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Find video protocols related to scientific articles indexed in Pubmed.
Evolution of mesh fixation for hernia repair.
Surg Technol Int
PUBLISHED: 11-15-2014
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Hernia repair remains one of the most common surgical procedures performed around the world. Over the past several decades, in response to various mesh-related complications and coinciding with the influx of laparoscopy into the field of general surgery, numerous advancements have been made in regards to the technology of mesh products being used in hernia repair today. Along these same lines, devices used for mesh fixation have evolved at a similar pace. The goal of this chapter is to review the various materials and methods of mesh fixation being utilized in both ventral and inguinal hernia repair today.
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Highly sensitive, localized surface plasmon resonance fiber device for environmental sensing, based upon a structured bi-metal array of nano-wires.
Opt Lett
PUBLISHED: 11-01-2014
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We demonstrate a bi-metal coated (platinum and gold or silver), localized surface plasmon resonance fiber sensor with an index sensitivity exceeding 11,900 nm/RIU, yielding an index resolution of 2×10-5 in the aqueous index regime. This is one of the highest index sensitivities achieved with an optical fiber sensor. The coatings consist of arrays of bi-metal nano-wires (typically 36 nm in radius and 20 ?m in length), supported by a silicon dioxide thin film on a thin substrate of germanium, the nano-wires being perpendicular to the longitudinal axis of the D-shaped fiber.
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Is the number of fast-food outlets in the neighbourhood related to screen-detected type 2 diabetes mellitus and associated risk factors?
Public Health Nutr
PUBLISHED: 11-01-2014
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We investigated whether a higher number of fast-food outlets in an individual's home neighbourhood is associated with increased prevalence of type 2 diabetes mellitus and related risk factors, including obesity.
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Advancing cancer patient care by integrating circulating tumor cell technology to understand the spatial and temporal dynamics of cancer.
Drug Dev. Res.
PUBLISHED: 09-09-2014
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Spatial and temporal dynamics of cancer, studied with physical science approaches at critical transition points of the disease can provide insight into the biology of cancer and the evolutionary changes that occur both naturally and in response to therapy. A very promising development in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as minimally invasive "liquid biopsies." We envision that the future utility of CTC will not simply be confined to enumeration, but also include their routine characterization using a high-content approach that investigates morphometrics, protein expression and genomic profiling. This novel approach guided by mathematical models to predict the spread of disease from the primary site to secondary site can bring the bench to the bedside for cancer patients. It is agnostic with reference to drug choice and treatment regimen, which also means that each patient is unique. The approach is Bayesian from a data collection perspective and is patient-centric rather than drug or new chemical entity-centric. The analysis of data comes from an understanding of commonalities and differences that are detected among patients with a given cancer type. Thus, patients are treated over the course of their disease with various drug regimens that reflects our real-time understanding of their evolving tumor genomics and response to treatment. This likely means that smaller cohorts of patients receive any given regimen but we hypothesize that it would lead to better patient outcomes than with the current classic approach to drug testing and development.
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Rapid regression of left ventricular outflow tract rhabdomyoma after sirolimus therapy.
Pediatrics
PUBLISHED: 09-01-2014
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The neonatal presentation of cardiac rhabdomyomas varies in severity from severe outflow tract obstruction to minimal cardiac dysfunction. The natural history for these lesions is spontaneous regression in the majority of cases. We describe a newborn boy with severe left ventricular outflow tract obstruction secondary to a large rhabdomyoma. The tumor infiltrated the paraaortic area and extended around the origin of the right coronary artery, making surgical resection challenging. Oral sirolimus therapy resulted in a rapid regression of the tumor and alleviation of outflow tract obstruction within 1 month of treatment. This is the first report of sirolimus therapy in alleviating critical left ventricular outflow tract obstruction in this condition.
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Long period grating in multicore optical fiber: an ultra-sensitive vector bending sensor for low curvatures.
Opt Lett
PUBLISHED: 07-01-2014
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Long period grating was UV inscribed into a multicore fiber consisting of 120 single mode cores. The multicore fiber that hosts the grating was fusion spliced into a single mode fiber at both ends. The splice creates a taper transition between the two types of fiber that produces a nonadiabatic mode evolution; this results in the illumination of all the modes in the multicore fiber. The spectral characteristics of this fiber device as a function of curvature were investigated. The device yielded a significant spectral sensitivity as high as 1.23??nm/m(-1) and 3.57??dB/m(-1) to the ultra-low curvature values from 0 to 1??m(-1). This fiber device can also distinguish the orientation of curvature experienced by the fiber as the long period grating attenuation bands producing either a blue or red wavelength shift. The finite element method (FEM) model was used to investigate the modal behavior in multicore fiber and to predict the phase-matching curves of the long period grating inscribed into multicore fiber.
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Humidity responsivity of poly(methyl methacrylate)-based optical fiber Bragg grating sensors.
Opt Lett
PUBLISHED: 07-01-2014
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The humidity response of poly(methyl methacrylate) (PMMA)-based optical fiber Bragg gratings (POFBGs) has been studied. The characteristic wavelength of the grating is modulated by water absorption-induced swelling and refractive index change in the fiber. This work indicates that anisotropic expansion may exist in PMMA optical fiber, reducing the humidity responsivity of the grating and introducing uncertainty in the responsivity from fiber to fiber. By pre-straining a grating, one can get rid of this uncertainty and simultaneously improve the POFBG response time.
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Diurnal variation in blood pressure and arterial stiffness in chronic kidney disease: the role of endothelin-1.
