The purpose of this case is to describe the complex perioperative management of a 30-year-old woman with congenital heart disease and multiple resternotomies presenting with pulmonary homograft dysfunction and evaluation for percutaneous pulmonary valve replacement. Transvenous, transcatheter Melody valve placement caused left main coronary artery occlusion and cardiogenic shock. An Impella ventricular assist device (VAD) provided rescue therapy during operating room transport for valve removal and pulmonary homograft replacement. ECMO support was required following surgery. Several days later during an attempted ECMO wean, her hemodynamics deteriorated abruptly. Transesophageal and epicardial echocardiography identified pulmonary graft obstruction, requiring homograft revision due to large thrombosis. This case illustrates a role for Impella VAD as bridge to definitive procedure after left coronary occlusion and describes management of complex perioperative ECMO support challenges. Venoarterial ECMO was then instituted via femoral vessels and she was transported to the ICU in critical condition. On the fourth day of ECMO support, she developed a large hemothorax requiring chest tube decompression, six units of RBCs, and two units of platelets. The heparin infusion was subsequently held and bleeding resolved over several hours. The following day, the patient was requiring minimal inotropic support and the decision was made to go to the operating room and attempt to wean ECMO. Unexpectedly, when ECMO was stopped her blood pressure suddenly dropped to 43/35 and the end tidal CO2 was lost (<10 mm Hg) despite adequate ventilation. Transesophageal echocardiography was urgently performed demonstrating probable RVOT graft obstruction ) in the catheterization laboratory. After initial balloon inflation, there was visible homograft enlargement, and simultaneous aortic root angiogram was performed demonstrating patent right and left coronary arteries (LCA). The right ventricular outflow tract was then prepared with successful placement of two Palmaz stents. Repeat coronary angiography demonstrated patent LCA prior to Melody valve deployment. The Melody valve was then deployed and the patient developed progressive, severe hypotension, bradycardia, and cardiogenic shock. Transthoracic echocardiogram (TTE) demonstrated akinesis of the lateral and anterior walls of the left ventricle (LV) and severe acute mitral valve regurgitation. She instantly developed severe pulmonary edema with fluid filling the endotracheal tube and anesthesia circuit . A repeatruction  with esttruction . Epicardtruction . The obsThis case illustrates the known potential complication from Melody valve implantation with left coronary artery compression –4 despit


Candida spp. sepsis. This is the first observational study describing the altered immune response of patients with candidemia. The authors included non-neutropenic critically ill patients with candidemia and non-septic controls, and excluded patients with human immunodeficiency virus infection, who had undergone solid or bone marrow transplantation or with other known causes of impaired immune response. The authors hypothesized that their findings may help explain why patients with fungal sepsis show a high mortality despite appropriate antifungal therapy.We read with great interest the article by Spec et al.  investigIn our opinion, the observed T-cell exhaustion associated with candidemia may also contribute to explain the paradox of the evidence published recently about invasive fungal infection (IFI) prevention . From ouImplications for future research may include potential additional mechanisms of impaired immunological function to fill the gap between bedside data and pre-clinical findings.IFI, invasive fungal infection


Improving Handover of Patients in Critical Care following Cardiac Surgery: an audit and successful implementation of an electronic quality improvement toolFollowing cardiac surgery, professional responsibility and accountability for patients is transferred from the operating theatre to critical care. Optimising 'handover' is imperative and we sought to improve safety, quality and effectiveness of this within our unit.A closed loop audit for all post-operative patients (Aug 2014 - Nov 2014) was performed to assess the handover process including personnel, environment and documentation on the electronic patient record (Metavision).Prior to the first cycle, relevant stakeholders were consulted - anaesthetists, cardiac surgeons and nurses. A subsequent survey determined 'gold standard criteria' for handover before undertaking the second cycle.A new electronic tool was created on Metavision to implement a change where specific anaesthetic and surgical representatives could document their plans including parameters and post-operative instructions.Our audit showed objective improvement in presence of team members, especially surgeons; more frequent 'sterile cockpit' environment; significantly better documentation to guide the critical care MDT.We demonstrated improvements in handover by following a system that utilizes the F1 racing model in the critical care setting. Moreover, a novel electronic tab dedicated for patient handover has significantly improved documentation. With ongoing challenges of maintaining continuity of care, we suggest other units adopt our strategy.


The ability to estimate societal cost-savings given a change in population lifestyles is of interest to health promotion specialists and decision makers. A population-based model named Risk factors, Health and Societal Costs (RHS) was developed to simulate changes in incidence and related societal costs of several chronic diseases after five to ten years, following assumed changes in four common risk factors for disease: obesity (BMI>30), daily tobacco smoking, lack of physical activity and risky consumption of alcohol.The RHS model is based on relative risks (RR) and potential impact fractions (IF) that simulate the changes in disease incidence of reducing the exposure to risk factors . RelativThe scenarios, which assume a certain reduction in population risk factor prevalence, show that considerable health gains and savings in societal costs can arise from modest changes in population lifestyle habits. As an example, a 1% reduction in prevalence in daily smoking under five years among Stockholm county population is estimated to lead to health gain of 64 QALYs and societal savings  of 13 million Swedish krona (1.2 million GBP).The RHS model estimates future cases of illness and related societal costs due to lifestyle risk factors in the population. By creating scenarios with assumed changes in risk factors, the model can estimate potential health gains and societal costs savings, which can be used as relevant arguments in discussions with decision-makers for a more health-promoting health care system.


Gluten related disorders a range of inflammatory disorders of the small intestine characterized by malabsorption after ingestion of gluten in individuals with a certain genetic background. Clinical presentation can vary from full-blown malabsorption to subtle and atypical symptoms. Diagnosis currently relies on clinicopathologic studies including mucosal biopsy, serologic tests, and the effects of a diet free of gluten on the symptoms. Mucosal pathologic features are also variable, ranging from mild abnormalities, including intraepithelial lymphocytosis, to completely flat mucosa . Since tCeliac diseaseNon Celiac Gluten Sensitivity


Movement disorders in idiopathic normal pressure hydrocephalus (iNPH) are represented by gait disturbance . However, upper extremity bradykinesia was frequently found among iNPH patients. We assessed their upper extremity function by quantitative finger tapping test and checked the correlation with other demographic factors.We evaluated the 10-second finger tapping movements of 8 patients  using magnetic-sensor coil system. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination and frontal assessment battery (FAB). The correlation of tapping parameters with clinical indicators was estimated.The patient's age correlated significantly with 6 of 21 finger-tapping parameters, including total tapping distance , coefficient of variation of maximum amplitude , energy balance , average maximum opening acceleration , tapping frequency , and average finger tapping interval . The severity of illness represented by iNPH grading scale correlated with other 2 parameters, including average maximum closing velocity  and coefficient of variation of maximum closing velocity .Our data support the diagnostic value of quantitative finger tapping test for estimating the severity of bradykinesia underlying the iNPH symptomatology. Though preliminary, different patterns of correlations found in this study could potentially indicate the fundamental processes discriminating aging and disease progression.


Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly that usually manifests as severe left-sided heart failure and mitral valve insufficiency during the first one to two months of life. The majority of these cases die in infancy if not corrected early upon presentation. Adulthood presentation is rare and most of the untreated patients who reach adulthood present with left ventricular dysfunction, severe mitral regurgitation, and sometimes myocardial infarction. Here we report a case of a 20-year-old woman with a history of exercise intolerance since childhood that was misinterpreted as asthma until a 2D-Echo revealed ALCAPA with RCA collaterals to the left anterior descending artery, preserved LV ejection fraction, and absence of apparent mitral valve abnormality. One month after the ALCAPA diagnosis, she successfully underwent surgical reconstruction of left main and pulmonary artery without any major complications. She had normal left ventricular function without apparent ischemic cardiac symptoms eighteen months after procedure. Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly occurring in 1 of 300,000 live births  and accoThe ALCAPA anomaly may result from abnormal septation of the conotruncus into the aorta and pulmonary artery, or from persistence of the pulmonary buds together with involution of the aortic buds that eventually form the coronary arteries. ALCAPA is usually an isolated cardiac anomaly that does not present prenatally because of the favorable fetal physiology that includes equivalent pressures in the main pulmonary artery and aorta secondary to a nonrestrictive patent ductus arteriosus, and the relatively equivalent oxygen concentrations due to parallel circulations. This results in normal myocardial perfusion and, therefore, no stimulus for collateral vessel formation between the right and left coronary artery systems is present. Shortly after birth, as the circulation becomes one in series, pulmonary artery pressure and resistance decrease, as does oxygen content of pulmonary blood flow. This causes a drop in antegrade flow and oxygen content of the anomalous left coronary artery, leading to myocardial ischemia. Furthermore, collateral circulation between the right and left coronary systems ensues and the left coronary artery flow reverses and enters the pulmonary trunk due to the low pulmonary arterial pressure, causing coronary steal phenomena. Consequently, fixed ischemia or myocardial infarction occurs. Eighty-five percent of all cases of ALCAPA present within the first two months of life. The typical clinical course involves severe left-sided heart failure and significant mitral valve insufficiency secondary to papillary muscle ischemia, permanent fibrosis, or left ventricular dilatation. The late presentation is extremely rare and usually with significant cardiac function compromise.A 20-year-old woman presents with chronic dyspnea on exertion and exercise intolerance that was attributed to and treated as presumed exercise-induced asthma since childhood. She experienced worsening left-sided chest heaviness and was subsequently referred to our institute. She has no coronary risk factors and no family history of premature coronary artery disease or congenital heart condition. Physical examination was normal except a subtle continuous murmur at apex and lower right sternal border. ECG showed sinus rhythm without ST or T wave changes . Chest X-ray showed no cardiomegaly . Serial cardiac enzymes were negative. In the light of cardiac murmur, an echocardiogram was obtained and revealed anomalous coronary arteries with a large left coronary artery to main pulmonary artery fistula. There was mild left ventricular enlargement with preserved left ventricular contractile function and an ejection fraction of 65%. The appearance of the left ventricle and left atrium was consistent with a systemic to pulmonary vascular shunt with increased stroke volumes in the left heart. There were no structural abnormalities of the aortic, mitral, tricuspid, or pulmonic valves, and there was very mild mitral regurgitation by Doppler. A subsequent cardiac catheterization confirmed the diagnosis of ALCAPA with retrograde filling through collaterals arising from an enlarged right coronary artery (12 mm) (As a rare congenital heart condition, ALCAPA even more rarely has a late presentation in adulthood as few of these patients survive past childhood without surgical repair . Among tIn infants, most of the patients with surgically corrected ALCAPA show normalization of both ventricular function and mitral valve insufficiency , 12. EstIn conclusion, even as a rare scenario of a rare disorder, diagnosis of adulthood ALCAPA should be considered not only in adult patients presenting with clear evidence of ischemic heart disease, left ventricular dysfunction, or arrhythmias, but also more importantly in patients with minor symptoms of exercise intolerance or dyspnea that could be easily misinterpreted or missed without high clinical suspicion and detailed physical and diagnostic evaluation, as early diagnosis and timely surgical treatment usually results in an excellent prognosis.Supplemental Figure 1: 12-lead ECG showed normal sinus rhythm with no specific ST and T changes.Supplemental Figure 2: Chest x-ray showed no cardiopulmonary pathology.Click here for additional data file.


Although intravascular injection of contrast media is very important in diagnostic radiology but may lead to acute renal failure and hospitalization. It seems that, pathogenesis of contrast media nephrotoxicity acts through renal vasoconstriction, medullary ischemia, tubular cell death and production of reactive oxygen species. Pretreatment with antioxidants attenuated renal side effects of contrast media in patients and laboratory animals.et al. used green tea (Camellia sinensis) extract in combat with contrast media nephrotoxicity in rats for the first time  have been completely observed by the author.None declared.


Spontaneous intracerebral hemorrhage (ICH) is a particularly severe type of stroke for which no specific treatment has been established yet. Although preclinical models of ICH have substantial methodological limitations, important insight into the pathophysiology has been gained. Mounting evidence suggests an important contribution of inflammatory mechanisms to brain damage and potential repair. Neuroinflammation evoked by intracerebral blood involves the activation of resident microglia, the infiltration of systemic immune cells and the production of cytokines, chemokines, extracellular proteases and reactive oxygen species (ROS). Previous studies focused on innate immunity including microglia, monocytes and granulocytes. More recently, the role of adaptive immune cells has received increasing attention. Little is currently known about the interactions among different immune cell populations in the setting of ICH. Nevertheless, immunomodulatory strategies are already being explored in ICH. To improve the chances of translation from preclinical models to patients, a better characterization of the neuroinflammation in patients is desirable. Intracerebral hemorrhages (ICH) account for 10–15% of all strokes  into neurotoxic components such as heme and iron which are major contributors to secondary brain injury  to various stimuli. Neuroinflammation after ICH involves the early activation of resident microglia, release of proinflammatory mediators and the influx of peripheral leukocytes and has major role in the pathophysiology of secondary brain damage  and mitogen-activated protein kinase signaling pathways  serum reduced BBB breakdown, axonal injury and neurological deficit  days. As cellular parts of the adaptive immune system, B cells participate in humoral immune responses, while T cells are involved in cellular immunity. T cells express either the CD4 or the CD8 cell surface marker determining their function: modulating immune responses or eliciting cytotoxicity.Increasing evidence suggests an important role of adaptive immunity and particularly T lymphocytes in secondary brain damage after ischemia  where it decreased peri-hematomal edema and reduced neurological impairment compared with control individuals  is one of the main effector molecule of T lymphocytes  is upregulated  and 64Cu-labeled nanoparticles conjugated with anti-ICAM-1 antibody  for PET imaging have been developed (Wunder et al., In vivo labelling is performed using MRI agents including iron-oxide nanoparticles (Stuber et al., To investigate the mechanisms underlying the trafficking of systemic immune cells into the brain, contrast media targeting endothelial selectin, ICAM and VCAM have been developed. These include in vivo neuroimaging has been barely used to investigate the ICH-induced inflammatory processes. In collagenase-induced ICH, enhanced MRI with microparticles of iron oxide targeted to VCAM-1 revealed the maximal VCAM-1 expression 24 h after ICH which returned to baseline 5 days following hemorrhage induction (Gauberti et al., The above detailed labeling methods are increasingly used in clinical and experimental studies to characterize inflammatory processes in neurologic disorders including cerebral ischemia, multiple sclerosis, Alzheimer’s and Parkinson’s disease (Jacobs and Tavitian, Inflammatory processes are increasingly recognized as important players in the pathophysiology of secondary brain damage after ICH. There is now solid information on the infiltration pattern of leukocytes in experimental ICH. The pathophysiological role of specific leukocyte populations is beginning to be better understood but little is known about the interactions among these immune cells. Because of the delayed nature of brain damage after ICH, adaptive immune cells may play an important role in the subacute and the regenerative phases after ICH. Translation of preclinical findings into the clinical setting is challenging because of limitations of current animal models of ICH. Moreover, the local and systemic neuroinflammatory response in ICH patients remains to be better characterized.All authors were involved in writing the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Suppression of lipid signal is a basic requirement in coronary magnetic resonance angiography (CMRA) because coronary arteries are embedded in epicardial fat and signal from fat can decrease coronary vessel conspicuity. Most CMRA scans are currently performed with fat suppression techniques such as Spectral Presaturation with Inversion Recovery (SPIR). However, methods based on spectrally-selective fat saturation are sensitive to B0 and B1 field inhomogeneities. Recent improvements in chemical shift based water fat separation methods such as Dixonprovides This work was performed on a 3T scanner  equipped with a 32-element cardiac receiver coil. Data were acquired in eight healthy volunteers  and eight patients with suspected coronary artery disease . Two different scans were performed in each of them: 1) Conventional whole heart CMRA with SPIR fat suppression and 2) two-point Dixon CMRA. Two experts readers, blinded to the methods used, scored the image quality for each dataset. In addition, signal-to-noise ratio of blood, fat and myocardium, contrast-to-noise ratio (CNR) between blood, fat and myocardium, and right coronary artery sharpness and length were measured to compare these two techniques quantitatively. A Wilcoxon Signed-Rank was used for statistical analysis for comparison between images acquired with Dixon and SPIR.All scans were successfully performed and produced good quality images in all volunteers. Figure These findings demonstrate that Dixon water-fat separation leads to higher SNR of coronary blood and myocardium and improved image quality scores for coronary artery visualization at high field strengths. Furthermore, the additional fat data that is available with Dixon protocols may be an important biomarker and improve the diagnostic value of CMRA.Wellcome Trust and ESPRC Medical Engineering Centre.


