bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the profiles of CB1 cannabinoid receptor signalling bias using joint kinetic modelling
Authors: Zhu Xiao , Finlay David B. , Glass Michelle , Duffull Stephen B. 
Published: April 2020

Background and PurposeBiased agonism describes the ability of ligands to differentially regulate multiple signalling pathways when coupled to a single receptor. Signalling is affected by rapid agonist‐induced receptor internalisation. Hence, the conventional use of equilibrium models may not be optimal, because (i) receptor numbers vary with time and, in addition, (ii) some pathways may show non‐monotonic profiles over time.Experimental ApproachData were available from internalisation, cAMP inhibition and phosphorylation of ERK (pERK) of the cannabinoid‐1 (CB1) receptor using a concentration series of six CB1 ligands (CP55,940, WIN55,212‐2, anandamide, 2‐arachidonylglycerol, Δ9‐tetrahydrocannabinol and BAY59,3074). The joint kinetic model of CB1 signalling was developed to simultaneously describe the time‐dependent activities in three signalling pathways. Based on the insights from the kinetic model, fingerprint profiles of CB1 ligand bias were constructed and visualised.Key ResultsA joint kinetic model was able to capture the signalling profiles across all pathways for the CB1 receptor simultaneously for a system that was not at equilibrium. WIN55,212‐2 had a similar pattern as 2‐arachidonylglycerol (reference). The other agonists displayed bias towards internalisation compared to cAMP inhibition. However, only Δ9‐tetrahydrocannabinol and BAY59,3074 demonstrated bias in the pERK–cAMP pathway comparison. Furthermore, all the agonists exhibited little preference between internalisation and pERK.Conclusion and ImplicationsThis is the first joint kinetic assessment of biased agonism at a GPCR (e.g. CB1 receptor) under non‐equilibrium conditions. Kinetic modelling is a natural method to handle time‐varying data when traditional equilibria are not present and enables quantification of ligand bias.
Key role of macrophages in tolerance induction via T regulatory type 1 (Tr1) cells
Authors: Mfarrej B , Jofra T , Morsiani C , Gagliani N , Fousteri G , Battaglia M 
Published: April 2020

SummaryT regulatory type 1 (Tr1) cells are a class of regulatory T cells (Tregs) participating in peripheral tolerance, hence the rationale behind their testing in clinical trials in different disease settings. One of their applications is tolerance induction to allogeneic islets for long-term diabetes-free survival. Currently the cellular and molecular mechanisms that promote Tr1-cell induction in vivo remain poorly understood. We employed a mouse model of transplant tolerance where treatment with granulocyte colony-stimulating factor (G-CSF)/rapamycin induces permanent engraftment of allogeneic pancreatic islets in C57BL/6 mice via Tr1 cells. The innate composition of graft and spleen cells in tolerant mice was analyzed by flow cytometry. Graft phagocytic cells were co-cultured with CD4+ T cells in vitro to test their ability to induce Tr1-cell induction. Graft phagocytic cells were depleted in vivo at different time-points during G-CSF/rapamycin treatment, to identify their role in Tr1-cell induction and consequently in graft survival. In the spleen, the site of Tr1-cell induction, no differences in the frequencies of macrophages or dendritic cells (DC) were observed. In the graft, the site of antigen uptake, a high proportion of macrophages and not DC was detected in tolerant but not in rejecting mice. Graft-infiltrating macrophages of G-CSF/rapamycin-treated mice had an M2 phenotype, characterized by higher CD206 expression and interleukin (IL)-10 production, whereas splenic macrophages only had an increased CD206 expression. Graft-infiltrating cells from G-CSF/rapamycin-treated mice-induced Tr1-cell expansion in vitro. Furthermore, Tr1-cell induction was perturbed upon in-vivo depletion of phagocytic cells, early and not late during treatment, leading to graft loss suggesting that macrophages play a key role in tolerance induction mediated by Tr1 cells. Taken together, in this mouse model of Tr1-cell induced tolerance to allogeneic islets, M2 macrophages infiltrating the graft upon G-CSF/rapamycin treatment are key for Tr1-cell induction. This work provides mechanistic insight into pharmacologically induced Tr1-cell expansion in vivo in this stringent model of allogeneic transplantation.
Guillain‐Barré syndrome: Novel treatment by complement inhibition
Authors: Misawa Sonoko , Suichi Tomoki 
Published: April 2020

