bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Targeting of MEK1/2 and RSK2 by Silybin Induces Cell-Cycle Arrest and Inhibits Melanoma Cell Growth
Authors: Lee Mee-Hyun , Huang Zunnan , Kim Dong Joon , Kim Sung-Hyun , Kim Myoung Ok , Lee Sung-Young , Xie Hua , Park Si Jun , Kim Jae Young , Kundu Joydeb Kumar , Bode Ann M. , Surh Young-Joon , Dong Zigang
Published: February 2013

Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-κB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell-cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. Cancer Prev Res; 6(5); 455–65. ©2013 AACR.
Immunological Biomarkers Improve the Accuracy of Clinical Risk Models of Infection in the Acute Phase of Ischemic Stroke
Authors: Salat David , Penalba Anna , García-Berrocoso Teresa , Campos-Martorell Mireia , Flores Alan , Pagola Jorge , Bustamante Alejandro , Quintana Manuel , Giralt Dolors , Molina Carlos , Alvarez-Sabín José , Montaner Joan
Published: February 2013

Infection is an independent risk factor for adverse outcome in stroke patients. The risk of developing an infection in this setting is partly related to a stroke-induced immunodepression, in which a shift to a predominant Th2 (immunosuppressive) phenotype has been postulated to play a major role. Our aim was to study whether clinical variables or changes in plasma cytokine expression can predict poststroke infections. Patients and Methods: Medical records of 92 stroke patients were reviewed, and the baseline concentration of cytokines from the Th1/Th2 system was determined. Clinical and serological predictors of incident infections and their prognostic significance were sought by means of univariate and multivariate analysis, and two predictive models for developing an infection were constructed by combining independent predictors (strictly clinical in one, and both clinical and serological in the other) for this outcome. The improvement conferred by the addition of immunological markers to the clinical model was assessed by comparing their respective ROC curves and by improvement (Net Reclassification Index and Integrated Discriminator Improvement) analysis. Results: Nineteen patients (20.7% of the study sample) developed an infection. Ongoing antiplatelet therapy at symptom onset (OR 0.02, 95% CI 0.001-0.23, p = 0.001), diabetes mellitus (OR 9.96, 95% CI 1.32-75.29, p = 0.03), IL-13 level <33 pg/ml (OR 84.16, 95% CI 2.53-2795.18, p = 0.01) and interferon-γ level >8.4 pg/ml (OR 60.17, 95% CI 1.78-2037.23, p = 0.02) were independently associated with the development of infections during hospital admission. The combined regression model predicted infection with an accuracy of 93.4%, an improvement in the predictive capacity of 17% (p < 0.001). Infection was associated with a worse neurological status at hospital discharge (median NIHSS score 11 (6-18) vs. 4 (1-11.5), p = 0.014). Conclusions: This study shows that bloodstream biomarkers are useful to improve the accuracy of clinical prognostic models for infection in the acute phase of stroke. The clinical predictors of infection in the acute phase of stroke are relatively well established in the medical literature, but further research to identify the optimal combination of biomarkers (possibly inflammatory and stress markers) to be included in a clinically useful model is needed. Such a model could be subsequently used in clinical trials to assess the effect of prophylactic and/or early antibiotic therapy in this setting, a currently controversial issue in this field.
Thrombotic risk factors in Chinese Budd-Chiari syndrome patients
Authors: He Chuangye , Yin Zhanxin , Niu Jing , Bai Ming , Yang Zhiping , Wu Kaichun , Fan Daiming , Qi Xingshun , Wu Feifei , Ren Weirong , Han Guohong
Published: February 2013

In Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemoglobinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China.
Short- and Long-range Neural Synchrony in Grapheme–Color Synesthesia
Authors: Volberg Gregor , Karmann Anna , Birkner Stefanie , Greenlee Mark W.
Published: February 2013