Eutrophication increases the phytoplankton biomass that can be supported during a bloom, and the resultant uptake of dissolved inorganic carbon during photosynthesis increases water-column pH (bloom-induced basification). This increased pH can adversely affect plankton growth. With OA, basification commences at a lower pH. Using experimental analyses of the growth of three contrasting phytoplankton under different pH scenarios, coupled with mathematical models describing growth and death as functions of pH and nutrient status, we show how different conditions of pH modify the scope for competitive interactions between phytoplankton species. We then use the models previously configured against experimental data to explore how the commencement of bloom-induced basification at lower pH with OA, and operating against a background of changing patterns in nutrient loads, may modify phytoplankton growth and competition. We conclude that OA and changed nutrient supply into shelf seas with eutrophication or de-eutrophication (the latter owing to pollution control) has clear scope to alter phytoplankton succession, thus affecting future trophic dynamics and impacting both biogeochemical cycling and fisheries.Human activity causes ocean acidification (OA) though the dissolution of anthropogenically generated CO Taken together with other climate change events, notably changes in temperature and water-column stability, OA has the potential for various impacts upon marine plankton communities and production  ,34. Studher [H+] , it is u sources ,37, to b


Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice surviving the acute stage of disease develop an immune-mediated demyelinating disease, characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Chemokines and their corresponding chemokine receptors are dynamically expressed throughout viral infection of the CNS, influencing neuroinflammation by regulating immune cell infltration and glial biology. This review is focused upon the pleiotropic chemokine receptor CXCR2 and its effects upon neutrophils and oligodendrocytes during JHMV infection and a number of other models of CNS inflammation. Intracranial infection of susceptible mice with the JHM strain of mouse hepatitis virus (JHMV) causes an acute encephalomyelitis followed by a chronic demyelinating disease. JHMV, after initially infecting ependymal cells lining the ventricles, rapidly disseminates to astrocytes, oligodendroglia, and microglia throughout the brain and spinal cord  chemokine family CXCL1 and CXCL2. CXCL1 and CXCL2 are potent chemoattractants for peripheral mononuclear cells (PMNs), binding and signaling through their receptor CXCR2 . Neutralization of CXCR2 almost completely abrogated neutrophil infiltration into the CNS Figures . Without+ T cells are all capable of direct permeabilization  induction, and their presence precedes axonal damage, demyelination, and clinical disease  chemokine signaling on oligodendroglia during JHMV-induced neuroinflammation. It will be important to analyze the effects of selectively ablating CXCR2 on oligodendroglia during JHMV-induced demyelination, while simultaneously manipulating the cellular sources of ELR-positive chemokines in the CNS that may promote neuroprotection during chronic JHMV-induced disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To meet these challenging demands, we and others developed physiologically relevant mouse models and characterized their hearts with planar AP mapping. Here, we summarize the progress toward panoramic fluorescence imaging and its prospects for the mouse heart. In general, several high-resolution cameras are synchronized and geometrically arranged for panoramic voltage mapping and the surface and blood vessel anatomy documented through image segmentation and heart surface reconstruction. We expect that panoramic voltage imaging will lead to novel insights about molecular arrhythmia mechanisms through quantitative strategies and organ-representative analysis of intact mouse hearts.To investigate the dynamics and propensity for arrhythmias in intact transgenic hearts comprehensively, optical strategies for panoramic fluorescence imaging of action potential (AP) propagation are essential. In particular, mechanism-oriented molecular studies usually depend on transgenic mouse hearts of only a few millimeters in size. Furthermore, the temporal scales of the mouse heart remain a challenge for panoramic fluorescence imaging with heart rates ranging from 200 min In addition, AP duration (APD) and the stability of cardiac repolarization are regulated by distinct K+ channel types, e.g., during ischemia activation of ATP-sensitive K+ channels (KATP) leads to APD shortening thereby preventing potentially detrimental intracellular Ca2+ overload. While each principle contributes to impulse generation, propagation and/or modulation in heart tissue, the molecular mechanisms of AP modulation and disease changes are exceedingly complex and depend on thorough analysis in intact heart tissue based on non-invasive imaging methods.Molecular physiology and genetic engineering studies have established complex genetic and cellular determinants of impulse propagation in mouse models. Four distinct molecular principles were identified: connexin channels at gap junctions control solute flux between myocytes and electrical current flow throughout the myocardial syncytium Figure ; cardiac2+ dye) have become a central strategy to study impulse propagation in transgenic mouse hearts in which EC coupling cycles occur an order of magnitude faster than human heart. High VSDI based resolution has allowed the functional characterization of anisotropic impulse propagation in mouse hearts. This has revealed the physiological relevance of select Nav1.5 channel membrane targeting mechanisms and led to the concept of distinct, locally confined pools of Nav1.5 channels at the intercalated disc (ICD) vs. the lateral cell membrane  or multiparametric imaging  and a planar resolution of 50–100 μm are achieved. Each sensor pixel records the fluorescent signal average of multiple cells. The tissue-specific propagation of epicardial AP wave fronts can be analyzed during sinus rhythm Figure  or durinFurthermore, both physiological and pathological changes of cardiac repolarization can be analyzed. Abnormal AP formation  as mechanism of triggered arrhythmias, abnormal AP propagation , and reentry contribute to arrhythmia initiation and/or propagation. Optical signals recorded by individual pixels can be analyzed to determine local APD, e.g., repolarization at 80% of the signal amplitude Figure . Similar2+ transients) cannot be analyzed continuously throughout the whole surface of the mouse heart, especially the spatially complex 3D impulse spread during fast arrhythmias. In addition, the high curvature-to-volume ratio of mouse hearts distorts fluorescent signals originating from shallow angles of peripheral boundaries, limiting the effective ROI of single camera approaches , while ex vivo imaging additionally facilitates detailed analysis about the time and location of residual chaotic activity in the heart. Finally, detailed experimental knowledge about the electrical activity on the cardiac surface together with internal tissue structures can be combined through 3D computational methods to reconstruct the hidden spatiotemporal dynamics of arrhythmias and therapeutic interventions inside the heart tissue in a non-invasive manner.External and internal cardioverter defibrillators (ICDs) are routinely used in clinical medicine, but electrical shocks can cause significant side effects including tissue damage and traumatic pain. Recently, a new strategy for arrhythmia control using low-energy antifibrillation pacing (LEAP) was developed. LEAP uses a series of five low-energy pulses to terminate atrial fibrillation 2+ transients. Recent data from transgenic mouse hearts identified novel molecular determinants of ion channel expression and targeting in cardiac myocytes with marked effects on the conduction properties of the ventricles. This led to the realization that complex molecular mechanisms underlie the anisotropic activation pattern of the intact hearts, namely ion channel complexes at gap junctions, lateral membranes, and T-tubules, and all with specific effects on conduction properties. In general, acquired or genetic changes result in decreased spatiotemporal AP propagation and conduction delay, which may contribute to arrhythmogenesis. Panoramic imaging of mouse and larger hearts will contribute to better understanding of arrhythmia propensity and onset, as well as support clinical translation of important new therapeutic concepts, in particular 3D-MIMS and LEAP.In summary, panoramic imaging of rabbit and larger mammalian hearts has been successfully developed whereas panoramic imaging of smaller, particularly transgenic mouse hearts will most likely be realized in the near future based on the success of VSDI and multiparametric readouts such as combined CaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Middle East respiratory syndrome (MERS) cases continue to be reported from the Middle East. Evaluation and testing of patients under investigation (PUIs) for MERS are recommended. In 2013–2014, two imported cases were detected among 490 US PUIs. Continued awareness is needed for early case detection and implementation of infection control measures. Middle East respiratory syndrome coronavirus (MERS-CoV) infection was first reported in September 2012 in a patient with fatal pneumonia in Saudi Arabia (http://www.cdc.gov/coronavirus/mers/index.html). The PUI guidance was created to assist health care providers determine which patients should be considered for MERS-CoV evaluation and testing. To inform state and local health departments of the basic demographic and clinical characteristics of PUIs and on assay use, we summarized the descriptive analysis of PUIs in the United States.Using World Health Organization guidelines and definitions  assays for detection of MERS-CoV , other pathogen testing was not performed or detected pathogens were not reported . Timely >2 weeks before specimen collection, testing using the CDC MERS-CoV serologic assay on a single serum specimen is recommended. CDC also recommends testing for common respiratory pathogens , but identification of a respiratory pathogen should not preclude MERS-CoV testing (Currently in the United States, the preferred method for detecting MERS in PUIs with recent symptom onset is to test lower respiratory, naso-oropharyngeal, and serum specimens by using the CDC rRT-PCR assay. For PUIs in whom symptom onset occurred The 2 US cases of imported MERS were detected in health care providers from Saudi Arabia. These cases prompted a CDC guidance update recommending evaluation and testing of persons with less severe respiratory illness who had strong epidemiologic risk factors, particularly heath care exposure, for MERS-CoV infection. Occupation, recent travel history, recent visit to a health care facility, and contact will ill persons should be determined when evaluating persons with respiratory illness. As testing increases, especially serologic testing, additional MERS cases, including mildly symptomatic cases and cases among younger persons are being identified. These cases highlight the range of severity of MERS-CoV infection and the need to consider testing persons with a compatible travel history who may not match the clinical profile of the initially described case-patients. CDC plans to revise MERS-CoV guidance as needed.


