bluuebunny/crossref_metadata_2025 huggingface dataset:
Endovenous Laser Ablation in the Treatment of Small Saphenous Varicose Veins
Authors: Samuel Nehemiah , Wallace T. , Carradice D. , Shahin Y. , Mazari F. A. K. , Chetter I. C.
Published: April 2012

Objective: The study was performed to evaluate the clinical and technical efficacy of endovenous laser ablation (EVLA) of small saphenous varicosities, particularly in relation to the site of endovenous access. Methods: Totally 59 patients with unilateral saphenopopliteal junction incompetence and small saphenous vein reflux underwent EVLA (810 nm, 14 W diode laser) with ambulatory phlebectomies. Small saphenous vein access was gained at the lowest site of truncal reflux. Patients were divided into 2 groups: access gained above mid-calf (AMC, n = 33) and below mid-calf (BMC, n = 26) levels. Outcomes included Venous Clinical Severity Scores (VCSS), Aberdeen Varicose Vein Questionnaire (AVVQ), patient satisfaction, complications, and recurrence rates. Results: Both groups demonstrated significant improvement in VCSS, AVVQ, generic quality of life Short Form 36, and EuroQol scores ( P < .05) up to 1 year. No differences were seen between AMC and BMC groups for complications (phlebitis: 2 [6%] and 1 [3.8%], P > .05; paresthesia: 2 [6%] and 5 [19%], P = .223) and recurrence (3 [9%] and 1 [3.8%], P = .623), respectively. Conclusions: The site of access in our study does not appear to influence complications specifically neural injury or recurrence rates.
Observing Court Responses to Victims of Rape and Sexual Assault
Authors: Smith Olivia , Skinner Tina
Published: April 2012

Despite years of policy reform in England and Wales, court responses to rape and sexual assault victims remain inadequate. Existing literature often relies on interviews, is outdated by policy, or ignores underlying assumptions. This study therefore observed rape and sexual assault trials, identifying underlying assumptions using critical discourse analysis (CDA). The main themes that arose were routine delays, notions of “rational” behavior, extreme interpretations of “beyond reasonable doubt” (BRD) and “burden of proof,” and winning as priority. These highlight the need to move beyond prioritizing shorter term change and begin addressing the fundamental inadequacies of court responses to rape and sexual assault victims.
Comparative cost efficiency across the European G5 countries of originators and a biosimilar erythropoiesis-stimulating agent to manage chemotherapy-induced anemia in patients with cancer
Authors: Aapro Matti , Cornes Paul , Sun Diana , Abraham Ivo
Published: April 2012

Objectives: To evaluate the comparative cost efficiency across the European Union G5 countries of the erythropoiesis-stimulating agents (ESAs) epoetin α (originator [Eprex®] and biosimilar [Binocrit®]; once weekly), epoetin β (NeoRecormon®; once weekly), and darbepoetin α (Aranesp®; once weekly or once every 3 weeks) under different scenarios of fixed and weight-based dosing in the management of chemotherapy-induced anemia.

Methods: Direct costs of ESA treatment were calculated for one patient with cancer undergoing chemotherapy (six cycles at 3-week intervals) with ESA initiated at week 4 and continued for 15 weeks. Five scenarios were developed under fixed and weight-based dosing: continuous standard dose for 15 weeks; sustained dose escalation to 1.5× or double the standard dose at week 7, continued for 12 weeks; and discontinued dose escalation to 1.5× or double the standard dose at week 7 for a 3-week period, then 9 weeks of standard dose.

Results: Under fixed dosing, the average cost of biosimilar epoetin α treatment across scenarios was €4643 (30,000 IU) or €6178 (40,000 IU). Corresponding estimates were €7168 for originator epoetin α, €7389 for epoetin β, €8299 for darbepoetin α once weekly, and €9221 for darbepoetin α once every 3 weeks. Under weight-based dosing, the average cost of biosimilar epoetin α treatment across scenarios was €4726. Corresponding estimates were €5484 for originator epoetin α, €5652 for epoetin β, and €8465 for both darbepoetin α once weekly and once every three weeks.

