Showing papers by "Charité published in 2011"
Edinburgh Royal Infirmary1, University of St. Gallen2, Charité3, Sahlgrenska University Hospital4, University of Texas MD Anderson Cancer Center5, University of Alberta6, Mayo Clinic7, McGill University8, University of Cagliari9, Cleveland Clinic10, Sapienza University of Rome11, Nottingham University Hospitals NHS Trust12
TL;DR: A framework exists on a framework for the definition and classification of cancer cachexia, a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.
Abstract: Summary To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] 2 ) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages—precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.
3,548 citations
Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
2,511 citations
TL;DR: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.
Abstract: A B S T R AC T BACKGROUND Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS We randomly assigned 410 patients who had advanced, low-grade or intermediategrade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. Results The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). Conclusions Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)
2,357 citations
TL;DR: Meta-analyses of all data provided compelling evidence that ABCA7 and the MS4A gene cluster are new Alzheimer's disease susceptibility loci and independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance.
Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).
1,771 citations
St James's University Hospital1, University College London2, Paris Descartes University3, Oslo University Hospital4, University of British Columbia5, University of Valencia6, Charité7, University of Duisburg-Essen8, Edinburgh Cancer Research Centre9, University of Copenhagen10, University of Helsinki11, Laval University12, University of Leeds13, Medical Research Council14, Cambridge University Hospitals NHS Foundation Trust15, Princess Margaret Cancer Centre16
TL;DR: In patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months, higher than the average for women with ovarian cancer.
Abstract: A B S T R AC T Background Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. Methods We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 addi tional cycles or until progression of disease. Outcome measures included progressionfree survival, first analyzed per protocol and then updated, and interim overall survival. Results
1,752 citations
TL;DR: In this paper, the authors developed guidelines for reporting reliability and agreement studies in interrater and intra-arater reliability and agreements, and proposed 15 issues that should be addressed when reporting such studies.
1,605 citations
TL;DR: Recommendations for the prevention and management of venous thrombo-embolism in pregnancy and puerperium and the associated risk groups according to risk factors: definition and preventive measures are presented.
Abstract: Table 1. Classes of recommendation
Table 2. Levels of evidence
Table 3. Estimated fetal and maternal effective doses for various diagnostic and interventional radiology procedures
Table 4. Predictors of maternal cardiovascular events and risk score from the CARPREG study
Table 5. Predictors of maternal cardiovascular events identified in congential heart diseases in the ZAHARA and Khairy study
Table 6. Modified WHO classification of maternal cardiovascular risk: principles
Table 7. Modified WHO classification of maternal cardiovascular risk: application
Table 8. Maternal predictors of neonatal events in women with heart disease
Table 9. General recommendations
Table 10. Recommendations for the management of congenital heart disease
Table 11. Recommendations for the management of aortic disease
Table 12. Recommendations for the management of valvular heart disease
Table 13. Recommendations for the management of coronary artery disease
Table 14. Recommendations for the management of cardiomyopathies and heart failure
Table 15. Recommendations for the management of arrhythmias
Table 16. Recommendations for the management of hypertension
Table 17. Check list for risk factors for venous thrombo-embolism
Table 18. Prevalence of congenital thrombophilia and the associated risk of venous thrombo-embolism during pregnancy
Table 19. Risk groups according to risk factors: definition and preventive measures
Table 20. Recommendations for the prevention and management of venous thrombo-embolism in pregnancy and puerperium
Table 21. Recommendations for drug use
ABPM
: ambulatory blood pressure monitoring
ACC
: American College of Cardiology
ACE
: angiotensin-converting enzyme
ACS
: acute coronary syndrome
AF
: atrial fibrillation
AHA
: American Heart Association
aPTT
: activated partial thromboplastin time
ARB
: angiotensin receptor blocker
AS
: aortic stenosis
ASD
: atrial septal defect
AV
: atrioventricular
AVSD
: atrioventricular septal defect
BMI
: body mass index
BNP
: B-type natriuretic peptide
BP
: blood pressure
CDC
: Centers for Disease Control
CHADS
: congestive heart failure, hypertension, age (>75 years), diabetes, stroke
CI
: confidence interval
CO
: cardiac output
CoA
: coarction of the aorta
CT
: computed tomography
CVD
: cardiovascular disease
DBP
: diastolic blood pressure
DCM
: dilated cardiomyopathy
DVT
: deep venous thrombosis
ECG
: electrocardiogram
EF
: ejection fraction
ESC
: European Society of Cardiology
ESH
: European Society of Hypertension
ESICM
: European Society of Intensive Care Medicine
FDA
: Food and Drug Administration
HCM
: hypertrophic cardiomyopathy
ICD
: implantable cardioverter-defibrillator
INR
: international normalized ratio
i.v.