Grapheme–color synesthesia is a perceptual phenomenon where single graphemes (e.g., the letter “E”) induce simultaneous sensations of colors (e.g., the color green) that were not objectively shown. Current models disagree as to whether the color sensations arise from increased short-range connectivity between anatomically adjacent grapheme- and color-processing brain structures or from decreased effectiveness of inhibitory long-range connections feeding back into visual cortex. We addressed this issue by examining neural synchrony obtained from EEG activity, in a sample of grapheme–color synesthetes that were presented with color-inducing versus non-color-inducing graphemes. For color-inducing graphemes, the results showed a decrease in the number of long-range couplings in the theta frequency band (4–7 Hz, 280–540 msec) and a concurrent increase of short-range phase-locking within lower beta band (13–20 Hz, 380–420 msec at occipital electrodes). Because the effects were both found in long-range synchrony and later within the visual processing stream, the results support the idea that reduced inhibition is an important factor for the emergence of synesthetic colors.
Out of the homeland: The Croatian Right and Gay Rights
Authors: Vuletic Dean
Published: February 2013

This article discusses how the Croatian right’s attitudes towards gay rights have been defined by nationalism and Europeanism. It focusses on the Croatian Democratic Union (Hrvatska demokratska zajednica, HDZ), which has dominated Croatian politics since it was first elected to government in 1990. It led Croatia to independence from Yugoslavia in 1991 and through the homeland War from 1991 to 1995, and it also started and finished Croatia’s negotiations for accession to the European Union from 2005 to 2011. The HDZ government did not actively address gay rights in Croatia in the 1990s, especially since it espoused a heteronationalism influenced by Roman Catholic teachings. Homosexuality was usually mentioned by HDZ officials only in negative terms, such as when allegations of it were used to discredit critics or opponents. Although the HDZ government had sought to integrate Croatia with Western Europe, it was isolated by the West in the late 1990s because of its authoritarian and nationalist tendencies. However, after its electoral defeat in 2000, the HDZ transformed itself into a more moderate right-wing party, and it returned to government in 2003. Subsequently, it had to actively address gay rights, as these had become a prominent political issue under the previous government and with the rise of a local gay movement. As the HDZ government placed EU accession at the centre of its programme, it also came under pressure from the EU to adopt anti-discrimination laws to protect sexual minorities. However, the HDZ continues to oppose the expansion of gay rights in debates on same-sex marriage or adoption rights for same-sex couples, which are not required for admission into the EU, and it continues to do this with references to traditional Croatian and Catholic values.
The Peaceful Mind Manual
Authors: Paukert Amber L. , Kraus-Schuman Cynthia , Wilson Nancy , Snow A. Lynn , Calleo Jessica , Kunik Mark E. , Stanley Melinda A.
Published: February 2013

Anxiety disorders are highly prevalent among individuals with dementia and have a significant negative impact on their lives. Peaceful Mind is a form of cognitive-behavioral therapy for anxiety in persons with dementia. The Peaceful Mind manual was developed, piloted, and modified over 2 years. In an open trial and a small randomized, controlled trial, it decreased anxiety and caregiver distress. The treatment meets the unique needs of individuals with dementia by emphasizing behavioral rather than cognitive interventions, slowing the pace, limiting the material to be learned, increasing repetition and practice, using cues to stimulate memory, including a friend or family member in treatment as a coach, and providing sessions in the home. The manual presented here includes modules that teach specific skills, including awareness, breathing, calming self-statements, increasing activity, and sleep management, as well as general suggestions for treatment delivery.
Dopamine-D2-Receptor Blockade Reverses the Association Between Trait Approach Motivation and Frontal Asymmetry in an Approach-Motivation Context
Authors: Wacker Jan , Mueller Erik M. , Pizzagalli Diego A. , Hennig Jürgen , Stemmler Gerhard
Published: February 2013

Individual differences in the behavioral approach system (BAS)—referred to as trait approach motivation or trait BAS)—have been linked to both frontal electroencephalogram (EEG) alpha asymmetry between left and right hemispheres (frontal alpha asymmetry) and brain dopamine. However, evidence directly linking frontal alpha asymmetry and dopamine is scarce. In the present study, female experimenters recorded EEG data in 181 male participants after double-blind administration of either a placebo or a dopamine D2 blocker. As expected, trait BAS was associated with greater left- than right-frontal cortical activity (i.e., greater right- than left-frontal EEG alpha) in the placebo group, but a reversed association emerged in the dopamine-blocker group. Furthermore, frontal alpha asymmetry was associated with a genetic variant known to modulate prefrontal dopamine levels (the catechol-O-methyltransferase Val158Met polymorphism). Finally, each of these effects was significant only in the subgroup of male participants interacting with female experimenters rated as most attractive; this finding suggests that associations between frontal alpha asymmetry and both dopamine and trait BAS are detectable only in approach-motivation contexts.
Treatment of Type C Pilon Fractures by External Fixator Combined With Limited Open Reduction and Absorbable Internal Fixation
Authors: Zhao Liangyu , Li Yongchuan , Chen Aimin , Zhang Zhiling , Xi Jiang , Yang Di
Published: February 2013

Introduction:

This study was conducted to evaluate the clinical outcome of the treatment of type C pilon fractures by using an external fixator combined with limited open reduction and absorbable internal fixation.

