Frequent Overlap Research Articles

Global survey of malaria rapid diagnostic test (RDT) sales, procurement and lot verification practices: assessing the use of the WHO\u2013FIND Malaria RDT Evaluation Programme (2011\u20132014)

BackgroundMalaria rapid diagnostic tests (RDTs) play a critical role in malaria case management, and assurance of quality is a key factor to promote good adherence to test results. Since 2007, the World Health Organization (WHO) and the Foundation for Innovative New Diagnostics (FIND) have coordinated a Malaria RDT Evaluation Programme, comprising a pre-purchase performance evaluation (product testing, PT) and a pre-distribution quality control of lots (lot testing, LT), the former being the basis of WHO recommendations for RDT procurement. Comprehensive information on malaria RDTs sold worldwide based on manufacturers’ data and linked to independent performance data is currently not available, and detailed knowledge of procurement practices remains limited.MethodsThe use of the PT/LT Programme results as well as procurement and lot verification practices were assessed through a large-scale survey, gathering product-specific RDT sales and procurement data (2011–14 period) from a total of 32 manufacturers, 12 procurers and 68 National Malaria Control Programmes (NMCPs).ResultsManufacturers’ reports showed that RDT sales had more than doubled over the four years, and confirmed a trend towards increased compliance with the WHO procurement criteria (from 83% in 2011 to 93% in 2014). Country-level reports indicated that 74% of NMCPs procured only ‘WHO-compliant’ RDT products, although procurers’ transactions datasets revealed a surprisingly frequent overlap of different products and even product types (e.g., Plasmodium falciparum-only and Plasmodium-pan) in the same year and country (60 and 46% of countries, respectively). Importantly, the proportion of ‘non-complying’ (i.e., PT low scored or not evaluated) products was found to be higher in the private health care sector than in the public sector (32% vs 5%), and increasing over time (from 22% of private sector sales in 2011 to 39% in 2014). An estimated 70% of the RDT market was covered by the LT programme. The opinion about the PT/LT Programmes was positive overall, and quality of RDTs as per the PT Programme was rated as the number one procurement criteria.ConclusionsThis survey provided in-depth information on RDT sales and procurement dynamics, including the largely unstudied private sector, and demonstrated how the WHO–FIND Programme has positively influenced procurement practices in the public sector.

Exaggerated Sexual Swellings and the Probability of Conception in Wild Sanje Mangabeys (Cercocebus sanjei)

Females of several catarrhine primate species exhibit exaggerated sexual swellings that change in size and coloration during the menstrual cycle and, in some species, gestation. Although their function remains under debate, studies indicate that swellings may contain information males could use to discern ovulation and the probability that a cycle will be conceptive. Here we combine visual ratings of swellings with hormonal data for a group of Sanje mangabeys (18 adult, 3 adolescent females) to determine if their swellings provide reliable information on female fertility. In all cases where ovulation was detected (N = 7), it occurred during maximum tumescence, and in 83.3% during the first two days of the “shiny phase,” a period during maximum tumescence when the swelling was brightest. There were no significant differences in maximum tumescence and shiny phase duration among cycles of different probability of conception, although there was a trend toward conceptive cycles exhibiting shorter shiny phases than nonconceptive ones. Only 25% (N = 4) of postconceptive swellings developed the shiny phase, and adolescents displayed the longest maximum tumescence and shiny phases. The conspicuous nature of the shiny phase and the frequent overlap between its onset and ovulation suggest that its presence serves as a general signal of ovulation and that the cycle has a high probability of being conceptive. It also suggests that swellings in some Sanje mangabeys are more accurate signals of fertility than in other primates.

Tu1118 - Frequent Clinicopathologic Overlap Precludes an Accurate Distinction Between Eosinophilic Esophagitis and Gastroesophageal Reflux Disease

Tu1118 - Frequent Clinicopathologic Overlap Precludes an Accurate Distinction Between Eosinophilic Esophagitis and Gastroesophageal Reflux Disease

Paradigms in chronic obstructive pulmonary disease: phenotypes, immunobiology, and therapy with a focus on vascular disease

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous syndrome that represents a major global health burden. COPD phenotypes have recently emerged based on large cohort studies addressing the...

Human Papillomavirus Genotyping of Incidental Malignant and Premalignant Lesions on Hemorrhoidectomy Specimens.

