bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heroin‐induced respiratory depression and the influence of dose variation: within‐subject between‐session changes following dose reduction
Authors: Tas Basak , Jolley Caroline J. , Kalk Nicola J. , van der Waal Rob , Bell James , Strang John 
Published: February 2020

AbstractBackground and aimsGlobally, more than 100 000 people die annually from opioid overdose. Opportunities to study physiological events in at‐risk individuals are limited. This study examined variation of opioid dose and impact on respiratory depression in a chronic injecting heroin user at separate time‐points during his long‐term diamorphine maintenance treatment.DesignA single‐subject study over 5 years during which participant underwent experimental studies on diamorphine‐induced respiratory depression, at changing maintenance doses.SettingA clinical research facility.ParticipantMale subject on long‐term injectable diamorphine (pharmaceutical heroin) maintenance treatment for heroin addiction.MeasurementsPhysiological measures of oxygen saturation (SpO2), end‐tidal carbon dioxide (ETCO2) and respiratory rate (RR) were used to indicate severity of respiratory depression.Findings(1) After diamorphine injection, respiratory regulation became abnormal, with prolonged apnoea exceeding 20 sec (maximum 56 sec), elevated ETCO2 (maximum 6.9%) and hypoxaemia (minimum SpO2 80%). (2) Abnormalities were greater with highest diamorphine dose: average SpO2 was 89.3% after 100 mg diamorphine versus 93.6% and 92.8% for the two 30‐mg doses. (3) However, long apnoeic pauses and high levels of ETCO2% were also present after lower doses.ConclusionsWith marked inter‐session variability, these findings corroborate observations of inconsistent relationships between opioid dose and overdose risk.
Late‐onset hypogonadism: Prostate safety
Authors: Miranda Eduardo P. , Torres Luiz Otávio 
Published: February 2020

AbstractBackgroundThere have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers.ObjectivesThe aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer.Materials and MethodsWe have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety.ResultsTestosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late‐onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non–high‐risk disease.ConclusionTestosterone replacement therapy could be considered for most men with late‐onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.
Health costs of post‐operative complications following rectal resection: a systematic review
Authors: Johnston Samuel , Louis Maleck , Churilov Leonid , Ma Ronald , Christophi Christopher , Weinberg Laurence 
Published: February 2020

AbstractBackgroundPost‐operative complications following rectal resection pose significant health and cost implications for patients and health providers. The objective of this study is to review the associated cost of complications following rectal resection. This included reporting on the proportion and severity of these complications, associated length of stay and surgical technique used. Studies were sourced from Embase OVID, MEDLINE OVID (ALL) and Cochrane Library databases by utilizing a search strategy.MethodsThis search contained studies from 1 January 2010 until 13 February 2019. Studies were included from the year 2010 to account for the implementation of enhanced recovery after surgery protocols. Studies that reported the financial cost associated with complications were included. Any indication for rectal resection was considered. Data was extracted into a formatted table and a narrative synthesis was performed.ResultsWe identified 13 eligible studies for inclusion. There was strong evidence to suggest that complications are associated with increased costs. There was considerable variation as to the costs attributable to complications ($1443 (P < 0.001) to $17 831 (P < 0.0012), n = 12). The presence of complications was associated with an increased length of stay (5.54 (P‐value not given) to 21.04 (P < 0.0001) days, n = 7). There was significant variation in the proportion of complications (6.41 to 64.71%, n = 8). Weak evidence existed around surgical technique used and the associated cost of complications. There was considerable heterogeneity among included studies.ConclusionsComplications following rectal resection increased health costs. Costs should be standardized and provide a clear methodology for their calculation. Complications should be standardized and include a grading of severity.
Regulation of integrin α6A by lactogenic hormones in rat pancreatic β‐cells: Implications for the physiological adaptation to pregnancy
Authors: Møldrup Annette , Lindberg Martin Nerup , Galsgaard Elisabeth D. , Henriksen Ulrik , Dalgaard Louise T. , Nielsen Jens Høiriis 
Published: February 2020