Conclusion: Managing chemotherapy-induced anemia with biosimilar epoetin α is consistently cost efficient over treatment with originator epoetin α, epoetin β, and darbepoetin α under both fixed and weight-based dosing scenarios.
Right Ventricular Dysfunction in Sepsis
Authors: Mykytenko James , Levin Ricardo , Wagner Chad E.
Published: April 2012

Current Surviving Sepsis Campaign guidelines inadequately address the limitations of central venous pressure monitoring, which are due, in part, to right and left ventricular dysfunction associated with sepsis. Septic cardiomyopathy is well described in the literature but is both underrecognized and undertreated clinically. Direct cardiac assessment with transesophageal echocardiography (TEE) has documented advantages, but is limited by single evaluations and the need for advanced training. Recently, a disposable, monoplane TEE probe that provides for serial echocardiographic assessments in unstable patients to guide medical management, or hemodynamic TEE (hTEE), has been introduced. This article reviews a case of a 48-year-old gentleman with a history of smoking, chronic obstructive pulmonary disease, and Child’s A cirrhosis who underwent an uneventful off-pump coronary artery bypass grafting and 2 days later developed septic shock from pneumonia complicated by right ventricular dysfunction. hTEE provided a rational guide to fluid resuscitation, vasopressor, and inotropic therapy with ensuing patient convalescence. Although there is a lack of hTEE experience among current intensivists, there is a desire to learn echocardiography as witnessed by the success of echocardiography courses and interest among critical care fellows. Future work to assess echocardiographic hemodynamic protocols and their effect on outcomes will be important.
Parathyroid Hormone–Related Protein in the Healthy and Injured Lung
Authors: Montgrain Philippe R. , Hastings Randolph H.
Published: April 2012

Parathyroid hormone–related protein (PTHrP) is an oncofetal protein with functional effects in normal and diseased lung. In the respiratory system, the hormone has implications for a variety of processes, including lung development, alveolar type II cell function and differentiation, cell proliferation, apoptosis, motility, and matrix interactions. PTHrP regulates branching morphogenesis and type II cell maturation in fetal lung through bidirectional interactions with lung fibroblasts. Consequently, it appears to have a role in the pathophysiology of respiratory distress syndrome and bronchopulmonary dysplasia. In adult lung, the molecule has autocrine actions on type II pneumocytes that stimulate phosphatidylcholine production, inhibit cell proliferation, and sensitize to apoptotic stimuli. Type II cell PTHrP levels fall after lung injury, inversely coordinated in time with their proliferation, suggesting that reduction in its growth inhibitory effect may contribute to the increase in type II cell numbers after injury. Air space levels of the protein are inversely related to the risk of lung injury or injury severity in neonatal and adult lung, consistent with its production by pneumocytes. Thus, PTHrP has clinical significance as a biomarker for injury and as a potential target for treatment.
When Do We Ostracize?
Authors: Wesselmann Eric D. , Wirth James H. , Pryor John B. , Reeder Glenn D. , Williams Kipling D.
Published: April 2012

Ostracism is a common, yet painful social experience. Given the harmful consequences of ostracism, why would groups ostracize their members? Previous research suggests that ostracism is a form of social control used to influence those group members perceived as burdensome. The authors propose that individuals will ostracize a group member only when it is justified (i.e., the member seems burdensome) but will compensate a member who is ostracized undeservedly. In Study 1, a group member was ostracized undeservedly by the other players during an online ball-tossing game. Participants allocated more tosses to that ostracized group member than an included one, compensating the ostracized member. In Study 2, participants continued to compensate an ostracized group member, unless that member was burdensome. Participants indicated punitive motives for ostracizing a burdensome group member. These experimental studies extend research on when individuals use ostracism as social control.
Anatomy of Functionally Single Ventricle
Authors: Wilkinson James L. , Anderson Robert H.
Published: April 2012

Hearts that have previously been called univentricular hearts, or single ventricles, can be described as having a univentricular atrioventricular connection. Most such hearts have two ventricular chambers, albeit one is small and incomplete—lacking an inlet component. The atriums of these hearts connect only to one of these ventricular chambers, which is usually the larger and dominant ventricle. Other hearts, with biventricular atrioventricular connections, may have hypoplasia of one ventricle, making it impossible to restore a biventricular circulation and such hearts are functionally univentricular. The term “functionally single ventricle” (or functionally univentricular heart) encompasses both these categories of malformation.
Interactive Effects of Church Attendance and Religious Tradition on Depressive Symptoms and Positive Affect
Authors: Schwadel Philip , Falci Christina D.
Published: April 2012

Using a survey of adults in Nebraska, we find that the association between church attendance and mental health varies across religious traditions and across two distinct dimensions of mental health—depressive symptoms and positive affect. Specifically, the association between church attendance and depressive symptoms differs for mainline Protestants, evangelical Protestants, and Catholics. Of these three religious traditions, only mainline Protestants report significantly lower levels of depressive symptoms when they attend church more often. Comparing across religious traditions, we find that among high attendees, evangelical Protestants report considerably more depressive symptoms than do Catholics; among low attendees, evangelicals report fewer depressive symptoms than do mainline Protestants. The results also show that church attendance is unrelated to positive affect for respondents as a whole and across the three religious traditions. We discuss how these differences in the relationship between church attendance and mental health comport with theological and social distinctions across religious traditions.
PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells
Authors: Federzoni Elena A. , Valk Peter J. M. , Torbett Bruce E. , Haferlach Torsten , Löwenberg Bob , Fey Martin F. , Tschan Mario P.
Published: April 2012

