Day after day, dentists in Eastern Washington and across the state see the frustration of our patients, who regularly pay increasing dental insurance premiums only to see their claims for necessary care questioned, delayed or denied. We are working to correct that problem by proposing fundamental changes in the practices of Washington Dental Service .
Carbon monoxide (CO) is an odorless, colorless, poisonous gas that can cause sudden illness and death if present in sufficient concentration in the ambient air. During a significant power outage, persons using alternative fuel or power sources such as generators or gasoline powered engine tools such as pressure washers might be exposed to toxic CO levels if the fuel or power sources are placed inside or too close to the exterior of the building causing CO to build up in the structure. The purpose of this HAN advisory is to remind clinicians evaluating persons affected by the storm to maintain a high index of suspicion for CO poisoning.
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Annals of Otology, Rhinology &Laryngology, Ahead of Print.
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Annals of Otology, Rhinology &Laryngology, Ahead of Print.
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Annals of Otology, Rhinology &Laryngology, Ahead of Print.
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Babesiosis: An illness caused by the parasite Babesia which is transmitted from animals to humans by ticks. In the US, it is typically contracted in the Northeast or Midwest -- in southern New England or New York State and in Wisconsin or Minnesota. The signs and symptoms include fever, chills, sweating, myalgias (muscle aches), fatigue, hepatosplenomegaly (enlargement of the liver and spleen) and hemolytic anemia (anemia due to break-up of red cells). Symptoms typically occur after an incubation period of 1 to 4 weeks and can last several weeks. The disease is more severe in patients who are immunosuppressed, splenectomized (lack their spleen), or elderly. It can cause death. Treatment involves antibiotics, usually clindamycin and quinine or atovaquone and azithromycin.
The parasite: While more than 100 species of Babesia have been reported, only a few have been identified as causing human infections. Babesia microti and Babesia divergens have been identified in most human cases, but variants (considered different species) have been recently identified. Little is known about the occurrence of Babesia species in malarial areas where Babesia can easily be misdiagnosed as Plasmodium (the agent of malaria).
The life cycle of the parasite: (This contains some technical information.) The B. microti life cycle involves two hosts, which includes a rodent, primarily the white-footed mouse, Peromyscus leucopus. During a blood meal, a Babesia-infected tick introduces sporozoites into the mouse host. Sporozoites enter erythrocytes and undergo asexual reproduction (budding). In the blood, some parasites differentiate into male and female gametes although these cannot be distinguished at the light microscope level. The definitive host is a tick, in this case the deer tick, Ixodes dammini (I. scapularis). Once ingested by an appropriate tick, gametes unite and undergo a sporogonic cycle resulting in sporozoites. Transovarial transmission (also known as vertical, or hereditary, transmission) has been documented for "large" Babesia spp. but not for the "small" babesia, such as B. microti.
Humans enter the cycle when bitten by infected ticks. During a blood meal, a Babesia-infected tick introduces sporozoites into the human host. Sporozoites enter erythrocytes and undergo asexual replication (budding). Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease. Humans are, for all practical purposes, dead-end hosts and there is probably little, if any, subsequent transmission that occurs from ticks feeding on infected persons. However, human to human transmission can occur through blood transfusions.
Deer are the hosts upon which the adult ticks feed and are indirectly part of the Babesia cycle as they influence the tick population. When deer populations increase, the tick population also increases, thus heightening the potential for transmission.
The diagnosis: Diagnosis can be made by microscopic examination of thick and thin blood smears stained with Giemsa. Repeated blood smears may need to be examined to make the diagnosis. Antibody detection by indirect fluorescent antibody (IFA) test is a complementary diagnostic test. Isolation of Babesia by inoculation of the patient's blood into hamsters or gerbils may also assist in diagnosis. Animals inoculated with infective blood typically develop parasitemia (parasites circulating in their bloodstream) within 1 to 4 weeks.
Treatments in include medication and exchange transfusions.
A storm in a wineglass has erupted between Italy and Britain after some British dentists claimed this past week that prosecco, the bubbly North Italian wine, causes chronic tooth decay . The Italians were particularly incensed by headlines, that, like The Daily Post in Wales, cautioned that prosecco "could be rotting your teeth, warn experts."
Air pollution is among the environmental problems that adversely affect people's health. There is a close relationship between medicine and environment, and as a consequence, there are ethical considerations surrounding the problem of air pollution. The present research aimed to determine physicians' attitude toward their ethical responsibility regarding air pollution, and their role in reducing it. This was a qualitative research using content analysis, conducted in Tehran University of Medical Sciences. The focus group included 21 physicians with specialties and subspecialties in pediatrics, infectious diseases, pulmonology, gynecology, and midwifery selected through predetermined sampling along with 13 personal in-depth interviews. A number of questions were asked regarding physicians' ethical responsibility to decrease environmental crises, particularly air pollution.
As a result, 4 themes and 20 subthemes were extracted by assessing the focus group and interviews. These four general themes included the role of a physician as 1) an ordinary person, 2) a special citizen and a role model, 3) a professional person with special personal and social commitments, and 4) an administrator of the healthcare system.
