bluuebunny/crossref_metadata_2025 huggingface dataset:
Survivin is highly expressed in CD34+38− leukemic stem/progenitor cells and predicts poor clinical outcomes in AML
Authors: Carter Bing Z. , Qiu Yihua , Huang Xuelin , Diao Lixia , Zhang Nianxiang , Coombes Kevin R. , Mak Duncan H. , Konopleva Marina , Cortes Jorge , Kantarjian Hagop M. , Mills Gordon B. , Andreeff Michael , Kornblau Steven M.
Published: May 2012

Survivin, a member of the inhibitors of apoptosis protein family, plays important roles in cell proliferation and survival and is highly expressed in various malignancies, including leukemias. To better understand its role in acute myeloid leukemia (AML), we profiled survivin expression in samples obtained from 511 newly diagnosed AML patients and in CD34+38− AML stem/progenitor cells using a validated reverse-phase protein array; we correlated its levels with clinical outcomes and with levels of other proteins in the same sample set. We found that survivin levels were higher in bone marrow than in paired peripheral blood leukemic cells (n = 140, P = .0001) and that higher survivin levels significantly predicted shorter overall (P = .016) and event-free (P = .023) survival in multivariate Cox model analysis. Importantly, survivin levels were significantly higher in CD34+38− AML stem/progenitor cells than in bulk blasts and total CD34+ AML cells (P < .05). Survivin expression correlated with the expressions of multiple proteins involved with cell proliferation and survival. Particularly, its expression strongly correlated with HIF1α in the stem/progenitor cell compartment. These results suggest that survivin is a prognostic biomarker in AML and that survivin, which is overexpressed in AML stem/progenitor cells, remains a potentially important target for leukemia therapy.
Proteasome inhibitors in multiple myeloma: 10 years later
Authors: Moreau Philippe , Richardson Paul G. , Cavo Michele , Orlowski Robert Z. , San Miguel Jesús F. , Palumbo Antonio , Harousseau Jean-Luc
Published: May 2012

Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these “second-generation” PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.
miR-107: a Toll-like receptor-regulated miRNA dysregulated in obesity and type II diabetes
Authors: Foley Niamh H , OˈNeill Luke A
Published: May 2012

Review on the link between miR-107 dyregulation and TLR4 inflammation in type 2 diabetes.

miRNAs are small noncoding RNAs that act as regulators of gene expression. Dysregulation of miRNAs has been shown to contribute to multiple disease processes. It has become apparent that miRNAs play a key role in the innate immune response, whereby a large number of miRNAs have been demonstrated to be regulated by TLRs, key initiators of the innate immune response to infection. Recently, the LPS receptor, TLR4, has been shown to down-regulate miR-107 in macrophages. In addition, miR-107 has been demonstrated to be dysregulated in murine and rodent models of obesity and insulin resistance, respectively, with miR-107 contributing to both conditions. With obesity and inflammation being so intrinsically associated, the link between the miR-107 expression levels, inflammation, and insulin resistance may be of particular importance in metabolic diseases. The decrease in miR-107 in response to TLR4 may be an attempt to limit insulin resistance, a feature of obesity-related inflammation. If this process is impaired, disease, such as T2D, might persist. This review aims to discuss a possible link between the molecular phenomena of obesity and inflammation and the role that miR-107 may contribute to these processes.
Targeting the B-Cell Lymphoma/Leukemia 2 Family in Cancer
Authors: Davids Matthew S. , Letai Anthony
Published: May 2012

The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer.
Ocular Toxicity of Targeted Therapies
Authors: Renouf Daniel J. , Velazquez-Martin Juan P. , Simpson Rand , Siu Lillian L. , Bedard Philippe L.
Published: May 2012

Molecularly targeted agents are commonly used in oncology practice, and many new targeted agents are currently being tested in clinical trials. Although these agents are thought to be more specific and less toxic then traditional cytotoxic chemotherapy, they are associated with a variety of toxicities, including ocular toxicity. Many of the molecules targeted by anticancer agents are also expressed in ocular tissues. We reviewed the literature for described ocular toxicities associated with both approved and investigational molecularly targeted agents. Ocular toxicity has been described with numerous approved targeted agents and also seems to be associated with several classes of agents currently being tested in early-phase clinical trials. We discuss the proposed pathogenesis, monitoring guidelines, and management recommendations. It is important for oncologists to be aware of the potential for ocular toxicity, with prompt recognition of symptoms that require referral to an ophthalmologist. Ongoing collaboration between oncologists and ocular disease specialists is critical as the use of molecularly targeted agents continues to expand and novel targeted drug combinations are developed.
The Wayward Life of Objects
Authors: Cheng Anne Anlin
Published: May 2012

What is reading; what can it do; and can we imagine a hermeneutics beyond suspicion? This brief essay meditates on the possibilities of what might be called a hermeneutics of susceptibility that can accommodate our ideological and aesthetic complicity in any act of reading while still understanding the political risks and gains of such acknowledgment. This is also an argument about how we read surfaces: the surfaces of texts, bodies, and objects.
What Can Reading Do?
Authors: Flint Kate
Published: May 2012