Hypertension
PUBLISHED: 06-04-2014
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Hypertension and arterial stiffness are important independent cardiovascular risk factors in chronic kidney disease (CKD) to which endothelin-1 (ET-1) contributes. Loss of nocturnal blood pressure (BP) dipping is associated with CKD progression, but there are no data on 24-hour arterial stiffness variation. We examined the 24-hour variation of BP, arterial stiffness, and the ET system in healthy volunteers and patients with CKD and the effects on these of ET receptor type A receptor antagonism (sitaxentan). There were nocturnal dips in systolic BP and diastolic BP and pulse wave velocity, our measure of arterial stiffness, in 15 controls (systolic BP, ?3.2±4.8%, P<0.05; diastolic BP, ?6.4±6.2%, P=0.001; pulse wave velocity, ?5.8±5.2%, P<0.01) but not in 15 patients with CKD. In CKD, plasma ET-1 increased by 1.2±1.4 pg/mL from midday to midnight compared with healthy volunteers (P<0.05). Urinary ET-1 did not change. In a randomized, double-blind, 3-way crossover study in 27 patients with CKD, 6-week treatment with placebo and nifedipine did not affect nocturnal dips in systolic BP or diastolic BP between baseline and week 6, whereas dipping was increased after 6-week sitaxentan treatment (baseline versus week 6, systolic BP: ?7.0±6.2 versus ?11.0±7.8 mm Hg, P<0.05; diastolic BP: ?6.0±3.6 versus ?8.3±5.1 mm Hg, P<0.05). There was no nocturnal dip in pulse pressure at baseline in the 3 phases of the study, whereas sitaxentan was linked to the development of a nocturnal dip in pulse pressure. In CKD, activation of the ET system seems to contribute not only to raised BP but also the loss of BP dipping. The clinical significance of these findings should be explored in future clinical trials.
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CUB Domain Containing Protein 1 (CDCP1) modulates adhesion and motility in colon cancer cells.
BMC Cancer
PUBLISHED: 04-16-2014
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Deregulated expression of the transmembrane glycoprotein CDCP1 (CUB domain-containing protein-1) has been detected in several cancers including colon, lung, gastric, breast, and pancreatic carcinomas. CDCP1 has been proposed to either positively or negatively regulate tumour metastasis. In this study we assessed the role of CDCP1 in properties of cells that are directly relevant to metastasis, namely adhesion and motility. In addition, association between CDCP1 and the tetraspanin protein CD9 was investigated.
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Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis.
J. Am. Soc. Nephrol.
PUBLISHED: 04-10-2014
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The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total ?-catenin and phospho-NF-?B expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total ?-catenin and phospho-NF-?B compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-?B and ?-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.
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Ancient human footprints in Ciur-Izbuc Cave, Romania.
Am. J. Phys. Anthropol.
PUBLISHED: 04-02-2014
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In 1965, Ciur-Izbuc Cave in the Carpathian Mountains of Romania was discovered to contain about 400 ancient human footprints. At that time, researchers interpreted the footprints to be those of a man, woman and child who entered the cave by an opening which is now blocked but which was usable in antiquity. The age of the prints (?10-15 ka BP) was based partly on their association with cave bear (Ursus spelaeus) footprints and bones, and the belief that cave bears became extinct near the end of the last ice age. Since their discovery, the human and bear evidence and the cave itself have attracted spelunkers and other tourists, with the result that the ancient footprints are in danger of destruction by modern humans. In an effort to conserve the footprints and information about them and to reanalyze them with modern techiques, Ciur-Izbuc Cave was restudied in summer of 2012. Modern results are based on fewer than 25% of the originally described human footprints, the rest having been destroyed. It is impossible to confirm some of the original conclusions. The footprints do not cluster about three different sizes, and the number of individuals is estimated to be six or seven. Two cases of bears apparently overprinting humans help establish antiquity, and C-14 dates suggest a much greater age than originally thought. Unfortunately, insufficient footprints remain to measure movement variables such as stride length. However, detailed three-dimensional mapping of the footprints does allow a more precise description of human movements within the cave.
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Towards the identification of a genetic basis for Landau-Kleffner syndrome.
Epilepsia
PUBLISHED: 03-28-2014
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To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases.
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Does early treatment improve outcomes in N-methyl-D-aspartate receptor encephalitis?
Dev Med Child Neurol
PUBLISHED: 03-19-2014
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N-methyl-d-aspartate (NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis in both children and adults. It is still unclear if the natural history of the condition in children is altered by early treatment with immunosuppressive therapy. We looked at the outcomes of five children (two males, three females; mean age 6y 9mo, range 4-8y) who were treated empirically for autoimmune encephalitis within a brief period of presentation. Features that led clinicians to suspect autoimmune encephalitis included prominent neuropsychiatric features, movement disorder, seizures, and dysautonomic features. Immunosuppressive therapy was carried out in all cases. In this series of children, in whom the median time from symptom onset to treatment was 5 days and median length of time for follow-up was 24 months, four out of the five (80%) recovered to their baseline. Early initiation of immunosuppressive therapy may result in improved clinical outcomes.
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Lessons learned from the Philadelphia Collaborative Preterm Prevention Project: the prevalence of risk factors and program participation rates among women in the intervention group.
BMC Pregnancy Childbirth
PUBLISHED: 03-12-2014
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BackgroundWomen who deliver preterm infants are at a much greater risk for repeating a preterm birth (PTB), compared to women without a history of PTB. However, little is known about the prevalence of the risk factors which account for this markedly increased risk. Moreover, little or nothing is known about the feasibility of providing treatments and services to these women, outside of the context of prenatal care, during the inter-conception period, which provides the best opportunity for successful risk-reduction interventions.MethodsThe Philadelphia Collaborative Preterm Prevention Project (PCPPP), a large randomized control trial designed to identify and reduce six major risk factors for a repeat preterm birth among women immediately following the delivering of a preterm infant. For the women assigned to the PCPPP treatment group, we calculated the prevalence of the six risk factors in question, the percentages of women who agreed to receive high quality risk-appropriate treatments or services, and the of rates of participation among those who were offered and eligible for these treatments or services.ResultsUrogenital tract infections were identified in 57% of the women, while 59% were found to have periodontal disease. More than 39% were active smokers, and 17% were assessed with clinical depression. Low literacy, and housing instability were identified in, 22 and 83% of the study sample, respectively. Among women eligible for intervention, the percentages who accepted and at least minimally participated in treatment ranged from a low of 28% for smoking, to a high of 85% for urogenital tract infection. Most PCPPP enrollees (57%) had three or more major risk factors. Participation rates associated with the PCPPP treatments or services varied markedly, and were quite low in some cases, despite considerable efforts to reduce the barriers to receiving care.ConclusionThe efficacy of individual level risk-reduction efforts designed to prevent preterm/repeat preterm in the pre- or inter-conception period may be limited if participation rates associated with interventions to reduce major risk factors for PTB are low. Achieving adequate participation may require identifying, better understanding, and eliminating barriers to access, beyond those associated with cost, transportation, childcare, and service location or hours of operation.Trial registrationClinicalTrials.gov (NCT01117922).