In the present research, physicians acquired a special attitude toward air pollution. The research population mentioned physicians' impact as role models for the society, as well as their educational, supervisory, informative, promotional, and administrative roles among their most important obligations regarding air pollution. It is recommended to conduct further studies on physicians' knowledge, attitude and practice regarding their responsibility toward environmental issues in order to investigate this important matter further.Publication date: Available online 2 September 2017
Source:Journal of Biomechanics
Author(s): Monica Piergiovanni, Elena Bianchi, Giada Capitani, Irene Li Piani, Lucia Ganzer, Luca G. Guidotti, Matteo Iannacone, Gabriele Dubini
The liver is organized in hexagonal functional units - termed lobules - characterized by a rather peculiar blood microcirculation, due to the presence of a tangled network of capillaries – termed sinusoids. A better understanding of the hemodynamics that governs liver microcirculation is relevant to clinical and biological studies aimed at improving our management of liver diseases and transplantation.Herein, we built a CFD model of a 3D sinusoidal network, based on in vivo images of a physiological mouse liver obtained with a 2-photon microscope. The CFD model was developed with Fluent 16.0 (ANSYS Inc., Canonsburg, PA), particular care was taken in imposing the correct boundary conditions representing a physiological state. To account for the remaining branches of the sinusoids, a lumped parameter model was used to prescribe the correct pressure at each outlet. The effect of an adhered cell on local hemodynamics is also investigated for different occlusion degrees.The model here proposed accurately reproduces the fluid dynamics in a portion of the sinusoidal network in mouse liver. Mean velocities and mass flow rates are in agreement with literature values from in vivo measurements. Our approach provides details on local phenomena, hardly described by other computational studies, either focused on the macroscopic hepatic vasculature or based on homogeneous porous medium model.
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Publication date: Available online 2 September 2017
Source:Journal of Biomechanics
Author(s): Duncan P. Fransz, Arnold Huurnink, Vosse A. de Boode, Idsart Kingma, Jaap H. van Dieën
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Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Albert Leung, Leslie Zun, Kimberly Nordstrom, Michael P. Wilson
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Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Rajeev Sharma, Vidit Kaushal, Mohit Tyagi, Ashish Mittal
BackgroundFiberoptic bronchoscope−guided tracheal intubation is the gold standard for managing patients with supraglottic growths. In infants with a large and overhanging epiglottis, the success of fiberoptic-guided intubation relies heavily on the available space between the inferior surface of the epiglottis and the posterior pharyngeal wall or, more specifically, the superior surface of the supraglottic growth.Case ReportWe describe the inability to negotiate the tip of the fiberscope between the epiglottis and the supraglottic growth and the successful use of direct laryngoscopy to improve the available space along with the usefulness of "bubbling of air" to locate the glottic opening in an infant.Why Should an Emergency Physician Be Aware of This?We emphasize the role of the emergency physician in managing such patients. Most of the time, the setting is not ideal in such emergency situations and the most qualified clinician to treat them is the emergency physician. The knowledge and skills of the emergency physician, along with awareness of the possible techniques for airway management, can be lifesaving.
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Publication date: Available online 1 September 2017
Source:The Journal of Emergency Medicine
Author(s): Michael B. Weinstock, Amal Mattu, Erik P. Hess
BackgroundThere is a wide variation in practice patterns among emergency medicine physicians; many factors weigh into the medical decision-making process including the health of the patient as well as short-term risk to the physician.ObjectiveThe objective of our discussion is to illustrate specific scenarios where medical decisions are focused on the physician's short-term risk, then to propose an approach to shifting the balance to the patient's long-term health.MethodsUsing recent data on the evaluation, disposition, and outcomes of patients with low-risk chest pain in the emergency department, we calculate the risk of outpatient evaluation compared to the common practice of admission or observation.ResultsPatients with low-risk chest pain and negative initial evaluation in the emergency department with 2 normal cardiac biomarkers, normal vital signs, and non-ischemic, interpretable ECGs, have an extremely low-risk of a short term clinically relevant adverse cardiac event. There is a suggestion of a higher patient risk from admission, prompting consideration that continued evaluation of the chest pain as an outpatient may be safer than admission or observation.ConclusionA test/intervention should be done if the risk of a missed diagnosis or adverse outcome is greater that the risk of the test/intervention. Involving the patient in the decision-making process may help to shift the management balance from the physician's short-term concern of their own risk, to the patient's long-term health.
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Publication date: Available online 2 September 2017
Source:The Journal of Emergency Medicine
Author(s): Fumihiro Ohchi, Nobuyasu Komasawa, Ryosuke Mihara, Kazuo Hattori, Toshiaki Minami
BackgroundNo study has ever compared the efficacy of various types of supraglottic devices (SGDs) for securing the airway under cricoid pressure.ObjectiveThis study aimed to evaluate the efficacy of six SGDs, LMA-ProSeal (ProSeal), LMA-Classic (Classic), Laryngeal Tube (LT), LMA-Supreme (Supreme), air-Q (air-Q), and i-gel (i-gel), in airway management under cricoid pressure using a manikin.MethodsFifteen novice doctors and 16 experienced doctors used the six SGDs under cricoid or sham pressure on an adult manikin. Insertion time, successful ventilation rate, and subjective insertion difficulty on a visual analogue scale (VAS) were measured.ResultsBoth novice and experienced doctors had a significantly lower ventilation success rate under cricoid pressure than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Novice doctors required a significantly longer insertion time under cricoid pressure than under sham pressure with all SGDs. Experienced doctors required a significantly longer insertion time under cricoid pressure than with sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs. Subjective insertion difficulty on VAS was significantly higher under cricoid pressure than under sham pressure with all six SGDs.ConclusionVentilation success rate under cricoid pressure was significantly lower than under sham pressure when using the ProSeal, Classic, and LT, but not when using the other three SGDs in both novice and experienced doctors.
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The majority of critically ill patients experience distress during their stay in the Intensive Care Unit (ICU), resulting from systemic illness, multiple interventions and environmental factors. Providing huma...
