bluuebunny/crossref_metadata_2025 huggingface dataset:
Sharing Oral History With Arctic Indigenous Communities: Ethical Implications of Bringing Back Research Results
Authors: Allemann Lukas , Dudeck Stephan
Published: November 2017

This article discusses ethical implications when sharing results in oral history research. We look at a case study of an Arctic community in Russian Lapland dealing with boarding school experiences. Bringing back research results about this topic provoked diverse reactions. We examine how the social life of stories and the social life of research are interconnected. By questioning the strict applicability of preformulated ethical research principles, we conclude that bringing back research results poses an opportunity to negotiate an appropriate form of reciprocity in research and to gain a deeper understanding of social processes in the communities under study. We identify principles of long-term engagement, collaborative methodologies, and inclusion into the cultural intimacy of the participating community as preconditions for a robust ground for ethics in oral history research.
The Applicability of Resilience Training to the Mitigation of Trauma-Related Mental Illness in Military Personnel
Authors: Thompson Summer R. , Dobbins Sarah
Published: November 2017

BACKGROUND: Ongoing participation by the United States in military operations around the world places military personnel at an increased potential for exposure to trauma, which may directly result in an increased risk for mental health issues. It is important to develop and test new approaches to prevent and mitigate the effects of trauma in military personnel. One such area of research is focused on psychological resilience to prevent the sequelae of trauma. OBJECTIVES: This article examines empirical research of resilience training in military personnel and discusses the potential applicability of such training in this population. DESIGN: In this literature review, four randomized control trials and one retrospective, parallel group study were reviewed. RESULTS: Each intervention had the goal of mitigating behavioral health issues after trauma exposure. The results of the various interventions were wide-ranging from no measurable difference in treatment groups to significant differences in outcomes. CONCLUSIONS: Despite the inconclusive results of our review, we have determined that resilience training for active duty service members to help prevent the deleterious effects of trauma on mental health is a compelling and necessary avenue for further research.
Association of Tissue-Specific DNA Methylation Alterations with α-Thalassemia Southeast Asian Deletion
Authors: Pangeson Tanapat , Sanguansermsri Phanchana , Sanguansermsri Torpong , Seeratanachot Teerapat , Suwanakhon Narutchala , Srikummool Metawee , Kaewkong Worasak , Mahingsa Khwanruedee
Published: November 2017

In the wild-type allele, DNA methylation levels of 10 consecutive CpG sites adjacent to the upstream 5′-breakpoint of α-thalassemia Southeast Asian (SEA) deletion are not different between placenta and leukocytes. However, no previous study has reported the map of DNA methylation in the SEA allele. This report aims to show that the SEA mutation is associated with DNA methylation changes, resulting in differential methylation between placenta and leukocytes. Methylation-sensitive high-resolution analysis was used to compare DNA methylation among placenta, leukocytes, and unmethylated control DNA. The result indicates that the DNA methylation between placenta and leukocyte DNA is different and shows that the CpG status of both is not fully unmethylated. Mapping of individual CpG sites was performed by targeted bisulfite sequencing. The DNA methylation level of the 10 consecutive CpG sites was different between placenta and leukocyte DNA. When the 10th CpG of the mutation allele was considered as a hallmark for comparing DNA methylation level, it was totally different from the unmethylated 10th CpG of the wild-type allele. Finally, the distinct DNA methylation patterns between both DNA were extracted. In total, 24 patterns were found in leukocyte samples and 9 patterns were found in placenta samples. This report shows that the large deletion is associated with DNA methylation change. In further studies for clinical application, the distinct DNA methylation pattern might be a potential marker for detecting cell-free fetal DNA.
A Guide to Topical Vehicle Formulations
Authors: Mayba Julia N. , Gooderham Melinda J.
Published: November 2017

Adherence to topical treatment for a variety of chronic skin conditions, such as psoriasis, acne, and atopic dermatitis, is known to be very poor. A number of factors contribute to this phenomenon, including lack of treatment efficacy and patient concerns regarding side effects, among others. At the forefront of barriers facing optimal patient adherence to topical treatment is choosing the ideal topical vehicle formulation. Medical professionals have demonstrated a lack of understanding with respect to the composition and nomenclature of the various topical formulations. In this review, we clarify the properties and definitions of the following topical formulations: ointments, creams, lotions, topical solutions, topical suspensions, gels, foams, and sprays. We also provide suggested areas of application for the aforementioned formulations and a succinct, patient-geared summary of their advantages and disadvantages. This review hopes to deliver a clear and concise practical summary of the most commonly encountered topical formulations for the treatment of cutaneous disease for medical professionals. This will allow clinicians to provide their patients with accurate information to facilitate informed choice of topical formulation, which may serve to improve treatment adherence.
Utopia, nostalgia, and femininity: visually promoting the Chinese Dream
Authors: Sun Zhen
Published: November 2017