: intravenous
LMWH
: low molecular weight heparin
LV
: left ventricular
LVEF
: left ventricular ejection fraction
LVOTO
: left ventricular outflow tract obstruction
MRI
: magnetic resonance imaging
MS
: mitral stenosis
NT-proBNP
: N-terminal pro B-type natriuretic peptide
NYHA
: New York Heart Association
OAC
: oral anticoagulant
PAH
: pulmonary arterial hypertension
PAP
: pulmonary artery pressure
PCI
: percutaneous coronary intervention
PPCM
: peripartum cardiomyopathy
PS
: pulmonary valve stenosis
RV
: right ventricular
SBP
: systolic blood pressure
SVT
: supraventricular tachycardia
TGA
: complete transposition of the great arteries
TR
: tricuspid regurgitation
UFH
: unfractionated heparin
VSD
: ventricular septal defect
VT
: ventricular tachycardia
VTE
: venous thrombo-embolism
WHO
: World Health Organization
Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes but are complements for textbooks and cover the European Society of Cardiology (ESC) Core Curriculum topics. Guidelines and recommendations should help the …
1,502 citations
Wellcome Trust Sanger Institute1, Université de Montréal2, University of Edinburgh3, University of Kiel4, Karolinska Institutet5, Cedars-Sinai Medical Center6, University of Cambridge7, University of Pennsylvania8, Casa Sollievo della Sofferenza9, University of Pittsburgh10, Université libre de Bruxelles11, University of Otago12, Johns Hopkins University13, Ludwig Maximilian University of Munich14, Charité15, Lille University of Science and Technology16, Cincinnati Children's Hospital Medical Center17, Ghent University18, Torbay Hospital19, University of Groningen20, Mater Health Services21, University of Liège22, University of Washington23, University of Utah24, QIMR Berghofer Medical Research Institute25, University of Paris26, University of Western Australia27, Tel Aviv University28, University of Dundee29, Harvard University30, University of Manchester31, Utrecht University32, University of Florence33, King's College London34, Yale University35, Royal Hospital for Sick Children36, Katholieke Universiteit Leuven37, Guy's and St Thomas' NHS Foundation Trust38, University of Barcelona39, University of Chicago40, University of Bern41, Agency for Science, Technology and Research42, University of California, San Francisco43, University of Toronto44, University of Oslo45, Leiden University46, University of Amsterdam47, Aarhus University48, National and Kapodistrian University of Athens49, Lithuanian University of Health Sciences50, Newcastle University51, Emory University52, Örebro University53, French Institute of Health and Medical Research54, Center for Applied Genomics55
TL;DR: A meta-analysis of six ulcerative colitis genome-wide association study datasets found many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1.
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
1,291 citations
TL;DR: The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis, particularly regarding sensitivity.
Abstract: Objective To evaluate new classifi cation criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only. Methods In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecifi ed sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/ or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard. Results In all, 24 ASAS centres included 266 patients, with a fi nal diagnosis of SpA being made in 66.2%. After adjustments a fi nal set of criteria showed the best balance between sensitivity (77.8%) and specifi city (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, infl ammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, infl ammatory back pain in the past, family history of SpA. The new criteria performed better than modifi ed versions of the ESSG (sensitivity 62.5%, specifi city 81.1%) and the Amor criteria (sensitivity 39.8%, specifi city 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specifi city 83.3%) than the modifi ed ESSG (sensitivity 79.1%, specifi city 68.8%) and Amor criteria (sensitivity 67.5%, specifi city 86.7%), respectively. Conclusions The new ASAS classifi cation criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.