In this response piece, I consider the variety of ways in which reading may be said to work upon a reader, and I bring out the importance of the idea of affect in this respect. I note that affect is frequently conceived of in a positive light, and my argument shifts to ask what happens if the reader is bored, puzzled, disgusted, irritated, or otherwise disengaged. Using Patricia Meyer Spacks's Boredom and Sianne Ngai's Ugly Feelings as critical works to support my case, I suggest that we should pay more attention to the ways in which reading may confuse or alienate us, and I maintain that these negative affects are ones of particular importance when we consider the global reach of the novel. How might we understand and negotiate what I term “unsatisfactory reading,” especially if it is provoked through the unfamiliarity of literary or social convention?
Reading Deliriously
Authors: Vadde Aarthi
Published: May 2012

This short piece argues that the demands of reading globally should change how we approach conversations about the ethical reading of minoritarian literature. Rather than assume a stable relationship between the imagined reader as subject and the text as object, we should consider how texts now participate in multiple cultures that trouble the boundaries between domestic and foreign, “us” and “them.” Reading deliriously outlines an approach to reading that values transnational circuits of comparison and aggregation for the way they might reconstruct the imagined reader as a navigator of world literary space rather than a protocitizen of world community. Instead of focusing on molding better citizens through reading, this piece calls for an ethics of global reading that reconsiders and expands the number of cultural systems and traditions from which the possibilities for belonging might emerge.
Novels, Newspapers, and Global War: New Realisms in the 1850s
Authors: Teukolsky Rachel
Published: May 2012

Both journalists and novelists showed a newly explicit interest in “realism” in the 1850s, especially in the wake of the devastating Crimean War (1853-56). This war was the first to be documented by an independent press, as new technologies of travel and printing allowed the British public to see the war as an immediate reality—especially in journalistic exposés of the war's mismanagement. Official narratives of glorious warfare were undercut by reports of mass suffering by common British soldiers. Widely read frontline reports by William Howard Russell of the Times provoked a shift in the focus of public sympathy from incompetent aristocratic officers to heroic working-class soldiers—thus moving Russell's reports into the realm of the realist novel, as its terms were being debated and defined in the 1850s. The essay compares Russell's journalism with George Eliot's AdamBede (1859), known for its famous statement of realist principles and its depiction of heroic common people set against the backdrop of the Napoleonic Wars. Though the novel takes place in the English countryside, the narrator invokes a presumed audience who differ profoundly from the novel's peasant characters—a cosmopolitan readership who are comparative in mindset and globally aware. Both realist novel and Crimean War journalism make traumatized working-class figures into symbols of a heroic nationhood, even while ultimately remaining distanced from these figures by addressing middle-class readers united by a state of technological modernity.
Influence of age on the association of GIRK4 with metabolic syndrome
Authors: Li Nanfang , Zhang Delian , Zhang Juhong , Guo Yanying , Yan Zhitao , Wang Hongmei , Zhou Ling , Hong Jing , Wang Xinling , A Zufeiya
Published: May 2012

Background

G protein-coupled inward rectifier K+ channel 4 (GIRK4) gene expressions have been implicated in the development of obesity, a key feature of metabolic syndrome (MetS). We investigated whether sequence variants of GIRK4 may represent metabolic risk factors for the Uygur Chinese population.

Methods

The entire GIRK4 gene, including all exons, the promoter and untranslated regions from 48 MetS individuals, was studied in order to identify genetic variations associated with the disorder. Targeted genotyping of four common single nucleotide polymorphisms (SNPs: rs11221497, rs6590357, rs4937391 and rs2604204) and one novel missense mutation (M210I) was performed using the TaqMan polymerase chain reaction method for 443 MetS and 786 non-MetS subjects.

Results

When all MetS cases were compared against all non-MetS controls, no significant association was found between the three SNPs (rs2604204, rs4937391 and rs6590357) and MetS status or metabolic traits. After adjustment, rs11221497 was associated with MetS (odds ratio (OR) [95% CI] = 0.731 [0.551–0.968], P= 0.029). Interestingly, when the MetS group was stratified into subclasses by age, an association was found for the three SNPs (rs2604204, rs4937391 and rs6590357) having estimated false discovery rates <0.001 and age of <50 y. After adjustment, the SNPs rs2604204, rs4937391 and rs6590357 were also associated with MetS in younger subjects: ORs [95% CI]: 1.678 [1.149–2.450], 1.839 [1.204–2.809] and 0.602 [0.379–0.958], respectively. All of the four SNPs showed a trend towards lower or higher metabolic traits ( P< 0.05) in younger subjects. In addition, a newly identified missense mutation (M210I) was not specifically related with MetS.