The concept of the Chinese Dream has become a primary developmental goal of the Chinese Communist Government since it was put forth by Xi Jinping in 2012. It has been promoted through different forms of media, of which propaganda posters have played a dominant role. The propaganda discourse regarding the Chinese Dream has been mainly articulated in both the verbal text in official documents and the visual text in the posters. This study focuses on analyzing the visual images represented in the posters and exploring how they accord with social and historical texts, particularly the official verbal text of the Chinese Dream, the historical text of the propaganda of the Communist Party of China, and the social–cultural text interrelated with the visual symbols. The approach of intertextuality and intervisualityis adopted for the analysis and interpretation. The study shows that the majority of the visual symbols used in the posters are transposed from the sign systems of Chinese traditional culture and the revolutionary discourse of the Communist Party of China. The political concept of the Chinese Dream has embodied the characteristics of utopia, nostalgia, and femininity. With the posters in public spaces, the visual propaganda of the Chinese Dream has turned it into a mundane movement of political culture. This study hopes to contribute to the understanding of the role of visual images in political discursive formations and integrated propaganda in post-socialist China.
What ethical resources are available to Alcohol and Other Drug practitioners? A systematic review
Authors: Silkoff David , Guillemin Marilys , Chenhall Richard , McDougall Rosalind
Published: November 2017

Clinical work in Alcohol and Other Drugs has not generally been an area of focus for ethicists. Likewise, ethics is not usually part of Alcohol and Other Drugs training or practice. This means that resources available to Alcohol and Other Drugs clinicians navigating ethical challenges are not widely available. This paper describes a systematic review of literature at the intersection of ethics and clinical practice in Alcohol and Other Drugs. The review will potentially benefit Alcohol and Other Drug practitioners by outlining what resources currently available and will also highlight potential directions for future research. The review searched for all published work in ethics at the intersection with Alcohol and Other Drugs. Searches within academic databases, the World Wide Web, and within journal Tables of Contents identified 18 relevant papers from 1985 onwards. An inductive process of categorisation produced two categories of this literature. The first was codes of ethics, further divided into rule-based codes (n = 4) and principle-based codes (n = 10). The second category was of empirical ethics (n = 4). Rule-based codes are not considered useful to practitioners. They can discourage reflection and potential irrelevance of rules. Principle-based codes are more useful, and principles specific to Alcohol and Other Drugs were identified in some literature. Empirical ethics enable the identification of ethics in everyday clinical work, rather than categorising ethics as a special case in particularly challenging circumstances. The four empirical ethics papers describe highly specific situations, guiding practitioners in these areas. This small body of work demonstrates that future research in empirical ethics is of potential benefit to research in ethics and to clinical practice in Alcohol and Other Drugs.
A case study of the co-production approach to the implementation of education for sustainable development in Thailand
Authors: Nuamcharoen Suwida , Dhirathiti Nopraenue S
Published: November 2017

Thailand is a good example of a developing country which is struggling with globally common problems in trying to find solutions for sustainable education development. Education is one of the important methods to build the mindset of Thai people toward sustainable development (SD). The co-production approach is a way of improving public services, including education for sustainable development (ESD). The study employs qualitative research techniques which aim at studying the implementation and co-production of ESD. Moreover, it is to explore and synthesize the implementation characteristics of co-producing ESD in Thailand. The research found 12 correlated indicators from the literature that link SD, ESD and co-production practices. They were categorized into input, process and output of the cycle of implementing and co-producing ESD. The indicators were examined within the context of the case study of Bansankong School. The researchers conducted in-depth interviews with stakeholders that included representatives from the school administration, families and communities, local authorities, other relevant institutions and volunteers. The results showed that factors in the process portion of the cycle of implementing and co-producing ESD tended to be more significant; these were community engagement, information technology and media usage, and the contingency approach. The factors in the input portion of the process, namely, self-reliance and self-efficiency of population and leadership, and the factor of mutual benefits in the output portion proved to be significant. The other seven factors, cultural adaptation, democratic participation, equitability, goal of sustainable future, interdependence, interdisciplinary approaches and collaborative approach and partnership, appeared to be non-significant.
Meeting the needs of local communities and businesses: From transactional to eco-leadership in the English further education sector
Authors: Boocock Andrew
Published: November 2017

