bluuebunny/crossref_metadata_2025 huggingface dataset:
A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease
Authors: Wright Lillianne H. , Menick Donald R.
Published: May 2016

Histone deacetylases (HDACs) play integral roles in many cardiovascular biological processes ranging from transcriptional and translational regulation to protein stabilization and localization. There are 18 known HDACs categorized into 4 classes that can differ on the basis of substrate targets, subcellular localization, and regulatory binding partners. HDACs are classically known for their ability to remove acetyl groups from histone and nonhistone proteins that have lysine residues. However, despite their nomenclature and classical functions, discoveries from many research groups over the past decade have suggested that nondeacetylase roles exist for class IIa HDACs. This is not surprising given that class IIa HDACs have, for example, relatively poor deacetylase capabilities and are often shuttled in and out of nuclei upon specific pathological and nonpathological cardiac events. This review aims to consolidate and elucidate putative nondeacetylase roles for class IIa HDACs and, where possible, highlight studies that provide evidence for their noncanonical roles, especially in the context of cardiovascular maladies. There has been great interest recently in exploring the pharmacological regulators of HDACs for use in therapeutic interventions for treating cardiovascular diseases and inflammation. Thus it is of interest to earnestly consider nonenzymatic and or nondeacetylase roles of HDACs that might be key in potentiating or abrogating pathologies. These noncanonical HDAC functions may possibly yield new mechanisms and targets for drug discovery.
Effects of hibernation on bone marrow transcriptome in thirteen-lined ground squirrels
Authors: Cooper Scott T. , Sell Shawn S. , Fahrenkrog Molly , Wilkinson Kory , Howard David R. , Bergen Hannah , Cruz Estefania , Cash Steve E. , Andrews Matthew T. , Hampton Marshall
Published: May 2016

Mammalian hibernators adapt to prolonged periods of immobility, hypometabolism, hypothermia, and oxidative stress, each capable of reducing bone marrow activity. In this study bone marrow transcriptomes were compared among thirteen-lined ground squirrels collected in July, winter torpor, and winter interbout arousal (IBA). The results were consistent with a suppression of acquired immune responses, and a shift to innate immune responses during hibernation through higher complement expression. Consistent with the increase in adipocytes found in bone marrow of hibernators, expression of genes associated with white adipose tissue are higher during hibernation. Genes that should strengthen the bone by increasing extracellular matrix were higher during hibernation, especially the collagen genes. Finally, expression of heat shock proteins were lower, and cold-response genes were higher, during hibernation. No differential expression of hematopoietic genes involved in erythrocyte or megakaryocyte production was observed. This global view of the changes in the bone marrow transcriptome over both short term (torpor vs. IBA) and long term (torpor vs. July) hypothermia can explain several observations made about circulating blood cells and the structure and strength of the bone during hibernation.
A Palpable Painless Axillary Mass as the Clinical Manifestation of Castleman’s Disease in a Patient with Hepatitis C Disease
Authors: Papazafiropoulou Athanasia K. , Angelidi Angeliki M. , Kousoulis Antonis A. , Christofilidis Georgios , Sagia Chariklia , Kaftanidou Liountmila , Manoloudaki Kassiani , Tsavari Aikaterini , Kranidiotis Georgios , Kamaratos Alexandros , Melidonis Andreas
Published: May 2016

Introduction. Castleman’s disease (CD) is a rare lymphoproliferative disorder. CD is divided into two clinical subtypes: the most common unicentric and the less usual multicentric subtype. The majority of unicentric CD affects the mediastinum, while neck, abdomen, and axilla are less common locations.Case Presentation. Herein, we describe a rare case of unicentric CD in the right axilla in a 36-year-old white male with a medical history of hepatitis C virus infection admitted to our hospital due to palpation of a painless mass in the right axilla. Complete excision of the lesion was performed and, one year after the diagnosis, patient was free of the disease.Conclusions. Although infrequent, it is important to include CD in the differential diagnosis when evaluating axillary lymphadenopathy particularly in young patients with a low-grade inflammation process and chronic disease even in the absence of an abnormal blood picture or organomegaly.
Evidences of Polymorphism Associated with Circadian System and Risk of Pathologies: A Review of the Literature
Authors: Valenzuela F. J. , Vera J. , Venegas C. , Muñoz S. , Oyarce S. , Muñoz K. , Lagunas C.
Published: May 2016