1,276 citations
TL;DR: Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.
1,228 citations
TL;DR: Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma.
Abstract: Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan–Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6–16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma.
Duke University1, Cleveland Clinic2, University of Alberta3, Stavanger University Hospital4, Pierre-and-Marie-Curie University5, University of California, San Francisco6, Veterans Health Administration7, University of Glasgow8, Université de Montréal9, University of Gothenburg10, University of North Carolina at Chapel Hill11, Charité12, University of Oslo13, Rabin Medical Center14, Johnson & Johnson15, Emory University16, Universidade Federal do Rio Grande do Sul17, Pontifical Catholic University of Chile18, Linköping University19, MetroHealth20, University of California, Los Angeles21, Janssen Pharmaceutica22, University of Maryland, Baltimore23, University of Florida24, University of Pennsylvania25, Dalhousie University26, Ford Motor Company27, Monash University28, Vilnius University29, University of Washington30, Mexican Social Security Institute31, University of Brescia32, Seoul National University33, Mayo Clinic34, Wrocław Medical University35, Mahidol University36, University of Otago37, University of Groningen38, Thomas Jefferson University39
TL;DR: In this article, Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies.
Abstract: A b s t r ac t Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, −0.4 percentage points; 95% CI, −1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.)
TL;DR: Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold.
Abstract: Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y
TL;DR: Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat neurological conditions such as aneurismal subarachnoid hemorrhage or traumatic brain injury.
Abstract: Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.
TL;DR: Everolimus plus octreotide LAR, compared with placebo plusOctreotide Larry, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome.
Saint Louis University1, University of Barcelona2, University of Alberta3, University of Erlangen-Nuremberg4, Boston University5, Uppsala University Hospital6, University of East Anglia7, University of California, San Francisco8, Duke University9, Western General Hospital10, National Institutes of Health11, Tufts University12, Kagoshima University13, University of California, Los Angeles14, SOCAR15, University of Cagliari16, Sapienza University of Rome17, Tufts Medical Center18, Tampa General Hospital19, University of Toulouse20, Charité21, Stony Brook University Hospital22
TL;DR: It is concluded that "Sarcopenia, ie, reduced muscle mass, with limited mobility" should be considered an important clinical entity and that most older persons should be screened for this condition.
University of Amsterdam1, Ghent University2, Imperial College London3, Charité4, University of Montpellier5, Medical University of Silesia6, Karolinska Institutet7, Umeå University8, Uppsala University9, Jagiellonian University10, University of Düsseldorf11, Medical University of Łódź12, Odense University Hospital13, University of Gothenburg14, University of Southampton15, Children's Hospital of Philadelphia16
TL;DR: This data indicates that rhinosinusitis in Europe is an underestimated disease, and the number of patients diagnosed with the disease and the severity of the disease should be increased.
Abstract: Background: Chronic rhinosinusitis (CRS) is a common health problem, with significant medical costs and impact on general health. Even so, prevalence figures for Europe are unavailable. In this st ...
TL;DR: It is accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears, and a comprehensive review of physiological and pathophysiological aspects of the meibomian glands is sought.
Abstract: The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named.
Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity.
Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function.
Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12
After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.
TL;DR: The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging.
Abstract: The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research for diagnostic imaging in women’s healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practices at the time at which they were issued. Although ISUOG has made every effort to ensure that guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. They are not intended to establish a legal standard of care because interpretation of the evidence that underpins the guidelines may be influenced by individual circumstances and available resources. Approved guidelines can be distributed freely with the permission of ISUOG (info@isuog.org).
TL;DR: The prognostic relevance of grip strength in various clinical and epidemiologic settings is outlined and its suitability as marker of nutritional status in cross-sectional as well as intervention studies is investigated.