Leadership in the post-incorporation English further education system has not been distributed in nature, but transactional, driven by the external demands of funding and inspection regimes. However, in the light of the current rhetoric of localism in further education policy there is a view that distributed leadership would be an appropriate alternative form of leadership within this context. This article reviews the education literature and argues that distributed leadership should be introduced to the sector, but that on its own this will be insufficient for addressing the government’s agenda of meeting the human capital needs of businesses,  needs-based equity for disadvantaged adults, or the wider benefits of education. This is because distributed leadership, whilst involving a dispersion of responsibility, may not equate to a dispersion of power. To disperse power to local areas and to facilitate an authentic distributed leadership focused on local stakeholders a policy of localism that encourages self-governance and open systems is needed. More specifically flexible accountability arrangements are required that encourage strategy and leadership at the local level. Such distributed leadership embedded within a local governance that facilitates dispersed power to key local stakeholders is similar to what is described as eco-leadership in the leadership literature.
Refining the ischemic penumbra with topography
Authors: Thirugnanachandran Tharani , Ma Henry , Singhal Shaloo , Slater Lee-Anne , Davis Stephen M , Donnan Geoffrey A , Phan Thanh
Published: November 2017

It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of “good” outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach.
Modelling of combustion acoustics sources and their dynamics in the PRECCINSTA burner test case
Authors: Grimm Felix , Dierke Jürgen , Ewert Roland , Noll Berthold , Aigner Manfred
Published: November 2017

A stochastic, hybrid computational fluid dynamics/computational combustion acoustics approach for combustion noise prediction is applied to the PRECCINSTA laboratory scale combustor (prediction and control of combustion instabilities in industrial gas turbines). The numerical method is validated for its ability to accurately reproduce broadband combustion noise levels from measurements. The approach is based on averaged flow field and turbulence statistics from computational fluid dynamics simulations. The three-dimensional fast random particle method for combustion noise prediction is employed for the modelling of time-resolved dynamics of sound sources and sound propagation via linearised Euler equations. A comprehensive analysis of simulated sound source dynamics is carried out in order to contribute to the understanding of combustion noise formation mechanisms. Therefrom gained knowledge can further on be incorporated for the investigation of onset of thermoacoustic phenomena. The method-inherent stochastic Langevin ansatz for the realisation of turbulence related source decay is analysed in terms of reproduction ability of local one- and two-point statistical input and therefore its applicability to complex test cases. Furthermore, input turbulence statistics are varied, in order to investigate the impact of turbulence on the resulting sound pressure spectra for a swirl stabilised, technically premixed combustor.
Opioid prescribing in general practice: use of a two-stage review tool to identify and assess high-dose prescribing
Authors: Ponton Rhys , Sawyer Richard
Published: November 2017

Background:

Long-term opioid analgesic prescribing in chronic non-cancer pain (CNCP) is a growing worldwide concern. This has implications for optimal healthcare management in general and chronic pain management specifically. This work documents the development of a review tool and its use in the South West of England in a locality that showed opioid prescribing levels higher than surrounding localities.

Methods:

An electronic tool which enabled calculation of total prescribed morphine-equivalent doses was developed to allow general practitioners (GPs) to undertake reviews of CNCP patients. This tool was used to assess strong opioid prescribing over a 3-month period at every GP practice (n = 41) in the locality. Every prescription for morphine, oxycodone, pethidine and fentanyl during this period was included. Aspects assessed included drug(s) prescribed, dose prescribed, whether tramadol was prescribed concurrently, whether the drugs were potentially being overused and/or whether the patient was in palliative care. Patients prescribed over 120 mg morphine equivalent per day were reviewed in greater depth, as this is an indication for specialist input.

Results:

In total, 1881 patients received a prescription in the assessment period. Morphine was the most commonly prescribed drug (n = 847). In all, 363 CNCP patients were prescribed a dose equal to or above 120 mg morphine a day, with a maximum morphine-equivalent dose of 890 mg being prescribed. Over 11% (n = 211) of patients were concurrently prescribed tramadol. The most frequently cited reason for prescription of high-dose opioids was found to be a musculoskeletal pain of the back, neck, joints or limbs. The care of 85 specific CNCP patients was reviewed and optimised.

Discussion:

No published work to date has documented such an in-depth analysis of primary-care opioid analgesic prescribing utilising prescriber data. Assessing total-dose morphine-equivalent prescribing using this method provides valuable insights into the potential need for urgent medication review. The tool developed may be of value to other GP practices following validation.
Liposomal adjuvant development for leishmaniasis vaccines
Authors: Askarizadeh Anis , Jaafari Mahmoud Reza , Khamesipour Ali , Badiee Ali
Published: November 2017

Leishmaniasis is a parasitic disease that ranges in severity from skin lesions to fatality. Since long-lasting protection is induced upon recovery from cutaneous leishmaniasis, development of an effective vaccine is promising. However, there is no vaccine for use in humans yet. It seems limited efficacy in leishmaniasis vaccines is due to lack of an appropriate adjuvant or delivery system. Hence, the use of particulate adjuvants such as liposomes for effective delivery to the antigen presenting cells (APCs) is a valuable strategy to enhance leishmaniasis vaccine efficacy. The extraordinary versatility of liposomes because of their unique amphiphilic and biphasic nature allows for using antigens or immunostimulators within the core, on the surface or within the bilayer, and modulates both the magnitude and the T-helper bias of the immune response. In this review article, we attempt to summarize the role of liposomal adjuvants in the development of Leishmania vaccines and describe the main physicochemical properties of liposomes like phospholipid composition, surface charge, and particle size during formulation design. We also suggest potentially useful formulation strategies in order for future experiments to have a chance to succeed as liposomal vaccines against leishmaniasis.
Wired for Innovation
Authors: Dougherty Ilona , Clarke Amelia
Published: November 2017