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Supraglottic airway devices (SGA) are commonly used in pediatric anesthesia and serve as primary or back-up devices for difficult airway management. Most SGA are marketed without proper clinical evaluation. Th...
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Posttraumatic edema in facial bone fracture patients may interfere with the operation field and delay the schedule. Thus, swiftly reducing the edema alleviates patient discomfort and advances the operation date. Ice packing and compression bandages are often used for such a purpose, but such methods are often inconvenient for the face. In this study, we aim to analyze the effect of light-emitting diode (LED) (590/830 nm)−based low-level laser therapy (LLLT) in posttraumatic edema in facial bone fracture patients.
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Enzymatically modified isoquercitrin (EMIQ) is produced from rutin using enzymatic hydrolysis followed by treatment with glycosyltransferase in the presence of dextrin to add glucose residues. EMIQ is absorbed...
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In 2016 Britons drank 40 million litres of the Italian sparkling wine last year, and dentists warn that its high sugar content could rot heavy drinkers' teeth. Tooth decay can set in when people regularly consume large amounts of the drink.
The authors regret to publish Dr. Fabio Falcini's affiliation incorrectly. Corrected affiliation is presented above.
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Posttraumatic edema in facial bone fracture patients may interfere with the operation field and delay the schedule. Thus, swiftly reducing the edema alleviates patient discomfort and advances the operation date. Ice packing and compression bandages are often used for such a purpose, but such methods are often inconvenient for the face. In this study, we aim to analyze the effect of light-emitting diode (LED) (590/830 nm)−based low-level laser therapy (LLLT) in posttraumatic edema in facial bone fracture patients.
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Previous studies suggest that preschoolers from low socioeconomic backgrounds engage in more screen time. Still, the factors in the social and physical home environment driving these differences in preschool c...
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Susanna Ambrosio, Carmen D. Saccà, Barbara Majello
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners. Here we present an overview of the role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in cancer.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Heng Xia, Dong Chen, Qijia Wu, Gang Wu, Yanhong Zhou, Yi Zhang, Libin Zhang
The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3′UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5′ and 3′ splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Marco Hatem-Vaquero, Mercedes Griera, Wieslawa Giermakowska, Alicia Luengo, Laura Calleros, Laura V. Gonzalez Bosc, Diego Rodríguez-Puyol, Manuel Rodríguez-Puyol, Sergio De Frutos
Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3β/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Ketki Patne, Radhakrishnan Rakesh, Vijendra Arya, Upasana Bedi Chanana, Ramesh Sethy, Pynskhem Bok Swer, Rohini Muthuswami
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known.In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells.From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Antonio Neme, Sabine Seuter, Carsten Carlberg
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24h ligand stimulation comprising >11,600 genomic loci, 78% of which were detected exclusively after 24h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH)2D3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH)2D3-modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Bu-Nam Jeon, Jae-Hyeon Yoon, Dohyun Han, Min-Kyeong Kim, Youngsoo Kim, Seo-Hyun Choi, Jiyang Song, Kyung-Sup Kim, Kunhong Kim, Man-Wook Hur
Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Pouya Salehipour, Mahsa Nematzadeh, Maryam Beigom Mobasheri, Mandana Afsharpad, Kamran Mansouri, Mohammad Hossein Modarressi
Testis specific gene antigen 10 (TSGA10) is a cancer testis antigen involved in the process of spermatogenesis. TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α. Although it has been shown that TSGA10 messenger RNA (mRNA) is mainly expressed in testis and some tumors, the transcription pattern and regulatory mechanisms of this gene remain largely unknown. Here, we report that human TSGA10 comprises at least 22 exons and generates four different transcript variants. It was identified that using two distinct promoters and splicing of exons 4 and 7 produced these transcript variants, which have the same coding sequence, but the sequence of 5'untanslated region (5'UTR) is different between them. This is significant because conserved regulatory RNA elements like upstream open reading frame (uORF) and putative internal ribosome entry site (IRES) were found in this region which have different combinations in each transcript variant and it may influence translational efficiency of them in normal or unusual environmental conditions like hypoxia. To indicate the transcription pattern of TSGA10 in breast cancer, expression of identified transcript variants was analyzed in 62 breast cancer samples. We found that TSGA10 tends to express variants with shorter 5'UTR and fewer uORF elements in breast cancer tissues. Our study demonstrates for the first time the expression of different TSGA10 transcript variants in testis and breast cancer tissues and provides a first clue to a role of TSGA10 5'UTR in regulation of translation in unusual environmental conditions like hypoxia.
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Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Lin Gan, Bernd Denecke
The differentiation process of embryonic stem cells is a comprehensive process regulated by a variety of factors in response to stimulus. Studies of this process can be focused on cell biology as well as on molecular biology level. In this paper we identified the co-regulation of molecular regulators and their interactions during cardiomyocyte specific differentiation of mouse embryonic stem cells based on parallel genome wide transcriptome analyses of mRNA and microRNA. Differentially expressed mRNAs and microRNAs were identified according to their expression profiles. Subsequently, a primary network was generated by using our genome wide profiling data, predicted sequence target information of transcription factors and microRNAs from various sources, validated microRNA target information, as well as tissue specific transcription factor binding information. Considering only validated microRNA target information and tissue specific transcription factor binding information secondary regulatory networks were extracted from the primary network to identify basic regulatory elements. Eight types of 3-node patterns were identified in this network. Novel regulatory modules, like Meis1 - Gata6 and miR-21/24 - Zic3, were discovered with high plausibility by this procedure without complicated and time-consuming experimental processes.
Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Peterson Kariuki Maina, Peng Shao, Xiongfei Jia, Qi Liu, Shaikamjad Umesalma, Maximo Marin, Donald Long, Samantha Concepción-Román, Hank Heng Qi
Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form—castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.
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Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): C. Boulard, A. Fatihi, L. Lepiniec, B. Dubreucq
The LAFL genes (LEC2, ABI3, FUS3, LEC1) encode transcription factors that regulate different aspects of seed development, from early to late embryogenesis and accumulation of storage compounds. These transcription factors form a complex network, with members able to interact with various other players to control the switch between embryo development and seed maturation and, at a later stage in the plant life cycle, between the mature seed and germination.In this review, we first summarize our current understanding of the role of each member in the network in the light of recent advances regarding their regulation and structure/function relationships. In a second part, we discuss new insights concerning the evolution of the LAFL genes to address the more specific question of the conservation of LEAFY COTYLEDONS 2 in both dicots and monocots and the putative origin of the network. Last we examine the current major limitations to current knowledge and future prospects to improve our understanding of this regulatory network.
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Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Samuele Gherardi, Matteo Bovolenta, Chiara Passarelli, Maria Sofia Falzarano, Paolo Pigini, Chiara Scotton, Marcella Neri, Annarita Armaroli, Hana Osman, Rita Selvatici, Francesca Gualandi, Alessandra Recchia, Marina Mora, Pia Bernasconi, Lorenzo Maggi, Lucia Morandi, Alessandra Ferlini, Giovanni Perini
The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2Mb and accounts for approximately 0,1% of the entire human genome. Mutations in this gene cause Duchenne and Becker Muscular Dystrophy, X-linked Dilated Cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16h, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques.Our results unveil a surprisingly powerful processivity of the RNA polymerase II along the entire 2.2Mb of the DMD locus with just one site of pausing around intron 52. We also discovered epigenetic marks highlighting the existence of four novel cis‑DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA.Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies.
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Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Gayathri Govindaraju, C.A. Jabeena, Devadathan Valiyamangalath Sethumadhavan, Nivethika Rajaram, Arumugam Rajavelu
In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite.
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Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Jordan K. Boutilier, Rhonda L. Taylor, Ramesh Ram, Elyshia McNamara, Quang Nguyen, Hayley Goullee, David Chandler, Munish Mehta, Lois Balmer, Nigel G. Laing, Grant Morahan, Kristen J. Nowak
Different genes encode the a-actin isoforms that are predominantly expressed in heart and muscle. Mutations in the skeletal muscle α-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.Author SummaryMutations in the skeletal muscle actin gene (ACTA1) cause a severe muscle disease that is usually fatal within the first year of life. Some patients with mutations in the ACTA1 gene do not have any ACTA1 protein present in their skeletal muscles. We have previously shown that some of these patients retain expression of the foetal isoform of the gene, cardiac actin (ACTC1). Further, patients who have ACTC1 expressed in their skeletal muscles have increased longevity and improved muscle function, suggesting that upregulation of ACTC1 may be a viable therapy for ACTA1 disease patients. Thus, we have investigated the mechanisms regulating expression of Actc1 in a genetically diverse population of different mouse strains with the aim of identifying the regulatory controls that cause the gene to be switched off. We identified a number of sequence variants present in Actc1 regulatory regions and show that increased promoter methylation is inversely correlated with Actc1 expression. We also show that expression of ACTC1 in humans is likely to be influenced by non-coding sequence variation in regulatory regions upstream and downstream of the gene. Our findings build on previous work and identify regulatory regions of the genome that can now be investigated further.
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Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Theresa Heider, Lisa Mutschelknaus, Vanja Radulović, Klaudia Winkler, Julia Kimmel, Nataša Anastasov, Michael J. Atkinson, Simone Moertl
The non-coding transcriptome, in particular microRNAs (miRNA), influences cellular survival after irradiation. However, the underlying mechanisms of radiation-induced miRNA expression changes and consequently target expression changes are poorly understood.In this study, we show that ionizing radiation decreases expression of the miR-23a~27a~24-2 cluster through transcriptional regulation by promoter methylation and at the post-transcriptional level by reduced processing through AGO-phosphorylation. Furthermore, we demonstrate that all three mature cluster miRNAs reduce apoptosis by increasing expression of the common target protein XIAP.These findings link a temporal succession of transcriptional and post-transcriptional regulatory mechanisms of the miR~23a~24-2~27a cluster, enabling a dynamic stress response and assuring cellular survival after radiation exposure.
Publication date: Available online 25 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ming-Hsien Chien, Wei-Jiunn Lee, Yi-Chieh Yang, Yin-Lin Li, Bo-Rong Chen, Tsu-Yao Cheng, Pei-Wen Yang, Ming-Yang Wang, Yi-Hua Jan, Yen-Kuang Lin, Jang-Ming Lee, Michael Hsiao, Jin-Shing Chen, Kuo-Tai Hua
KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.
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Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Zhiwen Fan, Zilong Li, Yuyu Yang, Shuai Liu, Junli Guo, Yong Xu
Hypoxia inducible factor 1 alpha (HIF-1α) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1α plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1α in trans‑activating the seven in absentia homolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1α started to occupy the SIAH1 promoter. Depletion of HIF-1α with siRNA or inhibition of HIF-1α with chetomin abrogated the induction of SIAH1 expression. HIF-1α knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1α interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1α also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1α dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis.