French Institute of Health and Medical Research1, Rockefeller University2, Paris Descartes University3, University of Debrecen4, Academy of Medical Sciences, United Kingdom5, Charité6, University of Zurich7, Ludwig Maximilian University of Munich8, Rappaport Faculty of Medicine9, Hiroshima University10, Uludağ University11, Boston Children's Hospital12
TL;DR: Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease.
Abstract: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
University of Amsterdam1, University of Manchester2, Charité3, National and Kapodistrian University of Athens4, Charles University in Prague5, Stavanger University Hospital6, Vilnius University7, University of Verona8, University of Szeged9, Erasmus University Rotterdam10, Wrocław Medical University11, Katholieke Universiteit Leuven12, St. John's University13, Karolinska Institutet14, University of Bern15
TL;DR: This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts and to improve patient care and mitigate the problem of undertreatment.
Abstract: Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) ≤10 and psoriasis area and severity index (PASI) ≤10 and dermatology life quality index (DLQI) ≤10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (ΔPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is ≥75%. The treatment regimen should be modified if improvement of PASI is 5 but can be continued if the DLQI is ≤5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians.
TL;DR: By comparison with early photoproducts, it is proposed how retinal translocation and rotation induce the gross conformational changes characteristic for Meta’II, and the structures can now serve as models for the large GPCR family.
Abstract: Structural studies of active states of the visual pigment rhodopsin, a G protein-coupled receptor, have previously been limited to apoprotein or opsin forms that do not contain the agonist all-trans-retinal. Two groups now report structures that reveal more details of the transformations involved in rhodopsin activation. Choe et al. solve the X-ray crystal structure of the metarhodopsin II intermediate of the photoreceptor rhodopsin, and Standfuss et al. determine the structure of a constitutively active mutant of rhodopsin bound to a peptide derived from the C-terminus of the G protein transducin. Here the X-ray crystal structure of the metarhodopsin II intermediate of the photoreceptor rhodopsin is solved. Comparison of this structure with previously published structures enabled the proposal of how retinal translocation and rotation induce the conformational changes observed in this structure. G-protein-coupled receptors (GPCRs) are seven transmembrane helix (TM) proteins that transduce signals into living cells by binding extracellular ligands and coupling to intracellular heterotrimeric G proteins (Gαβγ)1. The photoreceptor rhodopsin couples to transducin and bears its ligand 11-cis-retinal covalently bound via a protonated Schiff base to the opsin apoprotein2. Absorption of a photon causes retinal cis/trans isomerization and generates the agonist all-trans-retinal in situ. After early photoproducts, the active G-protein-binding intermediate metarhodopsin II (Meta II) is formed, in which the retinal Schiff base is still intact but deprotonated. Dissociation of the proton from the Schiff base breaks a major constraint in the protein and enables further activating steps, including an outward tilt of TM6 and formation of a large cytoplasmic crevice for uptake of the interacting C terminus of the Gα subunit3,4,5. Owing to Schiff base hydrolysis, Meta II is short-lived and notoriously difficult to crystallize. We therefore soaked opsin crystals with all-trans-retinal to form Meta II, presuming that the crystal’s high concentration of opsin in an active conformation (Ops*)6,7 may facilitate all-trans-retinal uptake and Schiff base formation. Here we present the 3.0 A and 2.85 A crystal structures, respectively, of Meta II alone or in complex with an 11-amino-acid C-terminal fragment derived from Gα (GαCT2). GαCT2 binds in a large crevice at the cytoplasmic side, akin to the binding of a similar Gα-derived peptide to Ops* (ref. 7). In the Meta II structures, the electron density from the retinal ligand seamlessly continues into the Lys 296 side chain, reflecting proper formation of the Schiff base linkage. The retinal is in a relaxed conformation and almost undistorted compared with pure crystalline all-trans-retinal. By comparison with early photoproducts we propose how retinal translocation and rotation induce the gross conformational changes characteristic for Meta II. The structures can now serve as models for the large GPCR family.
TL;DR: Practical advice for the application of exercise in heart failure and how to overcome traditional barriers is provided, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention.