This conceptual article argues that young people’s brains are “wired for innovation” and that society should better engage this age-group to access its innovation potential. Research published in the neuroscience and developmental psychology literature shows that between 15 and 25 years of age adolescents and emerging adults possess traits of successful innovators. They are collaborative, creative, observant, curious, willing to experiment, willing to challenge the status quo, risk-takers, action oriented, and visionary. In addition, Millennials and Generation Z are coming of age in a context that provides them with innovation ability during adolescence and emerging adulthood beyond that of previous generations. This article proposes that organizations able to effectively engage young people will be more innovative. Also, when young people are meaningfully engaged, society is more likely to find solutions needed to tackle social, environmental, and economic challenges.
Muscle atrophy and recovery of individual thigh muscles as measured by magnetic resonance imaging scan during treatment with cast for ankle or foot fracture
Authors: Yamauchi Koun , Yoshiko Akito , Suzuki Shigetoshi , Kato Chisato , Akima Hiroshi , Kato Takayuki , Ishida Koji
Published: November 2017

Purpose:

We aimed to longitudinally investigate individual thigh muscle changes using magnetic resonance imaging (MRI) during treatment with cast of ankle or foot fracture. Moreover, we aimed to demonstrate whether measurements of muscle cross-sectional area (CSA) are sensitive to muscle changes, contributing to simpler methods in clinical application .

Methods:

Ten patients undergoing treatment with cast of acute ankle or foot fractures were studied. Axial MRI (1.5 T) was conducted around the affected mid-thigh region after the injury (Pre), after maintaining a nonweight-bearing (NWB) period (approximately 28 days), and after finishing rehabilitation (recovery). Regarding individual thigh muscles, the total CSAs corresponding to 40% of the femoral length (FL) and the CSAs at 5% interval of the FL were longitudinally measured. Standardized response means (SRMs) were accessed for sensitivity in the muscle changes.

Results:

The total CSAs at NWB were significantly lower than those at Pre in vastus lateralis (10.9% ± 5.4%), vastus intermedius (8.4% ± 6.7%), and vastus medialis (11.2% ± 6.9%) ( p < 0.01 for all). In contrast, at recovery, the only significant muscle atrophy relative to that at Pre was observed in the semitendinosus of the proximal 15% and 10% CSAs ( p < 0.01 and p = 0.01, respectively). In all muscles, SRM using a single-slice CSA at or near the muscle belly was high.

Conclusion:

Thigh muscle changes differ according to the variations in individual muscles. CSA measurements at or near the muscle belly are simple methods and sensitive indicators of these muscle changes.
Hallucinations Are Real to Patients With Dementia
Authors: Hamdy R. C. , Kinser A. , Lewis J. V. , Copeland R. , Depelteau A. , Kendall-Wilson T. , Whalen K.
Published: November 2017

In this case study, we present a patient with preexistent posttraumatic stress disorder and psychosis who has been recently diagnosed with Dementia with Lewy Bodies. He is experiencing vivid hallucinations. What went wrong between him and his wife as a result of these hallucinations is presented. Alternative actions that could have been used are suggested.

Objectives

At the end of this case study, readers will know the following: The characteristic clinical features of Dementia with Lewy Bodies (DLB). Patients experiencing hallucinations should not be contradicted, to them, these hallucinations are real. Easy distractibility and short attention span can be exploited to avert or defuse potentially catastrophic situations. Patients with dementia should not have access to loaded guns.
Tympanometric Patterns of Children with Allergic Rhinitis Treated at a Tertiary Health Institution
Authors: Fasunla Ayotunde James , Ijitola Julius Olowo , Nwaorgu Onyekwere George
Published: November 2017

Objectives

To determine the prevalence of otitis media with effusion (OME) and compare patterns of tympanogram between children with and without allergic rhinitis in Ibadan, Nigeria.

Study Design

A case‐control study of children (2‐7 years) with AR from May 2015 to March 2016.

Setting

Tertiary hospital.

Subjects and Methods

Consecutive 86 children with AR and 86 healthy controls (nonallergic) participated in the study. A structured questionnaire was administered to parents or caregivers of the participants to obtain relevant sociodemographic and clinical information. Diagnosis of AR was by symptomatology and nasal cytology. Both groups had ear, nose, and throat examination and tympanometric evaluation. OME was diagnosed according to Jerger’s tympanometric patterns.