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Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment.
Br J Clin Pharmacol
PUBLISHED: 01-31-2014
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In September 2012 the UK's Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single '100?mg?l(-1) ' nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60?min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.
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Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: clinical associations.
J. Heart Lung Transplant.
PUBLISHED: 01-16-2014
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Elevated serum uric acid is detected in pulmonary arterial hypertension (PAH) and is associated with poor patient outcomes. High serum uric acid is an independent risk factor for cardiovascular disease and renal impairment. We analyzed the effects of endothelin receptor antagonism on serum uric acid in PAH patients participating in the Sitaxentan to Relieve Impaired Exercise (STRIDE)-2/2X trial, and the impact of uric acid on 6-minute walk distance (6MWD), time to clinical worsening (TtCW) and survival.
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Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis.
Cerebrovasc. Dis.
PUBLISHED: 01-10-2014
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The cause of cerebral small vessel disease is not fully understood, yet it is important, accounting for about 25% of all strokes. It also increases the risk of having another stroke and contributes to about 40% of dementias. Various processes have been implicated, including microatheroma, endothelial dysfunction and inflammation. A previous review investigated endothelial dysfunction in lacunar stroke versus mostly non-stroke controls while another looked at markers of inflammation and endothelial damage in ischaemic stroke in general. We have focused on blood markers between clinically evident lacunar stroke and other subtypes of ischaemic stroke, thereby controlling for stroke in general.
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Body mass index and waist circumference cut-points in multi-ethnic populations from the UK and India: the ADDITION-Leicester, Jaipur heart watch and New Delhi cross-sectional studies.
PLoS ONE
PUBLISHED: 01-01-2014
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To derive cut-points for body mass index (BMI) and waist circumference (WC) for minority ethnic groups that are risk equivalent based on endogenous glucose levels to cut-points for white Europeans (BMI 30 kg/m2; WC men 102 cm; WC women 88 cm).
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Prevalence and causes of prescribing errors: the PRescribing Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study.
PLoS ONE
PUBLISHED: 01-01-2014
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Study objectives were to investigate the prevalence and causes of prescribing errors amongst foundation doctors (i.e. junior doctors in their first (F1) or second (F2) year of post-graduate training), describe their knowledge and experience of prescribing errors, and explore their self-efficacy (i.e. confidence) in prescribing.
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Weight change, genetics and antiepileptic drugs.
Expert Rev Clin Pharmacol
PUBLISHED: 12-02-2013
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Weight gain caused by antiepileptic drugs (AEDs) constitutes a serious problem in the management of people with epilepsy. AEDs associated with weight gain include sodium valproate, pregabalin and vigabatrin. Excessive weight gain can lead to non-compliance with treatment and to an exacerbation of obesity-related conditions. The mechanisms by which AEDs cause weight gain are not fully understood. It is likely that weight change induced by some AEDs has a genetic underpinning, and recent developments in DNA sequencing technology should speed the understanding, prediction and thus prevention of serious weight change associated with AEDs. This review focuses on the biology of obesity in the context of AEDs. Future directions in the investigations of the mechanism of weight change associated with these drugs and the use of such knowledge in tailoring the treatment of specific patient groups are explored.
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Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomised controlled trial.
Lancet
PUBLISHED: 11-28-2013
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Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.
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RefSeq: an update on mammalian reference sequences.
Nucleic Acids Res.
PUBLISHED: 11-19-2013
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The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of annotated genomic, transcript and protein sequence records derived from data in public sequence archives and from computation, curation and collaboration (http://www.ncbi.nlm.nih.gov/refseq/). We report here on growth of the mammalian and human subsets, changes to NCBIs eukaryotic annotation pipeline and modifications affecting transcript and protein records. Recent changes to NCBIs eukaryotic genome annotation pipeline provide higher throughput, and the addition of RNAseq data to the pipeline results in a significant expansion of the number of transcripts and novel exons annotated on mammalian RefSeq genomes. Recent annotation changes include reporting supporting evidence for transcript records, modification of exon feature annotation and the addition of a structured report of gene and sequence attributes of biological interest. We also describe a revised protein annotation policy for alternatively spliced transcripts with more divergent predicted proteins and we summarize the current status of the RefSeqGene project.
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Current status and new features of the Consensus Coding Sequence database.
Nucleic Acids Res.
PUBLISHED: 11-11-2013
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The Consensus Coding Sequence (CCDS) project (http://www.ncbi.nlm.nih.gov/CCDS/) is a collaborative effort to maintain a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assemblies by the National Center for Biotechnology Information (NCBI) and Ensembl genome annotation pipelines. Identical annotations that pass quality assurance tests are tracked with a stable identifier (CCDS ID). Members of the collaboration, who are from NCBI, the Wellcome Trust Sanger Institute and the University of California Santa Cruz, provide coordinated and continuous review of the dataset to ensure high-quality CCDS representations. We describe here the current status and recent growth in the CCDS dataset, as well as recent changes to the CCDS web and FTP sites. These changes include more explicit reporting about the NCBI and Ensembl annotation releases being compared, new search and display options, the addition of biologically descriptive information and our approach to representing genes for which support evidence is incomplete. We also present a summary of recent and future curation targets.
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A case of small-bowel obstruction secondary to inadvertent ingestion of impression material.
J Am Dent Assoc
PUBLISHED: 11-02-2013
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Small-bowel obstruction (SBO) is responsible for approximately 12 to 16 percent of surgical hospital admissions and more than 300,000 operations annually in the United States. This has resulted in more than $2.3 billion in health care delivery per year. SBO is a serious complication, carrying a 10 percent risk of mortality.
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Preliminary report of a sutureless onlay technique for incisional hernia repair using fibrin glue alone for mesh fixation.