Patients and Methods:

Twenty-five type C pilon fractures, including 4 open fractures, were included in this retrospective study. The procedure of first-stage manipulation and external fixation spanning the ankle joint was conducted as early as possible. For the second stage, the tibial and fibular fractures were reduced and fixed with absorbable screws or rods through a limited incision. Clinical and radiographic evaluations were performed. The American Orthopaedic Foot & Ankle Society score (AOFAS) was obtained for evaluation of function. Twenty-one patients were followed postoperatively for a minimum of 18 months.

Results:

The mean time of union was 4.8 months. Delayed union of the distal tibia occurred in 1 patient. Minor infection occurred in 8 patients and deep infection in 1 patient. No skin necrosis, malunion, loss of reduction, nonunion, or fixation failure was observed during the follow-up period. No hardware removal was needed, nor was adverse tissue reaction to the implants observed. An excellent or good AOFAS outcome was obtained in 81% (17/21) of the patients.

Conclusions:

External fixator combined with limited open reduction and absorbable internal fixation was a reliable treatment for closed and open AO/OTA type C pilon fractures of the distal tibia.

Level of Evidence:

Level IV, retrospective case series.
News about the European Parliament: Patterns and external drivers of broadsheet coverage
Authors: Gattermann Katjana
Published: February 2013

Few political communication studies deal with the European Parliament during non-election times even though it takes decisions in a wide range of policy areas. This study examines the patterns and external drivers of European Parliament broadsheet coverage by analysing 2155 articles from six European Union countries during a routine period (2005–2007). Generally, it finds that the European Parliament receives regular coverage. However, developments in the domestic context also influence European Parliament news coverage. Public support for the European Union increases the number of reports about the European Parliament. While national elections do not compromise its news coverage, higher levels of party political contestation over the European Union and trust towards the national parliament lead to lower coverage. The implications are discussed with reference to the European Parliament’s democratic legitimacy.
The essentialism of whiteness: Abandoning empirical engagement
Authors: de Montigny Gerald AJ
Published: February 2013

This article examines social workers’ attention to privilege, white privilege, and oppression as ideological practice. It suggests alternative methods for accounting for troubles in social relations derived from ethnomethodology.

Findings

Although presented as progressive, the methods used by anti-racist social workers to account for interaction as organized by racism and privilege rely on practices for working up race and privilege isomorphic with those used by racists and white supremacists.

Applications

Alternative methods to account for troubles in relations are suggested which draw on an abiding attention to every-day socially organized practices.
Safety and Effectiveness of an Endoscopic Suturing Device in a Human Colonic Treat-and-Resect Model
Authors: Pauli Eric M. , Delaney Conor P. , Champagne Bradley , Stein Sharon , Marks Jeffrey M.
Published: February 2013

Background. Despite advances in many areas of therapeutic endoscopy, the development of an effective endoscopic suturing device has been elusive. The purpose of this trial was to evaluate the safety and effectiveness of a suturing device to place and secure sutures within normal, in vivo human colonic tissue prior to surgical resection. Methods. Patients undergoing elective colectomy were enrolled in this treat-and-resect model. The Overstitch endoscopic suturing device (Apollo Endosurgery, Austin, TX) was used to place sutures in healthy colonic tissue during a 15-minute, time-limited period. Following colectomy, the explanted tissue was evaluated to determine the depth of suture penetration and the effectiveness of the suture/cinch element. Clinical and operative data were recorded. Results. Four patients (50% female) were enrolled. Seven sutures were successfully placed, incorporating a total of 10 tissue bites in a mean of 13.5 minutes. On inspection of the explanted tissue, all sutures were found to be located subserosal (no full thickness bites were taken). The suture and cinch elements were judged to be effective in the majority of cases. One device-related issue did not inhibit the ability to oppose tissue or place the cinch. There were no intraoperative or postoperative complications. Conclusions. The Overstitch permitted safe and effective suturing in an in vivo human colon model. The sutures were placed at a consistent subserosal depth and at no point risked iatrogenic injury to adjacent structures. Technical issues with the device were infrequent and did not inhibit the ability to place sutures effectively.
HIV+ children and their families in the UK: results from a family-clinic based ‘look-back’ exercise in London
Authors: Campbell Tomás , Griffiths Jayne , Beer Hannah , Legemah Precious , Saine Mbalu
Published: February 2013