Routine histopathologic examination of hemorrhoidectomy specimens is controversial having been described as not useful and expensive with few of these common cases demonstrating incidental lesions. However, unexpected premalignant and malignant lesions have been detected on excised hemorrhoids. The high-risk human papillomavirus (HR-HPV) types associated with these incidentally identified high-grade lesions are presently unknown. We aimed to identify cases of incidental high-grade anal intraepithelial neoplasia (HG-AIN) and anal squamous cell carcinoma incidentally discovered on hemorrhoidectomy specimens, genotype HR-HPVs from these lesions, and assess p53 and p16 expression by immunohistochemistry to identify risk factors for their development. With institutional approval, cases with associated demographics from 1995 to 2015 were reviewed to identify and confirm incidental HG-AIN or squamous cell carcinoma in hemorrhoidectomy specimens. Genotyping for HR-HPV types and immunohistochemical staining for p53 and p16 was performed. Statistical analysis comparing HPV genotypes, p53 and p16 staining, and potential risk factors by the Fisher exact test was performed. In the largest series of incidental high-grade lesions on hemorrhoidectomy, HPV 16 was the most common HR-HPV detected though multiple-type infections were common including some HPV 16/18-negative cases. By genotyping, HPV 39 was significantly associated with IV-drug abuse history (P=0.0015) and HIV-positive status (P=0.037), whereas HPV 58 detection correlated with chemotherapy-induced immunosuppression (P=0.029). There was frequent overlap between p53 staining and HPV positivity, particularly when HPV 31 was detected. We also identified several mimickers of HG-AIN that may present diagnostic challenges in these specimens. Our data support continued routine examination of hemorrhoidectomy specimens and suggest that adjunctive studies such as immunohistochemistry for challenging cases may be useful.

Computed tomography angiography versus angiography for guiding percutaneous coronary interventions in bifurcation lesions – A prospective randomized pilot study

BackgroundThere is no data on the impact of coronary computed tomography angiography (coronary CTA), as an addition to angiography, on the outcomes of percutaneous coronary interventions (PCI) in bifurcation lesions. MethodsPatients with stable coronary artery disease scheduled for elective bifurcation PCI were randomized 1:1 to planning the procedure based on coronary CTA and angiography (CTA group) or angiography alone (CA group). The primary efficacy endpoint was the immediate angiographic result. Secondary efficacy endpoints were: a) procedural characteristics and b) postprocedural fractional flow reserve (FFR) in the side branch (SB) in a subgroup of patients. Safety outcomes were: a) periprocedural myocardial infarction, b) contrast use and c) radiation dose. ResultsPCI of 45 lesions in the CTA group and 47 lesions in the CA group was performed. Postprocedural lumen diameters in the main branch (MB) and SB, frequency of SB compromise or occlusion and mean SB FFR values were not different between study groups. Two or more stents were implanted less frequently in the CTA group than in the CA group (18% vs. 43%, p = 0.01). This difference was driven by less frequent MB 2-stent overlap in the CTA group (7 vs. 21%, p = 0.046) and numerically less SB stenting (11% vs. 21%, p = 0.07). Proximal optimization technique was used more frequently in the CTA group (44% vs. 21%, p = 0.018). ConclusionsCTA-assisted bifurcation PCI leads to similar immediate results compared with angiography alone, however is associated with higher use of single-stent procedures with proximal optimization, less frequent 2-stent overlap and less SB stenting.

The Effect of Peripheral CRF Peptide and Water Avoidance Stress on Colonic and Gastric Transit in Guinea Pigs.

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common gastrointestinal (GI) diseases; however, there is frequent overlap between FD and IBS patients. Emerging evidence links the activation of corticotropin releasing factor (CRF) receptors with stress-related alterations of gastric and colonic motor function. Therefore, we investigated the effect of peripheral CRF peptide and water avoidance stress (WAS) on upper and lower GI transit in guinea pigs. Dosages 1, 3, and 10 µg/kg of CRF were injected intraperitoneally (IP) in fasted guinea pigs 30 minutes prior to the intragastric administration of charcoal mix to measure upper GI transit. Colonic transits in non-fasted guinea pigs were assessed by fecal pellet output assay after above IP CRF doses. Blockade of CRF receptors by Astressin, and its effect on GI transit was also analyzed. Guinea pigs were subjected to WAS to measure gastrocolonic transit in different sets of experiments. Dose 10 µg/kg of CRF significantly inhibited upper GI transit. In contrast, there was dose dependent acceleration of the colonic transit. Remarkably, pretreatment of astressin significantly reverses the effect of CRF peptide on GI transit. WAS significantly increase colonic transit, but failed to accelerate upper GI transit. Peripheral CRF peptide significantly suppressed upper GI transit and accelerated colon transit, while central CRF involved WAS stimulated only colonic transit. Therefore, peripheral CRF could be utilized to establish the animal model of overlap syndrome.

