bluuebunny/crossref_metadata_2025 huggingface dataset:
Chondrogenic potential of bone marrow–derived mesenchymal stem cells on a novel, auricular-shaped, nanocomposite scaffold
Authors: Patel Kavi H , Nayyer Leila , Seifalian Alexander M
Published: December 2013

Reconstruction of the human auricle remains a challenge to plastic surgeons, and current approaches are not ideal. Tissue engineering provides a promising alternative. This study aims to evaluate the chondrogenic potential of bone marrow–derived mesenchymal stem cells on a novel, auricular-shaped polymer. The proposed polyhedral oligomeric silsesquioxane-modified poly(hexanolactone/carbonate)urethane/urea nanocomposite polymer has already been transplanted in patients as the world’s first synthetic trachea, tear duct and vascular bypass graft. The nanocomposite scaffold was fabricated via a coagulation/salt-leaching method and shaped into an auricle. Adult bone marrow–derived mesenchymal stem cells were isolated, cultured and seeded onto the scaffold. On day 21, samples were sent for scanning electron microscopy, histology and immunofluorescence to assess for neocartilage formation. Cell viability assay confirmed cytocompatability and normal patterns of cellular growth at 7, 14 and 21 days after culture. This study demonstrates the potential of a novel polyhedral oligomeric silsesquioxane-modified poly(hexanolactone/carbonate)urethane/urea scaffold for culturing bone marrow–derived mesenchymal stem cells in chondrogenic medium to produce an auricular-shaped construct. This is supported by scanning electron microscopy, histological and immunofluorescence analysis revealing markers of chondrogenesis including collagen type II, SOX-9, glycosaminoglycan and elastin. To the best of our knowledge, this is the first report of stem cell application on an auricular-shaped scaffold for tissue engineering purposes. Although many obstacles remain in producing a functional auricle, this is a promising step forward.
Sales force control system: Review and perspectives
Authors: Echchakoui Said
Published: December 2013

This article provides a critical overview of the sales force control system. Based on previous research, an integrative model of control system consequences and antecedents is proposed. The literature review revealed numerous theoretical and empirical gaps. In particular, the ambiguity of the relationship between the sales force control and the marketing personnel, the lack of consensus on the criteria for choosing an appropriate type of control, and the conflicting results of the influence of the control system. Three main avenues of research are suggested: first, to clarify the relationship between the sales force control and the marketing personnel; second, to consider a resource-based view as a theoretical basis for the choice of a type of control; and, third, to study some moderating and mediating variables that may explain the origin of the ambiguous consequences of the control system. Those variables are culture and sales manager satisfaction with territory design.
Pharmacogenomics of acute lymphoid leukemia: new insights into treatment toxicity and efficacy
Authors: Relling Mary V. , Ramsey Laura B.
Published: December 2013

Childhood acute lymphoblastic leukemia (ALL) provides an outstanding model for pharmacogenomic research: it is a drug-responsive disseminated cancer that is cured with medications alone in ∼ 85% of patients, but relapse remains unacceptably high for some subgroups. Inherited genomic variation contributes to the risk of relapse and to the risk of short- and long-term serious adverse effects of therapy. Our goal is to identify the inherited genomic variants that contribute to interindividual differences in response in patients with ALL. We discuss results of whole-genome interrogations of germline DNA in ALL.
Therapeutic applications: natural killer cells in the clinic
Authors: Miller Jeffrey S.
Published: December 2013

Natural killer (NK) cells recognize targets stressed by malignant transformation or infection (particularly CMV). We now know that NK cells can be long-lived and remember past exposures. They become educated by interaction with MHC class I molecules to gain potent function to kill targets and produce cytokines. In the clinical setting, haploidentical NK cells can be transferred adoptively to treat cancer. Persistence and in vivo expansion of NK cells depends on lymphodepleting chemotherapy to make space for the release of endogenous IL-15. In vivo expansion is also enhanced by cytokine administration. IL-2 has been used at low doses to stimulate NK cells in vivo, but has the down side of stimulating CD25hi regulatory T cells. IL-15 is now being tested and has the advantage of avoiding inhibitory regulatory T cell stimulation. In refractory acute myeloid leukemia, leukemia clearance is correlated with the persistence and in vivo expansion of NK cells after adoptive transfer. Limitations to NK cell therapy include poor in vivo survival and lack of specificity. Monoclonal antibodies and bispecific or trispecific killer engagers to target CD16 on NK cells to enhance recognition of various tumor antigens and ADAM17 inhibition to prevent CD16 shedding after NK cell activation should promote enhanced killing of cancer with specificity. Future strategies to exploit favorable donor immunogenetics or to expand NK cells ex vivo from blood, progenitors, or pluripotent progenitors may overcome immune barriers of adoptive transfer and comparative clinical trials will be needed to test these approaches.
Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome
Authors: Diz-Küçükkaya Reyhan
Published: December 2013