Am Surg
PUBLISHED: 10-30-2013
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The Rives repair for ventral/incisional (V/I) hernias involves sublay mesh placement requiring retrorectus dissection and transfascial stitches. Chevrel described a repair by onlaying mesh after a unique primary fascial closure. Although Chevrel fixated mesh to the anterior fascia with sutures, he used fibrin glue for fascial closure reinforcement. We describe an onlay technique with mesh fixated to the anterior fascia solely with fibrin glue without suture fixation. From January 2010 to January 2012, 50 patients underwent a V/I hernia onlay technique with fibrin glue mesh fixation. Records were reviewed for technical details, demographics, mesh characteristics, and postoperative outcomes. Primary fascial closure with interrupted permanent suture was done with or without myofascial advancement flaps. Onlay polypropylene mesh was placed providing 8 cm of overlap. Fibrin glue was applied over the prosthesis and subcutaneous drains were placed. Mean age was 62.4 years. Mean body mass index was 30.1 kg/m(2). Average mesh size was 14.5 cm × 19.1 cm. Mean operative time was 144.4 minutes (range, 38 to 316 minutes). Mean discharge was postoperative Day 2.9 (range, 0 to 15 days). Morbidity included eight seromas, one hematoma, and three wound infections. Seventeen patients required components separation. Mean follow-up was 19.5 months with no recurrences. This is the first series describing fibrin glue alone for mesh fixation for V/I hernia repair. It allows for immediate prosthesis fixation to the anterior fascia. Early results are promising. Potential advantages include less operative time, less technical difficulty, and less long-term pain. A prospective trial is needed to evaluate this approach.
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Jim Peters--sportsman, soldier, surgeon.
BJU Int.
PUBLISHED: 10-17-2013
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Jim Peters, a country boy who excelled academically and in the sporting arena was a Victorian urological pioneer. His passion for teaching and belief in the development of Australasian urology resulted in the establishment of two of Melbournes earliest Urology Units (which are now major academic University departments), the creation of a formal urological training program and the promotion of Australian urology within the International urological community.
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A new method for respiratory-volume monitoring based on long-period fibre gratings.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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Respiratory-volume monitoring is an indispensable part of mechanical ventilation. Here we present a new method of the respiratory-volume measurement based on a single fibre-optical long-period sensor of bending and the correlation between torso curvature and lung volume. Unlike the commonly used air-flow based measurement methods the proposed sensor is drift-free and immune to air-leaks. In the paper, we explain the working principle of sensors, a two-step calibration-test measurement procedure and present results that establish a linear correlation between the change in the local thorax curvature and the change of the lung volume. We also discuss the advantages and limitations of these sensors with respect to the current standards.
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The road from AKI to CKD: the role of endothelin.
Kidney Int.
PUBLISHED: 10-02-2013
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The incidence of acute kidney injury (AKI) is increasing. It is now widely accepted that patients surviving an episode of AKI have a significant risk of progression to chronic kidney disease (CKD) and even end-stage renal failure. Zager and colleagues describe the role of endothelin-1 (ET-1) in the progression of AKI to CKD and provide a basis for the potential use of ET receptor antagonists as a therapeutic strategy in AKI.
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Assessing and addressing cardiovascular risk in adults with Turner syndrome.
Clin. Endocrinol. (Oxf)
PUBLISHED: 10-01-2013
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Turner syndrome (TS), the result of a structurally abnormal or absent X chromosome, occurs in one in 2 000 live born females. The phenotype is highly variable, but short stature and gonadal dysgenesis are usually present. The main objective in adults with TS is health surveillance, but TS still causes a reduction in life expectancy of up to 13 years, with cardiovascular disease, congenital or acquired, as the major cause of an early death. While it has been established that all women with TS should undergo in-depth cardiovascular examination at diagnosis, advice on the cardiovascular management of women with TS is limited. Here, we provide a summary of our current practice within a multidisciplinary team, supported by our expertise in various aspects of cardiovascular risk management, and the evidence from research where it is available, with the aim of providing optimal support to our patients with TS.
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Quantification of human urinary exosomes by nanoparticle tracking analysis.
J. Physiol. (Lond.)
PUBLISHED: 09-23-2013
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Abstract? Exosomes are vesicles that are released from the kidney into urine. They contain protein and RNA from the glomerulus and all sections of the nephron and represent a reservoir for biomarker discovery. Current methods for the identification and quantification of urinary exosomes are time consuming and only semi-quantitative. Nanoparticle tracking analysis (NTA) counts and sizes particles by measuring their Brownian motion in solution. In this study, we applied NTA to human urine and identified particles with a range of sizes. Using antibodies against the exosomal proteins CD24 and aquaporin 2 (AQP2), conjugated to a fluorophore, we could identify a subpopulation of CD24- and AQP2-positive particles of characteristic exosomal size. Extensive pre-NTA processing of urine was not necessary. However, the intra-assay variability in the measurement of exosome concentration was significantly reduced when an ultracentrifugation step preceded NTA. Without any sample processing, NTA tracked exosomal AQP2 upregulation induced by desmopressin stimulation of kidney collecting duct cells. Nanoparticle tracking analysis was also able to track changes in exosomal AQP2 concentration that followed desmopressin treatment of mice and a patient with central diabetes insipidus. When urine was stored at room temperature, 4°C or frozen, nanoparticle concentration was reduced; freezing at -80°C with the addition of protease inhibitors produced the least reduction. In conclusion, with appropriate sample storage, NTA has potential as a tool for the characterization and quantification of extracellular vesicles in human urine.
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A systematic review of the effect of paracetamol on blood pressure in hypertensive and non-hypertensive subjects.
Br J Clin Pharmacol
PUBLISHED: 09-21-2013
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To review current evidence on the effect of paracetamol on blood pressure (BP), the quality of the previous studies and the validity of the results, and to summarize these findings.
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The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men.