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Publication date: Available online 8 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Vineeta Sharma, Surbhi Kohli, Vani Brahmachari
Animals from different phyla including arthropods tolerate water stress to different extent. This tolerance is accompanied by biochemical changes which in turn are due to transcriptional alteration. The changes in transcription can be an indirect effect on some of the genes, ensuing from the effect of stress on the regulators of transcription including epigenetic regulators. Within this paradigm, we investigated the correlation between stress response and epigenetic modification underlying gene expression modulation during desiccation stress in Canton-S. We report altered resistance of flies in desiccation stress for heterozygote mutants of PcG and TrxG members. Pc/+ mutant shows lower survival, while ash1/+ mutants show higher survival under desiccation stress as compared to Canton-S. We detect expression alteration in stress related genes as well the genes of the Polycomb and trithorax complex in Canton-S subjected to desiccation stress. Concomitant with this, there is an altered enrichment of H3K27me3 and H3K4me3 at the upstream regions of the stress responsive genes. The enrichment of activating mark, H3K4me3, is higher in non-stress condition while H3K27me3, the repressive mark, is more pronounced under stress condition, which in turn, can be correlated with the binding of Pc and Ash1. Our results show that desiccation stress induces dynamic switching in expression and enrichment of PcG and TrxG in the upstream region of genes, which correlates with histone modifications. We provide evidence that epigenetic modulation could be one of the mechanisms to adapt to the desiccation stress in Drosophila. Thus, our study proposes the interaction of epigenome and environmental factors.
Publication date: August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 8
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A provincial government report found last year that dental procedures cost up to 44 per cent more in Alberta than in neighbouring provinces. Does this inflated cost have an impact on dental health? You bet.
The aim of the study was to show how many X-ray technicians who work in radiology department at public-sector hospitals in Sulaimani city are affected by doses of X-ray from X-ray machines, fluoroscopy, and CT scan through examining 12 hematological parameters. The study group included 24 seemingly healthy female and male X-ray technicians. The group was subdivided into 12 female X-ray technicians having average ages of 39 and 14 years of 4 hourly per day of services. As well as, 12 male X-ray technicians having average ages of 41 and 15 years of 5 hourly per day of services. A group of 24 healthy control subjects was selected from outside of the hospitals; the group was subdivided into 12 females having average age of 33 years and 12 males having average of 39 years matched with the first group to reveal any alteration in hematological parameters. The statistical analysis of hematological parameters showed that among the female group, the parameter mean cell volume (MCV) was decreased significantly (P < 0.009) but the parameter mean cell hemoglobin concentration (MCHC) increased significantly (P < 0.049) compared to that among the control groups. The results showed that among the male group, the mean values of total white blood cells (tWBC) (P < 0.003) and platelet (PLT) counts (P < 0.03) decreased significantly compared with those among the control groups whereas no significant difference was observed between the rest of blood cell counts in the female and male groups. We concluded that chronic exposure to X-ray can produce significant increase in MCV and significant decrease in MCHC parameters in female X-ray technicians and significant decrease in the number of tWBC and PLT parameters in male X-ray technicians.
The acoustic radiation is a compact bundle of fibers conveying auditory information from the medial geniculate nucleus of the thalamus to the auditory cortex. Topographical knowledge of this bundle in primates is scarce and in vivo diffusion-based tractography reconstructions in humans remains challenging, especially with the most widely used MRI acquisition protocols. Therefore, the AR represents a notable anatomical omission in the neurobiological investigation of acoustic and linguistic functional mechanisms in humans. In this study, we combine blunt micro-dissections and advanced diffusion tractography methods to provide novel insights into the topographical anatomy of this bundle in humans. Evidences from ex vivo blunt micro-dissection in three human (two right) hemispheres are compared to the 3D profile of this bundle as reconstructed by tractography techniques in four healthy adult data sets provided by the Human Connectome Project. Both techniques show the unique trajectory of the AR, a transversal course from the midline to the lateral convexity of the posterior temporal lobe. Blunt dissections demonstrated three portions of this bundle that we defined as the genu, stem, and fan, revealing the intimate relationships that each of these components has with neighboring association and projection pathways. Probabilistic tractography and ultra-high b values provided results comparable to blunt micro-dissections and highlighted the main limitations in tracking the AR. This is, to our knowledge, the first ex vivo/in vivo integrated study providing novel and reliable information about the precise anatomy of the AR, which will be important for future investigations in the neuroscientific, clinical, and surgical field.
| Piled Higher & Deeper by Jorge Cham | www.phdcomics.com | |
| title: "Surveys" - originally published 9/1/2017 For the latest news in PHD Comics, CLICK HERE! | ||
Background
Mesothelioma is increasingly recognised as a global health issue and the assessment of its global burden is warranted.
ObjectivesTo descriptively analyse national mortality data and to use reported and estimated data to calculate the global burden of mesothelioma deaths.
MethodsFor the study period of 1994 to 2014, we grouped 230 countries into 59 countries with quality mesothelioma mortality data suitable to be used for reference rates, 45 countries with poor quality data and 126 countries with no data, based on the availability of data in the WHO Mortality Database. To estimate global deaths, we extrapolated the gender-specific and age-specific mortality rates of the countries with quality data to all other countries.
ResultsThe global numbers and rates of mesothelioma deaths have increased over time. The 59 countries with quality data recorded 15 011 mesothelioma deaths per year over the 3 most recent years with available data (equivalent to 9.9 deaths per million per year). From these reference data, we extrapolated the global mesothelioma deaths to be 38 400 per year, based on extrapolations for asbestos use.