Results

The mean ± SD ages of cases and controls were 3.80 ± 1.72 and 3.78 ± 1.71 years, respectively. All cases presented with watery nasal discharge, bouts of sneezing, and nasal itching. The duration of AR symptoms was 18 ± 13 months. Among cases and controls, Jerger’s type A tympanogram was the most common pattern, while type C was the least common. Thirty‐nine (45.3%) children with AR had OME, as compared with 8 (9.3%) controls, and the difference was statistically significant (P <. 001; odds ratio = 8.090; 95% CI = 3.48‐18.79).

Conclusion

Prevalence of OME was significantly high among children with AR. Jerger’s type B and C tympanograms were more common among children with AR than the healthy pediatric population. This background information supports the need for routine tympanometric evaluation of children with AR.
Aging of hematopoietic stem cells
Authors: de Haan Gerald , Lazare Seka Simone
Published: November 2017

Hematopoietic stem cells (HSCs) ensure a balanced production of all blood cells throughout life. As they age, HSCs gradually lose their self-renewal and regenerative potential, whereas the occurrence of cellular derailment strongly increases. Here we review our current understanding of the molecular mechanisms that contribute to HSC aging. We argue that most of the causes that underlie HSC aging result from cell-intrinsic pathways, and reflect on which aspects of the aging process may be reversible. Because many hematological pathologies are strongly age-associated, strategies to intervene in aspects of the stem cell aging process may have significant clinical relevance.
Anemia at older age: etiologies, clinical implications, and management
Authors: Stauder Reinhard , Valent Peter , Theurl Igor
Published: November 2017

Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodysplastic syndrome (MDS), develop preferentially in elderly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutritional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller number of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idiopathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic criteria for MDS or other hematologic diseases are not fulfilled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cognitive capacities and quality of life. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and detailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and innovative concepts in the management of these patients.
Age-related clonal hematopoiesis
Authors: Shlush Liran I.
Published: November 2017

Age-related alterations in the human blood system occur in B cells, T cells, cells of the innate system, as well as hematopoietic stem and progenitor cells (HSPCs). Interestingly, age-related, reduced genetic diversity can be identified at the stem cell level and also independently in B cells and T cells. This reduced diversity is most probably related to somatic mutations or to changes in the microenvironmental niche. Either process can select for specific clones or cause repeated evolutionary bottlenecks. This review discusses the age-related clonal expansions in the human HSPC pool, which was termed in the past age-related clonal hematopoiesis (ARCH). ARCH is defined as the gradual, clonal expansion of HSPCs carrying specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematological malignancies. ARCH is associated not just with chronological aging but also with several other, age-related pathological conditions, including inflammation, vascular diseases, cancer mortality, and high risk for hematological malignancies. Although it remains unclear whether ARCH is a marker of aging or plays an active role in these various pathophysiologies, it is suggested here that treating or even preventing ARCH may prove to be beneficial for human health. This review also describes a decision tree for the diagnosis and follow-up for ARCH in a research setting.
Frailty and the management of hematologic malignancies
Authors: Abel Gregory A. , Klepin Heidi D.
Published: November 2017

The majority of blood cancers occur in the elderly. This fact conspires with an aging population in many countries to make rigorous assessment for frailty increasingly important for hematologic oncologists. In this review, we first define frailty and its relevance for patients with hematologic malignancy. Next, we review current data regarding the effect of domains of frailty on outcomes for blood cancers including myelodysplastic syndromes, acute leukemia, non-Hodgkin lymphomas such as chronic lymphocytic leukemia, and multiple myeloma. Finally, after presenting assessment and treatment options for the practicing hematologist, we propose elements of a new research agenda for geriatric hematology: the exchange of age limits for rigorous frailty screening, development of disease-specific measures, and inclusion of functional and patient-reported outcomes alongside survival.
A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma
Authors: Amengual Jennifer E. , Lichtenstein Renee , Lue Jennifer , Sawas Ahmed , Deng Changchun , Lichtenstein Emily , Khan Karen , Atkins Laine , Rada Aishling , Kim Hye A. , Chiuzan Codruta , Kalac Matko , Marchi Enrica , Falchi Lorenzo , Francescone Mark A. , Schwartz Lawrence , Cremers Serge , O’Connor Owen A.
Published: November 2017

Key Points

The combination of romidepsin and pralatrexate is safe and well tolerated in patients with relapsed/refractory lymphoma. The combination led to an overall response rate of 71% (10/14, with 4/14 complete responses) in patients with relapsed/refractory T-cell lymphoma.
Management of newly diagnosed immune thrombocytopenia: can we change outcomes?
Authors: Neunert Cindy E.
Published: November 2017