The circadian system is a supraphysiological system that modulates different biological functions such as metabolism, sleep-wake, cellular proliferation, and body temperature. Different chronodisruptors have been identified, such as shift work, feeding time, long days, and stress. The environmental changes and our modern lifestyle can alter the circadian system and increase the risk of developing pathologies such as cancer, preeclampsia, diabetes, and mood disorder. This system is organized by transcriptional/tranductional feedback loops of clock genesClock,Bmal1,Per1–3,andCry1-2. How molecular components of the clock are able to influence the development of diseases and their risk relation with genetic components of polymorphism of clock genes is unknown. This research describes different genetic variations in the population and how these are associated with risk of cancer, metabolic diseases such as diabetes, obesity, and dyslipidemias, and also mood disorders such as depression, bipolar disease, excessive alcohol intake, and infertility. Finally, these findings will need to be implemented and evaluated at the level of genetic interaction and how the environment factors trigger the expression of these pathologies will be examined.
A Flexible and Scalable Architecture for Real-Time ANT+ Sensor Data Acquisition and NoSQL Storage
Authors: Mehmood Nadeem Qaisar , Culmone Rosario , Mostarda Leonardo
Published: May 2016

Wireless Personal or Body Area Networks (WPANs or WBANs) are the main mechanisms to develop healthcare systems for an ageing society. Such systems offer monitoring, security, and caring services by measuring physiological body parameters using wearable devices. Wireless sensor networks allow inexpensive, continuous, and real-time updates of the sensor data, to the data repositories via an Internet. A great deal of research is going on with a focus on technical, managerial, economic, and social health issues. The technical obstacles, which we encounter, in general, are better methodologies, architectures, and context data storage. Sensor communication, data processing and interpretation, data interchange format, data transferal, and context data storage are sensitive phases during the whole process of body parameter acquisition until the storage. ANT+ is a proprietary (but open access) low energy protocol, which supports device interoperability by mutually agreeing upon device profile standards. We have implemented a prototype, based upon ANT+ enabled sensors for a real-time scenario. This paper presents a system architecture, with its software organization, for real-time message interpretation, event-driven based real-time bidirectional communication, and schema flexible storage. A computer user uses it to acquire and to transmit the data using a Windows service to the context server.
Idiopathic Intractable Diarrhoea Leading to Torsade de Pointes
Authors: Mouyis Kyriacos , Okonko Darlington , Missouris Constantinos G.
Published: May 2016

An 81-year-old lady was admitted to our hospital with a 3-year history of noninfective diarrhoea and recurrent syncopal events over the last 3 months. Her initial electrocardiogram (ECG) revealed trigeminy and prolonged QTc interval. She had a structurally normal heart with no coronary artery disease. Investigations revealed low potassium at 3.0 mmol/L. Sigmoidoscopy and colonoscopy suggested a possible diagnosis of diverticulitis. Soon after admission she had an unresponsive episode with spontaneous recovery. Telemetry and Holter analysis confirmed multiple episodes of polymorphic ventricular tachycardia (Torsade de Pointes). Following electrolyte supplementation the episodes of polymorphic VT improved. Due to the protracted nature of the diarrhoea, the recurrent syncopal events, and recurrent hypokalaemia documented over recent years, an Implantable Cardioverter Defibrillator (ICD) was sanctioned by the multidisciplinary team (MDT). In summary, chronic diarrhoea may result in life threatening polymorphic VT due to hypokalaemia and QTc prolongation. In these patients an ICD may be considered.
A Rare Case of Ovarian Filariasis in Abidjan
Authors: Brahima Doukouré , Alain Didier Abouna , Gonat Serge Pacôme Dou , Nguiessan Alphonse Aman , Abdoul Koffi , Jean-Marie Diomandé Mohenou Isidore
Published: May 2016

Ovarian filariasis is an exceptional disease and displays a major diagnostic problem even in endemic areas. We reported the case of a 19-year-old patient who had ovarian cyst which was revealed by chronic pelvic pain. The histological examination of oophorectomy specimen led to theWuchereria bancroftifilariasis of the ovary. The anatomopathologic examination is required for the diagnosis of this disease.
Construction of an Early Risk Warning Model of Organizational Resilience: An Empirical Study Based on Samples of R&D Teams
Authors: Chen Si-hua
Published: May 2016

Facing fierce competition, it is critical for organizations to keep advantages either actively or passively. Organizational resilience is the ability of an organization to anticipate, prepare for, respond to, and adapt to incremental change and sudden disruptions in order to survive and prosper. It is of particular importance for enterprises to apprehend the intensity of organizational resilience and thereby judge their abilities to withstand pressure. By conducting an exploratory factor analysis and a confirmatory factor analysis, this paper clarifies a five-factor model for organizational resilience of R&D teams. Moreover, based on it, this paper applies fuzzy integrated evaluation method to build an early risk warning model for organizational resilience of R&D teams. The application of the model to a company shows that the model can adequately evaluate the intensity of organizational resilience of R&D teams. The results are also supposed to contribute to applied early risk warning theory.
Ultrastructural Changes and Death of Leishmania infantum Promastigotes Induced by Morinda citrifolia Linn. Fruit (Noni) Juice Treatment
Authors: Almeida-Souza Fernando , Taniwaki Noemi Nosomi , Amaral Ana Cláudia Fernandes , Souza Celeste da Silva Freitas de , Calabrese Kátia da Silva , Abreu-Silva Ana Lúcia
Published: May 2016