ConclusionsAlthough the validity of our extrapolation method depends on the adequate identification of quality mesothelioma data and appropriate adjustment for other variables, our estimates can be updated, refined and verified because they are based on commonly accessible data and are derived using a straightforward algorithm. Our estimates are within the range of previously reported values but higher than the most recently reported values.
ConclusionIn contrast to previously reported series, in this cohort endoscopic resection of sinonasal tumors appears to be followed by an improvement in QoL, which is sustained over a 2‐year period. Level of Evidence2b. Laryngoscope, 2017 (Source: The Laryngoscope)
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ConclusionsApproximately one‐quarter of children with EoE present under 5 years of age with multiple esophageal symptoms, comorbidities, and allergen‐sensitization profiles. These patients demonstrate substantial clinicohistologic improvement following therapy. Level of Evidence4 Laryngoscope, 2017 (Source: The Laryngoscope)
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(Source: The Laryngoscope)
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ConclusionVerrucous carcinoma of the sinonasal tract is associated with a generally favorable prognosis. Age, primary site, and surgical therapy are independent predictors of OS and DSS, respectively. We present the first population‐based analysis of sinonasal VC, thus clarifying the prognosis and reinforcing the management of this malignancy. Level of Evidence4. Laryngoscope, 2017 (Source: The Laryngoscope)
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ConclusionModified UPPP was effective in improving nocturnal respiration and daytime sleepiness in OSAS patients at both 6‐ and 24‐month follow‐up. Patients with tonsil size 2, and 3 to 4, benefitted similarly from surgery with improved respiration. Level of Evidence2b. Laryngoscope, 2017 (Source: The Laryngoscope)
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Atherosclerosis is the development of lipid-laden plaques in arteries and is nowadays considered as an inflammatory disease. It has been shown that high doses of ionizing radiation, as used in radiotherapy, can increase the risk of development or progression of atherosclerosis. To elucidate the effects of radiation on atherosclerosis, we propose a mathematical model to describe radiation-promoted plaque development. This model distinguishes itself from other models by combining plaque initiation and plaque growth, and by incorporating information from biological experiments. It is based on two consecutive processes: a probabilistic dose-dependent plaque initiation process, followed by deterministic plaque growth. As a proof of principle, experimental plaque size data from carotid arteries from irradiated ApoE \(^\) mice was used to illustrate how this model can provide insight into the underlying biological processes. This analysis supports the promoting role for radiation in plaque initiation, but the model can easily be extended to include dose-related effects on plaque growth if available experimental data would point in that direction. Moreover, the model could assist in designing future biological experiments on this research topic. Additional biological data such as plaque size data from chronically-irradiated mice or experimental data sets with a larger variety in biological parameters can help to further unravel the influence of radiation on plaque development. To the authors' knowledge, this is the first biophysical model that combines probabilistic and mechanistic modeling which uses experimental data to investigate the influence of radiation on plaque development.
Environmental factors including pollution affect human health, and the unifying factor in determining toxicity and pathogenesis for a wide array of environmental factors is oxidative stress. Here, we created the oxidative environment with 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH) and consequent cardiac remodeling in chick embryos. The metabolite fingerprint of heart tissue was obtained from Fourier transform infrared (FTIR) spectroscopic analysis. The global lipidomic analysis was done using electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) by precursor ion scanning and neutral loss scanning methods. Further, the fatty acid levels were quantified in AAPH-treated H9c2 cardiomyoblasts with gas chromatography-mass spectrometry (GC-MS). Lipidomic fingerprinting study indicated that majority of differentially expressed phospholipids species in heart tissue belonged to ether phosphatidylcholine (ePC) species, and we conclude that excess oxidative environment may alter the phospholipid metabolism at earlier stages of cardiac remodeling.
Chemical composition and antifungal activity of essential oils of Algerian Mentha species were studied. Chemical compositions of different Mentha species oils (Mentha rotundifolia, M. spicata, M. pulegium, and M. piperita) were investigated by capillary GC and GC/MS, and their antifungal activities were evaluated by means of paper disc diffusion method and minimum inhibitory concentration (MIC) assays. In total, 98 components from all Mentha species were identified. All oils were rich in monoterpene-oxygenated components. In addition, we reported fumigant antifungal activity of Algerian Mentha essential oils against four fungi: Botrytis cinerea, Penicillium expansum, Monilinia laxa, and M. fructigena. All oils demonstrated very good inhibition especially against B. cinerea, M. laxa, and M. fructigena. Both Monilinia fungi were extremely sensitive to all Algerian Mentha oils, which suggests that Mentha essential oils have the potential to be used as bio-pesticides to protect fruit trees, such as apple and pear trees, and provides an alternative to chemical pesticides.
Background
Multiple sclerosis (MS) is a chronic multifaceted demyelinating and neurodegenerative disease of the central nervous system (CNS) of presumed autoimmune origin.1
Patients with MS are characterised by a spatial and temporal dissemination of neurological sign and symptoms, by the presence of multifocal lesions in the periventricular white matter on MRI scans and by an immunoglobulin synthesis within the CNS.1 Further diagnostic tools are desirable, and the use of blood and cerebrospinal fluid (CSF) biomarkers may contribute to the comprehension of the disease's pathogenesis and progression.
Autophagy is an evolutionarily conserved and genetically controlled cellular process where intracellular components are sequestered within double-membrane vesicles (autophagosomes), which then fuse with lysosomes where the material is degraded.2 Autophagy also occurs as mitophagy, which is responsible for the removal of aberrant, aged and wasted mitochondria. Interestingly, autophagic/mitophagic pathways have been found deregulated in various human diseases. In particular, it...