Is local produce more expensive? Challenging perceptions of price in local food systems

ABSTRACTThis research examines price in local food systems to identify whether the perception that local is more expensive is justified. This study seeks to contribute to the field by addressing the dearth of quantitative price and availability research and building upon existing empirical research by considering a broader range of distribution channels and organic produce. Without a stronger understanding of pricing structures and distribution models, local food initiatives are based on assumptions rather than evidence. Using a case-study approach of the Region of Waterloo (Ontario, Canada), price and product data were collected at 11 outlets over a 6-month period. The study involved regression analysis of six locally produced fruits and vegetables based on local, Ontario, and organic attributes associated with the products and comparison with consumer willingness-to-pay research. Results show that local produce in the case study is not consistently more expensive than the non-local option. Both price discounts and premiums are found, depending on the product. These findings challenge the “local is more expensive” assumption and support suggestions that local food systems can be spaces for social inclusion. The organic attribute is associated with a price premium in all cases and may create confusion among consumers given frequent overlap between the local and organic attributes. Proponents of local food can use the results of this study to inform programme and policy development. Most notably, the study suggests that education around the distinction between local and organic as well as challenges to the price perception could be of benefit.

Frequent Clinical Overlap of Histiocytic Neoplasms and WHO-Classified Myeloid Malignancies Leads to Functional Insights into the Cell-of-Origin of Histiocytoses

The identification of mutations in BRAFV600E and other kinases in systemic histiocytoses changed our understanding of the pathophysiology of these disorders from inflammatory non-malignant conditions to clonal disorders driven by altered MAP kinase signaling. In addition, BRAFV600E mutations have recently been noted in bone marrow (BM) CD34+ cells of patients with Langerhans Cell Histiocytosis (LCH), suggesting that LCH represents a clonal disorder arising from hematopoietic stem/progenitor cells (HSPCs). However, it is unknown if HSPCs from LCH or other histiocytoses patients can functionally give rise to these disorders. Moreover, whether or not patients with histiocytosis have additional hematological disorders related to the presence of HSPC-based mutations is unclear. Here we attempted to understand the spectrum of hematological disorders in patients with histiocytoses and the cell-of-origin of histiocytic neoplasms by functionally analyzing HSPCs from histiocytoses patients.We first analyzed a multicenter cohort of 190 adult histiocytoses patients. This unexpectedly identified a high frequency of patients with a co-existing myeloid malignancy. Of the 190 patients, 9.5% (18/190) were diagnosed with Erdheim-Chester Disease (ECD) and/or LCH concomitantly with a classic MPN (3.7%; 7/190), MPN/MDS overlap (4.7%; 9/190), or MDS (1.1%; 2/190) (Figure). This clinical observation was confirmed by detection of co-existing histiocytoses-associated kinase mutations (including BRAF, MAP2K1, NRAS, or KRAS mutations) with JAK2 or CALR mutations, as well as other mutations recurrently found in myeloid malignancies (such as IDH1/2, ASXL1, and TET2 mutations (Figure)). These data therefore reveal a heretofore-unrecognized clinical overlap of adult-onset systemic histiocytoses and WHO-classified myeloid malignancies while further highlighting the possibility of an aberrant HSPC origin for histiocytic neoplasms. In most cases, the BRAF/MAP2K1/RAS mutation predominated in the histiocytic lesion while the JAK2/CALR mutation predominated in the BM/peripheral blood suggesting likely distinct clones driving each clinical condition.Next, to test the self-renewal and differentiation capacity of HSPCs from histiocytoses patients, CD34+ cells were purified from 8 patients including 6 with ECD or LCH plus a concomitant myeloid neoplasm, and 2 with ECD alone. 0.1-0.8x106 CD34+ cells from each patient were transplanted by intrafemoral injection into sublethally irradiated NOD/SCID IL2Rγ transgenic human GM-CSF, IL-3, and SCF expressing (NSG-SGM3) mice. Human engraftment was monitored by monthly flow cytometric analysis of peripheral blood until mice became moribund. Thereafter, animals were sacrificed and tissues were analyzed using flow cytometry, histology, immunohistochemistry, and sequencing analyses to detect driver mutations identified in the histiocytosis/co-occurring myeloid neoplasm.Successful engraftment of human myeloid cells was verified in grafts generated from 2/8 patients after a mean of 90 days (range: 60-120 days). This included lethal engraftment of KRAS-mutated ECD patient cells at 90 days manifested by infiltration of human hCD45+ cells co-expressing human myeloid and monocyte lineage markers hCD33 and hCD14 in the bone marrow, spleen, liver, lung, and kidney (Figure). Immunostains revealed that tissues were infiltrated by an hCD45+hCD163+hCD68+ population of foamy histiocytes, characteristic of ECD (Figure). Furthermore, genomic analysis of DNA from the engrafted animals BM and spleen revealed the same KRASG12S mutation found in the donor patients ECD lesion. Engraftment of a patient diagnosed with concomitant BRAFV600E-mutant ECD and ASXL1/TET2-mutant CMML was seen at 60 days. In this case, however, only engraftment of human CMML was detected without evidence of the BRAFV600E-mutant ECD component.This study suggests that adult histiocytic neoplasms frequently co-occur with other myeloid neoplasms. Moreover, histiocytosis disease-driver mutations are present in the CD34+ HSPCs, which we show for the first time can initiate disease that resembles human histiocytosis in a patient-derived xenograft. Importantly, however, even though the CD34+ compartment gives rise to both the histiocytic and myeloid neoplasm disease component, each disease is likely initiated by distinct precursors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS.

Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and idiopathic transverse myelitis (ITM). Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF) metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls). Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

Neural changes associated to procedural learning and automatization process in Developmental Coordination Disorder and/or Developmental Dyslexia.

Recent theories hypothesize that procedural learning may support the frequent overlap between neurodevelopmental disorders. The neural circuitry supporting procedural learning includes, among others, cortico-cerebellar and cortico-striatal loops. Alteration of these loops may account for the frequent comorbidity between Developmental Coordination Disorder (DCD) and Developmental Dyslexia (DD). The aim of our study was to investigate cerebral changes due to the learning and automatization of a sequence learning task in children with DD, or DCD, or both disorders. fMRI on 48 children (aged 8-12) with DD, DCD or DD+DCD was used to explore their brain activity during procedural tasks, performed either after two weeks of training or in the early stage of learning. Firstly, our results indicate that all children were able to perform the task with the same level of automaticity, but recruit different brain processes to achieve the same performance. Secondly, our fMRI results do not appear to confirm Nicolson and Fawcett's model. The neural correlates recruited for procedural learning by the DD and the comorbid groups are very close, while the DCD group presents distinct characteristics. This provide a promising direction on the neural mechanisms associated with procedural learning in neurodevelopmental disorders and for understanding comorbidity.

Mikrostruktura in lastnosti visoko temperaturnega območja zvara (HAZ) termo-mehansko obdelanega jekla S700MC z visoko mejo plastičnosti

The aim of the study was to determine the properties and microstructure of the high-temperature heat affected zone (HAZ) of S700MC steel heated to a temperature of 1250 °C and cooled at different speeds. The simulation of the thermal cycles was performed using a welding thermal cycles simulator. Samples with a cross-section 10 mm × 10 mm × 55 mm were submitted to metallographic analysis, impact tests, hardness measurements and tensile tests. Welding thermal cycles with cooling times t8/5 = (3, 5, 10, 15, 30, 60 and 120) s and a maximum temperature cycle temperature of Tmax = 1250 °C were used. The welding thermal thermomechanical processing cycles differ significantly, especially with high rates of heating and cooling in the SWC, short time holding at the maximum temperature and frequent overlap of two or more cycles during the multi-layer welding. One of the elements in the evaluation of steel weldability is the analysis of the austenite phase transformation during cooling. Steel hardness tests on simulated HAZ regions cooling times increasing from 3 s to 120 s, showed reductions by approximately 40 HV, while, regardless of the length of the cooling time t8/5, the impact resistance was very low, at the level of a few J/cm. The tensile strength, hardness and toughness indicates a secondary role of austenite in the control of welded joints transformation strength and plastic properties, the analysis of the phase transition not shown to be a reliable basis for assessment of the weldability of this steel group.