Advances in antiretroviral treatment have resulted in a growing number of HIV+ children surviving into adolescence and adulthood. However, HIV remains a chronic condition compounded by additional psychosocial stressors associated with living with HIV. The gold standard for treatment of HIV+ children and young people is within a family context. This ‘look-back’ exercise was conducted within an HIV family clinic context in London. HIV+ children’s clinical notes were examined with the aim of describing the medical and social context of the families attending the clinic. Results showed that families are living with many psychosocial challenges that may have an impact on their ability to respond effectively to the challenge of living with HIV disease.
Soccer, Broadcasting, and Narrative
Authors: Barnfield Andrew
Published: February 2013

Soccer broadcasts have been explored in a number of interesting ways, uncovering racial difference, gendered stereotypes, domestic viewing experiences, nationalistic discourse, and national styles of production. What is lacking, however, is how the viewer comprehends space and time in the live broadcast. Such literatures neglect the hybrid nature of televised soccer as a combination of visual and verbal communication. Understanding and experiencing a televised soccer match is a formulation of visual principles and verbal understanding of temporality within the narrative of a live broadcast. These principles are materialized through the screen and develop an unconscious understanding of movement, spatiality, and temporality differing from a cinematic unconscious through the cutting and sequencing of footage and border moments—screen wipe, frames, cuts—which work in combination with commentary to establish a microgeography of the screen. Viewers of televised soccer, therefore, establish a comprehension of time and space which is distinctive and differs from reportage.
Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids
Authors: Lombard Marli C , N’Da David D , Tran Van Ba Christophe , Wein Sharon , Norman Jennifer , Wiesner Lubbe , Vial Henri
Published: February 2013

Background

Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs.

Methods

In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 – 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2.

Results

Hybrids 1 – 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os.

Conclusions

These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated.
Expression of Interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection
Authors: Du Wen-Jun , Zhen Jun-Hui , Zeng Zhao-Qing , Zheng Zhao-Min , Xu Yan , Qin Lai-Ying , Chen Shi-Jun
Published: February 2013

Background/objectives

As a proinflammatory cytokine, interleukin-17 (IL-17) contributes to the inflammation of many autoimmune diseases. We examined IL-17 levels in serum and tissues from patients with chronic hepatitis B virus infection (HBV), and especially evaluated the role of IL-17 in the pathogenesis and progression of liver fibrosis.

Materials and methods

Whole venous blood was obtained from four patient groups: chronic hepatitis B (CHB, n = 47), liver cirrhosis (LC, n = 49), primary hepatocellular carcinoma (PHC, n = 44), chronic liver failure (CLF, n = 33), and a normal control group (n = 20). HBsAg was positive in all patients. Liver biopsy samples were acquired from asymptomatic HBsAg carriers (ASC, n = 35), CHB (n = 57), and LC (n = 31) patients. We performed ELISA to measure IL-17 levels in serum samples, and used reverse RT-PCR to measure IL-17 mRNA levels in peripheral blood mononuclear cells (PBMC). IL-17 protein expression was detected in liver biopsy tissues by immunohistochemistry.

Results

Compared to normal controls, serum IL-17 protein and mRNA levels were significantly higher in the four infection groups. LC patients exhibited the highest serum IL-17 and PBMC mRNA levels. No significant differences were found between the other three groups. High levels of IL-17 were also observed in tissues from CHB and LC patients, compared to ASC. IL-17 expression was mainly located in the portal area and was positively correlated with inflammation grade and fibrosis stage.

Conclusions

IL-17 expression was found to be increased with increasing degrees of liver fibrosis. This suggests that IL-17 may not only induce the inflammation, but also contribute to disease progression and chronicity.

