bluuebunny/crossref_metadata_2025_split huggingface dataset:
Swedish national population‐based study shows an increased risk of depression among patients with Hirschsprung disease
Authors: Amin Leila , Skoglund Charlotte , Wester Tomas , Granström Anna Löf 
Published: March 2019

AbstractAimHirschsprung disease is usually treated during infancy. The long‐term impact on mental health has not been well studied. The aim of this study was to assess the risk for depressive disorders in individuals with Hirschsprung disease.MethodsThis was a nationwide, population‐based cohort study. The study exposure was Hirschsprung disease and the study outcome was depression. The exposed cohort included all individuals with Hirschsprung disease, registered in the Swedish National Patient Register between 1964 and 2013 and the unexposed cohort included ten age‐ and sex‐matched controls per patient. The diagnosis of depression was confirmed by diagnosis in the Swedish National Patient Register.ResultsThe cohort included 739 (76.5% males) individuals with Hirschsprung disease and 7390 (76.5% males) controls. Among the patients with Hirschsprung disease, 35 (4.7%) of the patients had had a depressive disorder and 187 (2.5%) of controls, hazard ratio 1.98, 95% confidence interval 1.38–2.84. The mean age at diagnosis of first depression was 21.9 years (SD ± 7) in Hirschsprung disease patients and 23.4 years (SD ± 7), p = 0.236 in the unexposed group. There were no significant gender differences.ConclusionWe found an increased risk of having depressive disorders among individuals with Hirschsprung disease compared to controls.
Structural insight into Class F receptors – What have we learnt regarding agonist‐induced activation?
Authors: Schulte Gunnar , Kozielewicz Paweł 
Published: March 2019

AbstractClass F receptors, including the ten Frizzleds (FZD1‐10) and SMO, mediate the effects of WNTs and hedgehog proteins and belong to the superfamily of G protein‐coupled receptors (GPCRs). While the recent, high‐resolution insight into mechanisms of GPCR activation provides a better understanding of receptor activation in Class A, B and C GPCRs, it remains unclear how Class F receptors bind their ligands, how ligand binding is translated to receptor activation and how signal initiation and specification are achieved. Here, we summarize recent efforts in elucidating Class F receptor structure and activation mechanisms and critically discuss the progress made in this area. A better understanding of the activation mechanisms of Class F receptors is required to engage in mechanism‐based and structure‐guided drug discovery to exploit the large therapeutic potential of targeting these receptors pharmacologically.
Retrograde perfusion in isolated perfused mouse lungs—Feasibility and effects on cytokine levels and pulmonary oedema formation
Authors: Krabbe Julia , Ruske Nadine , Kanzler Stephanie , Reiss Lucy Kathleen , Ludwig Andreas , Uhlig Stefan , Martin Christian 
Published: March 2019

AbstractRetrograde lung vascular perfusion can appear in high‐risk surgeries. The present report is the first to study long‐term retrograde perfusion of isolated perfused mouse lungs (IPLs) and to use the tyrosine kinase ephB4 and its ligand ephrinB2 as potential markers for acute lung injury. Mouse lungs were subjected to anterograde or retrograde perfusion with normal‐pressure ventilation (NV) or high‐pressure ventilation (=overventilation, OV) for 4 hours. Outcome parameters were cytokine, ephrinB2 and ephB4 levels in perfusate samples and bronchoalveolar lavage (BAL), and the wet‐to‐dry ratio. Anterograde perfusion was feasible for 4 hours, while lungs receiving retrograde perfusion presented considerable collapse rates. Retrograde perfusion resulted in an increased wet‐to‐dry ratio when combined with high‐pressure ventilation; other physiological parameters were not affected. Cytokine levels in BAL and perfusate, as well as levels of soluble ephB4 in BAL were increased in OV, while soluble ephrinB2 BAL levels were increased in retrograde perfusion. BAL levels of ephrinB2 and ephB4 were also determined in vivo, including mice ventilated for 7 hours with normal‐volume ventilation (NVV) or high‐volume ventilation (HVV) with increased levels of ephB4 in HVV BAL compared to NVV. Retrograde perfusion in IPL is limited as a routine method to investigate effects due to collapse for yet unclear reasons. If successful, retrograde perfusion has an influence on pulmonary oedema formation. In BAL, ephrinB2 seems to be up‐regulated by flow reversal, while ephB4 is a marker for acute lung injury.
Routine sequencing in CLL has prognostic implications and provides new insight into pathogenesis and targeted treatments
Authors: Hu Boyu , Patel Keyur P. , Chen Hsiang‐Chun , Wang Xuemei , Wang Feng , Luthra Rajyalakshmi , Routbort Mark J. , Kanagal‐Shamanna Rashmi , Medeiros Leonard J. , Yin Cheng C. , Zuo Zhuang , Ok Chi Y. , Loghavi Sanam , Tang Guilin , Tambaro Francesco P. , Thompson Philip , Burger Jan , Jain Nitin , Ferrajoli Alessandra , Bose Prithviraj , Estrov Zeev , Keating Michael J. , Wierda William G. 
Published: March 2019