The search for new treatments against leishmaniasis has increased due to high frequency of drug resistance registered in endemics areas, side effects, and complications caused by coinfection with HIV. Morinda citrifolia Linn., commonly known as Noni, has a rich chemical composition and various therapeutic effects have been described in the literature. Studies have shown the leishmanicidal activity of M. citrifolia; however, its action on the parasite has not yet been elucidated. In this work, we analyzed leishmanicidal activity and ultrastructural changes in Leishmania infantum promastigotes caused by M. citrifolia fruit juice treatment. M. citrifolia fruit extract showed a yield of 6.31% and high performance liquid chromatography identified phenolic and aromatic compounds as the major constituents. IC50 values were 260.5 µg/mL for promastigotes and 201.3 µg/mL for intracellular amastigotes of L. infantum treated with M. citrifolia. Cytotoxicity assay with J774.G8 macrophages showed that M. citrifolia fruit juice was not toxic up to 2 mg/mL. Transmission electron microscopy showed cytoplasmic vacuolization, lipid inclusion, increased exocytosis activity, and autophagosome‐like vesicles in L. infantum promastigotes treated with M. citrifolia fruit juice. M. citrifolia fruit juice was active against L. infantum in the in vitro model used here causing ultrastructural changes and has a future potential for treatment against leishmaniasis.
Control of Drug Dissolution Rate from Film Dosage Forms Containing Valsartan
Authors: Murata Yoshifumi , Kofuji Kyoko , Maida Chieko
Published: May 2016

Film dosage forms (FDs) containing valsartan (VST), a popular antihypertensive drug, were prepared using a casting method with sodium alginate and other polysaccharides as the film base. Drug dissolution profiles of the FDs were investigated in limited medium. The FDs were 170–200 μm thick and were easy to handle. All FDs immediately swelled and disintegrated in the medium. About 23% of the VST incorporated into the FD prepared with 1.5% sodium alginate dissolved at 5 min. The initial dissolution rate of VST increased upon the addition of chitosan to the film base; this effect was not observed in the case of chitin. On the other hand, the rate apparently decreased upon modification with alginic acid. In addition, the solubility of VST in the dissolution medium was changed by the addition of chitosan or alginic acid. FDs prepared with polysaccharides are useful for simplifying the administration of drugs to patients, and the drug dissolution rate from FDs can be controlled by modification.
Uncommon Presentation of Isolated Jejunal Lymphoma Masquerading as Crohn’s Disease
Authors: Sattavan Swati , Aggarwal Lalit , Dikshit Priyadarshi
Published: May 2016

Primary gastrointestinal lymphoma is a rare entity, commonly involving stomach, small bowel, and colorectum. The usual location for small bowel B cell lymphoma is distal ileum due to abundant lymphoid tissue. We are reporting the case of a 53-year-old lady presumptively diagnosed as Crohn’s disease on clinical and radiological grounds but histopathologically proven to be an unusual variant of isolated primary non-Hodgkin’s lymphoma.
Game Models on Optimal Strategies in a Tourism Dual-Channel Supply Chain
Authors: Yang Lei , Ji Jingna , Chen Kebing
Published: May 2016

This paper explores a two-echelon tourism supply chain consisting of a hotel and an online travel agency. The upside hotel rooms can be sold through the downside hotel alliance and online travel agency. The hotel alliance, selling rooms at a lower price, is a direct sale platform with a negligible entry fee. Notwithstanding, the online travel agency sells the room at a higher price with related personalized service. Customers will be refunded partially in case of their cancellation or no-show. An integrated model and two decentralized models based on Bertrand and Stackelberg games are developed, respectively. The results show that when the wholesale price is lower than a certain value, both the hotel and the online travel agency can gain more profit from the Stackelberg game than that from the Bertrand game. In the case that the hotel allows overbooking, the optimal overbooking quantity is obtained. If the overbooking proportion is too high, overbooking is profitable for the hotel only when the overbooking cost is lower than a certain value. At the end of the study, some experiments are conducted to analyze the sensitivity of the optimal prices and profits in the light of certain parameters.
The Research of Improved Grey GM (1, 1) Model to Predict the Postprandial Glucose in Type 2 Diabetes
Authors: Wang Yannian , Wei Fenfen , Sun Changqing , Li Quanzhong
Published: May 2016

Diabetes may result in some complications and increase the risk of many serious health problems. The purpose of clinical treatment is to carefully manage the blood glucose concentration. If the blood glucose concentration is predicted, treatments can be taken in advance to reduce the harm to patients. For this purpose, an improved grey GM (1, 1) model is applied to predict blood glucose with a small amount of data, and especially in terms of improved smoothness it can get higher prediction accuracy. The original data of blood glucose of type 2 diabetes is acquired by CGMS. Then the prediction model is established. Finally, 50 cases of blood glucose from the Henan Province People’s Hospital are predicted in 5, 10, 15, 20, 25, and 30 minutes, respectively, in advance to verify the prediction model. The prediction result of blood glucose is evaluated by the EGA, MSE, and MAE. Particularly, the prediction results of postprandial blood glucose are presented and analyzed. The result shows that the improved grey GM (1, 1) model has excellent performance in postprandial blood glucose prediction.
Volatiles from Subtropical Convolvulaceae That Interfere with Bacterial Cell‐to‐Cell Communication as Potential Antipathogenic Drugs
Authors: Luciardi María C. , Pérez Hernández María V. , Muruaga Nora , Bardón Alicia , Arena Mario E. , Cartagena Elena
Published: May 2016