J Sports Sci Med
PUBLISHED: 09-01-2013
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This study examined the combined effects of aerobic exercise intensity and duration on serum brain-derived neurotrophic factor (sBDNF) levels in healthy human adult males aged 18-25 years. Forty five participants were randomly assigned to one of six exercise conditions based on varying intensity (80% or 60% of heart rate reserve, or control) and duration (20 or 40 min). Vigorous (80% heart rate reserve, "Vig") and moderate (60% heart rate reserve, "Mod") exercise was carried out on cycle ergometers. Control subjects remained seated and at rest during the exercise period. Pre- and post-exercise blood draws were conducted and sBDNF measured. Physical exercise caused an average ~ 32% increase in sBDNF levels relative to baseline that resulted in concentrations that were 45% higher than control conditions. Comparing the six conditions, sBDNF levels rose consistently among the four exercise conditions (Vig20 = 26.38 ± 34.89%, Vig40 = 28.48 ± 19.11%, Mod20 = 41.23 ± 59.65%, Mod40 = 30.16 ± 72.11%) and decreased consistently among the controls (Con20 = -14.48 ± 16.50, Con40 = -10.51 ± 26.78). Vig conditions had the highest proportion of subjects that experienced a significant (? 10%) increase in sBDNF levels, followed by Mod and control conditions. An analysis of modeled sBDNF integrals (area under the curve) demonstrated substantially greater values for Vig40 and Mod40 conditions compared to Vig20 and Mod20 conditions. Collectively, these results demonstrate that neither duration (20 vs. 40 min) nor intensity (60 vs. 80% HR reserve) significantly affects the benefits of exercise if only the sBDNF increase at a single post-exercise time point is considered. However, when comparing either the probability of achieving a significant BDNF gain or the integral (i.e. the volume of circulating BDNF over time) the Vig40 condition offers maximal benefits. Thus, we conclude that the future study of aerobic exercise effects on BDNF-mediated neuroprotection should take the volume of BDNF release over time into account. Key PointsAerobic exercise caused a ~32% increase in serum BDNF in adult human males while serum BDNF decreased 13% in sedentary control subjects.Vigorous intensity (80% heart rate reserve), long duration (40 min) exercise offered the greatest probability of a significant BDNF elevation.Long duration exercise offered the greatest numerical benefits in terms of BDNF integral.Neither intensity nor duration affected the mean elevation in BDNF amplitude caused by exercise.
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Endothelin antagonism and its role in the treatment of hypertension.
Curr. Hypertens. Rep.
PUBLISHED: 08-06-2013
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Hypertension contributes greatly to global disease burden and in many patients current treatments do not adequately control blood pressure (BP). Endothelin-1 (ET-1) is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, including the hypertension that is often associated with chronic kidney disease (CKD) and the metabolic syndrome. ET receptor antagonists, currently licensed for the treatment of pulmonary arterial hypertension and scleroderma-related digital ulcers, are being investigated for the treatment of hypertension. Clinical trials have addressed the use of ET receptor antagonists as monotherapy in primary hypertension, as an add-on therapy in resistant hypertension and in CKD. This review will evaluate the current evidence regarding the therapeutic potential of ET receptor antagonists in hypertension, as well as highlighting important issues that still need to be addressed.
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An anatomically unbiased approach for analysis of renal BOLD magnetic resonance images.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 07-17-2013
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Oxygenation defects may contribute to renal disease progression, but the chronology of events is difficult to define in vivo without recourse to invasive methodologies. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) provides an attractive alternative, but the R2* signal is physiologically complex. Postacquisition data analysis often relies on manual selection of region(s) of interest. This approach excludes from analysis significant quantities of biological information and is subject to selection bias. We present a semiautomated, anatomically unbiased approach to compartmentalize voxels into two quantitatively related clusters. In control F344 rats, low R2* clustering was located predominantly within the cortex and higher R2* clustering within the medulla (70.96 ± 1.48 vs. 79.00 ± 1.50; 3 scans per rat; n = 6; P < 0.01) consistent anatomically with a cortico-medullary oxygen gradient. An intravenous bolus of acetylcholine caused a transient reduction of the R2* signal in both clustered segments (P < 0.01). This was nitric oxide dependent and temporally distinct from the hemodynamic effects of acetylcholine. Rats were then chronically infused with angiotensin II (60 ng/min) and rescanned 3 days later. Clustering demonstrated a disruption of the cortico-medullary gradient, producing less distinctly segmented mean R2* clusters (71.30 ± 2.00 vs. 72.48 ± 1.27; n = 6; NS). The acetylcholine-induced attenuation of the R2* signal was abolished by chronic angiotensin II infusion, consistent with reduced nitric oxide bioavailability. This global map of oxygenation, defined by clustering individual voxels on the basis of quantitative nearness, might be more robust in defining deficits in renal oxygenation than the absolute magnitude of R2* in small, manually selected regions of interest defined exclusively by anatomical nearness.
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An audit of first afebrile seizure management in an Irish tertiary pediatric setting.
Eur. J. Pediatr.
PUBLISHED: 06-30-2013
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The objective of this study was to compare the first afebrile seizure management with internationally recognized standards in an Irish tertiary pediatric setting. Twenty-one management standards were derived from a combination of British (NICE 2004) and North American (AAN 2003) guidelines. Cases of first afebrile seizure presenting to a pediatric emergency department between July 2007 and June 2010 were assessed against the standards. On completion, the standards developed were presented to the relevant stakeholders, a nurse-developed parental advice sheet was introduced, and a re-audit was performed from July 2010 to June 2011. Forty children were identified in the initial audit period (A1) and 41 over the re-audit (A2). No case achieved full compliance with the devised standards in the audit period. A median compliance score of 15 (range 5-20) was achieved in A1 and 17 (range 11-21) in A2 [mean rank 31.93 versus 49.85; p(1,1)?
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Management of acute fever in children: Guideline for community healthcare providers and pharmacists.
S. Afr. Med. J.
PUBLISHED: 06-27-2013
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Fever is a normal physiological response to illness that facilitates and accelerates recovery. Although it is often associated with a self-limiting viral infection in children, it may also be a presenting symptom of more serious conditions requiring urgent medical care. Therefore, it is essential to distinguish between a child with fever who is at high risk of serious illness and who requires specific treatment, hospitalisation or specialist care, and those at low risk who can be managed conservatively at home. This guideline aims to assist pharmacists, primary healthcare workers and general practitioners in risk-stratifying children who present with fever, deciding on when to refer, the appropriate use of antipyretic medication and how to advise parents and caregivers. 
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Development and characterization of glutamyl-protected N-hydroxyguanidines as reno-active nitric oxide donor drugs with therapeutic potential in acute renal failure.