SummaryChronic lymphocytic leukaemia (CLL) is a genetically heterogeneous disease characterised by genomic alterations and gene mutations that may portend worse survival or resistance to treatments. A total of 680 blood or bone marrow samples underwent targeted sequencing of 29 genes previously identified as being mutated in CLL, which were correlated to known prognostic clinical characteristics. Overall, 400 (59%) patients were treatment‐naïve (TN) and 280 (41%) were relapsed/refractory (R/R). Most patients (70%) had ≥1 mutation, with TP53 (22%), SF3B1 (18%), NOTCH1 (13%) and ATM (13%) being the most commonly mutated genes. A higher proportion of R/R patients had mutations in SF3B1 (P = 0·01) and TP53 (P < 0·001). Patients with mutated IGHV CLL more often had mutations in KLHL6 (P = 0·001) and MYD88 (P < 0·001). Pairwise associations showed mutational co‐occurrences in the TN group including SF3B1/ATM [false discovery rate (FDR) < 0·05] and NOTCH1/POT1 (FDR < 0·01). Recurrent mutations resulting in premature truncation prior to the ubiquitination domains of NOTCH1 in its PEST domain and BIRC3 in its RING domain can produce proteins that constitutively activate CLL. Frequent missense mutations, such as K700E in SF3B1 and E571K in XPO1, have unknown function but are most likely to be activating mutations. Future directions include using these mutations to identify pathways for therapeutic targeting and rational drug design.
Plasma histamine elevation in a large cohort of sickle cell disease patients
Authors: Allali Slimane , Lionnet François , Mattioni Sarah , Callebert Jacques , Stankovic Stojanovic Katia , Bachmeyer Claude , Arlet Jean‐Benoit , Brousse Valentine , de Montalembert Mariane , Chalumeau Martin , Grateau Gilles , Maciel Thiago T. , Launay Jean‐Marie , Hermine Olivier , Georgin‐Lavialle Sophie 
Published: March 2019

SummaryThe role of mast cells has been questioned in sickle cell disease (SCD). We performed a prospective study evaluating plasma histamine and tryptase levels in a cohort of paediatric and adult patients, in steady state (n = 132) and during vaso‐occlusive crisis (VOC) (n = 121). Histamine level was elevated in 18% of patients in steady state and in 61% during VOC. Median histamine level was significantly higher during VOC than in steady state (24·1 [7·0–45·0] vs 9·6 [6·2–14·4] nmol/l, P < 0·0001). Tryptase level was slightly increased during VOC without reaching pathological values. These results suggest a role of mast cell activation in SCD pathophysiology.
The role of plasma exchange in the management of autoimmune disorders
Authors: Zanatta Elisabetta , Cozzi Martina , Marson Piero , Cozzi Franco 
Published: March 2019

SummaryTherapeutic plasma exchange (TPE) has been mainly used in the treatment of autoimmune diseases. The main mechanisms of action of TPE include the removal of circulating autoantibodies, immune complexes, complement components, cytokines and adhesion molecules, along with sensitization of antibody‐producing cells to immunosuppressant agents. TPE is useful in autoimmune haematological, renal, rheumatic and neurological diseases, and is recommended for acute disorders, together with relapsed or worsened chronic diseases that are often unresponsive to conventional treatments. The American Society for Apheresis and the British Society of Haematology have published guidelines on the clinical use of apheresis procedures, indicating the different levels of efficacy of TPE. Based on the evidence from current literature and our personal experience, this review discusses the indications and the suggested regimens for TPE in autoimmune haematological and non‐haematological disorders.
Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease
Authors: Fitz Nicholas F. , Nam Kyong Nyon , Koldamova Radosveta , Lefterov Iliya 
Published: March 2019