Conclusions

GIRK4 sequence variants appear to associate with MetS in the Uygurian population, and this association may be influenced by age.
Minimizing human dignity: staff perception of abuse in health care
Authors: Swahnberg Katarina , Berterö Carina
Published: May 2012

In earlier studies we have shown that abuse in health care (AHC) is commonly reported among both male and female patients. In this study, we present an evaluation of an intervention against AHC based on Forum Play. The evaluation was conducted by means of pre- and postintervention interviews with the staff at a woman's clinic. The interviews were analysed using the constant comparative method. The results of this postintervention study stand out in loud contrast to the results of the preintervention studies. Staff had moved from a distant and fluctuating awareness of AHC to a standpoint characterized by both moral imagination and a sense of responsibility.
Withdrawal of treatment from minimally conscious patients
Authors: Heywood Rob
Published: May 2012

This article explores the taxing legal questions that are raised in the context of withdrawing life sustaining treatment from patients who are in a minimally conscious state. The Court of Protection, for the first time in England, was recently asked to rule on this issue. This paper analyses the legal and ethical implications of this decision moving forward.
Evaluation of case consultations in clinical ethics committees
Authors: Førde Reidun , Pedersen Reidar
Published: May 2012

If ethics consultation services influence medical decisions it is important to evaluate how ethical dilemmas are dealt with by clinical ethics committees (CECs). Such evaluation is rare. This study presents a feasible and practical method of evaluating case discussions in CECs and the results emerging from the use of this method. A written presentation of an end-of-life dilemma was sent to all Norwegian ethics committees. The committees were asked to deal with the case as they would do if it was a real case, and to prepare a written report of the discussion. A majority of the committees approached the case systematically. All emphasized the importance of good communication with the next of kin. However, their conclusions varied, medical facts were interpreted differently, possible patient suffering was dealt with differently, and some committees revealed insufficient legal knowledge. Such findings are useful in the future education of committee members.
Compromising on assisted suicide: is ‘turning a blind eye’ ethical?
Authors: Mullock Alexandra
Published: May 2012

Following the decision of the House of Lords in Purdy, the Director of Public Prosecutions was required to promulgate guidance as to how prosecutorial discretion is exercised over the decision of whether to prosecute or not under the Suicide Act 1961. The resulting policy essentially confirms that if a lay person, who is motivated wholly by compassion, provides minor and reluctant assistance to a mentally competent adult, he or she is extremely unlikely to be prosecuted. Consequently, prosecutorial policy over cases of complicity in suicide might be viewed as presenting a procedural compromise between explicitly allowing and robustly prohibiting assisted suicide. This paper explores the legal and ethical implications of compromising over complicity in suicide.
Ocular cryptococcosis as a presenting manifestation of cryptococcal meningitis in a patient with HIV
Authors: Chai S-M , Teoh S C
Published: May 2012

We describe a case of cryptococcal meningitis in a patient known to have HIV who presented initially with ocular cryptococcosis. This case highlights to clinicians the need to be aware of this association and to carry out relevant investigations so as to treat these patients appropriately.
Role of fluconazole in a case of rapid onset ritonavir and inhaled fluticasone-associated secondary adrenal insufficiency
Authors: St Clair K , Maguire J D
Published: May 2012

A 52-year-old man with well-controlled HIV infection taking ritonavir and increasing doses of inhaled fluticasone for chronic bronchitis developed thrush. Within days of discontinuing fluticasone and initiating fluconazole, he presented with fatigue, malaise, lower-extremity oedema and orthostasis. Testing confirmed exogenous Cushing's syndrome and secondary adrenal insufficiency. Although ritonavir–fluticasone interactions have been previously reported as a cause for adrenal insufficiency, we propose that fluconazole increased the rapidity of onset and severity of symptoms through synergistic inhibition of the adrenal axis.
Reactive arthritis responding to antiretroviral therapy in an HIV-1-infected individual
Authors: Scott C , Brand A , Natha M
Published: May 2012

Reactive arthritis (ReA) is an autoimmune seronegative spondyloarthropathy that occurs in response to a urogenital or enteric infection. Several studies have reported a link between ReA and HIV infection. We report a case of an HIV-1-infected patient diagnosed with a disabling ReA who failed to respond to conventional therapy but whose symptoms resolved rapidly after starting antiretroviral therapy (ART). Clinicians may not be cognizant to this phenomenon and so this case report serves to remind clinicians that initiation of antiretroviral therapy should be considered in HIV-infected patients with ReA who are refractory to standard therapy.
Simultaneous triple point-of-care testing for HIV, syphilis and hepatitis B virus to prevent mother-to-child transmission in India
Authors: Pai N P , Kurji J , Singam A , Barick R , Jafari Y , Klein M B , Chhabra S , Shivkumar P
Published: May 2012

