHL), MEDLINE (Ovid), PubMed Plus, and Google Scholar. Search terms included combinations of asthma, peak flow, inhaler, asthma action plan, management, and literacy. The search was restricted to English-language publications and to studies recently conducted in the United States. Ten articles were retained that met these inclusion and exclusion criteria. Taken together, these data indicate that low health literacy is associated with less accurate metered-dose inhaler technique, less use of peak flow meters and asthma action plans, less ability to calculate peak flow zones, higher rates of emergency department visits and hospitalizations for asthma, and less desire to participate in decision making. Low health literacy is common and is a barrier to effective asthma self-management. Asthma educators are uniquely prepared to evaluate health literacy and to develop novel training programs that maximize the individual’s potential for independent asthma self-management.
Munc13-4 is a limiting factor in the pathway required for platelet granule release and hemostasis
Authors: Ren Qiansheng , Wimmer Christian , Chicka Michael C. , Ye Shaojing , Ren Yi , Hughson Frederick M. , Whiteheart Sidney W.
Published: April 2010

Activation-dependent platelet granule release is mediated by integral membrane proteins called soluble N-ethylmaleimide–sensitive fusion protein attachment protein receptors (SNAREs) and their regulators; however, the mechanisms for this process are ill-defined. To further characterize platelet secretion, we analyzed the function of platelets from Unc13dJinx mice. Platelets from these animals lack the putative vesicle priming factor, Munc13-4, and have a severe secretion defect. Release from dense granules was completely ablated and that from α-granules and lysosomes was severely compromised. Unc13dJinx platelets showed attenuated aggregation and, consequently, Unc13dJinx mice had prolonged tail-bleeding times. The secretion defect was not due to altered expression of SNAREs or SNARE regulators, defective granule biogenesis, or faulty platelet activation. The defective release could be rescued by adding recombinant Munc13-4 to permeabilized Unc13dJinx platelets. In wild-type mouse platelets, Munc13-4 levels were lower than those of SNAREs suggesting that Munc13-4 could be a limiting component of the platelets' secretory machinery. Consistently, Munc13-4 levels directly correlated with the extent of granule release from permeabilized platelets and from intact, heterozygous Unc13dJinx platelets. These data highlight the importance of Munc13-4 in platelets and indicate that it is a limiting factor required for platelet secretion and hemostasis.
Gene up-regulation in response to predator kairomones in the water flea, Daphnia pulex
Authors: Miyakawa Hitoshi , Imai Maki , Sugimoto Naoki , Ishikawa Yuki , Ishikawa Asano , Ishigaki Hidehiko , Okada Yasukazu , Miyazaki Satoshi , Koshikawa Shigeyuki , Cornette Richard , Miura Toru
Published: April 2010

Background

Numerous cases of predator-induced polyphenisms, in which alternate phenotypes are produced in response to extrinsic stimuli, have been reported in aquatic taxa to date. The genusDaphnia(Branchiopoda, Cladocera) provides a model experimental system for the study of the developmental mechanisms and evolutionary processes associated with predator-induced polyphenisms. InD. pulex, juveniles form neckteeth in response to predatory kairomones released byChaoboruslarvae (Insecta, Diptera).

Results

Previous studies suggest that the timing of the sensitivity to kairomones inD. pulexcan generally be divided into the embryonic and postembryonic developmental periods. We therefore examined which of the genes in the embryonic and first-instar juvenile stages exhibit different expression levels in the presence or absence of predator kairomones. Employing a candidate gene approach and identifying differentially-expressed genes revealed that the morphogenetic factors,Hox3,extradenticleandescargot, were up-regulated by kairomones in the postembryonic stage and may potentially be responsible for defense morph formation. In addition, the juvenile hormone pathway genes,JHAMTandMet, and the insulin signaling pathway genes,InRandIRS-1, were up-regulated in the first-instar stage. It is well known that these hormonal pathways are involved in physiological regulation following morphogenesis in many insect species. During the embryonic stage when morphotypes were determined, one of the novel genes identified by differential display was up-regulated, suggesting that this gene may be related to morphotype determination. Biological functions of the up-regulated genes are discussed in the context of defense morph formation.