Inherited platelet disorders (IPDs) are a heterogeneous group of diseases affecting platelet production, morphology, and function. The degree of thrombocytopenia and functional abnormality of platelets determines the clinical manifestations. Although severe deficiencies may cause excessive bleeding beginning in early childhood, most of IPDs have mild bleeding tendencies and therefore are not always easy to distinguish from acquired platelet disorders. The diagnosis of IPD may require extensive laboratory investigation, because current routine laboratory tests are not satisfactory for differential diagnosis in some cases, and most of the specific tests are not readily available in many countries. This review summarizes the classification and clinical and molecular characteristics of known IPDs, including Bernard-Soulier syndrome and Glanzmann thrombasthenia, with a focus on current challenges in the laboratory diagnosis and management of bleeding in these patients.
Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies
Authors: Crawley James T. B. , Scully Marie A.
Published: December 2013

VWF is a multimeric plasma glycoprotein that specifically recruits platelets to sites of vessel injury. VWF multimeric size is central to this function, with larger multimers being more hemostatically active. Regulation of VWF multimeric size is mediated by the plasma metalloprotease ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13). This enzyme can only recognize and cleave VWF when it is unraveled by rheological shear forces of the flowing blood. After the exposure of cryptic exosites, VWF recognition by ADAMTS13 involves multiple interactions that enable the protease to cleave VWF. Loss of VWF multimer size regulation caused by severe ADAMTS13 deficiency (either inherited or acquired) is associated with the microvascular thrombotic disorder thrombotic thrombocytopenic purpura (TTP). The sequelae associated with TTP are widely thought to be linked to hyperreactive circulating VWF that cause unwanted platelet aggregation in the high shear environment of the microvasculature. Diagnosis of TTP is primarily made through a combination of symptoms, analysis of plasma ADAMTS13 activity, and detection of inhibitory anti-ADAMTS13 antibodies. Current frontline treatments for TTP include plasma exchange, which serves to remove inhibitory antibodies (in acquired TTP) and provide a source of functional ADAMTS13, and steroids to treat the autoimmune component of acquired TTP. The use of anti-CD20 therapy has also exhibited encouraging results in the treatment of acquired TTP. Newer therapeutic strategies that are currently being explored or are in development include recombinant ADAMTS13, a hyperreactive ADAMTS13 variant, and anti-VWF therapy. This review discusses the basic biochemistry of VWF and ADAMTS13, their dysfunction in TTP, and therapeutic approaches for the amelioration of TTP.
Drug discovery in academic institutions
Authors: Frye Stephen V.
Published: December 2013

Although academic science has always provided a fundamental understanding of the biological and clinical basis of disease, the opportunity and imperative for academics to contribute more directly to the discovery of new medicines continues to grow. Embedding medicinal chemists with cancer biologists creates collaborative opportunities for drug discovery and the design and synthesis of chemical biology tool compounds (chemical probes) to better elucidate the role of specific proteins and pathways in biology and disease. Two case studies are presented here: (1) the discovery of inhibitors of mer kinase to treat acute lymphoblastic leukemia in children and (2) the discovery of chemical probes targeting epigenetic regulators. These case studies provide lessons in target selection strategies, the requirement for iterative optimization of lead compounds (useful drugs/probes rarely come directly from a screen), and the value of mutually dependent collaborations between medicinal chemists and cancer biologists.
Antibody-drug conjugates: the chemistry behind empowering antibodies to fight cancer
Authors: Drachman Jonathan G. , Senter Peter D.
Published: December 2013

For more than a century, the concept of a “magic bullet” to deliver cytotoxic therapy to the site of disease has been envisioned but only recently have technological advances enabled antibody-drug conjugates to fulfill that dream. The recent approvals of brentuximab vedotin and ado-trastuzumab emtansine and emerging data for many molecules in clinical trials highlight the potential for antibody-drug conjugates to offer new therapeutic options for patients. This chapter reviews the evolution, state of the art, and potential future improvements that are enabling rapid development of this important class of cancer therapeutics.
Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease
Authors: Gluckman Eliane
Published: December 2013