An innovative simultaneous triple point-of-care (STPOC) screening strategy for syphilis, hepatitis B and HIV with Determine® tests was offered to pregnant women presenting for antenatal care and evaluated for feasibility and preference in rural India. Of 1066 participants approached, 1046 consented, of which 1002 (96.0%) completed the strategy. Only 9% reported any history of testing in their current pregnancy. With STPOC screening, 989 women (98.7%) tested negative and 13 had preliminary positive results for infection. The total time taken was 45 minutes per participant. Mothers and infants were provided prophylaxis/treatment for HIV, syphilis and hepatitis B, with interventions initiated within 3–5 days. STPOC was preferred by 99.3% (95%CI: 98.8–99.8%) of participants, facilitated early simultaneous screening for the three infections, timely initiation of prophylaxis/treatment and was feasible in this rural setting. These data suggest that multiplexed STPOC screening for syphilis, hepatitis B and HIV in pregnancy would be desirable for women in rural India.
The contribution of antenatal care to the coverage and correlates of HIV testing among adults in Zimbabwe 2005–06
Authors: Saito S , Wu Y , Nankabirwa V , Nash D
Published: May 2012

Expanding the availability, utilization and coverage of HIV testing services is a critical step towards primary prevention and successful delivery of antiretroviral therapy (ART) in Zimbabwe. We used data from the Zimbabwe Demographic and Health Survey (2005–2006) to examine the coverage and correlates of recent HIV testing (HIV testing <24 months preceding the survey) among HIV-positive and HIV-negative adults. We estimated the relative contribution of HIV testing in both the antenatal care (ANC) setting and non-ANC settings. Uptake of recent HIV testing was 14.4% among women and 11.1% among men, with HIV testing in ANC accounting for 42.3% and 10.3% of all recent testing among women and men, respectively. In the multivariate analyses, recent pregnancies and being aware of ART were independent correlates after controlling for demographic and socioeconomic variables. HIV testing in ANC was an important contributor to HIV testing coverage in Zimbabwe by reaching not only pregnant women but also their partners.
Immune reconstitution inflammatory syndrome associated with disseminated Mycobacterium sherrisii infection
Authors: Ho J , Balm M , Huggan P , Chew NSY , Venkatachalam I , Archuleta S
Published: May 2012

Mycobacterium sherrisii is a recently described mycobacterium closely related to Mycobacterium simiae. There have been only a few reports of this organism causing disease, predominantly in the setting of HIV with severe immunosuppression. We report the first case of disseminated M. sherrisii associated with immune reconstitution inflammatory syndrome.
Prevalence of sexually transmitted infections among women attending antenatal clinics in Tanga, north eastern Tanzania
Authors: Chiduo M , Theilgaard Z P , Bakari V , Mtatifikolo F , Bygbjerg I , Flanholc L , Gerstoft J , Christiansen C B , Lemnge M , Katzenstein T L
Published: May 2012

This study aimed to determine the prevalence of sexually transmitted infections (STIs) among HIV-infected and uninfected pregnant women in Tanga, Tanzania. Retrospective data on syphilis and HIV status during 2008–2010 were collected from antenatal clinic (ANC) records. Prospective data were collected from HIV-infected ( n = 105) and HIV-uninfected pregnant women ( n = 100) attending ANCs between April 2009 and August 2010. Syphilis prevalence showed a declining trend (3.1%, 1.4% and 1.3%), while HIV prevalence was stable (6.1%, 6.4% and 5.4%) during 2008–2010. HIV-infected women had significantly higher prevalence of trichomoniasis (18.8% versus 5.0%; P < 0.003) and candidiasis (16.5% versus 2.0%; P < 0.001) while the higher rate of gonorrhoea (3.5% versus 0%; P = 0.095) was not statistically significant when compared with HIV-uninfected women. There were no statistically significant differences in prevalence of chlamydial infection (0% versus 3.0%; P = 0.156) or syphilis (2.4% versus 3.0%; P = 1) between HIV-infected and uninfected women. Other STIs were common in both HIV-infected and uninfected pregnant women.
A surgical approach to anogenital disease: guidance on providing a minor surgery service in sexual health and genitourinary medicine
Authors: Sonnex C
Published: May 2012

Certain anogenital conditions require surgical intervention and although the specialty training curriculum for genitourinary (GU) medicine mentions skin biopsy as the only surgical skill required for training, most practitioners could usefully provide a more extensive surgical or ‘minor ops’ service. The purpose of this paper is to provide guidance for practitioners considering starting a minor surgery service, outlines the equipment required and describes commonly used techniques such as skin biopsy, cryotherapy, excision, electrosurgery and laser ablation.
RNASTAR: An RNA STructural Alignment Repository that provides insight into the evolution of natural and artificial RNAs
Authors: Widmann Jeremy , Stombaugh Jesse , McDonald Daniel , Chocholousova Jana , Gardner Paul , Iyer Matthew K. , Liu Zongzhi , Lozupone Catherine A. , Quinn John , Smit Sandra , Wikman Shandy , Zaneveld Jesse R.R. , Knight Rob
Published: May 2012