Conclusions

It is suggested that, following the reception of kairomone signals, the identified genes are involved in a series of defensive phenotypic alterations and the production of a defensive phenotype.
The transcription factor Krüppel homolog 1is linked to hormone mediated social organization in bees
Authors: Shpigler Hagai , Patch Harland M , Cohen Mira , Fan Yongliang , Grozinger Christina M , Bloch Guy
Published: April 2010

Background

Regulation of worker behavior by dominant queens or workers is a hallmark of insect societies, but the underlying molecular mechanisms and their evolutionary conservation are not well understood. Honey bee and bumble bee colonies consist of a single reproductive queen and facultatively sterile workers. The queens' influences on the workers are mediated largely via inhibition of juvenile hormone titers, which affect division of labor in honey bees and worker reproduction in bumble bees. Studies in honey bees identified a transcription factor, Krüppel-homolog 1 (Kr-h1), whose expression in worker brains is significantly downregulated in the presence of a queen or queen pheromone and higher in forager bees, making this gene an ideal candidate for examining the evolutionary conservation of socially regulated pathways in Hymenoptera.

Results

In contrast to honey bees, bumble bees foragers do not have higher Kr-h1 levels relative to nurses: in one of three colonies levels were similar in nurses and foragers, and in two colonies levels were higher in nurses. Similarly to honey bees, brain Kr-h1 levels were significantly downregulated in the presence versus absence of a queen. Furthermore, in small queenless groups, Kr-h1 levels were downregulated in subordinate workers with undeveloped ovaries relative to dominant individuals with active ovaries. Brain Kr-h1 levels were upregulated by juvenile hormone treatment relative to a vehicle control. Finally, phylogenetic analysis indicates that KR-H1 orthologs are presence across insect orders. Though this protein is highly conserved between honey bees and bumble bees, there are significant differences between orthologs of insects from different orders.

Conclusions

Our results suggest that Kr-h1 is associated with juvenile hormone mediated regulation of reproduction in bumble bees. The expression of this transcription factor is inhibited by the queen and associated with endocrine mediated regulation of social organization in two species of bees. Thus, KR-H1 may transcriptionally regulate a conserved genetic module that is part of a pathway that has been co-opted to function in social behavior, and adjusts the behavior of workers to their social environmental context.
A survey of well conserved families of C2H2 zinc-finger genes in Daphnia
Authors: Seetharam Arun , Bai Yang , Stuart Gary W
Published: April 2010

Background

A recent comparative genomic analysis tentatively identified roughly 40 orthologous groups of C2H2 Zinc-finger proteins that are well conserved in "bilaterians" (i.e. worms, flies, and humans). Here we extend that analysis to include a second arthropod genome from the crustacean, Daphnia pulex.

Results

Most of the 40 orthologous groups of C2H2 zinc-finger proteins are represented by just one or two proteins within each of the previously surveyed species. Likewise, Daphnia were found to possess a similar number of orthologs for all of these small orthology groups. In contrast, the number of Sp/KLF homologs tends to be greater and to vary between species. Like the corresponding mammalian Sp/KLF proteins, most of the Drosophila and Daphnia homologs can be placed into one of three sub-groups: Class I-III. Daphnia were found to have three Class I proteins that roughly correspond to their Drosophila counterparts, dSP1, btd, CG5669, and three Class II proteins that roughly correspond to Luna, CG12029, CG9895. However, Daphnia have four additional KLF-Class II proteins that are most similar to the vertebrate KLF1/2/4 proteins, a subset not found in Drosophila. Two of these four proteins are encoded by genes linked in tandem. Daphnia also have three KLF-Class III members, one more than Drosophila. One of these is a likely Bteb2 homolog, while the other two correspond to Cabot and KLF13, a vertebrate homolog of Cabot.

Conclusion

Consistent with their likely roles as fundamental determinants of bilaterian form and function, most of the 40 groups of C2H2 zinc-finger proteins are conserved in kind and number in Daphnia. However, the KLF family includes several additional genes that are most similar to genes present in vertebrates but missing in Drosophila.
Inhibition of metastasis, angiogenesis, and tumor growth by Chinese herbal cocktail Tien-Hsien Liquid
Authors: Chia Jean-San , Du Jia-Ling , Hsu Wei-Bin , Sun Andy , Chiang Chun-Pin , Wang Won-Bo
Published: April 2010

Background

Advanced cancer is a multifactorial disease that demands treatments targeting multiple cellular pathways. Chinese herbal cocktail which contains various phytochemicals may target multiple dys-regulated pathways in cancer cells and thus may provide an alternative/complementary way to treat cancers. Previously we reported that the Chinese herbal cocktail Tien-Hsien Liguid (THL) can specifically induce apoptosis in various cancer cells and have immuno-modulating activity. In this study, we further evaluated the anti-metastatic, anti-angiogenic and anti-tumor activities of THL with a series ofin vitroandin vivoexperiments.