Approaches to the Diagnosis and Treatment of OCD with Comorbid Tic Disorders

Bidirectional overlap has long been described between obsessive–compulsive disorder (OCD) and tic disorders. Similar features, including underlying neurobiological genesis in frontal-striatal circuitry, familiality, relatively early onset, waxing and waning course, and overlapping phenomenology in repetitive behaviors, suggest different variations of the same disorder. Nevertheless, some differences have been described between OCD and tic disorders: tics begin early in childhood and typically attenuate or remit by late adolescence, whereas OCD tends to onset later and persist, and tic disorders are far more common in males than is the case in OCD. Individuals with OCD plus comorbid tics may represent a specific sub-type of OCD or tic disorders, and possess some important phenomenological differences from those with OCD without tics; for example, tic-related OCD tends to have earlier onset, higher prevalence in males, prominent symmetry, evening-up, counting, and “just-right” phenomenology, when compared with non-tic-related OCD. Recent DSM-5 classification changes now recognize presence of tics as a specifier in diagnosis of OCD; despite a 40 % prevalence rate of comorbid tics in childhood-onset OCD, there is still little data regarding risk factors, validated distinguishing features, course and treatment of this diagnostic group. Prominence of premonitory sensory phenomena, urges or sensations experienced prior to the repetitive behaviors, is no longer thought to distinguish complex motor tics from compulsions. Well established treatments of OCD include cognitive behavioral interventions and pharmacotherapy, specifically the serotonin re-uptake inhibitors (SRIs); although these treatments are also beneficial in tic-related OCD, some studies suggest that at least for pharmacotherapy, SRIs may not be as effective in OCD patients with comorbid tics. Given the frequent overlap of OCD and tics, and the recent designation of tic-related OCD as an OCD specifier, more investigation of the comorbid subtype is clearly needed.

The Vampire Goes to College: Essays on Teaching with the UndeadLisa A.Nevárez, Editor. Jefferson: McFarland, 2014.

Vampire Goes to College: Essays on with the Undead Lisa A. Nevarez, Editor. Jefferson: McFarland, 2014.There's no denying that are popular; one only has to browse book shelves, flip channels, or watch the previews for upcoming films to see a plethora of vampire stories. Incorporating these popular culture into college courses has a history of promoting engagement and enrollment. television show Buffy the Vampire Slayer and its spin-off Angel have been analyzed extensively and taught at the collegiate level along with the more traditional texts like Bram Stoker's Dracula and the film Nosferatu. However, students are quick to point out that even a show as recent as Buffy is old by their standards. Vampire Goes to College does mention these works, but the greater focus is on including more contemporary vampires, such as are found in HBO's Tru Blood, the CW's Vampire Diaries, and the Twilight series of books and films. historical vampire is not ignored, but the contemporary texts are the main focus as they are considered more accessible and engaging to students. Lisa A Nevarez writes in the Introduction that, The of the vampire is a notable example of an exciting way to catch students at their most eager and to share with them the manifold ways academics discourse about that very figure (6). With this worthy goal in mind, the essays within Vampire Goes to College showcase examples of courses that incorporate vampire literature to promote student interaction with new material or even familiar works in new manners in order to increase engagement in the classroom.The Vampire Goes to College is designed to provide insight for instructors looking to include vampire literature in courses. idea that students have an existing interest in the subject is the foundation for many of the approaches included in the book, for as Leslie Ormandy states at the beginning of her essay, Students love vampires (204). essays cover multiple types of courses at varying levels of study and are organized into five sections based on approaches to the texts: Teaching the Historical Vampire, Teaching the Diverse Vampire, Writing the Vampire, Teaching the Textual Vampire, and Engaging the Student. There is frequent overlap of texts and concepts between the sections, particularly relating to encouraging stu dent research and engagement. variety of approaches from different perspectives provides a wealth of information for teachers in different disciplines. …

A Graph-Based Digital Pathology Approach To Describe Lymphocyte Clustering Patterns After Renal Transplantation