Virtual Slides

The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5306959258322482
Percutaneous endoscopic gastrostomy site metastasis from head and neck squamous cell carcinoma: Case series and literature review
Authors: Huang Andrew T , Georgolios Alexandros , Espino Sasa , Kaplan Brian , Neifeld James , Reiter Evan R
Published: February 2013

Objectives

To present our experience with head and neck squamous cell carcinoma (HNSCC) seeding of percutaneous endoscopic gastrostomy (PEG) sites and to review all reported cases to identify risk factors and develop strategies for complication avoidance.

Materials and methods

The records of 4 patients with PEG site metastasis from HNSCC were identified from the authors’ institution. Thirty-eight further cases were reviewed following a PubMed search and evaluation of references in pertinent articles.

Results

Review of 42 cases revealed the average time from PEG to diagnosis of metastatic disease to be 8 months. Average time to death from detection of PEG disease was 5.9 months. One-year survival following PEG metastasis was 35.5% with an overall mortality of 87.1%.

Conclusion

PEG site metastatic disease portends a poor prognosis. Early detection and aggressive therapy may provide a chance of cure. Changes in PEG technique or in timing of adjunctive therapies are possible avenues in further research to prevent this complication.
Activation and employment support policies in OECD countries. An overview of current approaches
Authors: Immervoll Herwig , Scarpetta Stefano
Published: February 2013

This note examines the balance of activation strategies in OECD countries, where this type of policy approach has a long tradition. Countries share the objective of strengthening employment and reducing benefit dependency and vulnerability among the working-age population, but the balance of policy measures differs widely. While debates on the effectiveness of active labour market policies have tended to focus on individual policy measures, this paper emphasizes the links between policy areas. We argue that an effective policy strategy rests on a finely tuned balance between income support, work incentives, as well as mutual obligations and active labour market programmes.

JEL codes

H31, H53, J08, J68
Experimental investigations on the phase equilibrium of semiclathrate hydrates of carbon dioxide in TBAB with small amount of surfactant
Authors: Joshi Abhishek , Sangwai Jitendra S , Das Kousik , Sami Nagham Amer
Published: February 2013

Experimental studies are carried out on a semiclathrate hydrate system of carbon dioxide in tetra-n-butyl-ammonium bromide (TBAB) with a small amount of surfactant, sodium dodecyl sulfate (SDS), for 5, 10, and 20 wt.% TBAB to determine the phase equilibrium temperature and pressure conditions. It is observed that the presence of SDS did not influence the equilibrium conditions of the semiclathrate hydrate. Re-nucleation (memory) effect of semiclathrate hydrates of CO2 is studied for few cases of TBAB concentration in an aqueous solution. The equilibrium pressure and temperature conditions obtained for memory effect and regular experimental run without memory effect were observed to be quite close. It is concluded that in the case of no memory effect, with increasing TBAB percentage in the system, the time required for nucleation is reduced. For the same TBAB concentration, the incipient pressure and temperature required for nucleation and re-nucleation of semiclathrate hydrates increase while the time required for re-nucleation decreases.
Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells
Authors: Sabbagh Laurent , Andreeva Daniela , Laramée Geneviève Dubeau , Oussa N A Eustache , Lew Déborah , Bisson Nicolas , Soumounou Youssouf , Pawson Tony , Watts Tania H
Published: February 2013

TRAF1 and LSP1 are direct binding partners, and cooperate to promote survival of primary T cells in response to 4-1BB co-stimulation.

4-1BB is a member of the TNFR superfamily, which contributes to the activation of signaling pathways required for the survival of activated and memory T cells. We have shown previously that TRAF1, an adaptor protein recruited to 4-1BB, is required for 4-1BB-mediated CD8 T cell survival in vivo. With the use of a proteomics approach in primary T cells, we have identified LSP1 as a novel protein recruited to the 4-1BB signaling complex in a TRAF1-dependent manner. Further characterization of the interaction between TRAF1 and LSP1 revealed that LSP1 requires the TRAF-N domain of TRAF1 for direct association. Similarly to TRAF1−/− T cells, LSP1−/− T cells exhibit impaired ERK activation following stimulation through 4-1BB and consequently, are unable to down-modulate expression of the proapoptotic Bcl-2 family member Bim. Moreover, we demonstrate that the absence of LSP1 expression leads to defective expansion and survival of T cells in response to 4-1BB stimulation. Thus, we have identified LSP1 as a new mediator involved in 4-1BB signaling and T cell survival. Collectively, our work shows that TRAF1 and LSP1 cooperate downstream of 4-1BB to activate ERK signaling and down-modulate the levels of Bim leading to enhanced T cell survival.
Tabloid Coloniality: A Popular Journalist Maps Empire
Authors: Driscoll Mark
Published: February 2013