Methods

The migration and invasion of cancer cells and endothelial cells was determined by Boyden chamber transwell assays. The effect of THL on pulmonary metastasis was done by injecting CT-26 colon cancer cells intravenously to syngenic mice. Thein vitroandin vivomicrovessel formation was determined by the tube formation assay and the Matrigel plug assay, respectively. Thein vivoanti-tumor effect of THL was determined by a human MDA-MB-231 breast cancer xenograft model. The expression of metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) was measured by gelatin zymography. The expression of HIF-1α and the phosphorylation of ERK1/2 were determined by Western blot.

Results

THL inhibited the migration and invasion ability of various cancer cellsin vitro, decreased the secretion of MMP-2, MMP-9, and uPA and the activity of ERK1/2 in cancer cells, and suppressed pulmonary metastasis of CT-26 cancer cells in syngenic mice. Moreover, THL inhibited the migration, invasion, and tube formation of endothelial cellsin vitro, decreased the secretion of MMP-2 and uPA in endothelial cells, and suppressed neovascularization in Matrigel plugs in mice. Besides its inhibitory effect on endothelial cells, THL inhibited hypoxia-induced HIF-1α and vascular endothelial growth factor-A expression in cancer cells. Finally, our results show that THL inhibited the growth of human MDA-MB-231 breast cancer xenografts inNOD-SCIDmice. This suppression of tumor growth was associated with decreased microvessel formation and increased apoptosis caused by THL.

Conclusion

Our data demonstrate that THL had broad-spectra anti-cancer activities and merits further evaluation for its use in cancer therapy.
Malaria in Brazil: an overview
Authors: Oliveira-Ferreira Joseli , Lacerda Marcus VG , Brasil Patrícia , Ladislau José LB , Tauil Pedro L , Daniel-Ribeiro Cláudio Tadeu
Published: April 2010

Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.
Potentially harmful advantage to athletes: a putative connection between UGT2B17 gene deletion polymorphism and renal disorders with prolonged use of anabolic androgenic steroids
Authors: Deshmukh Nawed , Petróczi Andrea , Barker James , Székely Andrea D , Hussain Iltaf , Naughton Declan P
Published: April 2010

Background and objective

With prolonged use of anabolic androgenic steroids (AAS), occasional incidents of renal disorders have been observed. Independently, it has also been established that there are considerable inter-individual and inter-ethnic differences, in particular with reference to the uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) gene, in metabolising these compounds. This report postulates the association of deletion polymorphism in the UGT2B17 gene with the occurrence of renal disorders on chronic exposure to AAS.

Presentation of the hypothesis

The major deactivation and elimination pathway of AASs is through glucuronide conjugation, chiefly catalyzed by the UGT2B17 enzyme, followed by excretion in urine. Excretion of steroids is affected in individuals with a deletion mutation in the UGT2B17 gene. We hypothesize that UGT2B17 deficient individuals are more vulnerable to developing renal disorders with prolonged use of AAS owing to increases in body mass index and possible direct toxic effects of steroids on the kidneys. Elevated serum levels of biologically active steroids due to inadequate elimination can lead to prolonged muscle build up. An increase in body mass index may cause renal injuries due to sustained elevated glomerular pressure and flow rate.

Testing the hypothesis

In the absence of controlled clinical trials in humans, observational studies can be carried out. Real time PCR with allelic discrimination should be employed to examine the prevalence of different UGT2B17 genotypes in patients with impaired renal function and AAS abuse. In individuals with the UGT2B17 deletion polymorphism, blood tests, biofluid analyses, urinalysis, and hair analyses following the administration of an anabolic steroid can be used to determine the fate of the substance once in the body.

Implications of the hypothesis

If the hypothesis is upheld, anabolic steroid users with a deletion mutation in the UGT2B17 gene may be exposed to an increased risk of developing renal disorders. In the current detecting - sanctioning anti-doping system, athletes motivated by the potential to evade detection owing to their unique genetic make-up could subject themselves to a serious health consequence. More research on AAS metabolism in the presence of UGT2B17 gene deletion is required. Benefit - harm evaluations in therapeutic use of anabolic steroids should also consider this potential link between UGT2B17 gene deletion polymorphism and renal disorders.
Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment
Authors: Beck Christine , Morbach Henner , Beer Meinrad , Stenzel Martin , Tappe Dennis , Gattenlöhner Stefan , Hofmann Ulrich , Raab Peter , Girschick Hermann J
Published: April 2010

Introduction

Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported.

Methods

Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome.

Results

Naproxen treatment was highly effective in general, inducing a symptom-free status in 43% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67% of them were clinically silent.

Conclusions

Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.