Introduction/ Background Renal transplantation (rTx) induces an adaptive immune response against foreign donor antigens mediated by lymphocytes of the recipient. Local accumulation of B- and T-cells is an important component of this response enabling and controlling immune cell interactions [1]. Combining digital microscopic images with network analysis [2][3] opens new perspectives to study the spa- tial dimension of lymphocyte clustering and to model their potential interactions. Aims The aim of this study is to characterize the range of B- and T-lymphocytic infiltrates below the threshold of rejection defined by theBanffclassification [4][5] and to propose a mathematical description of immune cell clustering for use in systems medicine approaches. Methods We established a workflow to comprehensively characterize lymphocyte clusters and compare their morphological features with organized structures such as secondary or tertiary lymphoid organs (TLO/SLO) [6]. 51 renal protocol and indication biopsies from 13 patients without evidence for severe rejection over 10 years were stained by CD3/CD20 duplex immunohisto- chemistry. Whole slide images (WSIs) were acquired to automatically detect biologically relevant regions of in- terest (ROIs) by means of density maps for lymphocytes (image analysis workflow illustrated in Fig. 1a). They are generated from single nuclei identification using an au- to-adaptive random forest pixelwise classifier (“nucleus container” module [7],Definiens,Germany). We imple- mented a graph-based tool in Java using individual cell coordinates to identify cell compartments (Fig. 1b) and applied it to each selected ROI. For this, a neighborhood graph is built by Delaunay triangulation and Euclidean distances. This analysis allows describing their specific clustering behavior based on features as described in [8]. The convex hull of the neighborhood graph allows a visualization of B- and T-cell compartments. Results We identified B-cell rich compartments in about 55% of 150 ROIs in kidney tissue after successful transplantation (examples in Fig. 2). The B-cell compartments in rTx tended towards smaller overall size with on average about 90 cells in a B-cell cluster compared to more than 600 B-cells observed in mature TLOs and SLOs and they showed less prominent spatial organization (average degree on average 3.92 instead of 4.97; degree shows generally Poisson distribution as illustrated in Fig. 3A). Further, the graph analysis confirmed lower B-cell density (Fig. 3B displays the exponential character of the spatial B-cell distribution in a selected ROI), a different ratio between T- and B-cell compartments, and more frequent overlap between both regions than in mature lymphoid structures. We conclude that the graph-based approach is feasible to distinguish relevant immune cell patterns in rTx and provides a useful mathematical description of neighborhood relationships between immune cells and their spatial organization. The workflow has the potential to improve throughput and robustness of immune cell evaluation for use in translational science.

Functional connectivity underpinnings of fatigue in “drug-naïve” patients with Parkinson's disease

Objective: fatigue is a common problem in patients with Parkinson's disease (PD) (1). Despite its clinical relevance, our understanding of fatigue pathophysiology is limited due to the frequent overlap with other confounding non motor symptoms (2) and the lack of structural or functional MRI studies. The aim if this study was, using resting-state (RS) fMRI, to investigate the functional correlates of fatigue in a restricted cohort of “drug-naïve” PD patients, with no depression, sleepiness and cognitively unimpaired.

Abstract 19386: The Mitochondrial Deacetylase Sirtuin 3 (sirt3) is Important in the Pathogenesis of Both Pulmonary Hypertension and Pulmonary Fibrosis: Potential for an “Overlap Syndrome” and a Common Therapy?

Introduction: Pulmonary arterial hypertension (PAH) is often associated with interstitial lung disease, like idiopathic pulmonary fibrosis (IPF). IPF pulmonary fibroblasts have a very similar pro-proliferative and anti-apoptotic phenotype similar to PAH vascular smooth muscle cells (SMC). As this phenotype is often associated with a cancer-like mitochondrial suppression, we hypothesized that a common mitochondria abnormality may underlie both PAH and IPF. We speculated that the loss of the mitochondrial deacetylase Sirt3, which we recently showed promotes PAH, will also promote IPF. Results: SIRT3 expression was decreased in human IPF-PH lungs (transplant recipients, n=7) and in Sirt3 wild type (Sirt3WT)+ bleomycin BLEO lungs (n=15 for each) and fibroblasts compared to healthy lungs (unused transplant tissue, n=3) and Sirt3WT. Sirt3 knockout (Sirt3KO) fibroblasts, like Sirt3WT+BLEO, had decreased mitochondrial function assessed by decreased pyruvate dehydrogenase activity, decreased respiration (Seahorse Assay) and increased mitochondrial membrane potential (TMRM dye in live cell imaging). Sirt3KO and Sirt3WT+BLEO fibroblasts had increased collagen production and smooth muscle actin expression (immunoblot). All of these findings are very similar to those in pulmonary artery SMCs from the same Sirt3KO animals, which develop spontaneous PAH. In vivo, Sirt3KO mice treated with BLEO developed worse IPF than Sirt3WT+BLEO (dynamic resistance 2±0.5 vs 1.4±0.2cmH2O.s/mL, dynamic elastance 20±3 vs 38±10cmH2O/mL). Intra-tracheal delivery of an adenovirus overexpressing SIRT3 improved both Sirt3KO+BLEO and Sirt3WT+BLEO compared to GFP-only adenovirus. We have previously showed that the same virus reverses PAH in rodents. Conclusion: Sirt3 downregulation plays an important role in the development of IPF. While the exact mechanisms by which Sirt3 is downregulated remains to be established, this work opens new perspectives for the treatment of IPF. Given the frequent overlap of IPF and pulmonary hypertension in the same patients, our data suggest the intriguing possibility that they both represent aspects of an “overlap syndrome”, which may benefit from similar therapeutic approaches, despite the differences in the “cell of origin”.