The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.
Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome
Authors: Kröger Nicolaus
Published: April 2012

Allogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse.
Infectivity in chimpanzees (Pan troglodytes) of plasma collected before HCV RNA detectability by FDA-licensed assays: implications for transfusion safety and HCV infection outcomes
Authors: Busch Michael P. , Murthy Krishna K. , Kleinman Steven H. , Hirschkorn Dale F. , Herring Belinda L. , Delwart Eric L. , Racanelli Vito , Yoon Joo Chun , Rehermann Barbara , Alter Harvey J.
Published: April 2012

Serial plasma aliquots (50 mL) obtained from 10 commercial donors who converted from hepatitis C virus (HCV) RNA negative to positive were transfused into 2 chimpanzees to assess infectivity during early HCV infection. Plasma, obtained 4 days before HCV RNA detectability by licensed assays, transmitted HCV infection to chimpanzee X355. The infectious PCR-negative plasma was subsequently shown to be positive in 2 of 23 replicates using a sensitive transcription-mediated amplification (TMA) assay, and estimated to contain 1.2 HCV RNA copies/mL (60 copies/50 mL transfused). Plasma units obtained up to 8 weeks earlier were not infectious in a second susceptible chimp, even when from donors with low-level, intermittent HCV RNA detection. Chimp x355 developed acute viremia with subsequent seroconversion, but cleared both virus and Ab in 17 weeks. When rechallenged 38 months later with 6000 RNA copies/mL from the same donor, X355 was transiently reinfected and again rapidly lost all HCV markers. We conclude that: (1) transfusions can transmit HCV infection before RNA detection, but the interval of test-negative infectivity is very brief; (2) early “blips” of HCV RNA appear noninfectious and can be ignored when calculating residual transfusion risk; and (3) markers of HCV infection can be lost rapidly after exposure to low-dose inocula.
Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions
Authors: Itoh Fumiko , Itoh Susumu , Adachi Tomomi , Ichikawa Kei , Matsumura Yutaka , Takagi Takahiro , Festing Maria , Watanabe Takuya , Weinstein Michael , Karlsson Stefan , Kato Mitsuyasu
Published: April 2012

Transforming growth factor-β (TGF-β) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC)–specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-β signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-β/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO embryos revealed hemorrhage leading to embryonic lethality around E12.5. EC-Smad2/3KO embryos exhibited no abnormality of vasculogenesis and angiogenesis in both the yolk sac and the whole embryo, whereas vascular maturation was incomplete because of inadequate assembly of mural cells in the vasculature. Wide gaps between ECs and mural cells could be observed in the vasculature of EC-Smad2/3KO mice because of reduced expression of N-cadherin and sphingosine-1-phosphate receptor-1 (S1PR1) in ECs from those mice. These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VE-cadherin, and S1PR1 expressions in the vasculature.
Clonal competition with alternating dominance in multiple myeloma
Authors: Keats Jonathan J. , Chesi Marta , Egan Jan B. , Garbitt Victoria M. , Palmer Stephen E. , Braggio Esteban , Van Wier Scott , Blackburn Patrick R. , Baker Angela S. , Dispenzieri Angela , Kumar Shaji , Rajkumar S. Vincent , Carpten John D. , Barrett Michael , Fonseca Rafael , Stewart A. Keith , Bergsagel P. Leif
Published: April 2012

Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.
Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial
Authors: Kumar Shaji K. , Hayman Suzanne R. , Buadi Francis K. , Roy Vivek , Lacy Martha Q. , Gertz Morie A. , Allred Jacob , Laumann Kristina M. , Bergsagel Leif P. , Dingli David , Mikhael Joseph R. , Reeder Craig B. , Stewart A. Keith , Zeldenrust Steven R. , Greipp Philip R. , Lust John A. , Fonseca Rafael , Russell Stephen J. , Rajkumar S. Vincent , Dispenzieri Angela
Published: April 2012