Abstract: The European Society of Cardiology heart failure guidelines firmly recommend regular physical activity and structured exercise training (ET), but this recommendation is still poorly implemented in daily clinical practice outside specialized centres and in the real world of heart failure clinics. In reality, exercise intolerance can be successfully tackled by applying ET. We need to encourage the mindset that breathlessness may be evidence of signalling between the periphery and central haemodynamic performance and regular physical activity may ultimately bring about favourable changes in myocardial function, symptoms, functional capacity, and increased hospitalization-free life span and probably survival. In this position paper, we provide practical advice for the application of exercise in heart failure and how to overcome traditional barriers, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention.
Charité1, Odense University Hospital2, Autonomous University of Barcelona3, University of Montpellier4, University of Southampton5, Norfolk and Norwich University Hospital6, St Thomas' Hospital7, Hiroshima University8, Medical University of South Carolina9, Johns Hopkins University School of Medicine10, Peking University11
TL;DR: A GA2LEN task force report concluded that chronic spontaneous urticaria is a “hidden epidemic” that needs to be addressed to address the unmet clinical needs of patients.
Abstract: Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic urticaria (CU), is more common than previously thought. At any time, 0.5-1% of the population suffers from the disease (point prevalence). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1-5 years but is likely to be longer in more severe cases, cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity). Chronic spontaneous urticaria has major detrimental effects on quality of life, with sleep deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in terms of direct and indirect health care costs as well as reduced performance at work and in private life. In the majority of patients, an underlying cause cannot be identified making a causal and/or curative treatment difficult. Nonsedating H₁-antihistamines are the mainstay of symptomatic therapy, but treatment with licensed doses relieves symptoms effectively in < 50% of patients. Although guideline-recommended updosing up to fourfold increases symptom control in many patients, a substantial number of patients have only little benefit from H₁ -antihistamines. Consequently, there is a great need for new therapeutic strategies.
TL;DR: In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes and the concept and definition of AKI might need re-assessment.
TL;DR: This work distinguishes brain myeloid subtypes with regard to their origin, function and fate in the brain and illustrates the divergent features of these cells during neurodegeneration.
Abstract: The diseased brain hosts a heterogeneous population of myeloid cells, including parenchymal microglia, perivascular cells, meningeal macrophages and blood-borne monocytes. To date, the different types of brain myeloid cells have been discriminated solely on the basis of their localization, morphology and surface epitope expression. However, recent data suggest that resident microglia may be functionally distinct from bone marrow- or blood-derived phagocytes, which invade the CNS under pathological conditions. During the last few years, research on brain myeloid cells has been markedly changed by the advent of new tools in imaging, genetics and immunology. These methodologies have yielded unexpected results, which challenge the traditional view of brain macrophages. On the basis of these new studies, we differentiate brain myeloid subtypes with regard to their origin, function and fate in the brain and illustrate the divergent features of these cells during neurodegeneration.
TL;DR: Successful reconstitution of CD4(+) T cells at the systemic level as well as in the gut mucosal immune system after CCR5Δ32/Δ 32 stem cell transplantation is demonstrated, suggesting that cure of HIV has been achieved in this patient.
TL;DR: Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis, and intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis.
TL;DR: In this paper, a study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure.
Abstract: Background—This study was designed to determine whether physician-led remote telemedical management (RTM) compared with usual care would result in reduced mortality in ambulatory patients with chronic heart failure (HF). Methods and Results—We enrolled 710 stable chronic HF patients in New York Heart Association functional class II or III with a left ventricular ejection fraction ≤35% and a history of HF decompensation within the previous 2 years or with a left ventricular ejection fraction ≤25%. Patients were randomly assigned (1:1) to RTM or usual care. Remote telemedical management used portable devices for ECG, blood pressure, and body weight measurements connected to a personal digital assistant that sent automated encrypted transmission via cell phones to the telemedical centers. The primary end point was death from any cause. The first secondary end point was a composite of cardiovascular death and hospitalization for HF. Baseline characteristics were similar between the RTM (n=354) and control (n=...