Sleep is a fundamental homeostatic process, and disorders of sleep can greatly affect quality of life. Parkinson's disease (PD) is highly comorbid for a spectrum of sleep disorders and deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to improve sleep architecture in PD. We studied local field potential (LFP) recordings in PD subjects undergoing STN-DBS over the course of a full-night's sleep. We examined the changes in oscillatory activity recorded from STN between ultradian sleep states to determine whether sleep-stage dependent spectral patterns might reflect underlying dysfunction. For this study, PD (n=10) subjects were assessed with concurrent polysomnography and LFP recordings from the DBS electrodes, for an average of 7.5 hours in 'off' dopaminergic medication state. Across subjects, we found conserved spectral patterns among the canonical frequency bands (delta 0–3 Hz, theta 3–7 Hz, alpha 7–13 Hz, beta 13–30 Hz, gamma 30–90 Hz and high frequency 90–350 Hz) that were associated with specific sleep cycles: delta (0–3 Hz) activity during non-rapid eye movement (NREM) associated stages was greater than during Awake, whereas beta (13–30 Hz) activity during NREM states was lower than Awake and rapid eye movement (REM). In addition, all frequency bands were significantly different between NREM states and REM. However, each individual subject exhibited a unique mosaic of spectral interrelationships between frequency bands. Our work suggests that LFP recordings from human STN differentiate between sleep cycle states, and sleep-state specific spectral mosaics may provide insight into mechanisms underlying sleep pathophysiology.
The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lym...
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Identifying older people affected by cancer who are more at risk of negative health outcomes is a major issue in health initiatives focusing on medical effectiveness. In this regard, psychological risk factors...
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Throughout most of sub-Saharan Africa (and, indeed, most resource-limited areas), lack of death registries prohibits linkage of cancer diagnoses and precludes the most expeditious approach to determining cance...
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A solitary fibrous tumour is a rare, mainly benign spindle cell mesenchymal tumour most commonly originating from the pleura. An intrapericardial location of a solitary fibrous tumour is extremely unusual. We ...
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To assess the trends in risk classification and primary therapy of Japanese prostate cancer patients who were diagnosed between 2004 and 2012.
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Introduction
Interpreting, performing and applying research is a key part of evidence-based medical practice, however, incorporating these within curricula is challenging. This study aimed to explore current provision of research skills training within medical school curricula, provide a student-focused needs assessment and prioritise research competencies.
MethodsA international, cross-sectional survey of final year UK and Irish medical students was disseminated at each participating university. The questionnaire investigated research experience, and confidence in the Medical Education in Europe (MEDINE) 2 consensus survey research competencies.
ResultsFully completed responses were received from 521 final year medical students from 32 medical schools (43.4% male, mean age 24.3 years). Of these, 55.3% had an additional academic qualification (49.5% Bachelor's degree), and 38.8% had been a named author on an academic publication. Considering audit and research opportunities and teaching experience, 47.2% reported no formal audit training compared with 27.1% who reported no formal research training. As part of their medical school course, 53.4% had not performed an audit , compared with 29.9% who had not participated in any clinical or basic science research. Nearly a quarter of those who had participated in research reported doing so outside of their medical degree course. Low confidence areas included selecting and performing the appropriate statistical test, selecting the appropriate research method, and critical appraisal. Following adjustment, several factors were associated with increased confidence including previous clinical research experience (OR 4.21, 2.66 to 6.81, P<0.001), additional degrees (OR 2.34, 1.47 to 3.75, P<0.001), and male gender (OR 1.90, 1.25 to 2.09, P=0.003). Factors associated with an increase in perceived opportunities included formal research training in the curriculum (OR 1.66, 1.12 to 2.46, P=0.012), audit skills training in the curriculum (OR 1.52, 1.03 to 2.26, P= 0.036) and research methods taught in a student selected component (OR 1.75, 1.21 to 2.54, P=0.003).
DiscussionNearly one-third of students lacked formal training on undertaking research, and half of students lacked formal audit training and opportunities to undertake audit as part of their medical school course. The presence of research training in the cirriculum was associated with an increase in perceived opportunities to participate in MEDINE2 research competencies. Female gender and a lack of previous research experience were significant factors influencing confidence and participation in research.
Purpose of the study
There are few studies on the value of authoring questions as a study method, the quality of the questions produced by students and student perceptions of student-authored question banks. Here we evaluate PeerWise, a widely used and free online resource that allows students to author, answer and discuss multiple-choice questions.
Study designWe introduced two undergraduate medical student cohorts to PeerWise (n=603). We looked at their patterns of PeerWise usage; identified associations between student engagement and summative exam performance; and used focus groups to assess student perceptions of the value of PeerWise for learning. We undertook item analysis to assess question difficulty and quality.
ResultsOver two academic years, the two cohorts wrote 4671 questions, answered questions 606 658 times and posted 7735 comments. Question writing frequency correlated most strongly with summative performance (Spearman's rank: 0.24, p=<0.001). Student focus groups found that: (1) students valued curriculum specificity; and (2) students were concerned about student-authored question quality. Only two questions of the 300 'most-answered' questions analysed had an unacceptable discriminatory value (point-biserial correlation <0.2).
ConclusionsItem analysis suggested acceptable question quality despite student concerns. Quantitative and qualitative methods indicated that PeerWise is a valuable study tool.