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Despite antenatal counseling and neonatal screening programs implemented in higher income countries, SCD is still associated with multiple morbidities and early mortality. To date, the only curative approach to SCD is hematopoietic stem cell transplantation, but this therapy is not yet established worldwide. The registries of the European Blood and Marrow Transplant (EBMT) and the Centre for International Blood and Marrow Transplant Research (CIBMTR) account, respectively, for 611 and 627 patients receiving transplantations for SCD. Most of these patients were transplanted with grafts from an HLA-identical sibling donor. The main obstacles to increasing the number of transplantations are a lack of awareness on the part of physicians and families, the absence of reliable prognostic factors for severity, and the perceived risk that transplantation complications may outweigh the benefits of early transplantation. Results show that more than 90% of patients having undergone an HLA-identical sibling transplantation after myeloablative conditioning are cured, with very limited complications. Major improvement is expected from the use of new reduced-toxicity conditioning regimens and the use of alternative donors, including unrelated cord blood transplantations and related haploidentical bone marrow or peripheral blood stem cell transplantations.
Update on the treatment of HIV-associated hematologic malignancies
Authors: Little Richard F. , Dunleavy Kieron
Published: December 2013

HIV is associated with an excess cancer risk, particularly of lymphoid malignancies. Modern therapeutics has changed the landscape of HIV disease and typical opportunistic complications of AIDS are now largely avoided. Although the risk of lymphoma has decreased, it still remains high. Nevertheless, treatment outcomes have improved due both to improvements in HIV medicine and in cancer therapeutics for the common lymphomas occurring in those with HIV infection. Other hematologic malignancies are rarely seen in HIV-infected patients, but the standardized risk ratio for many of these cancers is higher than in the background population. Principles of cancer care and appreciation for HIV infection as a comorbid condition can guide physicians in setting realistic goals and treatment for this patient population. In many cases, expected outcomes are very similar to the HIV-unrelated patients and therapeutic planning should be based on this understanding. Treatment tolerance can be predicted based on the status of the HIV disease and the cancer therapy being administered. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with HIV infection.
Transfusion therapy for sickle cell disease: a balancing act
Authors: Chou Stella T.
Published: December 2013

Transfusion therapy is a key intervention in decreasing morbidity and mortality in patients with sickle cell disease (SCD). Current indications for acute and chronic transfusion therapy have significantly increased the number of RBC units transfused to patients with SCD worldwide. This review summarizes transfusion management for the treatment or prevention of neurologic and perioperative complications, acute chest syndrome, and acute anemia associated with SCD. Despite the recognized benefits of transfusion therapy, it is not without the risks of iron overload, alloimmunization, and delayed hemolytic transfusion reactions. Transfusional iron overload management includes automated RBC exchange, noninvasive imaging to monitor iron burden, and iron chelation with parenteral or oral agents. Although limited and extended RBC antigen matching reduces antibody formation, the prevalence of RBC alloimmunization in patients with SCD remains high. Recent studies demonstrate that RH genetic diversity in patients with SCD contributes to Rh alloimmunization, suggesting that even more refined RBC matching strategies are needed. Advances in molecular blood group typing offer new opportunities to improve RBC matching of donors and recipients and can be of particular benefit to patients with SCD.
The old and new: PCCs, VIIa, and long-lasting clotting factors for hemophilia and other bleeding disorders
Authors: Ragni Margaret V.
Published: December 2013

What is the correct use of established clotting factors, prothrombin complex concentrates (PCCs), and activated factor VII in bleeding complications of trauma, surgery, and old and new oral anticoagulants? How will new clotting factors, specifically the long-acting factors, change the hemostatic management of coagulation deficiency disorders? From bench to bedside, comparative coagulation studies and clinical trials of modified clotting factors are providing insights to help guide hemostatic management of congenital and acquired bleeding disorders. Comparative thrombin-generation studies and preclinical and clinical trials suggest that PCCs and fresh-frozen plasma are effective in reversing the anticoagulant effects of warfarin, yet there are few data to guide reversal of the new oral anticoagulants dabigatran and rivaroxaban. Although coagulation studies support the use of PCCs to reverse new oral anticoagulants, correlation with clinical response is variable and clinical trials in bleeding patients are needed. For congenital bleeding disorders, exciting new technologies are emerging from the bench. Data from clinical trials of molecularly modified coagulation factors with extended half-lives suggest the possibility of fewer infusions, reduced bleeds, and better quality of life in persons with hemophilia. Preclinical studies of other novel prohemostatic approaches for hemophilia and other congenital coagulation disorders include RNA interference silencing of antithrombin, monoclonal anti-tissue factor pathway inhibitor (anti-antibody, anti-tissue factor pathway inhibitor) aptamer, bispecific anti-IXa/X antibody, and fucoidans. Understanding the comparative coagulation studies of established prohemostatic agents, the pharmacokinetics of new long-acting clotting factors, and their correlation with bleeding outcomes will provide opportunities to optimize the hemostatic management of both congenital and acquired hemostatic disorders.
Consequences and management of iron overload in sickle cell disease
Authors: Porter John , Garbowski Maciej
Published: December 2013