AbstractGuillain‐Barré syndrome (GBS) is an immune‐mediated polyneuropathy that can cause acute flaccid tetraparesis and respiratory failure. Intravenous immunoglobulin and plasmapheresis were established as a standard of care, but 20% to 30% of patients require mechanical ventilation during the acute phase and up to 20% of patients cannot walk independently even 1 year after the onset. As the pathophysiology of GBS has been elucidated, complement activation draws attention as a key treatment point. In acute motor axonal neuropathy, anti‐ganglioside antibody deposition and resulting complement activation lead to nerve conduction failure and eventually axonal degeneration. In acute inflammatory demyelinating polyneuropathy, although the process has not been clearly revealed, autopsied specimens showed that terminal complement complex rimmed the surface of the Schwann cells. Eculizumab is an antibody to the complement protein C5 and can potently inhibit complement activation. In a murine model with anti‐ganglioside antibody–mediated neuropathy, eculizumab can avert respiratory failure and motor neuropathy. A randomized controlled phase II trial showed that eculizumab might be effective also for GBS patients. Inhibition of complement activation can be a new therapeutic option in the near future.
Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications
Authors: Foster Alison , Chalot Basile , Antoniadi Thalia , Schaefer Elise , Keelagher Rebecca , Ryan Gavin , Thomas Quentin , Philippe Christophe , Bruel Ange‐Line , Sorlin Arthur , Thauvin‐Robinet Christel , Bardou Marc , Luu Maxime , Quenardelle Veronique , Wolff Valerie , Woodley Jessica , Vabres Pierre , Lim Derek , Igbokwe Rebecca , Joseph Annie , Walker Harriet , Jester Andrea , Ellenbogen Jonathan , Johnson Diana , Rooke Bethanie , Moss Celia , Cole Trevor , Faivre Laurence 
Published: April 2020

AbstractHeterozygous activating variants in platelet‐derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long‐term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contractures, camptodactyly, widely spaced teeth, and constriction rings. We also propose novel occasional features including craniosynostosis, ocular pterygia, anterior chamber cleavage syndrome, early osteoporosis, increased pigmentation, recurrent haematomas, predisposition to cellulitis, nail dystrophy, carpal tunnel syndrome, recurrent hypoglycaemia in infancy, joint dislocation, and splenomegaly. Importantly, we report fusiform aneurysm of the basilar artery in two patients. Complications include thrombosis and stroke in the oldest reported patient and fatal rupture at the age of 21 in the patient with the novel variant. We conclude that cerebrovascular complications are part of the phenotypic spectrum of KOGS and KOGS‐like disorders and suggest vascular imaging is indicated in these patients.
The Suppression of Inferences From Counterfactual Conditionals
Authors: Espino Orlando , Byrne Ruth M. J. 
Published: April 2020

AbstractWe examine two competing effects of beliefs on conditional inferences. The suppression effect occurs for conditionals, for example, “if she watered the plants they bloomed,” when beliefs about additional background conditions, for example, “if the sun shone they bloomed” decrease the frequency of inferences such as modus tollens (from “the plants did not bloom” to “therefore she did not water them”). In contrast, the counterfactual elevation effect occurs for counterfactual conditionals, for example, “if she had watered the plants they would have bloomed,” when beliefs about the known or presupposed facts, “she did not water the plants and they did not bloom” increase the frequency of inferences such as modus tollens. We report six experiments that show that beliefs about additional conditions take precedence over beliefs about presupposed facts for counterfactuals. The modus tollens inference is suppressed for counterfactuals that contain additional conditions (Experiments 1a and 1b). The denial of the antecedent inference (from “she did not water the plants” to “therefore they did not bloom”) is suppressed for counterfactuals that contain alternatives (Experiments 2a and 2b). We report a new “switched‐suppression” effect for conditionals with negated components, for example, “if she had not watered the plants they would not have bloomed”: modus tollens is suppressed by alternatives and denial of the antecedent by additional conditions, rather than vice versa (Experiments 3a and 3b). We discuss the implications of the results for alternative theories of conditional reasoning.
Targeted next generation sequencing (NGS) to classify melanocytic neoplasms
Authors: Zarabi Samaneh K. , Azzato Elizabeth M. , Tu Zheng Jin , Ni Ying , Billings Steven D. , Arbesman Josh , Funchain Pauline , Gastman Brian , Farkas Daniel H. , Ko Jennifer S. 
Published: April 2020