Thallium (Tl) is a toxic heavy metal that causes oxidative stress both in vitro and in vivo. In this work, we evaluated the production of oxygen (ROS)- and nitrogen (RNS)-reactive species in adherent PC12 (PC12adh) cells exposed for 0.5–6 h to Tl(I) or Tl(III) (10–100 µM). In this system, Tl(I) induced mostly H2O2 generation while Tl(III) induced H2O2 and ONOO·− generation. Both cations enhanced iNOS expression and activity, and decreased CuZnSOD expression but without affecting its activity. Tl(I) increased MnSOD expression and activity but Tl(III) decreased them. NADPH oxidase (NOX) activity remained unaffected throughout the period assessed. Oxidant levels returned to baseline values after 6 h of incubation, suggesting a response of the antioxidant defense system to the oxidative insult imposed by the cations. Tl also affected the glutathione-dependent system: while Tl(III) increased glutathione peroxidase (GPx) expression and activity, Tl(I) and Tl(III) decreased glutathione reductase (GR) expression. However, GR activity was mildly enhanced by Tl(III). Finally, thioredoxin-dependent system was evaluated. Only Tl(I) increased 2-Cys peroxiredoxins (2-Cys Prx) expression, although both cations increased their activity. Tl(I) increased cytosolic thioredoxin reductase (TrxR1) and decreased mitochondrial (TrxR2) expression. Tl(III) had a biphasic effect on TrxR1 expression and slightly increased TrxR2 expression. Despite of this, both cations increased total TrxR activity. Obtained results suggest that in Tl(I)-exposed PC12adh cells, there is an early response to oxidative stress mainly by GSH-dependent system while in Tl(III)-treated cells both GSH- and Trx-dependent systems are involved.
Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As reviewed here, both of these tumour suppressors promote the maintenance of genome stability via homologous recombination. Thus, related assays may be particularly relevant to cancer risk. Progress in implementing functional assays to assess missense variants of BRCA1 and BRCA2 is considered here, along with current limitations and the path to more impactful assay systems. While functional assays have been developed to independently evaluate BRCA1 and BRCA2 VUS, high-throughput assays with sufficient sensitivity to characterise the large number of identified variants are lacking. Additionally, because of relatively low conservation of certain domains of BRCA1, and of BRCA2, between humans and rodents, heterologous expression in rodent cells may have limited reliability or capacity to assess variants present throughout either protein. Moving forward, it will be important to perform assays in human cell lines with relevance to particular tumour types, and to strengthen risk predictions based on multifactorial statistical analyses that also include available data on cosegregation and tumour pathology.
Background
A subset of high-risk procedures present significant safety threats due to their (1) infrequent occurrence, (2) execution under time constraints and (3) immediate necessity for patient survival. A Just-in-Time (JIT) intervention could provide real-time bedside guidance to improve high-risk procedural performance and address procedural deficits associated with skill decay.
ObjectiveTo evaluate the impact of a novel JIT intervention on transvenous pacemaker (TVP) placement during a simulated patient event.
MethodsThis was a prospective, randomised controlled study to determine the effect of a JIT intervention on performance of TVP placement. Subjects included board-certified emergency medicine physicians from two hospitals. The JIT intervention consisted of a portable, bedside computer-based procedural adjunct. The primary outcome was performance during a simulated patient encounter requiring TVP placement, as assessed by trained raters using a technical skills checklist. Secondary outcomes included global performance ratings, time to TVP placement, number of critical omissions and System Usability Scale scores (intervention only).
ResultsGroups were similar at baseline across all outcomes. Compared with the control group, the intervention group demonstrated statistically significant improvement in the technical checklist score (11.45 vs 23.44, p<0.001, Cohen's d effect size 4.64), the global rating scale (2.27 vs 4.54, p<0.001, Cohen's d effect size 3.76), and a statistically significant reduction in critical omissions (2.23 vs 0.68, p<0.001, Cohen's d effect size –1.86). The difference in time to procedural completion was not statistically significant between conditions (11.15 min vs 12.80 min, p=0.12, Cohen's d effect size 0.65). System Usability Scale scores demonstrated excellent usability.
ConclusionA JIT intervention improved procedure perfromance, suggesting a role for JIT interventions in rarely performed procedures.
Commentary on: Grogan A, Coughlan M, Prizeman G, et al. The patients' perspective of international normalized ratio self-testing, remote communication of test results and confidence to move to self-management. J Clin Nurs 2017 doi: 10.1111/jocn.13767. [Epub ahead of print: 23 Feb 2017].
Implications for practice and researchPatient self-testing and self-management programmes that augment education and telehealth approaches present a safe, sustainable and acceptable model of care for individuals with routine anticoagulation monitoring and management needs.
There is need for further research of patient self-testing and self-management programmes that addresses patient selection and building patient confidence.
ContextWarfarin remains a key agent for thromboprophylaxis. However, it is not without complications. A narrow therapeutic range translates to a fine balance between thrombosis and bleeding. Given warfarin's sometimes unpredictable nature, achieving quality anticoagulation can be challenging. Regular monitoring and careful titration of therapy are required in accordance with a patient's international normalised ratio...
This technical innovation describes the development of a novel device to aid technologists in reducing exposure variation and repeat imaging in computed and digital radiography. The device consists of a color video and depth camera in combination with proprietary software and user interface. A monitor in the x-ray control room displays the position of the patient in real time with respect to automatic exposure control chambers and image receptor area. The thickness of the body part of interest is automatically displayed along with a motion indicator for the examined body part. The aim is to provide an automatic measurement of patient thickness to set the x-ray technique and to assist the technologist in detecting errors in positioning and motion before the patient is exposed. The device has the potential to reduce the incidence of repeat imaging by addressing problems technologists encounter daily during the acquisition of radiographs.