Increasing chronic bacterial infections create an urgent need for new antimicrobial agents or strategies for their control. Targeting virulence is one of the alternative approaches to find new medicines to treat persistent infections due to bacteria with biofilm‐phenotype which are more resistant to antibiotics than their planktonic counterparts having an extreme capacity for evading the host defences. A bioguided study of sixteen extracts from flowers and leaves of four subtropical Convolvulaceae species provided evidence of the occurrence of antipathogenic natural products active against Gram positive and negative bacteria. Particularly, volatile metabolites from Merremia dissecta creeper, a food and medicinal plant, were able to interfere with the Pseudomonas aeruginosa quorum sensing system by a strong decrease of N‐acyl homoserine lactone (AHL) biosynthesis (63–75%), which attenuated the virulence factor expression like biofilm (55%) and elastase activity (up to 27%), key factors that enable the colonization and dissemination of the infection in the host. Control of the P. aeruginosa biofilm and the QS process by phytochemicals, such as (+) spathulenol, isolated from a bioactive extract of M. dissecta leaves would be a good strategy for the development of new and effective antipathogenic drugs.
A Protocol for Provably Secure Authentication of a Tiny Entity to a High Performance Computing One
Authors: Tomović Siniša , Mihaljević Miodrag J. , Perović Aleksandar , Ognjanović Zoran
Published: May 2016

The problem of developing authentication protocols dedicated to a specific scenario where an entity with limited computational capabilities should prove the identity to a computationally powerful Verifier is addressed. An authentication protocol suitable for the considered scenario which jointly employs the learning parity with noise (LPN) problem and a paradigm of random selection is proposed. It is shown that the proposed protocol is secure against active attacking scenarios and so called GRS man-in-the-middle (MIM) attacking scenarios. In comparison with the related previously reported authentication protocols the proposed one provides reduction of the implementation complexity and at least the same level of the cryptographic security.
Upregulated Glucose Metabolism Correlates Inversely with CD8+ T-cell Infiltration and Survival in Squamous Cell Carcinoma
Authors: Ottensmeier Christian H. , Perry Kate L. , Harden Elena L. , Stasakova Jana , Jenei Veronika , Fleming Jason , Wood Oliver , Woo Jeongmin , Woelk Christopher H. , Thomas Gareth J. , Thirdborough Stephen M.
Published: May 2016

Antibodies that block T-cell–regulatory checkpoints have recently emerged as a transformative approach to cancer treatment. However, the clinical efficacy of checkpoint blockade depends upon inherent tumor immunogenicity, with variation in infiltrating T cells contributing to differences in objective response rates. Here, we sought to understand the molecular correlates of tumor-infiltrating T lymphocytes (TIL) in squamous cell carcinoma (SCC), using a systems biologic approach to integrate publicly available omics datasets with histopathologic features. We provide evidence that links TIL abundance and therapeutic outcome to the regulation of tumor glycolysis by EGFR and HIF, both of which are attractive molecular targets for use in combination with immunotherapeutics. Cancer Res; 76(14); 4136–48. ©2016 AACR.
Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy
Authors: Picarda Elodie , Ohaegbulam Kim C. , Zang Xingxing
Published: May 2016

B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen-presenting cells, B7-H3 plays an important role in the inhibition of T-cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy. Based on the clinical success of inhibitory immune checkpoint blockade (CTLA-4, PD-1, and PD-L1), mAbs against B7-H3 appear to be a promising therapeutic strategy worthy of development. An unconventional mAb against B7-H3 with antibody-dependent cell-mediated cytotoxicity is currently being evaluated in a phase I clinical trial and has shown encouraging preliminary results. Additional therapeutic approaches in targeting B7-H3, such as blocking mAbs, bispecific mAbs, chimeric antigen receptor T cells, small-molecule inhibitors, and combination therapies, should be evaluated, as these technologies have already shown positive results in various cancer settings. A better understanding of the B7-H3 pathway in humans will surely help to further optimize associated cancer immunotherapies. Clin Cancer Res; 22(14); 3425–31. ©2016 AACR.
Current and Emerging Clinical Applications of Multispectral Optoacoustic Tomography (MSOT) in Oncology
Authors: McNally Lacey R. , Mezera Megan , Morgan Desiree E. , Frederick Peter J. , Yang Eddy S. , Eltoum Isam-Eldin , Grizzle William E.
Published: May 2016