The March 1, 1919, mobilization for Korean independence was the single largest threat to Japan's imperial rule in its half century of existence. Referred to reverently as the Sam'il Undong, the protest was initially centered in Seoul but quickly spread into towns and villages. Japanese colonial elites were stunned by the large-scale protests. After gathering themselves and violently repressing the movement, the colonists reacted to the demonstrations in the standard fashion of consolidating the imperial binaries (civilized/savage, rational/irrational) they had deployed earlier in Taiwan and Korea to dismiss the protests as “barbaric” (yaban) and “blind recklessness.” However, these binaries also point to desires for connection and solidarity with Koreans. Using psychoanalytic postcolonial theory, I try to show some of the latent desires on the part of Japanese elites as they reacted to the March 1 movement.
The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes
Authors: Yang Hsin-ya , Charles Roch-Philippe , Hummler Edith , Baines Deborah L. , Isseroff R. Rivkah
Published: February 2013

Cellular directional migration of in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC) in addition to its function of regulating sodium transport in kidney has recently been found modulate cell locomotory speed. Here we tested if ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC may mediate galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing.
Forced-air patient warming blankets disrupt unidirectional airflow
Authors: Legg A. J. , Hamer A. J.
Published: February 2013

We have recently shown that waste heat from forced-air warming blankets can increase the temperature and concentration of airborne particles over the surgical site. The mechanism for the increased concentration of particles and their site of origin remained unclear. We therefore attempted to visualise the airflow in theatre over a simulated total knee replacement using neutral-buoyancy helium bubbles. Particles were created using a Rocket PS23 smoke machine positioned below the operating table, a potential area of contamination. The same theatre set-up, warming devices and controls were used as in our previous study. This demonstrated that waste heat from the poorly insulated forced-air warming blanket increased the air temperature on the surgical side of the drape by > 5°C. This created convection currents that rose against the downward unidirectional airflow, causing turbulence over the patient. The convection currents increased the particle concentration 1000-fold (2 174 000 particles/m3 for forced-air warming vs 1000 particles/m3 for radiant warming and 2000 particles/m3 for the control) by drawing potentially contaminated particles from below the operating table into the surgical site.

Cite this article: Bone Joint J 2013;95-B:407–10.
New polyethylenes in total hip replacement
Authors: García-Rey E. , García-Cimbrelo E. , Cruz-Pardos A.
Published: February 2013

Between 1999 and 2001, 90 patients underwent total hip replacement using the same uncemented acetabular and femoral components with a 28 mm metallic femoral head but with prospective randomisation of the acetabular liner to either Durasul highly cross-linked polyethylene or nitrogen-sterilised Sulene polyethylene. We assessed 83 patients at a minimum follow-up of ten years. Linear penetration of the femoral head was estimated at six weeks, six and 12 months and annually thereafter, using the Dorr method, given the non-spherical shape of the acetabular component.

There was no loosening of any component; only one hip in the Sulene group showed proximal femoral osteolysis. The mean penetration of the femoral head at six weeks was 0.08 mm (0.02 to 0.15) for the Durasul group and 0.16 mm (0.05 to 0.28) for the Sulene group (p = 0.001). The mean yearly linear penetration was 64.8% lower for the Durasul group at 0.05 mm/year (sd 0.035) for the Sulene group and 0.02 mm/year (sd 0.016) for the Durasul (p < 0.001). Mean linear femoral head penetration at ten years was 61% less in the Durasul than Sulene group. Highly cross-linked polyethylene gives excellent results at ten years.