Immune thrombocytopenia resulting from antibody-mediated platelet destruction combined with impaired platelet production is a common cause of thrombocytopenia. The decision to treat newly diagnosed patients is based on several factors including ceasing hemorrhagic manifestations, increasing the platelet count, prevention of bleeding, and inducing remission. Current standard first-line therapy is a course of corticosteroids. Although this treatment paradigm increases the platelet count in the majority of patients, a high percentage relapse after discontinuation of corticosteroid therapy. For this reason, intensification of first-line therapy that results in superior long-term remission rates would be desirable. This manuscript focuses primarily on adults with idiopathic thrombocytopenic purpura (ITP), highlighting pediatric data and practice when applicable. The primary aim is to outline upfront strategies for treatment-naive patients with ITP to enhance remission rates, taking into account assessment of the risks and benefits of these approaches.
Anisotropic Müller glial scaffolding supports a multiplex lattice mosaic of photoreceptors in zebrafish retina
Authors: Nagashima Mikiko , Hadidjojo Jeremy , Barthel Linda K. , Lubensky David K. , Raymond Pamela A.
Published: November 2017

Background

The multiplex, lattice mosaic of cone photoreceptors in the adult fish retina is a compelling example of a highly ordered epithelial cell pattern, with single cell width rows and columns of cones and precisely defined neighbor relationships among different cone types. Cellular mechanisms patterning this multiplex mosaic are not understood. Physical models can provide new insights into fundamental mechanisms of biological patterning. In earlier work, we developed a mathematical model of photoreceptor cell packing in the zebrafish retina, which predicted that anisotropic mechanical tension in the retinal epithelium orients planar polarized adhesive interfaces to align the columns as cone photoreceptors are generated at the retinal margin during post-embryonic growth.

Methods

With cell-specific fluorescent reporters and in vivo imaging of the growing retinal margin in transparent juvenile zebrafish we provide the first view of how cell packing, spatial arrangement, and cell identity are coordinated to build the lattice mosaic. With targeted laser ablation we probed the tissue mechanics of the retinal epithelium.

Results

Within the lattice mosaic, planar polarized Crumbs adhesion proteins pack cones into a single cell width column; between columns, N-cadherin-mediated adherens junctions stabilize Müller glial apical processes. The concentration of activated pMyosin II at these punctate adherens junctions suggests that these glial bands are under tension, forming a physical barrier between cone columns and contributing to mechanical stress anisotropies in the epithelial sheet. Unexpectedly, we discovered that the appearance of such parallel bands of Müller glial apical processes precedes the packing of cones into single cell width columns, hinting at a possible role for glia in the initial organization of the lattice mosaic. Targeted laser ablation of Müller glia directly demonstrates that these glial processes support anisotropic mechanical tension in the planar dimension of the retinal epithelium.

Conclusions

These findings uncovered a novel structural feature of Müller glia associated with alignment of photoreceptors into a lattice mosaic in the zebrafish retina. This is the first demonstration, to our knowledge, of planar, anisotropic mechanical forces mediated by glial cells.
Time-domain full-waveform inversion of exponentially damped wavefield using the deconvolution-based objective function
Authors: Choi Yunseok , Alkhalifah Tariq
Published: November 2017

Full-waveform inversion (FWI) suffers from the cycle-skipping problem when the available frequency-band of data is not low enough. We have applied an exponential damping to the data to generate artificial low frequencies, which helps FWI to avoid cycle skipping. In this case, the least-squares misfit function does not properly deal with the exponentially damped wavefield in FWI because the amplitude of traces decays almost exponentially with increasing offset in a damped wavefield. Thus, we use a deconvolution-based objective function for FWI of the exponentially damped wavefield. The deconvolution filter includes inherently a normalization between the modeled and observed data; thus, it can address the unbalanced amplitude of a damped wavefield. We specifically normalize the modeled data with the observed data in the frequency-domain to estimate the deconvolution filter and selectively choose a frequency-band for normalization that mainly includes the artificial low frequencies. We calculate the gradient of the objective function using the adjoint-state method. The synthetic and benchmark data examples indicate that our FWI algorithm generates a convergent long-wavelength structure without low-frequency information in the recorded data.
Prenatal High Estradiol Exposure Induces Sex-Specific and Dietarily Reversible Insulin Resistance Through Decreased Hypothalamic INSR
Authors: Wang Hui-Hui , Zhou Cheng-Liang , Lv Min , Yang Qian , Li Ju-Xue , Hou Min , Lin Jing , Liu Xin-Mei , Wu Yan-Ting , Sheng Jian-Zhong , Huang He-Feng
Published: November 2017