Accurate detection and characterization of cancers are key for providing timely intervention and effective treatments. Current imaging technologies are particularly limited when it comes to detecting very small tumors in vivo, i.e., very early cancers or metastases, differentiating viable tumor from surrounding dead tumor tissue, and evaluating tumor metabolism within tissue. Optoacoustic imaging offers potential solutions to these imaging problems because of its ability to image optical absorption properties of both intrinsic tissue chromophores and exogenous contrast agents without the involvement of ionizing radiation. Optoacoustic imaging uses pulsed laser to induce localized thermoelastic expansion that generates acoustic waves detectable by an ultrasound transducer. To date, multispectral optoacoustic tomography (MSOT) has primarily been used in preclinical research; however, its use in translational and clinical research is expanding. This review focuses on current and emerging applications of optoacoustic imaging for molecular imaging of cancer using both exogenous and endogenous contrast agents and sheds light on potential future clinical applications. Clin Cancer Res; 22(14); 3432–9. ©2016 AACR.
Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma
Authors: Markowitz Daniel , Powell Caitlin , Tran Nhan L. , Berens Michael E. , Ryken Timothy C. , Vanan Magimairajan , Rosen Lisa , He Mingzhu , Sun Shan , Symons Marc , Al-Abed Yousef , Ruggieri Rosamaria
Published: May 2016

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient–derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage–induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient–derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799–808. ©2016 AACR.
Non-Transgenic Mouse Models of Kidney Disease
Authors: Rabe Michael , Schaefer Franz
Published: May 2016

Animal models are essential tools to understand the mechanisms underlying the development and progression of renal disease and to study potential therapeutic approaches. Recently, interventional models suitable to induce acute and chronic kidney disease in the mouse have become a focus of interest due to the wide availability of genetically engineered mouse lines. These models differ by their damaging mechanism (cell toxicity, immune mechanisms, surgical renal mass reduction, ischemia, hypertension, ureter obstruction etc.), functional and histomorphological phenotype and disease evolution. The susceptibility to a damaging mechanism often depends on strain and gender. The C57BL/6 strain, the most commonly used genetic background of transgenic mice, appears to be relatively resistant against developing glomerulosclerosis, proteinuria and hypertension. This review serves to provide a comprehensive overview of interventional mouse models of acute and chronic kidney disease.
Food Web Structure Shapes the Morphology of Teleost Fish Brains
Authors: Edmunds Nicholas B. , McCann Kevin S. , Laberge Frédéric
Published: May 2016

Previous work showed that teleost fish brain size correlates with the flexible exploitation of habitats and predation abilities in an aquatic food web. Since it is unclear how regional brain changes contribute to these relationships, we quantitatively examined the effects of common food web attributes on the size of five brain regions in teleost fish at both within-species (plasticity or natural variation) and between-species (evolution) scales. Our results indicate that brain morphology is influenced by habitat use and trophic position, but not by the degree of littoral-pelagic habitat coupling, despite the fact that the total brain size was previously shown to increase with habitat coupling in Lake Huron. Intriguingly, the results revealed two potential evolutionary trade-offs: (i) relative olfactory bulb size increased, while relative optic tectum size decreased, across a trophic position gradient, and (ii) the telencephalon was relatively larger in fish using more littoral-based carbon, while the cerebellum was relatively larger in fish using more pelagic-based carbon. Additionally, evidence for a within-species effect on the telencephalon was found, where it increased in size with trophic position. Collectively, these results suggest that food web structure has fundamentally contributed to the shaping of teleost brain morphology.
Robot Assisted Radical Prostatectomy in Kidney Transplant Recipients. Our Clinical Experience and a Systematic Review
Authors: Moreno Sierra Jesús , Ciappara Paniagua M. , Galante Romo M.I. , Senovilla Pérez J.L. , Redondo González E. , Galindo Herrero M.I. , Novo Gómez N. , Blázquez Izquierdo J.
Published: May 2016

Introduction: Radical prostatectomy is a more skillful procedure in kidney graft recipients. Robotic surgery can provide a useful minimally invasive tool. Objectives: The study aims to evaluate the robotic-assisted laparoscopic prostatectomy (RALP) in kidney transplant recipients, describing intra/postoperative complications, renal and oncological outcomes. Methods: This is a retrospective study conducted in a single institution of 84 RALP. Four of them were kidney transplant recipients. Side of the renal graft, clinical stage, intra/postoperative events, operating time, creatinine levels before/after intervention and oncologic follow-up were recorded. A systematic review of the literature was performed. Results: Aged 61.25 ± 7.76 years, interval between renal transplantation and RALP: 10 ± 3.16 years. Mean prostate specific antigen: 7.1 ± 2.8 ng/ml, 2 patients were cT1c and 2 cT2a. Preoperative biopsies: Gleason score 3 + 3 in 3 patients, 3 + 4 in 1 patient. Charlson comorbidity index mean was 4.82 ± 0.82. No intra/postoperative events were reported. Mean operating time: 196 ± 20.8 min. Positive surgical margins: 2/4 patients. Pathological analysis: Gleason 3 + 4 in 2 patients and Gleason 3 + 3 in the others 2. A patient developed a bladder neck sclerosis. No differences between pre/postoperative creatinine. Three patients are free of biochemical recurrence and 1 patient required adjuvant radiotherapy. Conclusion: RALP in renal transplant recipients is a safe and feasible technique for localized prostate cancer. No difference in oncological outcomes and no impairments on renal function were found.
Cerebral Venous Sinus Thrombosis Involving the Straight Sinus May Result in Infarction and/or Hemorrhage
Authors: Zhou Geng , Li MingHua , Zhu YueQi , Zhao JunGong , Lu HaiTao
Published: May 2016