Automated RNA alignment algorithms often fail to recapture the essential conserved sites that are critical for function. To assist in the refinement of these algorithms, we manually curated a set of 148 alignments with a total of 9600 unique sequences, in which each alignment was backed by at least one crystal or NMR structure. These alignments included both naturally and artificially selected molecules. We used principles of isostericity to improve the alignments from an average of 83%–94% isosteric base pairs. We expect that this alignment collection will assist in a wide range of benchmarking efforts and provide new insight into evolutionary principles governing change in RNA structural motifs. The improved alignments have been contributed to the Rfam database.
Incorporating global features of RNA motifs in predictions for an ensemble of secondary structures for encapsidated MS2 bacteriophage RNA
Authors: Bleckley Samuel , Schroeder Susan J.
Published: May 2012

The secondary structure of encapsidated MS2 genomic RNA poses an interesting RNA folding challenge. Cryoelectron microscopy has demonstrated that encapsidated MS2 RNA is well-ordered. Models of MS2 assembly suggest that the RNA hairpin–protein interactions and the appropriate placement of hairpins in the MS2 RNA secondary structure can guide the formation of the correct icosahedral particle. The RNA hairpin motif that is recognized by the MS2 capsid protein dimers, however, is energetically unfavorable, and thus free energy predictions are biased against this motif. Computer programs called Crumple, Sliding Windows, and Assembly provide useful tools for prediction of viral RNA secondary structures when the traditional assumptions of RNA structure prediction by free energy minimization may not apply. These methods allow incorporation of global features of the RNA fold and motifs that are difficult to include directly in minimum free energy predictions. For example, with MS2 RNA the experimental data from SELEX experiments, crystallography, and theoretical calculations of the path for the series of hairpins can be incorporated in the RNA structure prediction, and thus the influence of free energy considerations can be modulated. This approach thoroughly explores conformational space and generates an ensemble of secondary structures. The predictions from this new approach can test hypotheses and models of viral assembly and guide construction of complete three-dimensional models of virus particles.
Training in Theatre: Are Bigger Hospitals Better?
Authors: Field M , Mitchell S , van Dellen D , Wall D , Roff S
Published: May 2012

The operating theatre is a central part of a surgeon's working life. Medical students are exposed to it as a learning opportunity and as an introduction to a possible career. Junior doctors experience the operating theatre as a learning and training experience as well as a process in which they play an active role. Despite its obvious importance as a learning environment, it has received comparatively little interest and research as a distinct environment. However, the environment within the operating theatre may have a profound impact on learning and on subsequent career choice.
Selecting Orthopaedic Trainees: A Comparative Analysis of Shortlisting Versus Interviewing
Authors: Rogers BA , Little NJ , Solan MC , Ricketts DM
Published: May 2012

Entry into higher surgical training schemes in orthopaedics remains competitive: in the UK there are currently more than six applicants for each available training post. In many countries the application process is similar with candidates submitting written data in the form of a CV or application form. This is used as a basis for longlisting (the selection of all candidates who possess the minimum job criteria), then shortlisting (the ranking of longlisted candidates) and, finally, an interview. At interview the successful candidates are selected.
An interview with Richard Dodds
Authors: Egerton Sibella , Egerton Oonagh
Published: May 2012

Richard Dodds fRCS was captain of the gold medal-winning Great Britain hockey team at the 1988 Olympics in Seoul and also won the bronze medal at the 1984 Olympics in Los Angeles. He is now a consultant orthopaedic surgeon at the Royal Berkshire Hospital in Reading. Sibella Egerton asked him for his insights on sport, surgery and life.
The LDS RCS(Eng): 150 years on and still going strong
Authors: Jones Judith
Published: May 2012

The Licence in Dental Surgery (LDS) originated in the 19th century and is the oldest continuously existing dental qualification in the UK. Records show that a letter sent to the Lancet in 1855 by a Mr Rymer of Croydon suggested that the Royal College of Surgeons should 'appoint a properly constituted board of examiners whose duties should be to hold periodical examinations of such candidates as were desirous of obtaining such a distinction, for instance as might be termed “licentiates in dentistry”. 'Sir John Tomes worked with the College and the Odontological Society and was instrumental in proposing a clause to be added to the Medical Bill of 1958 'to grant the Royal College of Surgeons of England power to institute and hold examinations for the purpose of testing the fitness of persons to practise as dentists, who may be desirous of being so examined, and to grant certificates of such fitness.'
The trainee-led MRCS mock OSCE: a useful and inexpensive adjunct in exam preparation
Authors: Lau Andrew , Gill Damien , Bullen Naomi
Published: May 2012

The new MRCS examination was introduced in October 2008. One major change was the integration of viva voce, clinical and communication skills components into the Part B objective structured clinical examination (OSCE). This was partly in response to changes to surgical training resulting in 'earlier specialisation [and] less exposure to the range of surgical specialties'.
Use of evidence from systematic reviews to inform commissioning decisions: a case study
Authors: Chambers Duncan , Grant Rod , Warren Erica , Pearson Sally-Anne , Wilson Paul
Published: May 2012