The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.
The diagnosis and treatment of venous thromboembolism
Authors: Wells Philip , Anderson David
Published: December 2013

Venous thromboembolism (VTE) is a common condition that can lead to complications such as postphlebitic syndrome, chronic pulmonary artery hypertension, and death. The approach to the diagnosis of has evolved over the years and an algorithm strategy combining pretest probability, D-dimer testing, and diagnostic imaging now allows for safe, convenient, and cost-effective investigation of patients. Patients with low pretest probability and a negative D-dimer can have VTE excluded without the need for imaging. The mainstay of treatment of VTE is anticoagulation, whereas interventions such as thrombolysis and inferior vena cava filters are reserved for special situations. Low-molecular-weight heparin has allowed for outpatient management of most patients with deep vein thrombosis at a considerable cost savings to the health care system. Patients with malignancy-associated VTE benefit from decreased recurrent rates if treated with long-term low-molecular-weight heparin. The development of new oral anticoagulants further simplifies treatment. The duration of anticoagulation is primarily influenced by underlying cause of the VTE (whether provoked or not) and consideration of the risk for major hemorrhage. Testing for genetic and acquired thrombophilia may provide insight as to the cause of a first idiopathic deep vein thrombosis, but the evidence linking most thrombophilias to an increased risk of recurrent thrombosis is limited.
Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies
Authors: Landgren Ola
Published: December 2013

After decades of virtually no progress, multiple myeloma survival has improved significantly in the past 10 years. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. Recent data show that multiple myeloma is consistently preceded by a precursor state (monoclonal gammopathy of undetermined significance [MGUS]/smoldering multiple myeloma [SMM]). This observation provides a framework for prospective studies focusing on transformation from precursor disease to multiple myeloma and for the development of treatment strategies targeting “early myeloma.” This review discusses current biological insights in MGUS/SMM, provides an update on clinical management, and discusses how the integration of novel biological markers, molecular imaging, and clinical monitoring of MGUS/SMM could facilitate the development of early treatment strategies for high-risk SMM (early myeloma) patients in the future.
Targeting B-cell receptor signaling: changing the paradigm
Authors: Fowler Nathan , Davis Eric
Published: December 2013

It is well known that signals emanating from the B-cell receptor (BCR) activate downstream pathways to regulate the development and survival of normal B cells. In B-cell malignancies, it is increasingly understood that similar pathways are activated through both tonic and chronic active BCR signaling to promote tumor viability and resistance to therapy. Recently, several active and oral agents have emerged that target key proximal kinases in the BCR pathway, including Bruton tyrosine kinase, PI3K, and spleen tyrosine kinase. In early clinical studies, these agents have shown significant activity across a broad range of B-cell lymphomas and chronic lymphocytic leukemia. Especially impressive responses have been reported in mantle cell lymphoma and chronic lymphocytic leukemia, and many patients remain on treatment with continued disease control. Toxicity profiles have been mild in the majority of early studies, without significant myelosuppression over prolonged dosing. Due to these attractive attributes, several agents targeting the BCR pathway are now entering early combination studies with traditional chemotherapeutics and/or other novel agents. It is clear that agents targeting the BCR pathway will significantly affect the design of future therapeutic regimens for B-cell malignancies. Future research will focus on understanding potential mechanisms of resistance, identifying biomarkers of response, and defining optimal combination regimens.
Dissecting follicular lymphoma: high versus low risk
Authors: Smith Sonali M.
Published: December 2013

Progress in the management of follicular lymphoma (FL) has translated to improved outcomes, with most patients surviving a decade or more from the time of diagnosis. However, the disease remains quite heterogeneous and a substantial number of patients have more aggressive disease with short responses to therapy and/or transformation to higher-grade lymphomas. Given the lack of a single standard approach, it is important to understand sources of heterogeneity among patients that influence initial management, surveillance strategies, and overall prognosis. Most of the validated tools, such as the Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI-2, apply to the frontline setting, and there is an unmet need for prognostic tools in relapsed and refractory disease states. In particular, the number of prior treatment regimens may be less important than the duration of response to the most recent regimen and the type of prior therapy received. Furthermore, despite awareness of progressive genetic and epigenetic derangements and a growing appreciation of the microenvironment's role in FL outcomes, there is no validated means of incorporating biologic data into clinical prognostic indices. This review highlights the current state of knowledge regarding risk stratification in FL.
Treatment of infant leukemias: challenge and promise
Authors: Brown Patrick
Published: December 2013

Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its unique biology that is increasingly pointing the way toward novel therapeutic approaches. This review highlights the key clinical, pathologic, and epidemiologic features of infant leukemia, including the high frequency of mixed lineage leukemia (MLL) gene rearrangements. The state of the art with regard to current approaches to risk stratified treatment of infant leukemia in the major international cooperative groups is discussed. Finally, exciting recent discoveries elucidating the molecular biology of infant leukemia are reviewed and novel targeted therapeutic strategies, including FLT3 inhibition and modulation of aberrant epigenetic programs, are suggested.
Hemophagocytic lymphohistiocytosis: pathogenesis and treatment
Authors: Janka Gritta E. , Lehmberg Kai
Published: December 2013

Hemophagocytic lymphohistiocytosis (HLH) is not an independent disease but rather a life-threatening clinical syndrome that occurs in many underlying conditions and in all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to the characteristic symptoms of HLH. Genetic defects in familial HLH and in immunodeficiency syndromes associated with albinism affect the transport, processing, and function of cytotoxic granules in natural killer cells and cytotoxic T lymphocytes. This leads to defective killing of target cells and a failure to contract the immune response. The defects are increasingly found also in adolescents and adults. Acquired HLH occurs in autoinflammatory and autoimmune diseases (macrophage activation syndrome) and in patients with iatrogenic immunosuppression or with malignancies, but also in otherwise healthy persons with infections. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed for the correction of the immune defect. Treatment modalities include immunosuppressive, immunomodulatory, and cytostatic drugs; T-cell antibodies; and anticytokine agents. Using immunochemotherapy, familial HLH, which had been invariably fatal, has become a curable disease with more than 50% survivors. Reduced intensity conditioning for HSCT, which is associated with less transplantation-related mortality, will further improve cure rates.
EBV and posttransplantation lymphoproliferative disease: what to do?
Authors: Zimmermann Heiner , Trappe Ralf U.
Published: December 2013

This review summarizes the available evidence and outlines our approach to the prophylaxis and management of posttransplantation lymphoproliferative disorder (PTLD) in adult solid organ transplantation recipients. We attempt to reduce immunosuppression as tolerated in every patient with suspected PTLD in close cooperation with their transplantation physician. There is no evidence to guide the decision when to initiate further treatment; we usually wait no longer than 4 weeks and always initiate further therapy unless there is a complete or at least good partial remission. If clinical and histological findings indicate rapidly progressive disease, we initiate additional therapy significantly earlier. CD20-positive PTLD accounts for approximately 75% of PTLD cases. Outside of clinical trials, we currently regard sequential therapy with rituximab and CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) chemotherapy as standard evidence-based treatment for CD20-positive PTLD unresponsive to immunosuppression. We also discuss our approach to the rare instance of adults with PTLD associated with primary EBV infection, localized (stage I) disease, rare PTLD subtypes, and refractory/relapsed disease based on the available retrospective data and our own experience. In addition to immunotherapy and chemotherapy, this includes local therapy approaches such as surgery and radiotherapy in stage I disease, plasmacytoma-like PTLD, and primary CNS PTLD. We also provide our view on the current indications for the use of allogeneic cytotoxic T cells, even though this treatment modality is so far unavailable in our clinical practice.
Ambient temperature and lung function in children with asthma in Australia
Authors: Li Shanshan , Baker Peter J. , Jalaludin Bin B. , Marks Guy B. , Denison Lyn S. , Williams Gail M.
Published: December 2013

The association between ambient temperature and lung function in children with asthma is still uncertain.

A panel of 270 children (aged 7–12 years) with asthma was recruited from six Australian cities. They performed three successive forced expiratory manoeuvres twice daily for 4 weeks. The highest peak expiratory flow rate (PEF) and forced expiratory volume in 1 s (FEV1) were stored for each session. During the same period, data were obtained daily on ambient temperature, relative humidity and air pollution. Mixed models were used to examine the effects of temperature on lung function, controlling for individual characteristics and environmental factors.

Ambient temperature was negatively related to both morning and evening PEF and FEV1for 0–3 days lag. In general, the effects of temperature were stronger in males than in females for evening PEF, while the effects were stronger in females for evening FEV1. Children with asthma living in southern cities were more sensitive to high temperature than those in the northernmost city.

Higher ambient temperature is associated with lower lung function in children with asthma. Preventive health policies will be required to protect children with asthma from increasingly frequent high temperatures.
Beyond the IFN-γ horizon: biomarkers for immunodiagnosis of infection withMycobacterium tuberculosis
Authors: Chegou Novel N. , Heyckendorf Jan , Walzl Gerhard , Lange Christoph , Ruhwald Morten
Published: December 2013

Latent infection withMycobacterium tuberculosis(LTBI) is defined by the presence ofM. tuberculosis-specific immunity in the absence of active tuberculosis. LTBI is detected using interferon-γ release assays (IGRAs) or the tuberculin-skin-test (TST). In clinical practice, IGRAs and the TSTs have failed to distinguish between active tuberculosis and LTBI and their predictive value to identify individuals at risk for the future development of tuberculosis is limited.