Aim: We retrospectively investigated the clinical profiles and neuroimaging data of patients with documented cerebral venous sinus thrombosis (CVST) to analyze the relationship between the sites of CVST and clinical manifestations. Methods: A total of 68 patients, who were examined and treated at our hospital, were identified after review and their data were retrospectively analyzed. Results: Initial non-contrast CT scan showed a definite spontaneous hyperdensity of one or several sinuses in 47 patients (69.1%) and was normal in the remaining patients (30.9%). Furthermore, the χ2 test revealed a significant difference (p = 0.001) in the infarction or hemorrhage rate between the patients with straight sinus thrombosis (SST; 19 of 28, 67.8%) and other subjects (9 of 39, 23.1%). Moreover, patients with SST had a 6.33-fold (95% CI 2.18-18.4) increased risk of infarction or hemorrhage. Conclusion: Our data suggested that infarction and/or hemorrhage was more common in CVST patients with SST.
How to Individuate the Powers of Knowledge and Opinion in Plato's Republic V
Authors: Prince Brian David
Published: May 2016

At the end of Republic V Socrates argues that differences between knowledge and opinion justify rule by philosophers in his ideal city; within this argument he gives a theory of powers. The theory contains a logical gap: Socrates mentions two criteria by which he individuates powers, yet assumes in his argument that both criteria will speak with a single voice. I argue that these criteria are two ways of picking out a power’s manifestation—that is, the change a power is directed toward; I shall call this view the Identity Reading. Since they refer to a single phenomenon, the results of consulting both criteria cannot differ. The Identity Reading both solves the logical problem with the argument and sheds light four other features of the passage. This reading also provides support for what Gail Fine has called the “contents analysis” of a power’s relation to its “objects,” as opposed to the “objects analysis.”
Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block
Authors: Syam Ninda , Chatel Stéphanie , Ozhathil Lijo Cherian , Sottas Valentin , Rougier Jean‐Sébastien , Baruteau Alban , Baron Estelle , Amarouch Mohamed‐Yassine , Daumy Xavier , Probst Vincent , Schott Jean‐Jacques , Abriel Hugues
Published: May 2016

Background

Transient receptor potential melastatin member 4 (
TRPM
4) is a nonselective cation channel.

TRPM
4

mutations have been linked to cardiac conduction disease and Brugada syndrome. The mechanisms underlying
TRPM
4‐dependent conduction slowing are not fully understood. The aim of this study was to characterize

TRPM
4

genetic variants found in patients with congenital or childhood atrioventricular block.

Methods and Results

Ninety‐one patients with congenital or childhood atrioventricular block were screened for candidate genes. Five rare

TRPM
4

genetic variants were identified and investigated. The variants were expressed heterologously in
HEK
293 cells. Two of the variants, A432T and A432T/G582S, showed decreased expression of the protein at the cell membrane; inversely, the G582S variant showed increased expression. Further functional characterization of these variants using whole‐cell patch‐clamp configuration showed a loss of function and a gain of function, respectively. We hypothesized that the observed decrease in expression was caused by a folding and trafficking defect. This was supported by the observation that incubation of these variants at lower temperature partially rescued their expression and function. Previous studies have suggested that altered
SUMO
ylation of
TRPM
4 may cause a gain of function; however, we did not find any evidence that supports
SUMO
ylation as being directly involved for the gain‐of‐function variant.

Conclusions

This study underpins the role of

TRPM
4

in the cardiac conduction system. The loss‐of‐function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding‐dependent altered trafficking. The ability to rescue this variant with lower temperature may provide a novel use of pharmacological chaperones in treatment strategies.
Derivation and Validation of a Modified Short Form of the Stroke Impact Scale
Authors: MacIsaac Rachael , Ali Myzoon , Peters Michele , English Coralie , Rodgers Helen , Jenkinson Crispin , Lees Kennedy R. , Quinn Terence J. ,   the VISTA Collaboration
Published: May 2016

Background

The Stroke Impact Scale (
SIS
) is a stroke‐specific, quality of life measure recommended for research and clinical practice. Completion rates are suboptimal and could relate to test burden. We derived and validated a short form SIS (SF‐SIS).