Light-chain (AL) amyloidosis remains incurable despite recent therapeutic advances. Given the activity of the lenalidomide-alkylating agent combination in myeloma, we designed this phase 2 trial of lenalidomide, cyclophosphamide, and dexamethasone in AL amyloidosis. Thirty-five patients, including 24 previously untreated, were enrolled. Nearly one-half of the patients had cardiac stage III disease and 28% had ≥ 3 organs involved. The overall hematologic response (≥ partial response [PR]) rate was 60%, including 40% with very-good partial response or better. Using serum-free light chain for assessing response, 77% of patients had a hematologic response. Organ responses were seen in 29% of patients and were limited to those with a hematologic response. The median hematologic progression-free survival was 28.3 months, and the median overall survival was 37.8 months. Hematologic toxicity was the predominant adverse event, followed by fatigue, edema, and gastrointestinal symptoms. A grade 3 or higher toxicity occurred in 26 patients (74%) including ≥ grade 3 hematologic toxicity in 16 patients (46%) and ≥ grade 3 nonhematologic toxicity in 25 patients (71%). Seven patients (20%) died on study, primarily because of advanced disease. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) is an effective combination for treatment of AL amyloidosis and leads to durable hematologic responses as well as organ responses with manageable toxicity. The trial was registered at www.clinicaltrials.gov (NCT00564889).
The ARIC predictive model reliably predicted risk of type II diabetes in Asian populations
Authors: Chin Calvin Woon-Loong , Chia Elian Hui San , Ma Stefan , Heng Derrick , Tan Maudrene , Lee Jeanette , Tai E Shyong , Salim Agus
Published: April 2012

Background

Identification of high-risk individuals is crucial for effective implementation of type 2 diabetes mellitus prevention programs. Several studies have shown that multivariable predictive functions perform as well as the 2-hour post-challenge glucose in identifying these high-risk individuals. The performance of these functions in Asian populations, where the rise in prevalence of type 2 diabetes mellitus is expected to be the greatest in the next several decades, is relatively unknown.

Methods

Using data from three Asian populations in Singapore, we compared the performance of three multivariate predictive models in terms of their discriminatory power and calibration quality: the San Antonio Health Study model, Atherosclerosis Risk in Communities model and the Framingham model.

Results

The San Antonio Health Study and Atherosclerosis Risk in Communities models had better discriminative powers than using only fasting plasma glucose or the 2-hour post-challenge glucose. However, the Framingham model did not perform significantly better than fasting glucose or the 2-hour post-challenge glucose. All
published
models suffered from poor calibration. After recalibration, the Atherosclerosis Risk in Communities model achieved good calibration, the San Antonio Health Study model showed a significant lack of fit in females and the Framingham model showed a significant lack of fit in both females and males.

Conclusions

We conclude that adoption of the ARIC model for Asian populations is feasible and highly recommended when local prospective data is unavailable.
Longitudinal seroepidemiologic study of the 2009 pandemic influenza A (H1N1) infection among health care workers in a children's hospital
Authors: Yen Ting-Yu , Lu Chun-Yi , Chang Luan-Yin , Tsai Yi-Ting , Huang Li-Min
Published: April 2012

Background

To probe seroepidemiology of the 2009 pandemic influenza A (H1N1) among health care workers (HCWs) in a children's hospital.

Methods

From August 2009 to March 2010, serum samples were drawn from 150 HCWs in a children's hospital in Taipei before the 2009 influenza A (H1N1) pandemic, before H1N1 vaccination, and after the pandemic. HCWs who had come into direct contact with 2009 influenza A (H1N1) patients or their clinical respiratory samples during their daily work were designated as a high-risk group. Antibody levels were determined by hemagglutination inhibition (HAI) assay. A four-fold or greater increase in HAI titers between any successive paired sera was defined as seroconversion, and factors associated with seroconversion were analyzed.

Results

Among the 150 HCWs, 18 (12.0%) showed either virological or serological evidence of 2009 pandemic influenza A (H1N1) infection. Of the 90 unvaccinated HCWs, baseline and post-pandemic seroprotective rates were 5.6% and 20.0%. Seroconversion rates among unvaccinated HCWs were 14.4% (13/90), 22.5% (9/40), and 8.0% (4/50) for total, high-risk group, and low-risk group, respectively. Multivariate analysis revealed being in the high-risk group is an independent risk factor associated with seroconversion.

Conclusion

The infection rate of 2009 pandemic influenza A (H1N1) in HCWs was moderate and not higher than that for the general population. The majority of unvaccinated HCWs remained susceptible. Direct contact of influenza patients and their respiratory samples increased the risk of infection.
A novel single nucleotide polymorphism within the NOD2 gene is associated with pulmonary tuberculosis in the Chinese Han, Uygur and Kazak populations
Authors: Zhao Mengyuan , Jiang Feng , Zhang Wanjiang , Li Fujian , Wei Liliang , Liu Jiyan , Xue Yun , Deng Xiling , Wu Fang , Zhang Le , Zhang Xing , Zhang Yuxiang , Fan Dapeng , Sun Xiaojun , Jiang Tingting , Li Ji-Cheng
Published: April 2012

Background

The present study aimed to investigate the genetic polymorphisms in exon 4 of the NOD2 gene in tuberculosis patients and healthy controls, in order to clarify whether polymorphisms in the NOD2 gene is associated with tuberculosis.