Headache is one of the most common causes of access to Emergency Departments (ED). Primary headaches and headaches secondary to benign conditions (e.g headache attributed to acute sinusitis) represent the majority of cases, while secondary life-threatening headaches are less frequent. The primary objective in the ED setting is to decide whether the headache is primary or secondary and recognize serious life-threatening conditions presenting with headache and requiring prompt medical diagnosis and care, such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage, cerebral venous sinus thrombosis (CVST), cervical artery dissection (CAD), brain tumors, pituitary apoplexy, spontaneous intracranial hypotension, or intracranial infections. Careful history taking and physical examination remain the most important part of the assessment of the headache patient. A thoro


Dictyostelium discoideum is triggered by starvation. When placed on a solid substrate, the starving solitary amoebae cease growth, communicate via extracellular cAMP, aggregate by tens of thousands and develop into multicellular organisms. Early phases of the developmental program are often studied in cells starved in suspension while cAMP is provided exogenously. Previous studies revealed massive shifts in the transcriptome under both developmental conditions and a close relationship between gene expression and morphogenesis, but were limited by the sampling frequency and the resolution of the methods.Development of the soil amoeba Here, we combine the superior depth and specificity of RNA-seq-based analysis of mRNA abundance with high frequency sampling during filter development and cAMP pulsing in suspension. We found that the developmental transcriptome exhibits mostly gradual changes interspersed by a few instances of large shifts. For each time point we treated the entire transcriptome as single phenotype, and were able to characterize development as groups of similar time points separated by gaps. The grouped time points represented gradual changes in mRNA abundance, or molecular phenotype, and the gaps represented times during which many genes are differentially expressed rapidly, and thus the phenotype changes dramatically. Comparing developmental experiments revealed that gene expression in filter developed cells lagged behind those treated with exogenous cAMP in suspension. The high sampling frequency revealed many genes whose regulation is reproducibly more complex than indicated by previous studies. Gene Ontology enrichment analysis suggested that the transition to multicellularity coincided with rapid accumulation of transcripts associated with DNA processes and mitosis. Later development included the up-regulation of organic signaling molecules and co-factor biosynthesis. Our analysis also demonstrated a high level of synchrony among the developing structures throughout development.D. discoideum development as a series of coordinated cellular and multicellular activities. Coordination occurred within fields of aggregating cells and among multicellular bodies, such as mounds or migratory slugs that experience both cell-cell contact and various soluble signaling regimes. These time courses, sampled at the highest temporal resolution to date in this system, provide a comprehensive resource for studies of developmental gene expression.Our data describe The online version of this article (doi:10.1186/s12864-015-1491-7) contains supplementary material, which is available to authorized users. D. discoideum exhibits a developmental program unique among model organisms , and the complete time series data sets are accessioned at the NCBI Gene Expression Omnibus .Further analyses of these data may focus on identifying additional co-regulated transcriptional regulators and target genes. The enhanced temporal resolution of these data provides more informative transcription profiles than previous studies. Perhaps clustering of genes by expression pattern will yield improved hypotheses regarding shared regulation and function. As future studies examine the phenotypic consequences of transcription factor knockout mutations, as well as the binding specificity of important transcriptional regulators, these data will serve as a critical reference point for inferring regulatory interactions. To facilitate exploration by the larger community, user-friendly analysis tools for these data are available at dictyExpress . These data may also be viewed and analyzed using the dictyExpress toolkit [www.dictyExpress.org].The additional material includes the Additional file