Methods and Results

We examined data from the Virtual International Stroke Trial Archive, generating derivation and validation populations. We derived an
SF
‐
SIS
by selecting 1 item per domain of
SIS
, choosing items most highly correlated with total domain score. Our validation described agreement of
SF
‐
SIS
with original
SIS
and the
SIS
‐16 and correlation with Barthel Index, modified Rankin Scale, National Institutes of Health Stroke Scale, and Euro‐QoL 5 dimensions visual analog scales. We assessed discriminative validity (associations between
SF
‐
SIS
and factors known to influence outcome [age, physiological parameters, and comorbidity]). We assessed face validity and acceptability by sharing the
SF
‐
SIS
with a focus group of stroke survivors and multidisciplinary stroke healthcare staff. From 5549 acute study patients (mean age 68.5 [
SD
13] years, mean
SIS
64 [
SD
32]) and 332 rehabilitation patients (mean age 65.7 [
SD
11] years, mean
SIS
61 [
SD
11]), we derived an 8‐item
SF
‐
SIS
that demonstrated good agreement with original
SIS
and good correlation with our chosen functional and quality of life measures (all ρ>0.70,
P
<0.0001). Significant associations were seen with our chosen predictors of stroke outcome in the acute group (
P
<0.0001). The focus group agreed with the choice of items for
SF
‐
SIS
across 7 of 8 domains
.

Conclusions

Using multiple, complementary methods, we have derived an SF‐
SIS
and demonstrated content, convergent, and discriminant validity. This shortened
SIS
should allow collection of robust quality of life data with less associated test burden.
Angiotensin‐Converting Enzyme Inhibitor Initiation and Dose Uptitration in Children With Cardiovascular Disease: A Retrospective Review of Standard Clinical Practice and a Prospective Randomized Clinical Trial
Authors: Roche S. Lucy , Timberlake Kathryn , Manlhiot Cedric , Balasingam Mervin , Wilson Judith , George Kristen , McCrindle Brian W. , Kantor Paul F.
Published: May 2016

Background

Angiotensin‐converting enzyme inhibitors (
ACEI
s) are a mainstay of medical management in pediatric cardiology. However, there are no data defining how best to initiate and uptitrate the dose of these medications in children.

Methods and Results

Retrospective chart review revealed only 24% of our pediatric cardiology inpatients were discharged on predefined optimal doses of
ACEI
s and few underwent further dose uptitration in the 8 weeks after hospital discharge. Therefore, 2 alternative protocols for initiation of captopril were compared in a prospective randomized clinical trial. A “rapid uptitration” protocol reached an optimal dose on day 3, whereas the alternative, “prolonged uptitration” protocol, reached an optimal dose on day 9. Forty‐6 patients (54% male) were recruited to the trial, with a median age of 0.7 year (
IQR
0.5–2.3 years). Captopril was initiated while in intensive care in 39% of patients and on the cardiology ward in 61%. There were no differences between the protocols in episodes of hypotension, symptomatic hypotension, or indices of renal function. Patients following the rapid protocol reached higher doses of captopril (0.93±0.24 versus 0.57±0.38 mg/kg per dose,
P
<0.0001) and were more likely to have achieved the predefined target (88% versus 43%,
P
=0.002) and optimal
ACEI
doses (80% versus 29%,
P
=0.001) before discharge.

Conclusions

A protocol of rapid
ACEI
dose uptitration for infants and children with cardiovascular disease can be introduced safely, even in patients receiving intensive care therapy. Compared with standard clinical practice or with a more prolonged protocol, rapid
ACEI
dose uptitration achieves a higher dosage in this population with no evident disadvantages.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov/
. Unique identifier:
NCT
00742040.
Impact of a Rural Regional Myocardial Infarction System of Care in Wyoming
Authors: Langabeer James R. , Smith Derek T. , Cardenas‐Turanzas Marylou , Leonard Benjamin L. , Segrest Wendy , Krell Chris , Owan Theophilus , Eisenhauer Michael D. , Gerard Daniela
Published: May 2016

Background

Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for patients presenting with ST‐segment elevation myocardial infarction; however, to be effective, PCI must be performed in a timely manner. Rural regions are at a severe disadvantage, given the relatively sparse number of PCI hospitals and long transport times.

Methods and Results

We developed a standardized treatment and transfer protocol for ST‐segment elevation myocardial infarction in the rural state of Wyoming. The study design compared the time‐to‐treatment outcomes during the pre‐ and postintervention periods. Details of the program, changes in reperfusion strategies over time, and outcome improvements in treatment times were reported. From January 1, 2013, to December 31, 2014, 889 patients were treated in 11 PCI‐capable hospitals (4 in Wyoming, 7 in adjoining states). Given the large geographic distance in the state (median of 47 miles between patient and PCI center), 52% of all patients were transfers, and 36% were administered fibrinolysis at the referral facility. Following the intervention, there was a significant shift toward greater use of primary PCI as the dominant reperfusion strategy (from 47% to 60%,
P
=0.002), and the median total ischemic time from symptom onset to arterial reperfusion was decreased by 92 minutes (
P
<0.001). There was a similar significant reduction in median time from receiving center door to balloon of 11 minutes less than the baseline time (
P
<0.01).