Methods

A case-control study was performed on the Chinese Han, Uygur and Kazak populations. Exon 4 of the NOD2 gene was sequenced in 425 TB patients and 380 healthy controls to identify SNPs.

Results

The frequency of T/G genotypes for the Arg587Arg (CGT → CGG) single nucleotide polymorphism (SNP) in NOD2 was found to be significantly higher in the Uygur (34.9%) and Kazak (37.1%) populations than the Han population (18.6%). Also, the frequency of G/G genotypes for the Arg587Arg SNP was significantly higher in the Uyghur (8.3%) and Kazak (5.4%) populations than the Han population (0.9%). Meanwhile, no significant difference was found in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Uyghur and Kazak populations (P > 0.05) whereas, a significant difference was observed in the Arg587Arg polymorphism between the tuberculosis patients and healthy controls in the Han population (P < 0.01). The odd ratio of 2.16 (95% CI = 1.31-3.58; P < 0.01) indicated that the Arg587Arg SNP in NOD2 may be associated with susceptibility to tuberculosis in the Chinese Han population.

Conclusions

Our study is the first to demonstrate that the Arg587Arg SNP in NOD2 is a new possible risk factor for tuberculosis in the Chinese Han population, but not in the Uyghur and Kazak populations. Our results may reflect racial differences in genetic susceptibility to tuberculosis.
Novel optoelectronic devices based on single semiconductor nanowires (nanobelts)
Authors: Ye Yu , Dai Lun , Gan Lin , Meng Hu , Dai Yu , Guo Xuefeng , Qin Guogang
Published: April 2012

Semiconductor nanowires (NWs) or nanobelts (NBs) have attracted more and more attention due to their potential application in novel optoelectronic devices. In this review, we present our recent work on novel NB photodetectors, where a three-terminal metal–semiconductor field-effect transistor (MESFET) device structure was exploited. In contrast to the common two-terminal NB (NW) photodetectors, the MESFET-based photodetector can make a balance among overall performance parameters, which is desired for practical device applications. We also present our recent work on graphene nanoribbon/semiconductor NW (SNW) heterojunction light-emitting diodes (LEDs). Herein, by taking advantage of both graphene and SNWs, we have fabricated, for the first time, the graphene-based nano-LEDs. This achievement opens a new avenue for developing graphene-based nano-electroluminescence devices. Moreover, the novel graphene/SNW hybrid devices can also find use in other applications, such as high-sensitivity sensor and transparent flexible devices in the future.
An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs
Authors: Wang Shuo , Wang Hua , Liang Wenquan , Huang Yongzhuo
Published: April 2012

Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.
Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity
Authors: Tsao Douglas , Wieskopf Jeffrey S. , Rashid Naim , Sorge Robert E. , Redler Rachel L. , Segall Samantha K. , Mogil Jeffrey S. , Maixner William , Dokholyan Nikolay V. , Diatchenko Luda
Published: April 2012

The subcutaneous and systemic injection of serotonin reduces cutaneous and visceral pain thresholds and increases responses to noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT) receptors are suggested to be associated with different types of pain responses. Here we show that serotonin also inhibits catechol Omethyltransferase (COMT), an enzyme that contributes to modultion the perception of pain, via non-competitive binding to the site bound by catechol substrates with a binding affinity comparable to the binding affinity of catechol itself ( Ki=44 μM). Using computational modeling, biochemical tests and cellular assays we show that serotonin actively competes with the methyl donor S-adenosyl-L-methionine (SAM) within the catalytic site. Binding of serotonin to the catalytic site inhibits the access of SAM, thus preventing methylation of COMT substrates. The results of in vivo animal studies show that serotonin-induced pain hypersensitivity in mice is reduced by either SAM pretreatment or by the combined administration of selective antagonists for β2- and β3-adrenergic receptors, which have been previously shown to mediate COMT-dependent pain signaling. Our results suggest that inhibition of COMT via serotonin binding contributes to pain hypersensitivity, providing additional strategies for the treatment of clinical pain conditions.
Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced
Authors: Hellevik Turid , Pettersen Ingvild , Berg Vivian , Winberg Jan Olof , Moe Bjørn T , Bartnes Kristian , Paulssen Ruth H , Busund Lill-Tove , Bremnes Roy , Chalmers Anthony , Martinez-Zubiaurre Iñigo
Published: April 2012

Background

Cancer-Associated Fibroblasts (CAFs) are significant components of solid malignancies and play central roles in cancer sustainability, invasion and metastasis. In this study we have investigated the invasive capacity and matrix remodelling properties of human lung CAFs after exposure to ablative doses of ionizing radiation (AIR), equivalent to single fractions delivered by stereotactic ablative radiotherapy (SART) for medically inoperable stage-I/II non-small-cell lung cancers.