Cite this article: Bone Joint J 2013;95-B:326–32.
“When can I return to driving?”
Authors: MacLeod K. , Lingham A. , Chatha H. , Lewis J. , Parkes A. , Grange S. , Smitham P. J.
Published: February 2013

Clinicians are often asked by patients, “When can I drive again?” after lower limb injury or surgery. This question is difficult to answer in the absence of any guidelines. This review aims to collate the currently available evidence and discuss the factors that influence the decision to allow a patient to return to driving. Medline, Web of Science, Scopus, and EMBASE were searched using the following terms: ‘brake reaction time’, ‘brake response time’, ‘braking force’, ‘brake pedal force’, ‘resume driving’, ‘rate of application of force’, ‘driving after injury’, ‘joint replacement and driving’, and ‘fracture and driving’. Of the relevant literature identified, most studies used the brake reaction time and total brake time as the outcome measures. Varying recovery periods were proposed based on the type and severity of injury or surgery. Surveys of the Driver and Vehicle Licensing Agency, the Police, insurance companies in the United Kingdom and Orthopaedic Surgeons offered a variety of opinions.

There is currently insufficient evidence for any authoritative body to determine fitness to drive. The lack of guidance could result in patients being withheld from driving for longer than is necessary, or returning to driving while still unsafe.

Cite this article: Bone Joint J 2013;95-B:290–4.
Pathology of the tendo Achillis
Authors: Ribbans W. J. , Collins M.
Published: February 2013

The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals’ tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases.

This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.

Cite this article: Bone Joint J 2013;95-B:305–13.
The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone
Authors: Nakamura T. , Grimer R. J. , Gaston C. L. , Watanuki M. , Sudo A. , Jeys L.
Published: February 2013

The aim of this study was to determine whether the level of circulating C-reactive protein (CRP) before treatment predicted overall disease-specific survival and local tumour control in patients with a sarcoma of bone.

We retrospectively reviewed 318 patients who presented with a primary sarcoma of bone between 2003 and 2010. Those who presented with metastases and/or local recurrence were excluded.

Elevated CRP levels were seen in 84 patients before treatment; these patients had a poorer disease-specific survival (57% at five years) than patients with a normal CRP (79% at five years) (p < 0.0001). They were also less likely to be free of recurrence (71% at five years) than patients with a normal CRP (79% at five years) (p = 0.04). Multivariate analysis showed the pre-operative CRP level to be an independent predictor of survival and local control. Patients with a Ewing’s sarcoma or chondrosarcoma who had an elevated CRP before their treatment started had a significantly poorer disease-specific survival than patients with a normal CRP (p = 0.02 and p < 0.0001, respectively). Patients with a conventional osteosarcoma and a raised CRP were at an increased risk of poorer local control.

We recommend that CRP levels are measured routinely in patients with a suspected sarcoma of bone as a further prognostic indicator of survival.

Cite this article: Bone Joint J 2013;95-B:411–18.
The effect of osteoarthritis of the knee on the biomechanics of other joints in the lower limbs
Authors: Metcalfe A. J. , Stewart C. , Postans N. , Dodds A. L. , Holt C. A. , Roberts A. P.
Published: February 2013

The aim of this study was to examine the loading of the other joints of the lower limb in patients with unilateral osteoarthritis (OA) of the knee. We recruited 20 patients with no other symptoms or deformity in the lower limbs from a consecutive cohort of patients awaiting knee replacement. Gait analysis and electromyographic recordings were performed to determine moments at both knees and hips, and contraction patterns in the medial and lateral quadriceps and hamstrings bilaterally. The speed of gait was reduced in the group with OA compared with the controls, but there were only minor differences in stance times between the limbs. Patients with OA of the knee had significant increases in adduction moment impulse at both knees and the contralateral hip (adjusted p-values: affected knee: p < 0.01, unaffected knee p = 0.048, contralateral hip p = 0.03), and significantly increased muscular co-contraction bilaterally compared with controls (all comparisons for co-contraction, p < 0.01).

The other major weight-bearing joints are at risk from abnormal biomechanics in patients with unilateral OA of the knee.