There is an urgent need to identify biomarkers that improve the clinical performance of current immunodiagnostic methods for tuberculosis prevention, diagnosis and treatment monitoring. Here, we review the landscape of potential alternative biomarkers useful for detection of infection withM. tuberculosis.We describe what individual markers add in terms of specificity for active/latent infection, prediction of progression to active tuberculosis and immunodiagnostic potential in high-risk groups' such as HIV-infected individuals and children.
Repeated open endotracheal suctioning causes gradual desaturation but does not exacerbate lung injury compared to closed endotracheal suctioning in a rabbit model of ARDS
Authors: Sakuramoto Hideaki , Shimojo Nobutake , Jesmin Subrina , Unoki Takeshi , Kamiyama Junko , Oki Masami , Miya Ken , Kawano Satoru , Mizutani Taro
Published: December 2013

Background

Although endotracheal suctioning induces alveolar derecruitment during mechanical ventilation, it is not clear whether repeated endotracheal suctioning exacerbates lung injuries. The present study aimed to determine whether repeated open endotracheal suctioning (OS) exacerbates lung injury compared to closed endotracheal suctioning (CS) during mechanical ventilation in an animal model of acute respiratory distress syndrome (ARDS).

Methods

Briefly, thirty six Japanese white rabbits were initially ventilated in pressure-controlled mode with a constant tidal volume (6 mL/kg). Then, lung injury was induced by repeated saline lavage. The rabbits were divided into four groups, namely: a) OS; b) CS; c) control with ARDS only; d) and healthy control (HC) without ARDS. Animals in all the groups were then ventilated with positive end expiratory pressure (PEEP) at 10 cm H2O. CS was performed using 6 French-closed suctioning catheters connected to endotracheal tube under the following conditions: a) a suctioning time and pressure of 10 sec and 140 mm Hg, respectively; and b) a suction depth of 2 cm (length of adapter) plus tracheal tube. OS was performed using the same conditions described for CS, except the ventilator was disconnected from the animals. Each endotracheal suctioning was performed at an interval of 30 min.

Results

PaO2/FIO2 (P/F) ratio for CS, control and HC groups remained at >400 for 6 hours, whereas that of the OS group progressively declined to 300 (p < 0.05), with each suctioning. However, no difference was observed either in lung injury score (histology) or in the expression pattern of inflammatory cytokines (tumor necrosis factor-α and interleukin-6) after 6 hours between the OS and CS groups in the circulatory as well as the pulmonary tissues.

Conclusions

Progressive arterial desaturation under conditions of repeated endotracheal suctioning is greater in OS than in CS time-dependently. However, OS does not exacerbate lung injury during mechanical ventilation when observed over a longer time span (6 hours) of repeated endotracheal suctioning, based on morphological and molecular analysis.
Effects of Interleukin-4 or Interleukin-10 gene therapy on trinitrobenzenesulfonic acid-induced murine colitis
Authors: Xiong Jing , Lin Ying-Hao , Bi Li-Hong , Wang Ji-De , Bai Yang , Liu Si-De
Published: December 2013

Background

Inflammatory bowel disease (IBD) is characterized by disturbance of pro-inflammatory cytokines and anti-inflammatory cytokines. Previous studies have demonstrated the effect of anti-inflammatory cytokines, such as interleukin-10 (IL-10) or IL-4 on IBD, but their data were controversial. This study further investigated the effect of IL-4 (IL-4), IL-10 and their combination on treatment of trinitrobenzenesulfonic acid (TNBS)-induced murine colitis.

Methods

pcDNA3.0 carrying murine IL-4 or IL-10 cDNA was encapsulated with LipofectAMINE 2000 and intraperitoneally injected into mice with TNBS-induced colitis. The levels of intestinal IL-4 and IL-10 mRNA were confirmed by quantitative-RT-PCR. Inflamed tissues were assessed by histology and expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-6.

Results

The data confirmed that IL-4 or IL-10 over-expression was successfully induced in murine colon tissues after intraperitoneal injection. Injections of IL-4 or IL-10 significantly inhibited TNBS-induced colon tissue damage, disease activity index (DAI) and body weight loss compared to the control mice. Furthermore, expression of IFN-γ, TNF-α and IL-6 was markedly blocked by injections of IL-4 or IL-10 plasmid. However, there was less therapeutic effect in mice injected with the combination of IL-4 and IL-10.