Methods

CAFs were isolated from lung tumour specimens from 16 donors. Initially, intrinsic radiosensitivity was evaluated by checking viability and extent of DNA-damage response (DDR) at different radiation doses. The migrative and invasive capacities of CAFs were thereafter determined after a sub-lethal single radiation dose of 18 Gy. To ascertain the mechanisms behind the altered invasive capacity of cells, expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) were measured in the conditioned media several days post-irradiation, along with expression of cell surface integrins and dynamics of focal contacts by vinculin-staining.

Results

Exposing CAFs to 1 × 18 Gy resulted in a potent induction of multiple nuclear DDR foci (> 9/cell) with little resolution after 120 h, induced premature cellular senescence and inhibition of the proliferative, migrative and invasive capacity. AIR promoted MMP-3 and inhibited MMP-1 appearance to some extent, but did not affect expression of other major MMPs. Furthermore, surface expression of integrins α2, β1 and α5 was consistently enhanced, and a dramatic augmentation and redistribution of focal contacts was observed.

Conclusions

Our data indicate that ablative doses of radiation exert advantageous inhibitory effects on the proliferative, migratory and invasive capacity of lung CAFs. The reduced motility of irradiated CAFs might be a consequence of stabilized focal contacts via integrins.
Initial infectious dose dictates the innate, adaptive, and memory responses to influenza in the respiratory tract
Authors: Marois Isabelle , Cloutier Alexandre , Garneau Émilie , Richter Martin V
Published: April 2012

Infectious dose of influenza determines inflammatory, innate, and adaptive CD8+ T cell responses, and modulates central and effector protective immunity to heterologous infection.

Factors from the virus and the host contribute to influenza virus pathogenicity and to the development of immunity. This study thoroughly examined the effects of an initial infectious dose of virus and unveiled new findings concerning the antiviral and inflammatory responses, innate and adaptive immunity, memory responses, and protection against secondary heterologous infection. Our results demonstrated that the initial infectious dose significantly affects the gene expression of antiviral (IFN-β) and inflammatory (TNF-α, IL-6, IL-1β) cytokines and of enzymes involved in nitrosative/oxidative stress (iNOS, HO-1, NQO1) early in the response to influenza. This response correlated with significantly increased recruitment of innate immune cells into the lungs of infected mice. We showed that this response also alters the subsequent accumulation of activated IFN-γ+ CD44hi CD62Llo influenza-specific CD8+ T cells into the lungs of infected mice through increased T cell-recruiting chemokine gene expression (CCL3, CCL4, CCL5, CXCL10). Furthermore, we demonstrated that the initial infectious dose determines the generation and the distribution of memory CD8+ T cell subsets without affecting trafficking mechanisms. This impacted on immune protection against heterologous infection. Lastly, we showed that the effects on innate and adaptive immunity were not dependent on influenza strain or on the genetic background of the host. Collectively, our data show for the first time and in detail that the initial infectious dose of influenza determines the development of several aspects of antiviral immunity. This study provides new insights on virus-host interaction in the generation of the global immune response to influenza.
Introduction to this special section: Marine and seabed technology
Authors: Ronen Shuki
Published: April 2012

About 70% of the Earth and much of its hydrocarbons are covered by water, but the ocean does not prevent us from using geophysical methods offshore. The ocean helps. Compared to land seismic surveys, marine is like looking under the lamp. Surface-towed seismic streamers are now the primary method for offshore geophysics, but before we had streamers, the only way to acquire geophysical data offshore was to put receivers on the seabed. Ocean-bottom cables and nodes started almost 80 years ago. Ewing, Wortzel, and Vine deployed autonomous ocean-bottom nodes they developed at Lehigh University. In independent efforts at that same time, Bullard, Gaskell, and Flavill used geophones on an ocean-bottom cable they developed at Cambridge University. The sources were dynamite. I do not know if any of these pioneering OBC and OBN surveys made it to the fledgling SEG. The young seismic industry was too busy with the challenges and opportunities of land seismic surveys to spare attention and talent offshore. The oil industry was focused onshore. The early ocean-bottom seismometers could not record a large amount of data and there was little interest in what they did record. Their usage was limited to academia, which has been using ocean-bottom nodes continuously since the 1930s.
Throwing a new light on time-lapse technology, metrics and 4D repeatability with SDR
Authors: Cantillo Juan
Published: April 2012