Conclusions

Rural systems of care for ST‐segment elevation myocardial infarction require increased levels of cooperation between emergency medical services agencies and hospitals. This study confirms that total ischemic times can be reduced through a coordinated rural statewide initiative.
Conditional knockout mice demonstrate function of Klf5 as a myeloid transcription factor
Authors: Shahrin Nur Hezrin , Diakiw Sonya , Dent Lindsay A. , Brown Anna L. , D’Andrea Richard J.
Published: May 2016

Key Points

Klf5 functions in hematopoiesis to regulate HSC and progenitor proliferation and localization in the bone marrow. Klf5 is required in the granulocyte lineage and positively affects neutrophil output at the expense of eosinophil production.
CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date
Authors: Park Jae H. , Geyer Mark B. , Brentjens Renier J.
Published: May 2016

Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies.
Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience
Authors: Morillo-Gutierrez Beatriz , Beier Rita , Rao Kanchan , Burroughs Lauri , Schulz Ansgar , Ewins Anna-Maria , Gibson Brenda , Sedlacek Petr , Krol Ladislav , Strahm Brigitte , Zaidman Irina , Kalwak Krzysztof , Talano Julie-An , Woolfrey Ann , Fraser Chris , Meyts Isabelle , Müller Ingo , Wachowiak Jacek , Bernardo Maria Ester , Veys Paul , Sykora Karl-Walter , Gennery Andrew R. , Slatter Mary
Published: May 2016

Key Points

Treosulfan, a low-toxicity alkylating agent, can be used effectively as part of conditioning for HSCT in children with CGD. Long-term follow-up is required to ascertain effects, particularly on gonadal function and compare with other regimens.
On determining uncertainties of magnetic resonance sounding estimated transmissivities for groundwater modeling
Authors: Vilhelmsen Troels Norvin , Christensen Steen , Auken Esben
Published: May 2016

The nuclear magnetic resonance sounding (MRS) method is used increasingly as a tool for hydrological investigations. Compared to other geophysical methods, the advantage of MRS is that it is directly sensitive to the presence of water in the subsurface. Data interpretations can also be used to get information about the subsurface pore structures, which under special conditions can be related to hydraulic properties such as aquifer transmissivity. However, to broaden the usage of this information in hydrological modeling, the uncertainties related to these transmissivity estimates must be determined. Otherwise, properly balanced weights cannot be given to the prior information obtained from MRS transmissivity estimates as compared to the hydrological data sets when used for groundwater model calibration. We have developed a methodology to estimate the uncertainties of MRS-based transmissivity estimates. Compared to previous studies, the methodology is well defined, and it takes into account important factors such as the uncertainties of the hydraulically estimated transmissivities, the uncertainty of the correlation factor in the petrophysical relation, and the uncertainties and correlations of the geophysically estimated parameters. We have determined the correlations and uncertainties of the geophysical parameters using a linear and a nonlinear method, and we find that the results are comparable.
Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty
Authors: Lippincott Margaret F. , Chan Yee-Ming , Delaney Angela , Rivera-Morales Dianali , Butler James P. , Seminara Stephanie B.
Published: May 2016

Context:

Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective:

To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal.

Participants:

Six men with congenital IHH and evidence for reversal.

Intervention:

Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24–2.4 nmol/kg) and GnRH (75 ng/kg).

Results:

Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin.

Conclusions:

The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.
Drosophila Ana1 is required for centrosome assembly and centriole elongation
Authors: Saurya Saroj , Roque Hélio , Novak Zsofia A. , Wainman Alan , Aydogan Mustafa G. , Volanakis Adam , Sieber Boris , Pinto David Miguel Susano , Raff Jordan W.
Published: May 2016

Centrioles organise centrosomes and cilia, and these organelles have an important role in many cell processes. In flies, the centriole protein Ana1 is required for the assembly of functional centrosomes and cilia. It has recently been shown that Cep135 (also known as Bld10) initially recruits Ana1 to newly formed centrioles, and that Ana1 then recruits Asl (known as Cep152 in mammals) to promote the conversion of these centrioles into centrosomes. Here, we show that ana1 mutants lack detectable centrosomes in vivo, that Ana1 is irreversibly incorporated into centrioles during their assembly and appears to play a more important role in maintaining Asl at centrioles than in initially recruiting Asl to centrioles. Unexpectedly, we also find that Ana1 promotes centriole elongation in a dose-dependent manner: centrioles are shorter when Ana1 dosage is reduced and are longer when Ana1 is overexpressed. This latter function of Ana1 appears to be distinct from its role in centrosome and cilium function, as a GFP–Ana1 fusion lacking the N-terminal 639 amino acids of the protein can support centrosome assembly and cilium function but cannot promote centriole over-elongation when overexpressed.