Conclusions

These data suggest that intraperitoneal injection of IL-4 or IL-10 plasmid was a potential strategy in control of TNBS-induced murine colitis, but their combination had less effect.
Allergen immunotherapy and allergic rhinitis: false beliefs
Authors: Calderón Moisés A , Frankland A William , Demoly Pascal
Published: December 2013

Background

Over the last 100 years, several persistent misconceptions or ‘false beliefs’ have built up around allergen immunotherapy and its use in allergic rhinitis. This is perhaps because enthusiastic physicians administered complex allergen extracts to a diverse population of patients suffering from heterogeneous atopic conditions. Here, we review evidence that counters seven of these ‘false beliefs.’

Discussion

1. The symptoms of allergic rhinitis can be more heterogeneous, more severe and more troublesome in everyday life than many physicians believe. Large-scale epidemiological surveys show that the majority of allergic rhinitis patients have at least one symptom severe enough to interfere with sleep quality, productivity and/or well-being. 2. Allergen immunotherapy is not necessarily suitable for all allergic rhinitis patients (notably those with mild symptoms). Recent evidence from double-blind, placebo-controlled, randomized clinical trials suggests that the more severe the disease, the greater the treatment effect. 3. Allergen immunotherapy is often accused of lack of efficacy (relative to pharmacotherapy, for example). However, there are now many meta-analyses, systematic reviews and high-quality clinical trials that find overwhelmingly in favor of the efficacy of allergen immunotherapy (including sublingual formulations) in allergic rhinitis induced by pollen and, increasingly, other allergens. 4. Natural-exposure and challenge-chamber trials have shown that symptom relief may become apparent within months or even weeks of the initiation of allergen immunotherapy. 5. In pollen-induced allergic rhinitis, several years of subcutaneous or sublingual allergen immunotherapy are associated with sustained clinical efficacy after subsequent treatment cessation – confirming the disease-modifying nature of this therapy. 6. Most patients seeking treatment for allergic rhinitis are polysensitized, and allergen immunotherapy has proven efficacy in large, robust clinical trials in these groups. Polysensitization is not a contraindication to allergen immunotherapy. 7. Sublingual allergen immunotherapy is safe for home administration. A recent review calculated that 1 billion doses were administered worldwide between 2000 and 2010 and found that the 11 case reports of anaphylaxis (all non-fatal) corresponded to non-standard practice.

Modern, evidence-based medicine has generated more than enough robust evidence to remove misconceptions about allergen immunotherapy and allergic rhinitis.
Analysis of copy number variations at 15 schizophrenia-associated loci
Authors: Rees Elliott , Walters James T. R. , Georgieva Lyudmila , Isles Anthony R. , Chambert Kimberly D. , Richards Alexander L. , Mahoney-Davies Gerwyn , Legge Sophie E. , Moran Jennifer L. , McCarroll Steven A. , O'Donovan Michael C. , Owen Michael J. , Kirov George
Published: December 2013

Background

A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.

Aims

To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n= 6882) and controls (n= 6316), and (b) combining our results with those from previous studies.

Method

We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.

Results

We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1,NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10−4).

Conclusions

We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.
“NOW I GET It!”
Authors: Davis Colin
Published: December 2013

This contribution to a symposium on “lyric philosophy” argues that there is much in Jan Zwicky's work that should make it attractive to literary critics, in particular her insistence that form and content are inextricably bound up with one another. Lyric compositions should not be assessed by reason and logic alone, she holds, and they should not be understood solely in terms of their propositional content. She acknowledges that full understanding employs the imagination and takes account of metaphor. However, some critics may be less willing to accept Zwicky's suggestion that there is a world, and an experience of the world, that is available to us without linguistic mediation and structuring. This article questions whether there a kind of meaning (the “it” of “Now I get it!”) that can be understood preverbally and intuitively. The discussion concludes with a consideration of Zwicky's comments on Rainer Maria Rilke's sonnet “Archaic Torso of Apollo.” Contrary to her own principles, she offers a prose summary of the poem that does not take account of its lyric form and thereby misses some of its most enigmatic features. Whereas Zwicky would have it that the reader of such a poem can achieve a preverbal intuition of its meaning, the article suggests that, when we attend carefully to the words of the poem, we will be intriguingly perplexed.
“Let Me Tell You a Story”
Authors: Spear Rachel N.
Published: December 2013

This article explores relations among trauma, writing, and healing while connecting writing pedagogy and literary studies to insist that courses move past product-focused pedagogies and student experiences alone. Merging theory with praxis, this article underscores the roles and experiences of all course participants, highlights stories of trauma as catalysts for transformation, and outlines a “wounded healer pedagogy”—a pedagogical approach contingent upon interconnectedness, driven by writing purposes, and linked to individual and communal healing processes.
Doing Time with Literacy Narratives
Authors: Berry Patrick W.
Published: December 2013