An adverse intrauterine environment may induce adult disease in offspring, but the mechanisms are not well understood. It is reported that fresh embryo transfer (ET) in assisted reproductive technology leads to high maternal estradiol (E2), and prenatal high E2 exposure increases the risk of organ disorders in later life. We found that male newborns and children of fresh ET showed elevated fasting insulin and homeostasis model of assessment for insulin resistance index (HOMA-IR) scores. Male mice with high prenatal estradiol exposure (HE) grew heavier than control mice and developed insulin resistance; they also showed increased food intake, with increased orexigenic hypothalamic neuropeptide Y (NPY) expression. The hypothalamic insulin receptor (INSR) was decreased in male HE mice, associated with elevated promoter methylation. Chronic food restriction (FR) in HE mice reversed insulin resistance and rescued hypothalamic INSR expression by correcting the elevated Insr promoter methylation. Our findings suggest that prenatal exposure to high E2 may induce sex-specific metabolic disorders in later life through epigenetic programming of hypothalamic Insr promoter, and dietary intervention may reverse insulin resistance by remodeling its methylation pattern.
The resurrection of the PIDDosome – emerging roles in the DNA-damage response and centrosome surveillance
Authors: Sladky Valentina , Schuler Fabian , Fava Luca L. , Villunger Andreas
Published: November 2017

The PIDDosome is often used as the alias for a multi-protein complex that includes the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the pro-form of an endopeptidase belonging to the caspase family, i.e. caspase-2. Yet, PIDD1 variants can also interact with a number of other proteins that include RIPK1 (also known as RIP1) and IKBKG (also known as NEMO), PCNA and RFC5, as well as nucleolar components such as NPM1 or NCL. This promiscuity in protein binding is facilitated mainly by autoprocessing of the full-length protein into various fragments that contain different structural domains. As a result, multiple responses can be mediated by protein complexes that contain a PIDD1 domain. This suggests that PIDD1 acts as an integrator for multiple types of stress that need instant attention. Examples are various types of DNA lesion but also the presence of extra centrosomes that can foster aneuploidy and, ultimately, promote DNA damage. Here, we review the role of PIDD1 in response to DNA damage and also highlight novel functions of PIDD1, such as in centrosome surveillance and scheduled polyploidisation as part of a cellular differentiation program during organogenesis.
Live imaging reveals distinct modes of neutrophil and macrophage migration within interstitial tissues
Authors: Barros-Becker Francisco , Lam Pui-Ying , Fisher Robert , Huttenlocher Anna
Published: November 2017

Cell motility is required for diverse processes during immunity and inflammation. Classically, leukocyte motility is defined as an amoeboid type of migration, however some leukocytes, like macrophages, also employ a more mesenchymal mode of migration. Here, we sought to characterize the mechanisms that regulate neutrophil and macrophage migration in vivo by using real-time imaging of leukocyte motility within interstitial tissues in zebrafish larvae. Neutrophils displayed a rounded morphology and rapid protease-independent motility, lacked defined paxillin puncta, and had persistent rearward polarization of stable F-actin and the microtubule network. By contrast, macrophages displayed an elongated morphology with reduced speed and increased directional persistence and formed paxillin-containing puncta but had a less-defined polarization of the microtubule and actin networks. We also observed differential effects of protease inhibition, microtubule disruption and ROCK inhibition on the efficiency of neutrophil and macrophage motility. Taken together, our findings suggest that larval zebrafish neutrophils and macrophage display distinct modes of migration within interstitial tissues in vivo.
TFCP2L1 represses multiple lineage commitment of mouse embryonic stem cells through MTA1 and LEF1
Authors: Liu Kuisheng , Zhang Yan , Liu Dahai , Ying Qi-Long , Ye Shoudong
Published: November 2017

TFCP2L1 is a transcription factor that is crucial for self-renewal of mouse embryonic stem cells (mESCs). How TFCP2L1 maintains the pluripotent state of mESCs, however, remains unknown. Here, we show that knockdown of Tfcp2l1 in mESCs induces the expression of endoderm, mesoderm and trophectoderm markers. Functional analysis of mutant forms of TFCP2L1 revealed that TFCP2L1 depends on its N-terminus and CP2-like domain to maintain the undifferentiated state of mESCs. The N-terminus of TFCP2L1 is mainly associated with the suppression of mesoderm and trophectoderm differentiation, while the CP2-like domain is closely related to the suppression of endoderm commitment. Further studies showed that MTA1 directly interacts with TFCP2L1 and is indispensable for the TFCP2L1-mediated self-renewal-promoting effect and endoderm-inhibiting action. TFCP2L1-mediated suppression of mesoderm and trophectoderm differentiation, however, seems to be due to downregulation of Lef1 expression. Our study thus provides an expanded understanding of the function of TFCP2L1 and the pluripotency regulation network of ESCs.
Multiple pathways facilitate the biogenesis of mammalian tail-anchored proteins
Authors: Casson Joseph , McKenna Michael , Haßdenteufel Sarah , Aviram Naama , Zimmerman Richard , High Stephen
Published: November 2017