AbstractThis study piloted a pan‐solid‐tumor next generation sequence (NGS)‐based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 “epithelioid” nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4‐15 mm); median thickness 2.25 mm (range 0.25‐12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4‐71) and all other lesions (median 8/tumor, range 3‐17) (P < 0.004) and malignant (median 16/tumor, range 4‐71) vs benign lesions (median 7/tumor, range 3‐14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS‐based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH‐non‐concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.
Night‐time is the right time? Late‐night drinking and assaults in Finnish public and private settings
Authors: Mäkelä Pia , Warpenius Katariina 
Published: April 2020

AbstractIntroduction and AimsThe risk of alcohol‐related injuries and violence increases in late‐night settings. We analysed temporal patterns of drinking and assaults and present an event‐level analysis of connections between night‐time drinking, estimated blood alcohol level, location and drinkers' age and sex.Design and MethodsMain data source is a Finnish general population (aged 18–69 years) survey carried out in 2016 (n = 1962), including event‐level data on drinking occasions in the previous 7 days (n = 1891). Statistical analyses consisted of tabulations and logistic regression analyses.ResultsFinns' drinking peaked around 8–9 pm on most days, with the greatest peaks on Fridays and Saturdays. The main pattern was similar for drinking occasions occurring in home surroundings and in licensed premises, but a larger proportion of the latter occurred in later hours of the day. Assaults had a similar weekday distribution, but the peak occurred several hours later, around 3–5 am. One explanation is that the mean estimated blood alcohol concentration strongly increased as the ending time of the drinking occasion extended later into the night, and the proportion of late‐night drinking was higher in licensed premises than home surroundings.Discussion and ConclusionsPeaks for assaults in public places temporally coincide with the late closing times of licensed premises and with high estimated blood alcohol concentrations among drinkers. The results underline a need to reduce harm from intoxication, which in public places could include restricted opening hours, increased law enforcement, improved responsible beverage service practices and other interventions to better manage aggression.
Rezidivierende mukokutane Infektionen durch PVL‐positive Staphylococcus aureus‐Stämme: Eine Herausforderung im klinischen Alltag
Authors: Balakirski Galina , Hischebeth Gunnar , Altengarten Julia , Exner Daniel , Bieber Thomas , Dohmen Jonas , Engelhart Steffen 
Published: April 2020

ZusammenfassungHintergrundRezidivierende mukokutane Infektionen durch PVL‐positive Staphylococcus (S.) aureus‐Stämme stellen in Deutschland ein zunehmendes Problem dar. In den letzten Jahren wurden Ausbrüche in Kindertagesstätten und Kommunen beschrieben. Dennoch liegen zurzeit keine diagnostischen Algorithmen oder Therapieempfehlungen für die entsprechenden Infektionen in Deutschland vor.MethodeEine Literaturrecherche in der Datenbank PubMed/MEDLINE erfolgte mit dem Ziel, einen diagnostischen und therapeutischen Algorithmus zu erarbeiten. Zudem wurden nationale und internationale Empfehlungen berücksichtigt.ErgebnissePanton‐Valentine Leukozidin (PVL) ist ein porenbildendes Protein, das von bestimmten S. aureus‐Stämmen produziert wird. Sowohl Methicillin‐sensible (MSSA) als auch Methicillin‐resistente S. aureus (MRSA)‐Stämme können das für die PVL‐Produktion verantwortliche Gen lukS‐lukF besitzen. Das klinische Bild der durch einen PVL‐positiven S. aureus verursachten Infektionen erstreckt sich von einzelnen rezidivierenden Abszessen bis hin zu einer ausgedehnten Furunkulose. Bei etwa 40 % der Patienten kommt es zu Rezidiven der Beschwerden trotz einer konsequenten Behandlung der Erstinfektion. Die Therapie variiert je nach klinischem Bild der jeweiligen Infektion. Zudem wird in der Literatur eine Screeninguntersuchung der Patienten und ihrer engen Kontaktpersonen sowie eine bakterielle Dekolonisation der Betroffenen empfohlen.SchlussfolgerungenDiese Arbeit fokussiert auf die Pathogenese und Risikofaktoren der rezidivierenden mukokutanen Infektionen durch PVL‐positive S. aureus‐Stämme und versucht einen diagnostischen und therapeutischen Algorithmus zur optimalen Patientenversorgung vorzuschlagen.
Sexuell übertragbare Koinfektionen bei Patienten mit anogenitalen Warzen – eine retrospektive Analyse von 196 Patienten
Authors: Mueller Simon M. , Menzi Sheryl , Kind André B. , Blaich Annette , Bayer Michael , Navarini Alexander , Itin Peter , Brandt Oliver 
Published: April 2020