Drawing on a semester-long qualitative study of teaching writing at a men’s medium-high security prison, this article explores the complex ways in which literacy and incarceration are configured in students’ narratives, as well as my own as their teacher.
Interplay between group size, huddling behavior and basal metabolism: an experimental approach in the social degus
Authors: Villegas Monica , Bozinovic Francisco , Sabat Pablo
Published: December 2013

Mammals exposed to low temperatures increase their metabolic rate to maintain constant body temperature and thus compensate heat loss. This high and costly energetic demand can be mitigated through thermoregulatory behavior such as social grouping or huddling, which helps to decrease metabolic rate as function of the numbers of individuals grouped. Sustained low temperatures in endothermic animals produce changes over time in rates of energy expenditure, by means of phenotypic plasticity. However, the putative modulating effect that huddling exerts on the flexibility of the basal metabolic rate (BMR) due to thermal acclimation remains unknown. We determined BMR values in Octodon degus, an endemic Chilean rodent, after being acclimated either to 15°C or 30°C during 60 days, both alone and in groups of 3 and 5 individuals. At 15°C, BMR of huddling individuals was 40% lower than that of animals housed alone. Moreover, infrared thermography revealed a significant increase in local surface temperatures in huddled animals. Furthermore, individual thermal conductance was lower in individuals acclimated to 15°C than at 30°C, but no differences were observed between single and grouped animals. Our results indicate that huddling prevent an increase in BMR when animals are acclimated to cold conditions and that this effect is proportional to the number of animals grouped.
Rhodopsin coexpression in UV photoreceptors of Aedes aegypti and Anopheles gambiae mosquitoes
Authors: Hu Xiaobang , Leming Matthew T. , Whaley Michelle A. , O'Tousa Joseph E.
Published: December 2013

Differential rhodopsin gene expression within specialized R7 photoreceptors cells divides the retinas of Aedes aegypti and Anopheles gambiae mosquitoes into distinct domains. Both mosquito species express the rhodopsin orthologs Aaop8 and Agop8, respectively, in a large subset of these R7 photoreceptors that function as ultraviolet receptors. We show here that a divergent subfamily of mosquito rhodopsins, Aaop10 and Agop10, are coexpressed in these R7 photoreceptors. The properties of the Ae. aegypti Aaop8 and Aaop10 rhodopsins were analyzed by creating transgenic Drosophila expressing these rhodopsins. Electroretinogram recordings, and spectral analysis of head extracts, obtained from the Aaop8 strain confirmed that Aaop8 is a ultraviolet-sensitive rhodopsin. Aaop10 was poorly expressed and capable of eliciting only small and slow light responses in Drosophila photoreceptors, and electroretinogram analysis suggested that it is a long wavelength rhodopsin with a maximal sensitivity near 500 nm. Thus, coexpression of Aaop10 rhodopsin with Aaop8 rhodopsin has the potential to modify the spectral properties of mosquito ultraviolet receptors. Retention of Op10 rhodopsin family members in the genomes of Drosophila species suggests this rhodopsin family may play a conserved role in insect vision.
The choice of payment method and wealth creation in divestitures
Authors: Као  , Cao Dinh Kien
Published: December 2013

We examine the motivations for different financing methods of U.S. acquirers

that buy divested assets. In contrast to the widely held opinion in the mergers

and acquisitions (M&As) literature that acquirers use more equity payment in

countries with high investor protection and low economic restrictiveness, this

study finds that acquirers prefer cash payment in those countries. However,

several deal, acquirer, and target characteristic significantly influence the

financing methods, as suggested in the M&A literature.

We also measure the announcement effects on acquirer’s value. Acquirers

realize more pronounced wealth effects in domestic transactions compared to

the effects in foreign transactions. Moreover, the effects for acquirers are more

favorable when the relative size of the transaction is high, a proportion of the

price is paid with equity, the assets are from bankrupt targets, and the acquirers’

size is relatively small.
The Ombudsman: Are Top Executives Paid Enough? An Evidence-Based Review
Authors: Jacquart Philippe , Armstrong J. Scott
Published: December 2013

Our review of the evidence found that the notion that higher pay leads to the selection of better executives is undermined by the prevalence of poor recruiting methods. Moreover, higher pay fails to promote better performance. Instead, it undermines the intrinsic motivation of executives, inhibits their learning, leads them to ignore other stakeholders, and discourages them from considering the long-term effects of their decisions on stakeholders. Relating incentive payments to executives’ actions in an effective manner is not possible. Incentives also encourage unethical behavior. Organizations would benefit from using validated methods to hire top executives, reducing compensation, eliminating incentive plans, and strengthening stockholder governance related to the hiring and compensation of executives.