Systematic reviews provide high-level evidence but there are barriers to their use by policy makers. This paper reports the preparation and evaluation of an evidence briefing, using systematic reviews and other existing sources of synthesised evidence, to support a possible reorganisation of services for young people with eating disorders in an English primary care trust. There was no evidence of differences in outcomes between community, outpatient and specialist inpatient treatment. The provision of specialist outpatient services appeared most cost-effective. The commissioning group agreed to move towards providing services on an outpatient basis. This work suggests that evidence briefings based on systematic reviews warrant further methodological development and evaluation.
Dutch Academic Collaborative Centres for Public Health: development through time – issues, dilemmas and coping strategies
Authors: Wehrens Rik , Bekker Marleen , Bal Roland
Published: May 2012

While much research utilisation literature shows an increasing emphasis on the added value of structural partnerships, which should facilitate prolonged interactions between researchers, policy makers and professionals, the question of how such collaborative structures develop over time and what consequences that has in terms of collaboration is usually neglected. This paper offers an empirical analysis of a Dutch partnership format developed over a period of four years, based on two interview rounds conducted between 2007 and 2010, supplemented with document analysis and a focus group. It focuses on changing challenges and dilemmas in different development stages and outlines which strategies are used.
The precautionary principle and evidence-based policy
Authors: Monaghan Mark , Pawson Ray , Wicker Kate
Published: May 2012

The precautionary principle recommends, in the face of pressing but unquantifiable threats, that decision makers should not wait indefinitely for the backing of evidence. As such, it represents another potential challenge to the turbulent fortunes of evidence-based policy. Through four contrasting case studies, this paper examines this challenge and formulates a preliminary model of the role of the precautionary principle in evidence-based policy. We conclude that although precaution may be a barrier to evidence-based policy making, this is not always so and depending on the contextual factors, it can also be enabling, encouraging policy makers to engage with the evidence.
The Impact of Brand Equity on Customer Acquisition, Retention, and Profit Margin
Authors: Stahl Florian , Heitmann Mark , Lehmann Donald R. , Neslin Scott A.
Published: May 2012

The authors investigate the relationships between brand equity and customer acquisition, retention, and profit margin, the key components of customer lifetime value (CLV). They examine a unique database from the U.S. automobile market that combines ten years of acquisition rate, retention rate, and customer profitability data with measures of brand equity from Young & Rubicam's Brand Asset Valuator (BAV) over the same period. They hypothesize and find that BAV brand equity is significantly associated with the components of CLV in expected and meaningful ways. For example, customer knowledge of a brand has an especially strong positive relationship with all three components of CLV. Notably, however, differentiation is a double-edged sword. While it is associated with higher customer profitability, it is also associated with lower acquisition and retention rates. The authors also find that marketing efforts exert indirect impacts on CLV through brand equity. Simulations show that changes in marketing, or exogenous changes in brand equity, can exert important effects on CLV. Overall, the findings suggest that the “soft” and “hard” sides of marketing need to be managed in a coordinated way. The authors conclude with a discussion of these and other implications for researchers and practitioners.
Levels of cytokines in umbilical cord blood in relation to spontaneous term labor
Authors: Tutdibi Erol , Hunecke Angela , Lindner Ulrike , Monz Dominik , Gortner Ludwig
Published: May 2012

Objective: Inflammatory mechanisms are thought to play an important role in the process of labor, both in preterm and spontaneous term delivery. We aimed to determine whether normal spontaneous vaginal delivery (SVD) at term was associated with an inflammatory activation compared with elective cesarean section (ECS) without previous onset of labor.

Methods: Cytokine concentrations were measured in venous cord blood obtained from 60 term newborns (ECS, n=35; SVD, n=25) born to mothers with clinically uneventful pregnancy and without signs of infection.

Results: Both study groups showed no differences in birth weight, umbilical artery pH, Apgar at 5 min, and gender distribution. Infants delivered by ECS had lower gestational age: mean, 38.5 weeks (range, 37.0–39.6 weeks) vs. mean, 39.8 weeks (range, 37.9–42.4 weeks) (P<0.001). Concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-17, IL-1 receptor antagonist, soluble IL-2 receptor α, granulocyte-macrophage colony-stimulating factor, interferon (IFN)-α2, IFN-γ, tumor necrosis factor (TNF)-α, TNF-β, and interferon inducible protein 10 were not different between ECS and SVD. Newborns after SVD displayed increased levels of transforming growth factor β1 (TGF-β1): mean, 8580 pg/mL (95% CI, 5554–11,606) vs. mean, 4864 pg/mL (95% CI, 2471–7257) (P<0.0012).