J. Med. Chem.
PUBLISHED: 06-20-2013
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Acute renal failure (ARF) has high mortality and no effective treatment. Nitric oxide (NO) delivery represents a credible means of preventing the damaging effects of vasoconstriction, central to ARF, but design of drugs with the necessary renoselectivity is challenging. Here, we developed N-hydroxyguanidine NO donor drugs that were protected against spontaneous NO release by linkage to glutamyl adducts that could be cleaved by ?-glutamyl transpeptidase (?-GT), found predominantly in renal tissue. Parent NO donor drug activity was optimized in advance of glutamyl adduct prodrug design. A lead compound that was a suitable substrate for ?-GT-mediated deprotection was identified. Metabolism of this prodrug to the active parent compound was confirmed in rat kidney homogenates, and the prodrug was shown to be an active vasodilator in rat isolated perfused kidneys (EC50 ?50 ?M). The data confirm that glutamate protection of N-hydroxyguanidines is an approach that might hold promise in ARF.
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Animal models of human disease: Inflammation.
Biochem. Pharmacol.
PUBLISHED: 06-15-2013
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Animals have been used as models to study inflammation and autoimmunity for more than 80 years. During that time it has been understood that although the use of such models is an important and necessary part of understanding human disease, they inevitably display significant differences from the human disease state. Since our understanding of human inflammation and autoimmunity is necessarily incomplete, it may be concluded that the animal models will also be reflective of the state of knowledge regarding such diseases. Nevertheless, animal models of rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis have been successfully used to enhance the understanding of the human disease and have made significant contributions to the development of powerful new therapies. However, there are exceptions. One of the most persistent has been the study of sepsis where the animal models have been woefully inadequate in uncovering targets for drug discovery and have led to repeated clinical failures. As will be explained, only by using newly developed genomics tools has it been possible to uncover the differences between sepsis in mice and sepsis in man. It is concluded that approaches using the newer genomic and proteomic data derived from human tissues, will make possible the development of animal models with more predictive power as aids to drug discovery.
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Medical students perceptions and knowledge about antimicrobial stewardship: how are we educating our future prescribers?
Clin. Infect. Dis.
PUBLISHED: 05-31-2013
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Better understanding of medical students perceptions, attitudes, and knowledge about antimicrobial prescribing practices could facilitate more effective education of these future prescribers.
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Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension.
Br. J. Nutr.
PUBLISHED: 05-23-2013
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Dietary polyphenols, such as those from grape products, may exert beneficial effects on cardiovascular health, including anti-hypertensive effects. We investigated the effect of a specific grape seed extract (GSE) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure (ABP) in untreated subjects with pre- and stage I hypertension. In addition, potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure (BP), and platelet aggregation, were explored. The study was designed as a double-blind, placebo-controlled, randomised, parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg. A 1-week run-in period was followed by an 8-week intervention period, during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo (microcrystalline cellulose). Before and after the intervention, daytime ABP readings, 24 h urine samples and fasting and non-fasting blood samples were taken. The mean baseline systolic BP was 135·8 (se 1·3) mmHg and diastolic BP was 81·5 (se 0·9) mmHg. BP values were modestly, but not significantly, affected by the polyphenol-rich GSE treatment v. placebo with an effect of - 3·0 mmHg for systolic BP (95 % CI - 6·5, 0·5) and - 1·4 mmHg for diastolic BP (95 % CI - 3·5, 0·6). Vasoactive markers including endothelin-1, NO metabolites and asymmetric dimethylarginine, plasma renin activity and platelet aggregation were not affected by the GSE intervention. Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension.
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Boric acid ingestion clinically mimicking toxic epidermal necrolysis.
J. Cutan. Pathol.
PUBLISHED: 05-15-2013
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The ingestion of large amounts of boric acid, a component of household insecticides, is a rare occurrence, characterized by a diffuse desquamative skin eruption, neutropenia, thrombocytopenia, delirium, acute renal failure and prolonged ileus. A 56-year-old male with a history of multiple previous suicide attempts was witnessed ingesting household roach killer and 4?days later presented to the hospital with lethargy, stiffness and a diffuse erythematous and desquamative eruption with bullous formation. He subsequently developed erythema of both palms as well as alopecia totalis. Histopathology from a right arm shave biopsy revealed a mostly intact epidermis with subtle vacuolar alteration of the basal layer, scattered intraepidermal apoptotic keratinocytes, parakeratosis with alternating layers of orthokeratosis and considerable superficial exfoliation; accompanying dermal changes included vasodilatation and mild perivascular inflammation. This report describes the cutaneous and systemic complications in a rare case of boric acid ingestion. There is little published material on the symptoms and histopathology following boric acid ingestion, but knowledge of this entity is important, both to differentiate it from other causes of desquamative skin rashes and to allow the initiation of appropriate clinical care.
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Influence of mounting on the hysteresis of polymer fiber Bragg grating strain sensors.
Opt Lett
PUBLISHED: 05-02-2013
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Fiber Bragg grating sensors recorded in poly(methyl methacrylate) fiber often exhibit hysteresis in the response of Bragg wavelength to strain, particularly when exposed to high levels of strain. We show that, when such a fiber grating sensor is bonded directly to a substrate, the hysteresis is reduced by more than 12 times, compared to the case where the sensor is suspended freely between two supports.
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Metabolic parameters associated with arterial stiffness in older adults with Type 2 diabetes: the Edinburgh Type 2 diabetes study.
J. Hypertens.
PUBLISHED: 03-16-2013
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Increased arterial stiffness, as measured by pulse wave velocity (PWV), is associated with increased cardiovascular risk in the general population. Few studies have examined factors associated with increased PWV in people with Type 2 diabetes. The aim of this study was to determine whether there was a link between PWV and clinical variables associated with central obesity, in men and women with Type 2 diabetes.
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Junior doctors perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of errors.
Br J Clin Pharmacol
PUBLISHED: 03-08-2013
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The aim of the study was to explore and compare junior doctors perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of those errors.
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A novel locus for episodic ataxia:UBR4 the likely candidate.
Eur. J. Hum. Genet.
PUBLISHED: 02-27-2013
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Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca(2+) protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca(2+) control within neuronal cells highlights its potential for a role in this form of EA.European Journal of Human Genetics advance online publication, 28 August 2013; doi:10.1038/ejhg.2013.173.
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Histamine-induced vasodilatation in the human forearm vasculature.
Br J Clin Pharmacol
PUBLISHED: 02-22-2013
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To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature.