Visual category perception is thought to depend on brain areas that respond specifically when certain categories are viewed. These category-sensitive areas are often assumed to be “modules” (with some degree of processing autonomy) and to act predominantly on feedforward visual input. This modular view can be complemented by a view that treats brain areas as elements within more complex networks and as influenced by network properties. This network-oriented viewpoint is emerging from studies using either diffusion tensor imaging to map structural connections or effective connectivity analyses to measure how their functional responses influence each other. This literature motivates several hypotheses that predict category-sensitive activity based on network properties. Large, long-range fiber bundles such as inferior fronto-occipital, arcuate and inferior longitudinal fasciculi are associated with behavioral recognition and could play crucial roles in conveying backward influences on visual cortex from anterior temporal and frontal areas. Such backward influences could support top-down functions such as visual search and emotion-based visual modulation. Within visual cortex itself, areas sensitive to different categories appear well-connected  and their responses can be predicted by backward modulation. Evidence supporting these propositions remains incomplete and underscores the need for better integration of DTI and functional imaging. A current challenge for visual neuroscience is to explain how perception of complex and meaningful objects is achieved. High-level vision is associated with anatomically-focal, functionally-defined brain areas in human occipitotemporal cortex, usually localized using functional magnetic resonance imaging (fMRI). These “category-sensitive” areas are typically inferred to be specialized for processing their preferred visual categories   or estimate their effective connectivity using functional brain imaging methods including fMRI, electroencephalography (EEG) or magnetoencephalography (MEG). However, few studies to date have combined DTI and effective connectivity techniques. DTI maps structural connections composed of axonal fiber tracts. In contrast, effective connectivity measures how functional responses influence (or “cause”) each other. However, they share the similar goal of inferring functional integration, with DTI showing which areas are connected and effective connectivity showing the experimental conditions under which these structural connections might enact their influence. Studies using these methods have not provided a comprehensive picture of human structural connections or the effective interactions supported by these structures. Nevertheless, the findings reviewed here suggest specific structural and effective network properties that are relevant to visual analysis of complex stimuli. These network properties include influences of major, long-range fiber bundles, backward connections from higher to lower-level areas and interactions between areas with dissimilar category preferences. These network properties can potentially explain diverse phenomena, including top-down, attentional and emotional modulation of visual cortex, oscillatory power changes and repetition-related response modulations. This review covers these findings, discusses the deficiencies of existing theories and describes how a functional integration approach is well-suited to advance understanding of visual processing in human occipitotemporal cortex. in vivo in humans.Responses in category-sensitive brain areas are likely to be influenced by the different types of connections associated with hierarchical networks. Hierarchical structures , which would then guide visual object processing via backward connections Bar, . SimilarVisual cortex appears to contain a hierarchical apparatus and therefore response specificity in visual cortex likely depends on distinguishable forward and backward influences. Moreover, mainstream computational models make important assumptions about the influences of forward and backward influences. While many models rely solely on forward influences, models such as predictive coding posit specific roles for backward connections. While the DTI and effective connectivity studies performed to date and reviewed herein do not yet support any particular computational theory in detail, they provide evidence for a role of backward influences during perception of high-level visual stimuli.Multiple areas that are sensitive to the same category have been described as hierarchies. At the most general level in visual cortex, all areas may be associated with the dorsal or ventral hierarchical streams . Effective and structural connectivity measures are complementary, even though their relationship is not fully understood , mostly oriented along a posterior-anterior axis. These bundles have been observed using human post-mortem dissection and can be imaged using DTI , arcuate/superior longitudinal (AF/SLF) and inferior occipitofrontal (IFOF) fasciculi. ILF projects down the length of the temporal lobe, with fibers terminating posteriorly in inferior occipital cortex (near OFA) and fusiform gyrus (near FFA) and anteriorly in the temporal pole, amygdala and hippocampus  and superior longitudinal (SLF) fasciculi share overlapping anatomical courses and are often considered together . The OFC/VMFC could influence visual areas directly, via IFOF, or indirectly, via the uncinate fasciculus, which connects OFC/VMFC to the anterior temporal lobe and the amygdala  in different fiber bundles. To date, the details of these dissociations are still not clear, as they are different in each study, with mixed evidence for a selective role of the ILF for face recognition. Although no major fiber bundle is likely to contribute to recognition of any single category (such as face or scene perception), the function of a given fiber bundle might contribute more to recognition of some categories than others. Thus, linking behavioral recognition performance to fiber bundle properties is a promising research method. Research linking fiber bundles with behavior has also been well-served by combining DTI with fMRI functional localization . These studies therefore only considered reciprocal models  OFC/VMFC via IFOF; (2) OFC/VMFC via the uncinate fasciculus and ILF; and (3) inferior frontal cortex via AF/SLF. Frontal influences on visual cortex have been tested in a number of effective connectivity studies, and these studies suggest that frontal areas can sensitize occipitotemporal visual areas to detect expected stimuli, particularly during visual search.The more prevalent evidence for this top-down modulation involves OFC or VMPFC  faces, chairs or houses during fMRI scanning, significant category-specific bilinear parameters were observed on connections from prefrontal cortex to face-, chair- and house-sensitive ventral temporal areas  Effective connectivity analyses should be combined with DTI to investigate the functional specialization of the major fiber bundles . (2) These fiber bundles may support fast feedforward shortcut pathways that trigger early influences of backward connections  may be useful for understanding computations outside the visual system. Oscillations are another widespread phenomenon which can be investigated using connectivity-based methods and have been proposed to be a fundamental mechanism for brain communication . Effective connectivity analysis cannot determine whether a connection between two areas is direct or indirect. Methods such as DTI, effective connectivity and conventional functional imaging methods based on the general linear model can overcome their weaknesses when used in conjunction.Effective connectivity analysis applied to fMRI data can also be problematic, due to the uninformative temporal resolution of the blood-deoxygenation response signal. This problem is acute for methods such as Granger Causality and structural equation modeling, which depend on exact timing of fMRI response signals to draw inferences about connectivity between underlying neuronal sources  computationally tractable; (2) includes all plausible models; and (3) can be adequately compared to model spaces used in similar studies. The present review presents the outcomes of model comparisons, even though the model spaces used by each study vary widely, often omit plausible models that are of theoretical interest or estimate the parameters of only one model. Newer methods such as post hoc model comparison (Rosa et al., A particularly vexing challenge in applyingThis article reviews recent work examining structural and effective connectivity associated with category-sensitive areas in high-level visual cortex in the human. These studies add to our knowledge of the functions of forward and backward interactions between visual areas and top-down influences from frontal areas and the amygdala. More work is needed to develop theory that moves beyond a focus on the modular nature of individual areas with only feedforward interactions. Structural and effective connectivity studies have not yet given us a complete picture of network interactions and, like any method, possess both strengths and limitations. Nevertheless, they allow direct testing of connectivity in ways that complement more conventional uses of brain imaging and therefore hold promise for answering numerous future research questions.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Advances in target-based drug discovery strategies have enabled drug discovery groups in academia and industry to become very effective at generating molecules that are potent and selective against single targets. However, it has become apparent from disappointing results in recent clinical trials that a major challenge to the development of successful targeted therapies for treating complex multifactorial diseases is overcoming heterogeneity in target mechanism among patients and inherent or acquired drug resistance. Consequently, reductionist target directed drug-discovery approaches are not appropriately tailored toward identifying and optimizing multi-targeted therapeutics or rational drug combinations for complex disease. In this article, we describe the application of emerging high-content phenotypic profiling and analysis tools to support robust evaluation of drug combination performance following dose-ratio matrix screening. We further describe how the incorporation of high-throughput reverse phase protein microarrays with phenotypic screening can provide rational drug combination hypotheses but also confirm the mechanism-of-action of novel drug combinations, to facilitate future preclinical and clinical development strategies. The evolution of many complex human diseases has generated multiple biological redundancies in the genetics, pathway signaling networks and pathophysiology of disease thus counteracting the efficacy of new therapeutics. In such complex diseases exemplified by cancer, neurodegeneration, cardiovascular, bacterial, and viral infections, combination therapies represent the standard of care  strategies provides a new opportunity to discover and prioritize drug combination and polypharmacology strategies objectively while appropriately tailoring their use to complex disease during early stage drug discovery  platform  and Compound Synergy Extension (Genedata Screener®). Such tools enable rapid drug combination screening across phenotypic assays at scale to enable a more transparent review of drug combination data placed into context of multiple drug combination sets to aid benchmarking and prioritization. Incorporation of genomically annotated patient derived cell panels into high capacity drug combination screening activity further supports pharmacogenomics and personalized healthcare approaches to drug combination strategies. High-content single cell analysis of specific phenotypic events over both dose and time enable a significantly more robust evaluation of the quality of drug combination data. Such considerations support the interpretation of whether synergistic and additive drug combination data occur at physiologically relevant doses.A limitation of screening large compound libraries in complex cell based assays compared with more traditional biochemical drug screening is throughput and cost. Both throughput and cost are particularly limiting when considering the evaluation of multiple drug combinations across a factorial dose-ratio matrix where the number of individual combination dose ratios increases quadratically with the number of agents under study. For practical reasons, medium to high-throughput phenotypic screening across cancer cell lines have traditionally employed simple single endpoint analysis of tumor cell viability or cell proliferation in 2D mono-culture  circumvents many of the challenges associated with co-dosing distinct components in vivo. Thus, application of more systematic approaches to evaluate the kinetics and sensitivity of drug combinations across broad dose ranges and multiple phenotypic parameters promise to enhance the quality and robustness of preclinical drug combination data and support more informed prioritization of the most appropriate combination strategies to move forward into in vivo and clinical settings.A significant challenge to translating effective drug combinations identified from in vitro or in vivo models ; the Human Antibody Initiative ; and the Human Protein Atlas Project (www.proteinatlas.org/) to derive high quality mono-specific antibodies are poised to further advance antibody-based proteomics into broader areas of human pathway biology. Correlation of basal RPPA post-translational dataset with compound EC50 values from phenotypic assays performed across cell panels has identified protein level markers of drug sensitivity and resistance  models is correlation of phenotypic response with genomic biomarkers. Such pharmacogenomic studies support biomarker discovery and patient stratification hypothesis. However, as described in this review article, adaptive resistance mechanisms that guide combination response are often operating only at the post-translational level. Thus, RPPA analysis applied to related monotherapy and drug combination arms can be correlated with additive, synergistic, or antagonist phenotypic response across a dose matrix study to identify pharmacodynamic biomarkers that confirm the mechanism-of-action of the drug combination effect and provide biomarkers to guide future clinical development.In 2010, the US FDA issued an updated draft guidance to support the further development of novel drug-combination therapies. Previous guidance recommended demonstrative evidence of a positive efficacy and safety response across all monotherapy and combination arms. The updated guidance now supports the proposal of clinical trial designs where single or multiple monotherapy arms can be left out on the grounds that no efficacy benefit would be expected. This new update now provides an opportunity to exploit synthetic lethality and multi-drug cocktails. Phenotypic screening campaigns are particularly suited to discovery of synthetic lethality by performing screens on matched pairs of cell models, representing suspected natural or engineered genetic vulnerabilities or distinct sensitivities to known agents. The latest advances in phenotypic screening technologies combined with high-throughput pathway profiling are now well placed to provide high quality preclinical data that provide for a more robust, transparent and objective prioritization of drug combinations.Both authors contributed to the conception of this review article, drafted the paper, and approved the version for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD ( Polycystic liver disease (PLD) is a collection of rare human disorders that result from structural changes in the biliary tree development ,2. GenetThree PLD entities are recognized in adults. Von Meyenburg complexes  with characteristic small, non-hereditary nodular cystic lesions [ORPHA386] ,5. IsolaThis paper reviews the pathological and clinical features of these 3 adult cystic disorders that share presence of numerous hepatic cysts with an intact biliary tree architecture.PLD is a rare inherited Mendelian disorder that is characterized by development of multiple hepatic cysts. The classification of PLD follows the histological changes that are due to ductal plate malformation (DPM) during fetal development ,7. Definth week of gestation by formation of single layered hepatoblasts surrounding the portal vein . Duplication of ductal plate cells forms a double layer that finally dilate to a tubular structure, the primitive bile duct. Hepatoblast differentiation to a biliary phenotype and tubulogenesis is stimulated by the Notch, TGF-β and canonical Wnt signaling pathways  and SEC63 [OMIM*608648] may confirm the clinical diagnosis and differentiate it from other PLD  and Caroli syndrome (CS). PLD is characterized by intrahepatic disease, a more late onset of disease in adulthood and absence of congenital hepatic fibrosis (CHF).Young and adult ADPKD patients are difficult to distinguish with other hepatorenal fibrocystic diseases such as ARPKD and other ciliopathies . ARPKD hCD is characterized by saccular, cystic dilations of the more larger intrahepatic biliary system. In CS large and small intrahepatic bile duct ecstasies are accompanied with CHF. CS has been typically associated with renal disease as in ARPKD . The incBoth PCLD and ADPKD have an autosomal dominant inheritance pattern and the recurrence risk is 50%. Genetic studies indicate an evident inter-familial clinical heterogeneity in PLD disease course among similar-aged patients. Secondly, intra-familial studies suggested a considerable phenotypic variability of hepatic cysts Figure . ClinicaThese considerations raise the question whether it is appropriate to screen members or children at-risk. Counseling should include discussion about insurance, employment and psychological factors. Genetic counseling is recommended in severely affected PLD and may afford differentiation between ADPKD and PCLD ,12.Molecular diagnostics may assist the counseling process to establish a firm diagnosis in symptomatic patients and families. In particular ADPKD, determination of the responsible gene is useful for those who are at-risk in order to develop a strategy to prevent severe progressive disease events or complications . If the VMC is an asymptomatic condition without long-term consequences and treatment is not warranted. The primary aim of PLD therapy is to reduce symptoms by curtailing hepatic cyst development. The treatment of choice is driven by individual complaints . AlthougThe first advice in PCLD and ADPKD is to stop oral anticonceptives ,78. AlthThe different invasive approaches with possible beneficial outcomes in independent studies include aspiration sclerotherapy, laparoscopic cyst deroofing or liver transplantation ,40,84. CTreatment of portal hypertension and ascites are not different from that in patients with other causes. In a selected patient group were invasive procedures such as a vascular or bile duct stent placement optional for decompression of the portal vein, inferior vena cava or bile duct, or in HVOO treatment ,85. In gRecent development of pharmacological options opened up new treatment strategies for severe PLD patients. Long-term follow-up studies with somatostatin analogues demonstrated that these agents consistently lower total liver volume in PLD patients ,87. A rePLD compromises a clinically heterogeneous liver phenotype identified in VMC, ADPKD and PCLD patients. Massively enlarged livers are present in a subset of ADPKD and PCLD. Genetics and environmental factors such as exogenous estrogen intake and number of pregnancies contribute to disease progression. A considerable intra-familial variability in liver phenotype and extra-hepatic features makes screening modalities uncertain in PCLD. Evaluation of PLD-related symptoms and quality of life are necessary to decide beneficial management.th September 2013; http://www.biobase-international.com/product/hgmd.Human Gene Mutation Database for Human Genetics Research; HGMD® Professional 2013.3 - 27AAA: Abdominal aorta aneurysm; ADPKD: Autosomal dominant polycystic kidney disease; ARPKD: Autosomal recessive polycystic kidney disease; CD: Caroli disease; CS: Caroli syndrome; CT: Computer tomography; CHF: congenital hepatic fibrosis; DPM: Ductal plate malformation; ER: Endoplasmic reticulum; HVOO: Hepatic venous outflow obstruction; ICA: Intracranial aneurysm; IVC: Inferior vena cava; LVH: Left ventricle hypertrophy; MELD: Model for end-stage liver disease; MRI: Magnetic resonance imaging; PC1: PC2 polycystin-1, -2; PCLD: Isolated polycystic liver disease ; PKD1: PKD2 polycystic kidney disease-1, -2; PLD: Polycystic liver disease; PRKCSH: Protein kinase C substrate 80 K-H ; SEC63: Saccharomyces cerevisiae homolog 63; VMC: Von Meyenburg complexes.Authors declare that they have no competing interests.WC researched the data and drafted the manuscript. WC and JD contributed to the content and wrote the article. JD is responsible for critical revision of the content. Both authors read and approved the final manuscript.


Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21–28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model. Development of seizures in children is often associated with focal cortical dysplasia  arise in part from deficits in astrocytic glutamate uptake.Many of the anatomical and electrophysiological characteristics of human FCD are reproduced following transcortical freeze-lesions in the newborn rat  to avoid receptor desensitization or excitotoxicity . Under physiological conditions, experimental evidence indicates it is difficult to overwhelm astrocytic glutamate transporters. High frequency stimulation for prolonged periods does not affect glutamate clearance from the ECS; Diamond and Jahr, in vivo, can effectively reduce glutamate to ambient levels when challenged repeatedly with 100-fold glutamate increases over physiological [Glu−]out levels  following neuronal activity and maintaining out and [Glu−]in. This is achieved by coupling glutamate transport to Na+ and K+ transport down their respective concentration gradients and the hyperpolarized astrocyte membrane potential (Anderson and Swanson, Glutamate uptake is achieved against a ~1000-fold concentration gradient between [GluOur data clearly indicate significant alterations in glutamate transporter function. We observed a near 10-fold reduction in TBOA sensitive transporter function. Furthermore, application of DHK, a GLT-1 specific non transportable inhibitor, suggests ~90% of the currents in both sham-operated and lesioned astrocytes are mediated by GLT-1. Application of the same concentration of glutamate in puffing experiments ruled out the possibility that the reduced glutamate transporter responses in the lesioned astrocytes were the result of less glutamate release following stimulation in lesioned animals. Inefficient clearance of glutamate by astrocytic glutamate transports following electrical stimulation contributed to an enhanced hyperexcitability in the dysplastic cortex, which can be explained in part by altered kinetics of the NDMA receptor-mediated currents.+ has been used to study reverse glutamate transport (Szatkowski et al., +, coupled with our reported depolarized membrane potential in glia cells would create the perfect environment for transporters to function in reverse (Brew and Attwell, + which plays a significant role in neuronal excitability.We postulated that the loss in GLT-1 transporter function would be paralleled by decreased protein and mRNA expression. To our surprise, this is not what we observed. Given our data, it seems likely that a change in transporter effectiveness may underlie the observed decreases in evoked transporter currents. The activity of glutamate transporters is affected by a variety of neuromodulators and second messenger systems. Decreases in transporter activity are induced by caffeine (Shin et al., in utero MAM cortical dysplasia model (Harrington et al., Elevated levels of extracellular glutamate have been reported in patients with epilepsy (During and Spencer, Susan L. Campbell performed whole cell voltage clamp electrophysiology in neurons and astrocytes, immunohistochemistry and contributed to the writing of the manuscript. John J. Hablitz oversaw aspects of experimental design, implementation and writing of the manuscript. Michelle L. Olsen performed whole cell voltage clamp electrophysiology in astrocytes, neurons, Western blots, qPCR, immunohistochemistry and writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Coronary perfusion pressure is a combination of proximal perfusion pressure and distal coronary artery pressure resulting from contraction and relaxation of the myocardium and the consequences on the microcirculation. Wave intensity analysis (WIA) defines dominant waves causing coronary filling during the cardiac cycle and allows separation of proximally and distally originating waves.Reduced myocardial perfusion has been shown to predict mortality in hypertrophic cardiomyopathy (HCM), however no study has assessed the relationship between coronary filling patterns and downstream absolute myocardial perfusion.To obtain data for WIA, simultaneous pressure and coronary flow velocity in the proximal coronary arteries was obtained in 20 patients with HCM at rest and with adenosine. Patients then underwent cardiovascular magnetic resonance (CMR) perfusion imaging at rest and with adenosine. Myocardial blood flow (MBF) was quantified from CMR perfusion images using a pixel-wise model-constrained deconvolution algorithm.All patients completed the study successfully. No patients had significant epicardial coronary artery disease. On WIA, distally originating waves predominated compared to proximally occurring waves. The backward expansion wave, which occurs due to myocardial relaxation, correlated with MBFat rest . On CMR, myocardial perfusion reserve was reduced (mean 1.52±0.42) withan endocardial to epicardial ratio that worsened with adenosine .Patients with HCM had predominantly distal waves governing coronary filling, emphasisingthe importance of the microcirculation in this disease. There was an increased backward compression wave during systole in keeping with compression of the microcirculation with a relative reduction in the size of the backward expansion wave. CMR demonstrated the downstream effects of these abnormalities, with reduced myocardial perfusion and an abnormal endocardial to epicardial ratio. Patients with a smaller backward expansion wave had a lower MBF, suggesting that impaired myocardial relaxation results in poorer myocardial perfusion.This work was funded by the British Heart Foundation and the NIHR Cardiovascular BRU.


Since INR was developed only to monitor long-term treatment of vitamin K antagonists (VKA), effects of other coagulation conditions, i.e., antiplatelet treatment, thrombocytopenia, hyperfibrinolysis or inherited platelet disorders can not be detected by INR measurements. A possible application for POC coagulometers in the prehospital setting is to assess INR in emergency patients treated with VKA. However, this issue was extensively studied in large (non-emergency) cohorts involving appropriate sample sizes and valid study designs [With great interest we read the recent article of Beynon et al. . The aut designs , 4.In the past decades, VKA accounted for the most prescribed anticoagulants worldwide in patients with atrial fibrillation and deep vein thrombosis. This practice is now under considerable change since non-vitamin K antagonist oral anticoagulants (NOAC) are available . The dimWe agree with the authors that the implementation of POC coagulometers might be feasible in pre-hospital emergency settings but the search for an easily available parameter enlightening the complexities of the entire coagulation system continues.


Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike. Cancer has been traditionally typified by a stepwise accumulation of mutations in key oncogenes and tumor suppressors . For decMeanwhile, tumors are often described as heterogeneous, owing to the intricate genetic diversity and assorted morphological phenotypes they embody . IntratuAdvances in next-generation sequencing techniques and the inception of The Cancer Genome Atlas (TCGA) have revealed extensive heterogeneity at the molecular level . HoweverIn this review, we will revisit the key milestones in tumor evolution, highlight the evolving concepts of tumor heterogeneity, and provide insight on the clinical challenges facing researchers and clinicians alike.Three hundred years after the invention of the microscope, concurrent with the dawn of Darwinian evolution, German physiologist Johannes Muller and his assistants applied microscopy to human tumor samples in 1833. Until this point, all recorded knowledge of tumors was collected with the naked eye, leaving layers of critical information untapped. Applying methods used by botanists and plant physiologists, Muller transformed pathology and modern medicine with his monograph on cancer. This led to his conjecture that tumors are composed of new cells within a diseased organ. Muller and colleagues morphologically distinguished carcinoma subtypes within a single tumor and noted variation among tumor-adjacent connective tissues, detailing the vast heterogeneity observed. It was Muller’s student, famed pathologist Rudolf Virchow, who later determined that all tumors derive from normal cells. Muller and Virchow transformed modern medicine not just by inventing the field of pathology, but also by recording some of the earliest evidence that tumors are heterogeneous , 10.All tumors possess some form of somatic mutation, and our current understanding of tumor heterogeneity is built upon the principle that acquired mutations are heritable . EssentiGenetic heterogeneity of tumors is rooted in one of the key hallmarks of cancer: genetic instability . Severalet al. challenged this with stochastic simulation of tumor evolution and reasoned that, though individually weak, the cooperative burden of small-scale accumulated passenger mutations has a present role in tumor progression, and may be the cause for complex oncological events that remain unanswered by the driver-centric model [Tumor cells undergo a series of genetic events that contribute to genomic instability throughout tumor progression Figure A. Howeveic model .Figure 2C. albicans suggest aneuploidy promotes fitness throughout drug resistance evolution, similar to cancer, contrasting S. cerevisiae, which displays growth deficits as a result of aneuploidy [S. cerevisiae diploids exhibit an increased number aneuploidy events under strong selection pressure [Genomic analyses have provided evidence that drastic rearrangement events such as aneuploidy, a defining feature of genetic instability and cancer, and chromothripsis drive cancer progression . Despiteeuploidy . Others pressure . ComparaIn the past 10 years, genetic sequencing data from independent laboratories and collective efforts from The Cancer Genome Atlas (TCGA) and ICGC  produced global genetic profiles of different types of cancer –36. As dThe epigenome is defined as the whole suite of epigenetic factors that regulate expression of the genome and includes both heritable and non-heritable cellular changes that have been shown to contribute to tumor development and progression . Temporaet al. found that epigenetic alterations can be influenced by adjacent genes [et al. applied ChIP-seq to show epigenetic enabling of the von Hippel-Lindau (VHL) tumor suppressor activation of hypoxia inducible factors (HIFs) for metastasis [et al. recently reported an increased variance of putative CpG sites in tumor cells compared to normal cells across several types of cancer [Next generation sequencing techniques have advanced the current understanding of the epigenome and further complicated the current concept of tumor heterogeneity. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) offers single nucleotide resolution, an unlimited dynamic range, and the capacity to multiplex samples . Recentlnt genes . Anothertastasis . More ovf cancer . Signifif cancer .Cancer evolution and heterogeneity is a long debated subject that questions the tumor origin. Borrowing principles of evolution and biodiversity, scientists have reasoned that tumors originate in stem cell populations, as the innate longevity of stem cells increases the chance of acquiring harmful mutations . Increasin vitro assays are not a true assessment of self-renewal capacity [et al. isolated the reputed CSC population using classical stem cell markers from patient peripheral blood and demonstrated that a subpopulation of progenitor cells could recapitulate AML in SCID mice and displayed potential for self-renewal. These findings formed the basis for the modern CSC hypothesis and led to the further identification of cancer stem-like cells tumor initiating cells in breast cancer and brain tumors [Early clonogenic and tumor sphere forming assays showed evidence of stem like cells in heterogeneous tumors; however, these capacity . Furthercapacity . Moreovecapacity . Lapidotn tumors .The traditional CSC hypothesis implies that cellular hierarchies exist in tissues with stem cells  or CSC (in tumors) at their respective apices . Chafferet al. compiled an extensive molecular taxonomy report across several different cancer types where tissue of origin provided the strongest identification signal [et al. provides direct evidence that the tumor stroma harbors a deregulated ECM that promotes malignancy and intratumoral heterogeneity in mammary gland models [It is abundantly clear that the evolutionary selection of fit clones is a system-wide process that occurs in a dynamic tissue milieu termed the tumor microenvironment (TME) . Bisselln signal . This ked models . Michor d models . These ret al. used 3D cell culture to demonstrate that hypoxia inhibits differentiation of colon cancer cells and maintains a stem-like phenotype [et al. demonstrated that myofibroblasts secrete factors that maintain the CSC population in colon cancer cell culture models [et al. reported basal breast cancers cells retain the ZEB1 promoter in a configuration allowing ample response to environmental signals [Stem cell self-renewal and differentiation is dictated by the microenvironment, or stem cell niche. Normal stem cell niches are generally located in hypoxic tissue niches  that promote the stem cell phenotype. Poorly vascularized tumors contain hypoxic regions with undifferentiated ‘stem-like’ tumor cells that survive under control of HIFs . Yeung ehenotype . In addie models . They sh signals . These ret al. recently demonstrated that, in the context of chronic liver inflammation, depletion of a p53-dependent senescence program in tumor cells results in increased cirrhosis and fibrosis that promotes adjacent epithelial malignant transformation and transient intratumoral heterogeneity [Studies on deregulation of the tumor secretome provide compelling evidence for the TME as a major contributor to compositional tumor heterogeneity. Substantial evidence supporting a role for inflammation in cancer progression has been reported in the last decade and is commonly accepted as a hallmark characteristic of the TME . One of ogeneity .The collective interplay between the CSCs and the TME results in compositional intratumor heterogeneity Figure B. HoweveThe dawning of the age of ‘omics’ brought with it great hope for discovery and validation of novel biomarkers, relevant drug targets, and disease-specific signatures . Powerfuet al. recently generated a computer model to further study multifocal prostate cancer based on data obtained from 152 human prostatectomy specimens evaluated by DNA microarray analysis, where they demonstrated heterogeneous individual foci with a common clonal precursor [et al. reported another mathematical model of personalized treatment that integrates dynamics of evolutionary genetics into analysis and treatment design. Their analyses of hypothetical cases as well as a simulated clinical trial of over 3 million qualified ‘patients’ showed that augmented and, occasionally counterintuitive, nonstandard treatment strategies may lead to improved patient survival compared with the current model of personalized medicine [Careful consideration of the complete tumor context is essential to understanding and developing more effective personalized treatments that address tumor heterogeneity. The first challenge is whether genetic and compositional profiling of multifocal tumors of monoclonal origin displaying intrafocal heterogeneity can be effectively manage . Multiforecursor . Beckmanmedicine .et al. showed evidence of two genetically distinct tumor cell subclones in communication to maintain the tumor population [et al. employed advanced genomics techniques to further understand the underlying mechanisms driving pancreatic cancer progression and metastasis. Despite showing vast genetic diversity, the authors were able to elucidate a distinct pattern of genomic instability [et al. recently used integrated genomics to characterize the functional role of key genetic driver mutations in luminal breast cancer and correlated specific genetic signatures with poor prognosis [A number of new concepts have emerged in recent years. The concept of intratumoral cell competition among heterogeneous clones reshaped our classic hierarchical view of heterogeneity and potentially can be exploited as therapeutic entry points in eradicating multifocal cancers . Cleary pulation . This letability . Moreoverognosis . Althouget al. used Pathway Recognition Algorithm using Data Integration on Genomic Models (PARADIGM) analyses based on copy number alterations (CNAs) and mRNA expression of data from the MicroMetastases Project (MicMa) cohort to show that integrated analysis of DNA copy number alteration and mRNA expression leads to improved prognostic discrimination of patients compared to separate analysis of any other molecular levels [With massive omics data generated from The Cancer Genome Atlas (TCGA), various algorithms and tools for recognition of activated and altered pathways exist for integrative analysis of two or more types of omics data and are rapidly proving worthwhile . Notablyr levels . Five dir levels . Similarr levels . Among tr levels .Taken together, future integrated omics analyses with consideration of compositional heterogeneity inferred by interplay between intratumoral subclones and TME will allow us to identify more robust biomarkers and devise therapeutic strategies for cancer treatment, such as staggering targeted therapies to keep selection pressures minimal . Mapping


IbGGPS, was isolated from sweetpotato storage roots. Green fluorescent protein (GFP) was fused to the C-terminus of IbGGPS to obtain an IbGGPS-GFP fusion protein that was transiently expressed in both epidermal cells of onion and leaves of tobacco. Confocal microscopic analysis determined that the IbGGPS-GFP protein was localized to specific areas of the plasma membrane of onion and chloroplasts in tobacco leaves. The coding region of IbGGPS was cloned into a binary vector under the control of 35S promoter and then transformed into Arabidopsis thaliana to obtain transgenic plants. High performance liquid chromatography (HPLC) analysis showed a significant increase of total carotenoids in transgenic plants. The seeds of transgenic and wild-type plants were germinated on an agar medium supplemented with polyethylene glycol (PEG). Transgenic seedlings grew significantly longer roots than wild-type ones did. Further enzymatic analysis showed an increased activity of superoxide dismutase (SOD) in transgenic seedlings. In addition, the level of malondialdehyde (MDA) was reduced in transgenics. qRT-PCR analysis showed altered expressions of several genes involved in the carotenoid biosynthesis in transgenic plants. These data results indicate that IbGGPS is involved in the biosynthesis of carotenoids in sweetpotato storage roots and likely associated with tolerance to osmotic stress.Sweetpotato highly produces carotenoids in storage roots. In this study, a cDNA encoding geranylgeranyl phyrophosphate synthase (GGPS), named  Carotenoids are widely produced in many plants and provide potent nutritional benefits to human and animal health. The biosynthetic pathway of carotenoids has gained relatively intensive investigations in different plants , 2. CaroGGPS cDNAs have been cloned from multiple plant species. A gene expression study using sunflower seedlings showed that the HaGGPS was expressed after 2 days of seed imbibition , 39ArabiIbGGPS gene was cloned from storage roots of sweetpotato. Subcellular localization, transgenic approach and metabolite analysis demonstrated its involvement in the biosynthesis of carotenoids. Transgenic plants showed its expression associated with an osmotic stress tolerance. These data will be instructional to future sweetpotato breeding for high production of carotenoids and stress-tolerant varieties.In conclusion, an


Antiphosphospholipid syndrome (APS) secundary to systemic lupus erythematosus (SLE) can be recognised in children with arterial or venous thrombosis. Amaurosis due to thrombosis of central retinal vene is rarely presenting manifestation of SLE with secondary APS.To present APS secundary to SLE with aggresive ophtalmological onset in 17 years old female.We report a patient with unilateral amaurosis due to thrombosis of central retinal vene. Amaurosis was a reason for her urgent admission at Ophtalmology. She was transferred to Pediatric rheumatology department as suspected SLE. The patient had rapidly developing disease. Eleven days after the attack of retinal vene thrombosis, she became febrile with malar rash, facial ulcer, neurological symptoms (right Mingazzini positive), arterial hypertension, haemathological abnormalities, proteinuria and immonological disorders. Head MRI-MRA was performed and suboclusion of left medial cerebral artery was found. The diagnosis of APS secundary to SLE was established.The patient significantly improved with aggresive immunosupresive and prompt anticoagulant therapy but ohtalmological complication have been improved slowly with uncertain prognosis.The patients with SLE related symptoms have to be reffered to rheumatologist immediately because APS secundary to SLE may have aggressive thrombotic onset and cause serious organs damages.None declared.