Conclusions: Our findings suggest that, in healthy, term neonates, the exposition to normal spontaneous delivery and labor is not associated with systemic activation of different inflammatory mediators compared with ECS except for TGF-β1. Further studies are needed to evaluate the immunomodulatory role of labor-associated TGF-β1 increase in fetal cord blood.
Is There a Relationship between Throbbing Pain and Arterial Pulsations?
Authors: Mirza Afia F. , Mo Jue , Holt Jenny L. , Kairalla John A. , Heft Marc W. , Ding Mingzhou , Ahn Andrew H.
Published: May 2012

Pain can have a throbbing quality, especially when it is severe and disabling. It is widely held that this throbbing quality is a primary sensation of one's own arterial pulsations, arising directly from the activation of localized pain-sensory neurons by closely apposed blood vessels. We examined this presumption more closely by simultaneously recording the subjective report of the throbbing rhythm and the arterial pulse in human subjects of either sex with throbbing dental pain—a prevalent condition whose pulsatile quality is widely regarded a primary sensation. Contrary to the generally accepted view, which would predict a direct correspondence between the two, we found that the throbbing rate (44 bpm ± 3 SEM) was much slower than the arterial pulsation rate (73 bpm ± 2 SEM,p< 0.001), and that the two rhythms exhibited no underlying synchrony. Moreover, the beat-to-beat variation in arterial and throbbing events observed distinct fractal properties, indicating that the physiological mechanisms underlying these rhythmic events are distinct. Confirmation of the generality of this observation in other pain conditions would support an alternative hypothesis that the throbbing quality is not a primary sensation but rather an emergent property, or perception, whose “pacemaker” lies within the CNS. Future studies leading to an improved understanding of the neurobiological basis of clinically relevant pain qualities, such as throbbing, will also enhance our ability to measure and therapeutically target severe and disabling pain.
Thrombin Activity Associated with Neuronal Damage during Acute Focal Ischemia
Authors: Chen Bo , Friedman Beth , Whitney Michael A. , Winkle Jessica A. Van , Lei I-Farn , Olson Emilia S. , Cheng Qun , Pereira Benedict , Zhao Lifu , Tsien Roger Y. , Lyden Patrick D.
Published: May 2012

Mechanisms of ischemic neuronal and vascular injury remain obscure. Here we test the hypothesis that thrombin, a blood-borne coagulation factor, contributes to neurovascular injury during acute focal ischemia. Stroke was induced in adult Sprague Dawley rats by occluding the middle cerebral artery. Intra-arterial thrombin infusion during ischemia significantly increased vascular disruption and cellular injury. Intravenous infusion of argatroban, a direct thrombin inhibitor, alleviated neurovascular injury. Immunostaining showed thrombin on neurons in the ischemic core. Using an activatable cell-penetrating peptide engineered to detect thrombin activity, we discovered that thrombin proteolytic activity was specifically associated with neuronal damage during ischemia. Protease activated receptor-1, the presumptive thrombin receptor, appeared to mediate ischemic neurovascular injury. Furthermore, rats receiving thrombin during ischemia showed cognitive deficit, whereas rats receiving argatroban retained intact learning and memory. These results suggest a potential role for thrombin contributing to neurovascular injury and several potential avenues for neuroprotection.
Filamin A Regulates Neural Progenitor Proliferation and Cortical Size through Wee1-Dependent Cdk1 Phosphorylation
Authors: Lian Gewei , Lu Jie , Hu Jianjun , Zhang Jingping , Cross Sally H. , Ferland Russell J. , Sheen Volney L.
Published: May 2012

Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated genefilamin A(FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that is characterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules. FlnA-dependent regulation of cytoskeletal dynamics is thought to direct neural progenitor migration and proliferation. Here we show that embryonicFlnA-null mice exhibited a reduction in brain size and decline in neural progenitor numbers over time. The drop in the progenitor population was not attributable to cell death or changes in premature differentiation, but to prolonged cell cycle duration. Suppression of FlnA led to prolongation of the entire cell cycle length, principally in M phase. FlnA loss impaired degradation of cyclin B1-related proteins, thereby delaying the onset and progression through mitosis. We found that the cdk1 kinase Wee1 bound FlnA, demonstrated increased expression levels after loss of FlnA function, and was associated with increased phosphorylation of cdk1. Phosphorylation of cdk1 inhibited activation of the anaphase promoting complex degradation system, which was responsible for cyclin B1 degradation and progression through mitosis. Collectively, our results demonstrate a molecular mechanism whereby FlnA loss impaired G2 to M phase entry, leading to cell cycle prolongation, compromised neural progenitor proliferation, and reduced brain size.
Doublecortin (DCX) Mediates Endocytosis of Neurofascin Independently of Microtubule Binding
Authors: Yap Chan Choo , Vakulenko Max , Kruczek Kamil , Motamedi Bashir , Digilio Laura , Liu Judy S. , Winckler Bettina
Published: May 2012