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p16 immunohistochemistry can be used to detect human papillomavirus in oral cavity squamous cell carcinoma.
J. Oral Maxillofac. Surg.
PUBLISHED: 02-15-2013
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Human papillomavirus (HPV) is of etiologic significance in the development of oral squamous carcinoma and is noted to result in p16 overexpression. Identification of HPV is clinically important because the presence of HPV has prognostic and epidemiologic associations. Detection of HPV by polymerase chain reaction (PCR) is expensive and not widely accessible. The authors examined p16 immunohistochemistry (IHC) as a surrogate marker for high-risk HPV and its use as an alternative test to PCR.
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Measurement of renal function in patients with chronic kidney disease.
Br J Clin Pharmacol
PUBLISHED: 01-25-2013
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Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.
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A new class of NO-donor pro-drugs triggered by ?-glutamyl transpeptidase with potential for reno-selective vasodilatation.
Chem. Commun. (Camb.)
PUBLISHED: 01-17-2013
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This communication describes the synthesis of a new class of N-hydroxyguanidine (NHG) pro-drugs which release nitric oxide (NO), triggered by the action of ?-glutamyl transpeptidase (?-GT), and have potential for the treatment of acute renal injury/failure (ARI/ARF).
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Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP).
BMC Pharmacol Toxicol
PUBLISHED: 01-14-2013
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Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20?hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.
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Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital.
Hepatology
PUBLISHED: 01-12-2013
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Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.
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Phosphodiesterase type 5 inhibition improves arterial stiffness after exercise but not exercise capacity in hypertensive men.
Am. J. Hypertens.
PUBLISHED: 01-07-2013
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Established hypertension is associated with abnormal exercise hemodynamics and reduced exercise capacity through mechanisms that may include contributions from arterial stiffness and endothelial vasomotor dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors prolong nitric oxide-mediated cyclic guanosine monophosphate (cGMP) signaling in vascular smooth muscle, and have beneficial effects on exercise tolerance in pulmonary hypertension and heart failure. Recent studies suggest they may also be useful antihypertensive agents. We hypothesized they would reduce arterial stiffness and increase exercise capacity in hypertensive men.
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Joint prevalence of diabetes, impaired glucose regulation, cardiovascular disease risk and chronic kidney disease in South Asians and White Europeans.
PLoS ONE
PUBLISHED: 01-03-2013
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Multiple vascular risk factors may confer very high risk, but the degree of commonality between risk factors is unclear, particularly among ethnic minorities. Furthermore, it is unknown what impact this commonality will have on the UK-based NHS Health Check Programme; a vascular disease prevention programme that screens individuals aged 40-74 years. We estimated the joint prevalence of diabetes, impaired glucose regulation (IGR), high cardiovascular disease (CVD) risk and chronic kidney disease (CKD) among White Europeans and South Asians who would be eligible for the Programme.
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Circulating microRNAs as potential markers of human drug-induced liver injury.
Hepatology
PUBLISHED: 11-03-2011
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New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ??Ct [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied Kings College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15).
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Exosomal transmission of functional aquaporin 2 in kidney cortical collecting duct cells.
J. Physiol. (Lond.)
PUBLISHED: 10-24-2011
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Exosomes are vesicles released following fusion of endosomes with the plasma membrane. Urine contains exosomes that are released from the entire length of the nephron and change in composition with kidney disease. Exosomes can shuttle information between non-renal cells via transfer of protein and RNA. In this study murine kidney collecting duct (mCCDC11) cells were used to demonstrate that exosomes can act as a signalling mechanism between cells. First, the release of exosomes by mCCDC11 cells was confirmed by multiple approaches. Following isopynic centrifugation, exosomal proteins flotillin-1 and TSG101 were identified in fractions consistent with exosomes. Electron microscopy demonstrated structures consistent in size and shape with exosomes. Exposure of mCCDC11 cells to the synthetic vasopressin analogue, desmopressin, did not affect exosomal flotillin-1 or TSG101 but increased aquaporin 2 (AQP2) in a dose- and time-dependent manner that was highly correlated with cellular AQP2 (exosomal AQP2 vs. cellular AQP2, Pearson correlation coefficient r = 0.93). To test whether the ratio of exosomal AQP2/flotillin-1 is under physiological control in vivo, rats were treated with desmopressin. The ratio of AQP2/flotillin-1 in the urinary exosome was significantly increased. Inter-cellular signalling by exosomes was demonstrated: exosomes from desmopressin-treated cells stimulated both AQP2 expression and water transport in untreated mCCDc11 cells (water flow across cells: control exosome treatment 52.8 ± 11 ?l cm(-2); AQP2-containing exosomes 77.4 ± 4 ?l cm(-2), P = 0.05, n = 4). In summary, the amount of AQP2 in exosomes released from collecting duct cells is physiologically regulated and exosomal AQP2 closely reflects cellular expression. Exosomes can transfer functional AQP2 between cells and this represents a novel physiological mechanism for cell-to-cell communication within the kidney.
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Humidity insensitive TOPAS polymer fiber Bragg grating sensor.
Opt Express
PUBLISHED: 10-15-2011
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We report the first experimental demonstration of a humidity insensitive polymer optical fiber Bragg grating (FBG), as well as the first FBG recorded in a TOPAS polymer optical fiber in the important low loss 850 nm spectral region. For the demonstration we have fabricated FBGs with resonance wavelength around 850 nm and 1550 nm in single-mode microstructured polymer optical fibers made of TOPAS and the conventional poly (methyl methacrylate) (PMMA). Characterization of the FBGs shows that the TOPAS FBG is more than 50 times less sensitive to humidity than the conventional PMMA FBG in both wavelength regimes. This makes the TOPAS FBG very appealing for sensing applications as it appears to solve the humidity sensitivity problem suffered by the PMMA FBG.
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Sildenafil citrate for the prevention of high altitude hypoxic pulmonary hypertension: double blind, randomized, placebo-controlled trial.
High Alt. Med. Biol.