Sensory modulation disorders in childhood epilepsy.

BackgroundAltered sensory sensitivity is generally linked to seizure-susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders.MethodsWe used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4–17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire).ResultsSensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory “sensitivity,” “sensory avoidance,” and “poor registration” but not “sensory seeking.” Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder.ConclusionsSensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy.

Updates in the approach to intrathoracic sarcomas.

Primary intrathoracic sarcomas constitute a rare, heterogeneous group of neoplasms that occur in the lung parenchyma, pleura, and mediastinum. Although pathologically diverse, they frequently show similar clinical and radiological features, and accurate histopathological diagnosis is therefore crucial for correct management and prognostication. The characterization of sarcomas can be difficult, as there is frequent overlap between the histological patterns of benign and malignant lesions, and between different malignant tumours and with non-mesenchymal neoplasms. This is particularly critical within the thorax, where many spindle cell neoplasms represent tumours of epithelial origin or metastatic disease. Immunohistochemistry and molecular genetic techniques are important ancillary contributors to histological interpretation, but several groups of tumours still lack reliable immunohistochemical markers or reproducible genetic changes. We review the pathology of the major types of intrathoracic sarcoma with reference to clinical factors, morphology, immunohistochemistry, and molecular genetics.

Evaluation of Molecular and Immunohistochemical Adjunct Modalities in the Diagnosis of Soft Tissue Neoplasms.

The accurate diagnosis of soft tissue neoplasms has crucial therapeutic and prognostic importance. There is frequent morphologic overlap between entities, and ancillary modalities are used in the vast majority of diagnoses. Immunohistochemistry is rapid and inexpensive, and in addition to the older markers that mainly detected cytoplasmic proteins, antibodies can indirectly detect tumor-specific genetic and molecular abnormalities. The use of molecular diagnostic techniques is now widespread, with molecular services often integrated into routine histopathology laboratories; as their cost and turnaround times begin to parallel those for immunohistochemistry, we compared the usefulness of ancillary immunohistochemistry, molecular genetic, and molecular cytogenetic techniques in the diagnosis of soft tissue lesions. We evaluated the number and contribution of immunohistochemical tests and panels and of ancillary molecular techniques in the primary histopathologic diagnosis of 150 soft tissue lesions. Ninety of 150 cases required either only one immunohistochemical panel or minimal immunohistochemistry for diagnosis, while 39/150 required 2 to 4 panels. In 5/150, ancillary molecular tests alone (without immunohistochemistry) were diagnostically sufficient. The majority of cases required one immunohistochemical panel for diagnosis, with a smaller proportion requiring a second, and a minority requiring a third or fourth (which mainly comprised neoplasms for which the final diagnosis was uncertain). Certain neoplasms required both extensive immunohistochemistry and ancillary molecular testing, despite which the final diagnosis was inconclusive. Ancillary molecular techniques now make a significant contribution to soft tissue tumor diagnosis, being required in over one third (52/150) of cases, and were useful in confirming or excluding tumors that were not possible to conclusively diagnose with histology and immunohistochemistry. Only a small proportion of soft tissue neoplasms (16/150; all benign) did not require immunohistochemistry or ancillary molecular methods, with morphology alone being sufficient for diagnosis.