ZusammenfassungHintergrund und ZieleAnogenitale Warzen (AGW) werden vorwiegend durch Niedrigrisiko‐Typen des humanen Papillomavirus (HPV) verursacht. Obgleich sie die häufigste sexuell übertragbare Virusinfektion darstellen, ist über Koinfektionen mit anderen sexuell übertragbaren Infektionen (sexual transmitted infections, STI) bei den betroffenen Patienten wenig bekannt. Ziel unserer Studie war es, die Rate der Koinfektionen mit STI bei Patienten mit AGW zu ermitteln, STI‐Koinfektionen zu spezifizieren und für jede STI die number needed to screen (NNS) zu berechnen.MethodenIn einer retrospektiven Querschnittsstudie wurden die Datensätze von AGW‐Patienten auswertet, die zwischen 2008–2016 in unserer Klinik behandelt wurden.Ergebnisse142/196 (72 %) Patienten waren in unterschiedlicher Weise auf Infektionen mit HIV, HBV, HCV, Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium und HSV untersucht worden. Die STI‐Koinfektionsrate bei allen getesteten Patienten betrug 24,6 %, was einer NNS von 4,1 zum Nachweis einer STI entspricht. Interessanterweise unterschied sich die Koinfektionsrate zwischen heterosexuellen Männern, homosexuellen Männern und Frauen nicht signifikant. Die NNS für Syphilis betrug 8,4, für HIV 14,0, für HCV 28,5 und für HBV 39,0. Die NNS bei asymptomatischen Patienten, die auf HSV, Chlamydia trachomatis und Mycoplasma genitalium getestet wurden, betrug 1,4, 5,3 bzw. 12,0.SchlussfolgerungAufgrund der hohen Prävalenz von STI‐Koinfektionen sollten AGW‐Patienten stets auf das Vorhandensein weiterer STI untersucht werden.
Linear patterns of the skin and their dermatoses
Authors: Senner Sonja , Eicher Laurie , Nasifoglu Suzan , Wollenberg Andreas 
Published: April 2020

SummaryKnowledge about the linear patterns of the skin is a key competence of dermatologists. Four major groups of linear patterns can be distinguished: Langer lines, dermatomes, Blaschko lines and exogenous patterns. Langer lines run in the direction of the underlying collagen fibers (least skin tension) and play an important diagnostic role for some exanthematous skin diseases. In the thoracodorsal region, the distribution of the Langer lines gives rise to what is referred to as a ’Christmas tree pattern’. A dermatome is an area of skin that is supplied by a single spinal nerve. Disorders with a neuronal origin follow this pattern of distribution. The lines of Blaschko delineate the lines of migration of epidermal cells during embryogenesis. Exogenous linear patterns are caused by external factors.The present CME article will highlight important skin disorders that primarily present in the form of one of the aforementioned patterns. In addition, we will also address skin conditions that may secondarily follow with these patterns (or distinctly not do so) as the result of various mechanisms such as the Koebner phenomenon, reverse Koebner phenomenon, and Wolf’s isotopic response.
Efficacy and safety of insulin glargine/lixisenatide fixed‐ratio combination (iGlarLixi 1:1) in Japanese patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic drugs: A randomized, 26‐week, open‐label, multicentre study: The LixiLan JP‐O2 randomized clinical trial
Authors: Terauchi Yasuo , Nakama Takahiro , Spranger Robert , Amano Atsushi , Inoue Takahiro , Niemoeller Elisabeth 
Published: April 2020