PUBLISHED: 10-04-2011
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Exaggerated hypoxic pulmonary vasoconstriction is a key factor in the development of high altitude pulmonary edema (HAPE). Due to its effectiveness as a pulmonary vasodilator, sildenafil has been proposed as a prophylactic agent against HAPE. By conducting a parallel-group double blind, randomized, placebo-controlled trial, we investigated the effect of chronic sildenafil administration on pulmonary artery systolic pressure (PASP) and symptoms of acute mountain sickness (AMS) during acclimatization to high altitude. Sixty-two healthy lowland volunteers (36 male; median age 21 years, range 18 to 31) on the Apex 2 research expedition were flown to La Paz, Bolivia (3650?m), and after 4-5 days acclimatization ascended over 90?min to 5200?m. The treatment group (n=20) received 50?mg sildenafil citrate three times daily. PASP was recorded by echocardiography at sea level and within 6?h, 3 days, and 1 week at 5200?m. AMS was assessed daily using the Lake Louise Consensus symptom score. On intention-to-treat analysis, there was no significant difference in PASP at 5200?m between sildenafil and placebo groups. Median AMS score on Day 2 at 5200?m was significantly higher in the sildenafil group (placebo 4.0, sildenafil 6.5; p=0.004) but there was no difference in prevalence of AMS between groups. Sildenafil administration did not affect PASP in healthy lowland subjects at 5200?m but AMS was significantly more severe on Day 2 at 5200?m with sildenafil. Our data do not support routine prophylactic use of sildenafil to reduce PASP at high altitude in healthy subjects with no history of HAPE. TRIALS REGISTRATION NUMBER: NCT00627965.
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Association of anthropometric obesity measures with chronic kidney disease risk in a non-diabetic patient population.
Nephrol. Dial. Transplant.
PUBLISHED: 09-29-2011
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Obesity is a risk factor for both chronic kidney disease (CKD) and cardiovascular disease. The association of simple indices of obesity with CKD remains poorly understood. Evidence suggests that measures of central obesity such as waist circumference (WC) and waist-to-hip ratio (WHR) are more accurate predictors of morbidity and cardiovascular risk than body mass index (BMI). This study aimed to investigate the association of BMI, WC and WHR with CKD risk in a population screened for type 2 diabetes.
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Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial.
Br. J. Haematol.
PUBLISHED: 09-09-2011
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The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16?years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.
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Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol.
Blood
PUBLISHED: 09-06-2011
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Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ? 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.
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Endothelin antagonism in patients with nondiabetic chronic kidney disease.
Contrib Nephrol
PUBLISHED: 08-30-2011
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The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Although current treatments for CKD focus on blood pressure and proteinuria reduction, many CKD patients have ongoing hypertension and residual proteinuria. Newer treatments are needed that not only act on these parameters, but also slow the progression of CKD and improve the cardiovascular risk profile of CKD patients. The endothelins (ETs) are a family of related peptides of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both cardiovascular disease and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness, as well endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In CKD patients, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET is likely also involved in the progression of renal disease, and data are emerging that suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.
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Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury.
J. Immunol.
PUBLISHED: 08-08-2011
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The immune system is alerted to cell death by molecules known as damage-associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia(-/-)) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia(-/-) mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options.
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Background incidence of liver chemistry abnormalities in pediatric clinical trials for conditions with and without underlying liver disease.
Regul. Toxicol. Pharmacol.
PUBLISHED: 06-16-2011
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The FDA provides guidance regarding pre-marketing liver chemistry subject stopping criteria. This study was undertaken to determine the background rates of liver chemistry abnormalities in pediatric clinical trials for conditions with and without underlying liver disease (LD).
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Recent decline in the incidence of human immunodeficiency virus infection among California men who have sex with men.
Am. J. Epidemiol.
PUBLISHED: 05-17-2011
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Monitoring the incidence of human immunodeficiency virus (HIV) infection among men who have sex with men (MSM) is imperative for developing targeted prevention programs and evaluating their effectiveness. The authors used California counseling and testing data to estimate the temporal trend in HIV incidence among MSM in California. HIV incidence rates were retrospectively calculated among MSM who had received at least 1 HIV test at a public California counseling and testing site between 1997 and 2007 and had a prior HIV-negative test from any HIV testing source. All study subjects were weighted on the basis of the interval between the last HIV-negative test and the current HIV test to account for the right-truncation bias introduced by more frequent testers. The authors observed that the HIV incidence rate among MSM in California increased from 2.0/100 person-years (95% confidence interval (CI): 1.8, 2.2) in 1997 to 2.4/100 person-years (95% CI: 2.2, 2.6) in 2003 and then decreased to 1.9/100 person-years (95% CI: 1.7, 2.0) in 2006. Trend analyses showed that both the increase (P < 0.001) and the decrease (P < 0.01) were statistically significant. The study showed that HIV incidence among MSM in California had decreased since 2003.
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Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 05-09-2011
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Adenosine A(2A) receptor activation after lung transplantation attenuates ischemia-reperfusion injury by reducing inflammation. However, the effect of adenosine A(2A) receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A(2A) receptor agonist in a clinically relevant porcine lung transplantation model.
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Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study.
Blood
PUBLISHED: 05-06-2011
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We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ? 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.
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Risk of cancer in patients exposed to gabapentin in two electronic medical record systems.
Pharmacoepidemiol Drug Saf
PUBLISHED: 05-04-2011
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High doses of gabapentin were associated with pancreatic acinar cell tumors in male Wistar rats, but there is little published epidemiological data regarding gabapentin and carcinogenicity. We explored the association between gabapentin and cancer in a US medical care program and followed up nominally significant associations in a UK primary care database.
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Evolution of the USANZ tie.
BJU Int.
PUBLISHED: 04-16-2011
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•?The Urological Society of Australia and New Zealand (USANZ) tie represents the dual nationality of the society, the ancient history of urology, and the continuing development of urology in Australia and New Zealand. •?The earliest badge of the Urological Society of Australasia (USA) was a cartoon depiction of the cystoscopic view of a prostate from the urethra. The inception of the USANZ tie began with the borrowing of the crest of the newly granted USA coat of arms (lynx holding an exploratorium) as the logo for the USA Annual Scientific Meeting Tie in 1988. This tie was adopted de facto as the USA Society Tie; it became the template for subsequent scientific meeting ties, from which the formal USANZ tie design was adapted in 2006, to coincide with and mark the new society name, from the USA to the USANZ. This paper traces the evolution of the USANZ tie.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.