Tail-anchored (TA) proteins are transmembrane proteins with a single C-terminal transmembrane domain, which functions as both their subcellular targeting signal and membrane anchor. We show that knockout of TRC40 in cultured human cells has a relatively minor effect on endogenous TA proteins, despite their apparent reliance on this pathway in vitro. These findings support recent evidence that the canonical TRC40 pathway is not essential for TA protein biogenesis in vivo. We therefore investigated the possibility that other ER-targeting routes can complement the TRC40 pathway and identified roles for both the SRP pathway and the recently described mammalian SND pathway in TA protein biogenesis. We conclude that, although TRC40 normally plays an important role in TA protein biogenesis, it is not essential, and speculate that alternative pathways for TA protein biogenesis, including those identified in this study, contribute to the redundancy of the TRC40 pathway.
Lower limb biomechanical analysis during an unanticipated step on a bump reveals specific adaptations of walking on uneven terrains
Authors: Panizzolo Fausto A. , Lee Sangjun , Miyatake Taira , Rossi Denise Martineli , Siviy Christopher , Speeckaert Jozefien , Galiana Ignacio , Walsh Conor J.
Published: November 2017

Although it is clear that walking over different irregular terrain is associated with altered biomechanics, there is little understanding of how we quickly adapt to unexpected variations in terrain. This study aims to investigate which adaptive strategies humans adopt when performing an unanticipated step on an irregular surface, specifically a small bump. Nine healthy male participants walked at their preferred walking speed along a straight walkway during five conditions: four involving unanticipated bumps of two different heights, and one level walking condition. Muscle activation of eight lower limb muscles and three-dimensional gait analysis were evaluated during these testing conditions. Two distinct adaptive strategies were found, which involved no significant change in total lower limb mechanical work or walking speed. An ankle-based strategy was adopted when stepping on a bump with the forefoot, whereas a hip-based strategy was preferred when stepping with the rearfoot. These strategies were driven by a higher activation of the plantarflexor muscles (6–51%), which generated a higher ankle joint moment during the forefoot conditions and by a higher activation of the quadriceps muscles (36–93%), which produced a higher knee joint moment and hip joint power during the rearfoot conditions. These findings provide insights into how humans quickly react to unexpected events and could be used to inform the design of adaptive controllers for wearable robots intended for use in unstructured environments that can provide optimal assistance to the different lower limb joints.
Transparent anemone shrimp (Ancylomenes pedersoni) become opaque after exercise and physiological stress in correlation with increased hemolymph perfusion
Authors: Bagge Laura E. , Kinsey Stephen T. , Gladman Justin , Johnsen Sönke
Published: November 2017

Whole-body transparency, an effective camouflage strategy in many aquatic species, can be disrupted by environmental and/or physiological stressors. We found that tail-flip escape responses temporarily disrupt the transparency of the anemone shrimp Ancylomenes pedersoni. After as few as three tail flips, the previously transparent abdominal muscle became cloudy. Eliciting additional tail flips to the point of exhaustion (16±1 s.e.m.; n=23) resulted in complete opacity, though the original transparency returned after 20–60 min of inactivity. We hypothesized that an exercise-induced increase in blood volume between muscle fibers creates regions of low refractive index fluid between high refractive index muscles, thereby increasing light scattering. We documented pre- and post-contraction perfusion by injecting Alexa Fluor 594 wheat germ agglutinin that labeled sarcolemmal surfaces and endothelial cells in contact with hemolymph and found more hemolymph perfused through the abdominal tissue post-exercise, presumably owing to more capillaries opening. In addition, we altered salinity (to 55‰ and 8‰), perforated the abdomen and injected a vasodilator. All three treatments increased both perfusion and opacity, lending further support to our hypothesis that increased hemolymph perfusion to the abdomen is one mechanism that can disrupt a shrimp's transparency. The fact that transparent shrimp at rest have little to no evidence of perfusion to their abdominal musculature (unlike the opaque shrimp Lysmata pederseni, which had more perfusion even at rest) indicates that they may experience significant physiological trade-offs in order to maintain their transparency; specifically, limiting blood flow and thereby reducing oxygen delivery may result in reduced performance.
Giving invertebrates an eye exam: an ophthalmoscope that utilizes the autofluorescence of photoreceptors
Authors: Stowasser Annette , Owens Madeline , Buschbeck Elke K.
Published: November 2017

One of the most important functional features of eyes is focusing light, as both nearsightedness and farsightedness have major functional implications. Accordingly, refractive errors are frequently assessed in vertebrates, but not in the very small invertebrate eyes. We describe a micro-ophthalmoscope that takes advantage of autofluorescent properties of invertebrate photoreceptors and test the device on the relatively well-understood eyes of jumping spiders and flies. In each case, our measurements confirmed previous findings with a greater degree of accuracy. For example, we could precisely resolve the layering of the anterior median eyes and could map out the extensive retina of the anterior lateral eyes of the spider. Measurements also confirmed that fly ommatidia are focused into infinity, but showed that their focal plane is situated slightly below the receptor surface. In contrast to other approaches, this device does not rely on reflective tapeta and allows for precise optical assessment of diverse invertebrate eyes.