AbstractAimsTo assess efficacy and safety of 26‐week treatment with insulin glargine/lixisenatide fixed‐ratio combination (iGlarLixi) compared with insulin glargine U100 (iGlar) in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs).Materials and MethodsThis phase 3, multicentre, open‐label, 1:1 randomized, parallel‐group study compared efficacy of iGlarLixi and iGlar in patients with T2DM, HbA1c of ≥7.5% to ≤9.5% and fasting plasma glucose ≤10.0 mmol/L (180 mg/dL). The primary endpoint was change in HbA1c from baseline to week 26.ResultsPatients were randomized to iGlarLixi (n = 260) or iGlar (n = 261) (mean age 59.7 years, baseline BMI 26.04 kg/m2, and HbA1c 8.04% [64.4 mmol/mol]). HbA1c reduction was significantly greater with iGlarLixi (−1.40% [−15.3 mmol/mol]) than with iGlar (−0.76% [−8.3 mmol/mol]). Significantly more iGlarLixi patients reached HbA1c <7% at week 26 (71.5% vs 38.5%, P < .0001), with significantly lower weight gain (LS mean difference −1.06 kg, P < .0001). Documented symptomatic hypoglycemia (plasma glucose ≤3.9 mmol/L [70 mg/dL]) was recorded in 14.2% of patients with iGlarLixi and 12.3% with iGlar. No severe hypoglycemia was reported in either group. Other than the expected gastrointestinal issues associated with glucagon‐like peptide 1 receptor agonists, we found no major difference in the incidence of TEAEs.ConclusionsHbA1c reduction was significantly greater with iGlarLixi than with iGlar; significantly more patients achieved HbA1c <7%, with no additional risk of hypoglycemia and without weight gain. iGlarLixi (1:1) provided an effective treatment option for Japanese patients with T2DM inadequately controlled on OADs.Clinical Trial Number: NCT02752828
Systemic immune‐inflammation index (SII) predicted clinical outcome in patients with coronary artery disease
Authors: Yang Ya‐Ling , Wu Cheng‐Hsueh , Hsu Pai‐Feng , Chen Su‐Chan , Huang Shao‐Sung , Chan Wan Leong , Lin Shing‐Jong , Chou Chia‐Yu , Chen Jaw‐Wen , Pan Ju‐Pin , Charng Min‐Ji , Chen Ying‐Hwa , Wu Tao‐Cheng , Lu Tse‐Min , Huang Po‐Hsun , Cheng Hao‐Min , Huang Chin‐Chou , Sung Shih‐Hsien , Lin Yenn‐Jiang , Leu Hsin‐Bang 
Published: April 2020

AbstractBackgroundThis study examines the predictive value of a novel systemic immune‐inflammation index (SII, platelet × neutrophil/lymphocyte ratio) in coronary artery disease (CAD) patients.MethodsA total of 5602 CAD patients who had undergone a percutaneous coronary intervention (PCI) were enrolled. They were divided into two groups by baseline SII score (high SII vs low SII) to analyse the relationship between SII groups and the long‐term outcome. The primary outcomes were major cardiovascular events (MACE) which includes nonfatal myocardial infarction (MI), nonfatal stroke and cardiac death. Secondary outcomes included a composite of MACE and hospitalization for congestive heart failure.ResultsAn optimal SII cut‐off point of 694.3 × 109 was identified for MACE in the CAD training cohort (n = 373) and then verified in the second larger CAD cohort (n = 5602). Univariate and multivariate analyses showed that a higher SII score (≥694.3) was independently associated with increased risk of developing cardiac death (HR: 2.02; 95% CI: 1.43‐2.86), nonfatal MI (HR: 1.42; 95% CI: 1.09‐1.85), nonfatal stroke (HR: 1.96; 95% CI: 1.28‐2.99), MACE (HR: 1.65; 95% CI: 1.36‐2.01) and total major events (HR: 1.53; 95% CI: 1.32‐1.77). In addition, the SII significantly improved risk stratification of MI, cardiac death, heart failure, MACE and total major events than conventional risk factors in CAD patients by the significant increase in the C‐index (P < .001) and reclassification risk categories by significant NRI (P < .05) and IDI (P < .05).ConclusionsSII had a better prediction of major cardiovascular events than traditional risk factors in CAD patients after coronary intervention.