Since Kragh and Christie's 2002 seminal paper on repeatability, nrms and predictability (PRED) have been the most widely used metrics for analyzing 4D noise in time-lapse studies. However, their values and behavior are rather counterintuitive, and they invariably end up stagnating above 15% and 0.95, respectively, in repeated marine data of variable quality. Moreover, their respective variations with regards to measurable differences in data, acquisition, and processing are still poorly understood from a quantitative standpoint. With the objective of improving our assessment, interpretation, and understanding of time-lapse repeatability, this paper introduces an analytical formulation of the 4D problem from the perspective of perturbation theory, building on the preliminary works of Calvert and high-quality data from our latest time-lapse campaigns in Gulf of Guinea. This framework brings to light blatant problems with our current repeatability metrics, and proposes a complementary set of QCs and best practices to get more out of 4D data. The cornerstone of this effort is the introduction of the new signal-to-distortion ratio (SDR) attribute as a true, reliable indicator of time-lapse repeatability. It provides the essential common ground on which different acquisition technologies, deployment and processing strategies are to be compared.
Directions in ocean-bottom surveying
Authors: de Kok Rob
Published: April 2012

The benefits of data acquired at the ocean bottom have repeatedly been demonstrated in various areas and under a wide range of conditions. Significant successes have for instance been booked over obstructed fields, in structurally complex areas, and in areas with shallow gas charging. Other promising fields of application, such as direct hydrocarbon indication (DHI) from combined S- and P- information, are maturing. The added value in these applications stems partly from the more favorable geometries of ocean-bottom system (OBS) surveying, such as wider ranges of offset and azimuth, and partly from the ability to record true vector fields of both P- and S-waves. In spite of the advantages, the share of OBS data in the seismic market has remained relatively small. Apart from the successes in areas with shallow gas charging, the potential of S-wave data has been left largely unexploited. The majority of the recent OBS campaigns aimed at the acquisition of superior P-wave data. Key obstacles to the more general application of OBS are the high cost of acquisition and the suboptimal quality of the data, particularly of the shear-wave component. Optimal data quality can be warranted by planting the sensors onto the seabed, so as to establish firm coupling to the subsurface. Unfortunately, planting of ocean-bottom sensors is currently time-consuming, and increases the survey duration and costs. There is thus a need for systems and methods that offer both high efficiency and consistent data quality. This paper first reviews the historic developments of OBS, follows with an analysis of the relevant quality and efficiency issues, and finishes with possible directions and solutions.
Evidence for an alternate molecular progression in prostate cancer
Authors: Vinall Ruth L. , Chen Jane Q. , Hubbard Neil E. , Sulaimon Shola S. , DeVere White Ralph W. , Borowsky Alexander D.
Published: April 2012

Tp53 mutations are common in prostate cancer (CaP), occurring with a frequency of ~30% and ~70% in localized and metastatic disease respectively. In vitro studies have determined several common mutations of Tp53 that have specific gain of function properties in addition to loss of function, including the ability to promote castrate resistant growth of CaP cells in some contexts. To date, a lack of suitable mouse models has prohibited investigation of the role played by p53 mutations in mediating CaP progression in vivo. Here we describe the effects of conditional expression of a mutant p53 that is equivalent to the human hotspot R273H into the prostate epithelium of mice. Heterozygous 'p53LSL.R270H/+' (129S4(Trp53tm3Tyj);Nkx3.1cre' (129S(Nkx3-1tm3CreMms) mice with prostate-specific expression of the p53.R270H mutation (p53R270H/+ Nkx3.1cre mice) bred on to a FVB/N background via speed congenesis to produce strain FVB.129S4(Trp53tm3Tyj/wt);FVB.129S(Nkx3-1tm3CreMms/wt) and littermate genotype negative control mice. These mice had significantly increased incidences of prostatic intraepithelial neoplasia (PIN) lesions that appeared earlier compared to the Nkx3.1 haploinsufficient (Nkx3.1cre het) littermate mice that did not express the Tp53 mutation. PIN lesions in these mice showed consistent progression, and invasive adenocarcinoma that evolved into a high grade, sarcomatoid or epithelial-mesenchymal transition (EMT) phenotype. PIN lesions were similar to those seen in PTEN conditional knockout mice, with evidence of AKT activation concomitant with neoplastic proliferation. Meanwhile, the invasive tumor phenotype was unlike any previously described mouse model of prostatic neoplasia. These data indicate the p53R270H mutation plays a role in CaP initiation. This finding has not previously been reported. Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insights into the mechanisms by which the p53R270H mutation mediates CaP progression.
Readiness of health-care institutions in KwaZulu-Natal to implement telepsychiatry
Authors: Chipps Jennifer , Mars Maurice
Published: April 2012