After 15 years of research into Alzheimer's disease (AD) therapeutics, including billions of US dollars provided by federal agencies, pharmaceutical companies, and private foundations, there are still no meaningful therapies that can delay the onset or slow the progression of AD. An understanding of the proteolytic processing of amyloid precursor protein (APP) and the hypothesis that pathogenic mechanisms in familial and sporadic forms of AD are very similar led to the assumption that pharmacological inhibition of secretases or immunological approaches to clear amyloid depositions in the brain would have been the core to drug discovery strategies and successful therapies. However, there are other understudied approaches including targeting genes, gene networks, and metabolic pathways outside the proteolytic processing of APP. The advancement of newly developed sequencing technologies and mass spectrometry, as well as the availability of animal models expressing human apolipoprotein E isoforms, has been critical in rationalizing additional AD therapeutics. The purpose of this review is to present one of those approaches, based on the role of ligand‐activated nuclear liver X and retinoid X receptors in the brain. This therapeutic approach was initially proposed utilizing in vitro models 15 years ago and has since been examined in numerous studies using AD‐like mouse models.Linked ArticlesThis article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
Chemistry, pharmacology, and cellular uptake mechanisms of thiometallate sulfide donors
Authors: Durham Tom , Zander David , Stomeo Niccolò , Minnion Magdalena , Hogarth Graeme , Feelisch Martin , Singer Mervyn , Dyson Alex 
Published: March 2019

Background and PurposeA clinical need exists for targeted, safe, and effective sulfide donors. We recently reported that ammonium tetrathiomolybdate (ATTM) belongs to a new class of sulfide‐releasing drugs. Here, we investigated the cellular uptake mechanisms of this drug class compared to sodium hydrosulfide (NaHS) and the effects of a thiometallate tungsten congener of ATTM, ammonium tetrathiotungstate (ATTT).Experimental ApproachIn vitro H2S release was determined by headspace gas sampling of vials containing dissolved thiometallates. Thiometallate and NaHS bioactivity was assessed by spectrophotometry‐derived sulfhaemoglobin formation. Cellular uptake dependence on the anion exchange protein (AE)‐1 was investigated in human red blood cells. ATTM/glutathione interactions were assessed by LC–MS/MS. Rodent pharmacokinetic and pharmacodynamic studies focused on haemodynamics and inhibition of aerobic respiration.Key ResultsATTM and ATTT both exhibit temperature‐, pH‐, and thiol‐dependence of sulfide release. ATTM/glutathione interactions revealed the generation of inorganic and organic persulfides and polysulfides. ATTM showed greater ex vivo and in vivo bioactivity over ATTT, notwithstanding similar pharmacokinetic profiles. Cellular uptake mechanisms of the two drug classes are distinct; thiometallates show dependence on AE‐1, while hydrosulfide itself was unaffected by inhibition of this pathway.Conclusions and ImplicationsThe cellular uptake of thiometallates relies upon a plasma membrane ion channel. This advances our pharmacological knowledge of this drug class, and further supports their utility as cell‐targeted sulfide donor therapies. Our results indicate that, as a more stable form, ATTT is better suited as a copper chelator. ATTM, a superior sulfide donor, may additionally participate in intracellular redox recycling.Linked ArticlesThis article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc
Long noncoding RNA ENST00000413528 sponges microRNA‐593‐5p to modulate human glioma growth via polo‐like kinase 1
Authors: Zhang Ren , Wei Ruo‐Lun , Du Wei , Zhang Li‐Wei , Du Tao , Geng Ya‐Dong , Wei Xin‐ting 
Published: March 2019