Doublecortin on X chromosome (DCX) is one of two major genetic loci underlying human lissencephaly, a neurodevelopmental disorder with defects in neuronal migration and axon outgrowth. DCX is a microtubule-binding protein, and much work has focused on its microtubule-associated functions. DCX has other reported binding partners, including the cell adhesion molecule neurofascin, but the functional significance of the DCX–neurofascin interaction is not understood. Neurofascin localizes strongly to the axon initial segment in mature neurons, where it plays a role in assembling and maintaining other axon initial segment components. During development, neurofascin likely plays additional roles in axon guidance and in GABAergic synaptogenesis. We show here that DCX can modulate the surface distribution of neurofascin in developing cultured rat neurons and thereby the relative extent of accumulation between the axon initial segment and soma and dendrites. Mechanistically, DCX acts via increasing endocytosis of neurofascin from soma and dendrites. Surprisingly, DCX increases neurofascin endocytosis apparently independently of its microtubule-binding activity. We additionally show that the patient allele DCXG253D still binds microtubules but is deficient in promoting neurofascin endocytosis. We propose that DCX acts as an endocytic adaptor for neurofascin to fine-tune its surface distribution during neuronal development.
Effects of Early-Life Abuse Differ across Development: Infant Social Behavior Deficits Are Followed by Adolescent Depressive-Like Behaviors Mediated by the Amygdala
Authors: Raineki Charlis , Cortés Millie Rincón , Belnoue Laure , Sullivan Regina M.
Published: May 2012

Abuse during early life, especially from the caregiver, increases vulnerability to develop later-life psychopathologies such as depression. Although signs of depression are typically not expressed until later life, signs of dysfunctional social behavior have been found earlier. How infant abuse alters the trajectory of brain development to produce pathways to pathology is not completely understood. Here we address this question using two different but complementary rat models of early-life abuse from postnatal day 8 (P8) to P12: a naturalistic paradigm, where the mother is provided with insufficient bedding for nest building; and a more controlled paradigm, where infants undergo olfactory classical conditioning. Amygdala neural assessment (c-Fos), as well as social behavior and forced swim tests were performed at preweaning (P20) and adolescence (P45). Our results show that both models of early-life abuse induce deficits in social behavior, even during the preweaning period; however, depressive-like behaviors were observed only during adolescence. Adolescent depressive-like behavior corresponds with an increase in amygdala neural activity in response to forced swim test. A causal relationship between the amygdala and depressive-like behavior was suggested through amygdala temporary deactivation (muscimol infusions), which rescued the depressive-like behavior in the forced swim test. Our results indicate that social behavior deficits in infancy could serve as an early marker for later psychopathology. Moreover, the implication of the amygdala in the ontogeny of depressive-like behaviors in infant abused animals is an important step toward understanding the underlying mechanisms of later-life mental disease associated with early-life abuse.
Caspase-6 Activity in a BACHD Mouse Modulates Steady-State Levels of Mutant Huntingtin Protein But Is Not Necessary for Production of a 586 Amino Acid Proteolytic Fragment
Authors: Gafni Juliette , Papanikolaou Theodora , DeGiacomo Francesco , Holcomb Jennifer , Chen Sylvia , Menalled Liliana , Kudwa Andrea , Fitzpatrick Jon , Miller Sam , Ramboz Sylvie , Tuunanen Pasi I. , Lehtimäki Kimmo K. , Yang X. William , Park Larry , Kwak Seung , Howland David , Park Hyunsun , Ellerby Lisa M.
Published: May 2012

Huntington's disease (HD) is caused by a mutation in the huntingtin (htt) gene encoding an expansion of glutamine repeats at the N terminus of the Htt protein. Proteolysis of Htt has been identified as a critical pathological event in HD models. In particular, it has been postulated that proteolysis of Htt at the putative caspase-6 cleavage site (at amino acid Asp-586) plays a critical role in disease progression and pathogenesis. However, whether caspase-6 is indeed the essential enzyme that cleaves Htt at this sitein vivohas not been determined. To evaluate, we crossed the BACHD mouse model with a caspase-6 knock-out mouse (Casp6−/−). Western blot and immunocytochemistry confirmed the lack of caspase-6 protein inCasp6−/−mice, regardless of HD genotype. We predicted theCasp6−/−mouse would have reduced levels of caspase-6 Htt fragments and increased levels of full-length Htt protein. In contrast, we found a significant reduction of full-length mutant Htt (mHtt) and fragments in the striatum of BACHDCasp6−/−mice. Importantly, we detected the presence of Htt fragments consistent with cleavage at amino acid Asp-586 of Htt in the BACHDCasp6−/−mouse, indicating that caspase-6 activity cannot fully account for the generation of the Htt 586 fragmentin vivo. Our data are not consistent with the hypothesis that caspase-6 activity is critical in generating a potentially toxic 586 aa Htt fragmentin vivo. However, our studies do suggest a role for caspase-6 activity in clearance pathways for mHtt protein.