We assessed the preparedness of health districts and designated hospitals in the KwaZulu-Natal (KZN) province for proposed telepsychiatry services. An e-health readiness questionnaire for developing countries was administered to managers of health districts and managers of designated psychiatric hospitals by telephone interview. Ten of the 11 district managers and managers/medical officers of 45 of 58 designated hospitals were interviewed. Notwithstanding some concerns regarding the tool, low levels of e-health readiness were found. District managers recorded e-health readiness scores of 137–217 out of 300. This was similar to the hospital managers, who recorded readiness scores of 121–260 out of 300. For telepsychiatry to succeed in KZN, an awareness programme will be required to facilitate the necessary change management.
Single-Stage Approximations for Optimal Policies in Serial Inventory Systems with Nonstationary Demand
Authors: Shang Kevin H.
Published: April 2012

Companies often face nonstationary demand due to product life cycles and seasonality, and nonstationary demand complicates supply chain managers' inventory decisions. This paper proposes a simple heuristic for determining stocking levels in a serial inventory system. Unlike the exact optimization algorithm, the heuristic generates a near-optimal solution by solving a series of independent single-stage systems. The heuristic is constructed based on three results we derive. First, we provide a new cost decomposition scheme based on echelon systems. Next, we show that the optimal base-stock level for each echelon system is bounded by those of two revised echelon systems. Last, we prove that the revised echelon systems are essentially equivalent to single-stage systems. We examine the myopic solution for these single-stage systems. In a numerical study, we find that the change of direction of the myopic solution is consistent with that of the optimal solution when system parameters vary. We then derive an analytical expression for the myopic solution and use it to gain insights into how to manage inventory. The analytical expression shows how future demand affects the current optimal local base-stock level; it also explains an observation that the safety stock at an upstream stage is often stable and may not increase when the demand variability increases over time. Finally, we discuss how the heuristic leads to a time-consistent coordination scheme that enables a decentralized supply chain to achieve the heuristic solution.
A Queueing Model to Evaluate the Impact of Patient “Batching” on Throughput and Flow Time in a Medical Teaching Facility
Authors: Dobson Gregory , Lee Hsiao-Hui , Sainathan Arvind , Tilson Vera
Published: April 2012

We consider the work flow in a medical teaching facility, examining the process that involves an initial patient exam by a resident physician, a subsequent conference between the resident and the attending physician, and the attending physician's visit with the patient. We create an analytical model of a tandem queue with finite buffer space to analyze the impact of different work prioritization policies on the throughput and the flow time of patients in the facility—measures that influence both the facility's finances and patients' satisfaction. We derive throughput-optimal policies and show that these policies involve dynamic batching. This finding is interesting because our model does not include any setup times, and setup times normally imply batching; rather it is the uncertain service times and the requirement for simultaneous service in the conference step that make batching optimal. The optimal dynamic batching policy is complex, so we consider a simpler static batching policy. We show that, in systems with limited buffer space, large batches can sometimes degrade efficiency by simultaneously increasing flow time and decreasing throughput. However, in general, both flow time and throughput increase with batch size. Flow time increases at a faster rate than throughput, so hospital management may want to consider what batch size is optimal given the value it places on the two measures.
Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses
Authors: Safian Diego , Fuentes Eduardo N , Valdés Juan Antonio , Molina Alfredo
Published: April 2012

The IGF-binding proteins (IGFBPs) play a dual role in the regulation of the activity and bioavailability of IGFs in different tissues. Diverse evidence has shown that IGFBPs can inhibit and/or potentiate IGF actions. In this study,igfbp1, 2, 3, 4, 5, and6were isolated in the fine flounder, a flat fish species that shows slow growth and inherent Gh resistance in muscle. Subsequently, the expression of alligfbps was assessed in the skeletal muscle of flounder that underwent different nutritional statuses.igfbp1was not expressed in muscle during any of the nutritional conditions, whereasigfbp3andigfbp5were the lowest and the highestigfbps expressed respectively. A dynamic expression pattern was found in all theigfbps expressed in skeletal muscle, which depended on the nutritional status and sampling period. During the fasting period,igfbp2, 4, and5were downregulated, whereasigfbp3was upregulated during part of the fasting period. The restoration of food modulated the expression of theigfbps dynamically, showing significant changes during both the long- and short-term refeeding.igfbp3andigfbp6were downregulated during short-term refeeding, whereasigfbp5was upregulated, andigfbp2andigfbp4remained stable. During long-term refeeding, the expression ofigfbp2, 4, 5, and6increased, whileigfbp3remained unchanged. In conclusion, this study shows for the first time the isolation of alligfbps in a single fish species, in addition to describing a dynamic nutritional and time-dependent response in the expression ofigfbps in the skeletal muscle of a nonmammalian species.