SummaryAimsIn this study, we examined the expression of lncRNA ENST00000413528 in glioma and determined its role in glioma development.MethodsLncRNA ENST00000413528 was detected in glioma tissues by lncRNA microarray. Then, we performed real‐time PCR, CCK‐8, colony formation assay, flow cytometry, caspase‐3/7 assay and animal experiment to detect the function of ENST00000413528 in glioma after ENST00000413528 knockdown. Subsequent bioinformatics analysis, luciferase reporter assays and RNA immunoprecipitation (RIP) assay western blotting indicated possible downstream regulatory molecules. The expression of PLK1 in glioma tissues was also examined by immunohistochemistry staining.ResultsExpression of ENST00000413528 was significantly increased in glioma tissues and LN229 and U251 cells. PLK1 protein could not be detected in peritumoral brain edema (PTBE) tissues; however, it showed an increasing number of positively cytoplasmic stained from WHO‐Grade II to Grade III gliomas. Knockdown of ENST00000413528 in glioma cells inhibited cell proliferation and colony formation abilities, induced the G0/G1 arrest of the cell cycle, and promoted apoptosis. The dual reporter assay and RNA immunoprecipitation assay verified the interaction between ENST00000413528 and miR‐593. We also demonstrated that polo‐like kinase 1 (PLK1) was regulated by miR‐593; PLK1 messenger RNA lacking 3’UTR partially reversed the effects caused by ENST00000413528 knockdown or miR‐593 upregulation.ConclusionlncRNA ENST00000413528 is closely related to the development of glioma via the miR‐593‐5p/PLK1 pathway.
Prevalence and determinants of exercise‐induced left ventricular dysfunction in patients with coronary artery disease
Authors: Honegger Ursina , Walter Joan E. , Mueller Deborah , Puelacher Christian , Schaerli Nicolas , Twerenbold Raphael , Badertscher Patrick , Boeddinghaus Jasper , Nestelberger Thomas , du Fay de Lavallaz Jeanne , Wussler Desiree , Pfister Otmar , Jeger Raban , Kaiser Christoph , Wild Damian , Schmidt‐Trucksäss Arno , Reichlin Tobias , Mueller Christian 
Published: March 2019

AbstractBackgroundThe phenomenon of exercise‐induced left ventricular dysfunction (LVD) is incompletely understood. Better understanding of its prevalence and determinants might help to address the current potential oversimplification of the relation between physical activity and cardiac health in patients with coronary artery disease (CAD).MethodsWe prospectively assessed the prevalence and determinants of exercise‐induced LVD in patients with stable CAD and normal LV function at rest undergoing bicycle rest/stress myocardial perfusion imaging single‐photon emission computed tomography (MPI‐SPECT). Exercise‐induced LVD was defined as a relevant (5% or more) drop in left ventricular ejection fraction after maximal exercise. High‐sensitivity cardiac troponin I/T (Hs‐cTnI/T) and N‐terminal probrain natriuretic peptide (NT‐proBNP) concentrations were measured before exercise to quantify cardiomyocyte injury and hemodynamic cardiac stress, respectively.ResultsAmong 317 patients, exercise‐induced LVD was present in 83 (26%) patients. Exercise‐induced LVD was associated with the extent of exercise‐inducible myocardial ischaemia as well as transient ischaemic dilatation. Still, 43% of patients developing exercise‐induced LVD did not have functionally relevant CAD. Neither baseline characteristics, nor the quantification of the extent of cardiomyocyte injury and hemodynamic cardiac stress using hs‐cTnI/T and NT‐proBNP concentrations, respectively, allowed predicting exercise‐induced LVD.ConclusionOne out of four patients with stable CAD develops exercise‐induced LVD after bicycle exercise test. While the extent of exercise‐inducible myocardial ischaemia is a predictor, other still unrecognized mechanisms also seem to play a major role, as nearly half of all patients with exercise‐induced LVD do not have functionally relevant CAD.
Low rates of acute and chronic GVHD with ATG and PTCy in matched and mismatched unrelated donor peripheral blood stem cell transplants
Authors: Prem Shruti , Atenafu Eshetu G , Al‐Shaibani Zeyad , Loach David , Law Arjun , Lam Wilson , Michelis Fotios V. , Thyagu Santhosh , Kim Dennis (Dong Hwan) , Howard Lipton Jeffrey , Kumar Rajat , Viswabandya Auro 
Published: March 2019