Cite this article: Bone Joint J 2013;95-B:348–53.
A Comparison of Initial Monotherapy with Norepinephrine Versus Vasopressin for Resuscitation in Septic Shock
Authors: Daley Mitchell J , Lat Ishaq , Mieure Katherine D , Jennings Heath R , Hall Jesse B , Kress John P
Published: February 2013

BACKGROUND

Early goal-directed therapy is a time-sensitive therapeutic algorithm with a tiered approach to target hypoperfusion and cardiovascular collapse within the first 6 hours of septic shock. The Surviving Sepsis Campaign guidelines recommend norepinephrine or dopamine as the initial vasoactive agent for resuscitation in septic shock, reserving the administration of vasopressin as adjunctive therapy.

OBJECTIVE

To determine whether vasopressin was noninferior to norepinephrine as the initial vasopressor to achieve a mean arterial pressure (MAP) goal in the first 6 hours of shock onset.

METHODS

This retrospective cohort study evaluated adults who received monotherapy with either norepinephrine or vasopressin as initial vasoactive therapy for the management of septic shock. Patients were excluded if the treatment arm was not monotherapy, if they were admitted to a cardiology or cardiothoracic surgery service, or if they lacked a comparator-based 1:1 frequency matching.

RESULTS

A total of 130 patients were included, 65 in each treatment arm. The proportion of patients who achieved a goal MAP in the vasopressin group was 63% (95% CI 51%–75%) and was 67.7% (95% CI 56%–79%) in the norepinephrine group. This observed difference between goal MAP attainment did not exceed the predefined noninferiority margin of −25% (CI for 4.7% difference −21.2% to 12%), suggesting noninferiority of vasopressin. No significant difference was identified between vasopressin and norepinephrine for final mean (SD) MAP achieved (75 [9.6] and 76.0 [8.2] mm Hg, respectively; p = 0.06) or the mean total change from baseline MAP to goal (14.1 [8.4] and 15.1 [9.1] mm Hg, respectively; p = 0.6).

CONCLUSIONS

Vasopressin was noninferior to norepinephrine for the achievement of a MAP goal in the first 6 hours from onset of septic shock. Further prospective analysis is warranted; however, the results are useful for consideration of alternative vasopressors in the setting of drug shortages.
Review on the Influence of Protocol Design on Clinical Outcomes in Rheumatoid Arthritis Treated with Rituximab
Authors: Shetty Shawn , Fisher Mark C , Ahmed A Razzaque
Published: February 2013

OBJECTIVE

To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab.

DATA SOURCES

A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed.

STUDY SELECTION AND DATA EXTRACTION

A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data.

DATA SYNTHESIS

Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-α) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the χ2 test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%).

CONCLUSIONS

In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF-α inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted.
Transforming potential program implementers in professional development: the project P.A.T.H.S. in Hong Kong
Authors: Shek Daniel T.L. , Yim Eunice P.Y. , Sun Rachel C.F.
Published: February 2013

High quality pre-implementation professional training is the cornerstone for successful implementation of positive youth development programs. A qualitative evaluation study was conducted to understand the experiences of the potential program implementers of the Project P.A.T.H.S. in Hong Kong. The findings showed that participants highly valued the learning experiences acquired from the training program, particularly in the areas of knowledge acquisition and personal growth. Participants who benefited from these dimensions developed attitudes and skills that are desirable for the implementation of the Project P.A.T.H.S. Implications about the conditions that are conducive to the P.A.T.H.S. training program in promoting knowledge, skills acquisition, retention, application, and generalization are discussed.
Development of an e-learning package on Service-Learning for university teachers: experience from Hong Kong
Authors: Shek Daniel T.L. , Chan Stephen C.F.
Published: February 2013

To help university teachers to understand Service-Learning and develop Service-Learning subjects, a 3-h+ e-learning package was developed at The Hong Kong Polytechnic University (PolyU). There are seven units in this e-learning package: introduction session (Unit 1), what is Service-Learning? (Unit 2), impact and benefits of Service-Learning (Unit 3), myths and positive attitudes toward Service-Learning (Unit 4), developing a Service-Learning subject at PolyU (Unit 5), self-reflection about Service-Learning (Unit 6), and concluding session (Unit 7). To understand the views of the users on the e-learning package, the package was offered before formal launching. For the first offering, three focus group sessions were held. Results showed that the users were satisfied with the structural arrangement of the e-learning package and agreed that the e-learning package was useful for them to understand more about Service-Learning. For the second offering, colleagues were generally satisfied with the e-learning package and demonstrated gain in knowledge on Service-Learning. Suggestions for improvement were noted.