New extensive use of thoracic ultrasound (TUS) takes information also from physical acoustic phenomena that are not directly convertible into images of the human body.This tenNo evaluation on technical issues feasibly , no comparison of the results of TUS and those of a reference standard (i.e. CXR);Diagnostic access bias , bias from reader/training experience on CXR (no paediatric radiologists);Imaging analysis bias i.e. absence of preliminary definition of the methods for imaging (CXR) interpretation, selection bias (patients from birth to adult undergoing chest radiography for suspected community acquired pneumonia).


Optical mapping provides long-range information of the genome and can more easily identify large structural variations. The ability of optical mapping to assay long single DNA molecules nicely complements short-read sequencing which is more suitable for the identification of small and short-range variants. Direct use of optical mapping to study population-level genetic diversity is currently limited to microbial strain typing and human diversity studies. Nonetheless, optical mapping shows great promise in the study of plant trait development, domestication and polyploid evolution. Here we review the current applications and future prospects of optical mapping in the field of plant comparative genomics.Optical mapping has been widely used to improve  Optical mapping is a molecular technique that produces fingerprints of DNA sequences in order to construct genome-wide maps . The seqde novo genome assembly and identification of relatively large structural variants in genetic diversity studies. While optical mapping is readily available across a wide range of organisms including bacterial, fungi, plant and mammalian genomes [Optical mapping offers several unique advantages over traditional mapping approaches, including single molecule analysis and the ability to assay long DNA molecules  data support each other, but are both inconsistent with linkage maps, especially in heterochromatic regions where recombination is scarce [Similar to optical maps, genetic maps could be a useful guide in anchoring scaffolds and identifying assembly issues ,19. Howes scarce . Similars scarce . Genome s scarce ,20.Genome ‘upgrades’ , or improvement of genome assemblies are possible through the incorporation of the optical mapping information into existing sequences. For example, optical mapping was essential in upgrading the rice Nipponbare reference genome in several important ways ,18. FirsSimilar to rice, optical maps have been extensively used to improve the Medicago genome assembly starting with release version Mt3.5, and were helpful both during the chromosomal anchoring and to correct errors in the linkage maps ,22. To bOptical mapping can be very useful in assisting the assembly of polyploid and highly heterozygous plant genomes, which are notoriously difficult to assemble . Many plDespite recent progress in genome assembly methodologies, a significant portion of many genomes remains inaccessible to assembly by short sequencing reads . A comprde novo assembly is still challenging and large amounts of true SVs may be lost during the assembly process. For most organisms, the ‘reference’ genome only represents a single individual and requires substantial amount of investment for the initial genome assembly and subsequent finishing. Most assemblies can only reach ‘draft’ status, often containing a large number of sequence gaps and assembly errors that could easily show up as false SVs during sequence comparisons.Pairwise sequence alignments between assembled genomes remains one of the most powerful tools for plant comparative genomics, and could identify SVs with the best accuracy if the assemblies themselves were correctly reconstructed. However, Split reads at the same position could indicate genomic breakpoints derived from inversions, deletions and insertions. Discordant pairs reveal spacing difference due to deletions or insertions, or presence-absence variations (PAVs). Read depth variations can be used to identify copy number variations (CNVs) that are likely derived from tandem or segmental duplications  retrotransposon-mediated gene duplication [Some important agronomic traits are directly caused by structural variations which could be studied with a whole genome association framework across varieties or diversity panels. For example, the lication . Currentet al. uncovered large structural variants that are associated with selective sweeps in Arabidopsis lines from Sweden, based on a suite of methods from ‘manual’ detection of breakpoints to de novo assembly. They acknowledged that many polymorphisms may be complex and difficult to resolve using short-read sequencing data [In addition to agronomic traits, a wide range of studies in plants, including domestication, polyploidy, population history and natural selection could benefit from optical mapping. Long ing data . Re-sequing data , althougBrassica napus genome, an allotetraploid merged from two diploid Brassica genomes [The application of optical mapping could reveal structural changes following polyploidy events in plants that might be difficult to study using other techniques. Studies show that homeologous exchanges (HEs) occur frequently between subgenomes inside polyploid genomes and often involve large chromosomal segments. This was studied in the  genomes . Each HE genomes . While r genomes . The dirOptical mapping is an important technique that can provide long genomic linkage information in a high-throughput manner, which has substantially improved the assemblies of several important model plant genomes sequenced to date. Direct comparisons of genome structures have so far been lacking in plants, but optical mapping shows great promises at revealing genomic regions that are not easily accessible through conventional sequencing methods. Optical mapping could become an integral part of the mapping tools in the study of plant domestication, polyploid evolution, and trait development.


Here we used a well-characterized panel of lung cancer cell lines to develop the most comprehensive view of cancer cell metabolism to date.Cancer cells display oncogene-driven rewiring of metabolism to produce energy and macromolecules for growth. Inhibition of growth-promoting metabolic pathways may prove to be a useful therapeutic strategy in cancer. We previously identified distinct metabolic platforms that enabled cancer cells to produce macromolecular precursors from glucose and glutamine, the two most abundant nutrients. However, neither the full breadth of cancer cell metabolic diversity, nor the complement of mechanisms by which tumor mutations elicit metabolic reprogramming, are known. Because metabolic flux can be analyzed in vivo.81 non-small cell lung cancer cell lines were analyzed for a set of well-defined metabolic parameters. These cell lines were also subjected to extensive genomic, epigenetic, and gene expression analysis, and tested for sensitivity to chemotherapeutic agents and genome-wide siRNA screens. These rich data sets will streamline the establishment of novel correlations between metabolism and molecular/cell biological features. All cell lines were characterized for nutrient utilization, nutrient addiction, and focused flux assays to trace the metabolism of isotope-labeled glucose and glutamine in identical culture condition. Ongoing experiments are assessing metabolism of the same cells grown The 81 cell lines displayed surprising metabolic heterogeneity. Although all cells used glucose and glutamine to produce biosynthetic precursors, contributions of these two nutrients varied considerably, as did the pathways used. For individual isotopic labeling patterns, differences of >30-fold were observed across the panel. Unsupervised clustering produced two metabolic superfamilies differentiated by relatively glucose carbon contribution into precursor pools, as well as numerous subfamilies which may correlate to different metabolic pathways. Although KRAS-mutant cells were distributed across panel, the LKB1/KRAS co-mutation cells aggregated into the low-glucose m0 superfamily. Ongoing work will examine the ability of metabolic phenotyping to predict combinatorial mutations and vulnerabilities to drugs and siRNAs.Focused metabolic assays can produce a highly informative view of the metabolic phenotyping among large panels of cell lines. It describes an unparalleled view of the connections between genetics, drug sensitivity and cell-autonomous metabolism in NSCLC.


Using our experience of over 500 patients who have undergone pre-biopsy mpMRI  and subsequent transperineal saturation prostate biopsy, we aim to:• Illustrate the commonly overlooked areas in diagnosing prostate cancer with mpMRI.• Emphasise technical factors that can contribute to suboptimal image interpretation.• Highlight normal anatomical structures and non-cancerous abnormalities that mimic tumour.• Demonstrate the use of mpMRI to direct further management.mpMRI may be used in the pre-biopsy setting to determine type of biopsy , and predict biopsy outcome to the extent that biopsies may be avoided altogether. Tumour localisation within the prostate gland aids targeted biopsy and influences treatment . Tumours with unusual appearances and those in uncommon sites hinder MRI interpretation, potentially leading to false-negative or –positive findings. These areas of pitfall can be divided into normal anatomical structures in the peripheral or transitional zones or non-cancerous abnormalities that mimic tumours (e.g. granulomatous prostatitis).It is also important to acknowledge that mpMRI itself has limitations. Technical challenges in relation to DWI may lower tumour sensitivity due to anatomical distortion, inadequate suppression of benign prostate tissue and suboptimal ADC map windowing.It is paramount that radiologists are aware of the commonly missed locations of prostate cancer, tumour mimics and the limitations of mpMRI, particularly in the context of a multidisciplinary team setting. This would serve to improve diagnostic accuracy, target areas for biopsy more precisely and correctly influence management.