AbstractIntroductionWe evaluated the combination of ATG and PTCy for GVHD prophylaxis in matched and mismatched unrelated PBSCTs for high‐risk hematological malignancies.MethodsWe treated 102 patients with reduced intensity conditioning (RIC) with fludarabine, busulfan, and TBI 200 cGy. GVHD prophylaxis included rabbit ATG (thymoglobulin at total dose of 4.5 mg/kg divided over days −3 to −1), PTCy (50 mg/kg/day on day +3 and on day +4), and cyclosporine. Clinical and outcome data were collected retrospectively.ResultsAmong 102 patients, 76 patients received 10/10 MUD transplants and 26 patients received 9/10 mismatched transplants. The median age was 59 years. At a median follow‐up of 15 months (range 0.6 to −33 months), the 1‐year OS in MUD and MMUD cohort was 75% and 50%, respectively (P = 0.027). The corresponding one‐year PFS was 67% and 35%, respectively (P = 0.0024). The incidence of grade 3‐4 acute GVHD was 11.8% in MUD and 3.8% in MMUD group, and that of NIH stage moderate/severe chronic GVHD in the 2 groups was 10.5% and 7.6%, respectively. Cytomegalovirus (CMV) reactivation was seen in 49% patients. The cumulative incidence of relapse was 21.1% in the MUD group and 42.3% in the MMUD group.ConclusionOur experience shows that PTCy and ATG can be combined for GVHD prophylaxis in matched unrelated donor PBSCTs with low rates of Gr3‐4 acute GVHD and chronic GVHD, and acceptable relapse rates.
Farriery for the foal: A review part 2: Therapeutic farriery
Authors: O'Grady S. E. 
Published: March 2019

SummaryThe extensive nature of this topic warrants this review paper to be divided into two parts: ‘Basic trimming in foals’ and ‘Therapeutic farriery in foals’. Management of the feet and limbs during this juvenile period will often dictate the success of the foal as a sales yearling or mature sound athlete. Overall hoof care in the foal is often a joint venture between the veterinarian and the farrier. The orthopaedic disorders discussed in this paper that require input from the two professions are flexural limb deformities (FLD) and angular limb deformities (ALD). The concept of protecting the foot from the deleterious effects of mal‐loading created by manyFLDs andALDs is just as important as using the symptomatology as an instrument to correct the deformity. This paper presents a review of the current information regarding the farriery for these two limb deformities while dispelling some of the anecdotal methodology, such as the use of toe extensions to treat flexural deformities, that presently exists. Considering the deficiency of information in the literature, segments of this text will be based on the author's extensive clinical practice, comprehensive clinical records and comparisons of case outcomes.
Multifunctionality debt in global drylands linked to past biome and climate
Authors: Ye Jian‐Sheng , Delgado‐Baquerizo Manuel , Soliveres Santiago , Maestre Fernando T. 
Published: March 2019

AbstractPast vegetation and climatic conditions are known to influence current biodiversity patterns. However, whether their legacy effects affect the provision of multiple ecosystem functions, that is, multifunctionality, remains largely unknown. Here we analyzed soil nutrient stocks and their transformation rates in 236 drylands from six continents to evaluate the associations between current levels of multifunctionality and legacy effects of the Last Glacial Maximum (LGM) desert biome distribution and climate. We found that past desert distribution and temperature legacy, defined as increasing temperature from LGM, were negatively correlated with contemporary multifunctionality even after accounting for predictors such as current climate, soil texture, plant species richness, and site topography. Ecosystems that have been deserts since the LGM had up to 30% lower contemporary multifunctionality compared with those that were nondeserts during the LGM. In addition, ecosystems that experienced higher warming rates since the LGM had lower contemporary multifunctionality than those suffering lower warming rates, with a ~9% reduction per extra degree Celsius. Past desert distribution and temperature legacies had direct negative effects, while temperature legacy also had indirect (via soil sand content) negative effects on multifunctionality. Our results indicate that past biome and climatic conditions have left a strong “functionality debt” in global drylands. They also suggest that ongoing warming and expansion of desert areas may leave a strong fingerprint in the future functioning of dryland ecosystems worldwide that needs to be considered when establishing management actions aiming to combat land degradation and desertification.