AbstractAimDuring pregnancy, the maternal β‐cell mass is increased in order to adapt to the physiological changes in insulin demand. Lactogenic hormones stimulate rodent β‐cell attachment and proliferation in vitro. The aim of this study was to identify adhesion molecules involved in expansion of the β‐cell mass during pregnancy in the rat.MethodsQuantitative RT‐PCR was used to evaluate the expression of several integrins and laminins in isolated neonatal rat islets in response to growth hormone (GH) and prolactin (PRL) treatment. Double‐immunofluorescence staining of rat pancreas was used to localize the expression of integrin α6β1. β‐cell proliferation was evaluated by incorporation of bromodeoxyuridine (BrdU). The role of STAT5 phosphorylation was tested by addition of STAT5 mutants.ResultsWe found that the mRNA level of integrin‐α6A, was upregulated 2.5‐fold by PRL or GH. During pregnancy, a biphasic 3.4‐4.5‐fold increase of integrin‐α6A and B mRNA levels was detected. A disintegrin peptide (DP) reduced the hormone‐stimulated mitotic activity in neonatal rat β‐cells from 2.9 ± 0.4‐fold to 1.3 ± 0.3‐fold. The hormone‐induced expression of α6β1 integrin was shown to be mediated via STAT5 as a dominant negative (DN) mutant prevented and a constitutive active (CA) mutant augmented the hGH‐stimulated expression. The DP was found to inhibit hGH‐induced transactivation of the PRL receptor promoter 1A and reduce the hGH‐induced phosphorylation of STAT5.ConclusionThese results show that integrin‐α6 in β‐cells is upregulated by lactogenic hormones and is required but not sufficient for the expansion of the β‐cell mass in pregnancy in the rat, which may have implications for the understanding and treatment of gestational diabetes mellitus.
Prospective serial diagnostic study: the effects of position and provocative tests on the diagnosis of oesophageal motility disorders by high‐resolution manometry
Authors: Misselwitz Benjamin , Hollenstein Michael , Bütikofer Simon , Ang Daphne , Heinrich Henriette , Fox Mark 
Published: February 2020

SummaryBackgroundStandard high‐resolution manometry (HRM) protocols are based on 10 single water swallows acquired in the supine position.AimsTo assess the impact of position, rapid drink challenge and solid test meal on the diagnosis of oesophageal motility disorders.MethodsSeventy‐two healthy volunteers (20‐76 years) and 366 consecutive patients (18‐90 years) completed HRM with 10 single water swallows in the supine and upright positions. Rapid drink challenge was performed twice, before and after the solid test meal. Diagnosis based on single water swallows in the supine position (Chicago Classification v3.0) was compared with results in the upright position and with provocative tests.ResultsOverall, diagnostic agreement in the supine and upright positions was present in 296/438 (67.6%) subjects. This increased to 90.0% when ineffective oesophageal motility was considered with normal motility. Integrated relaxation pressure was 4 mm Hg higher in the supine position. There was a higher prevalence of inconsistent, likely false positive, diagnoses of outlet obstruction in the supine compared to the upright position (16/20 vs 1/4 patients, P = 0.0007). Similarly, the difference in concordance for the diagnosis of oesophago‐gastric junction obstruction or achalasia between single water swallows in the supine and upright positions with solid test meal was significant (12/29 (41.4%) vs 12/14 (85.7%), P = 0.0087).ConclusionDiagnostic agreement for oesophageal motility disorders based on single water swallows in the upright and supine positions was moderate, with frequent discordant findings for ineffective motility and outlet obstruction. HRM studies can be performed in either position, using appropriate reference values. Rapid drink challenge or solid test meal can resolve diagnostic discrepancies.
Energy balance in lactating goats: Response to mixture of conjugated linoleic acid
Authors: Granados‐Rivera Lorenzo D. , Hernández‐Mendo Omar , Maldonado‐Jáquez Jorge A. 
Published: February 2020

AbstractThe objective of this study was to determine the energy balance in early lactating local goats when supplemented with conjugated linoleic acid. Fifteen local goats from the north‐east of Mexico were used. Three treatments were evaluated: (a) Control (Base diet); (b) CLA 50 g; and (c) CLA 90 g. The CLA was a mixture of micro‐encapsulated FA, which supplied c9, t11 and t10, c12. Goats had an adaptation period of 2 weeks and 7 experimental weeks. The variables evaluated were body weight, DMI, milk yield, and fat, protein, and lactose yield, FA milk profile, and energy balance. The analysis of the data was analyzed as repeated measures using the PROC MIXED procedure and Tukey test (p < .05). In milk of goats from the treatment 90 g of the isomer t10, c12 CLA (p < .05) the milk fat content and milk fat yield with respect to the control treatment were reduced and the energy balance was improved. In goats treated with 11 g of t10, c12 CLA increased (p < .05) milk yield and milk lactose content. These results suggest that energy not used to synthesize dairy fat was used to increase milk yield and improve energy balance.
Development of a structured clinical pharmacology review for specialist support for management of complex polypharmacy in primary care
Authors: Threapleton Christopher J.D. , Kimpton James E. , Carey Iain M. , DeWilde Stephen , Cook Derek G. , Harris Tess , Baker Emma H. 
Published: February 2020

AimsPolypharmacy is widespread and associated with medication‐related harms, including adverse drug reactions, medication errors and poor treatment adherence. General practitioners and pharmacists cite limited time and training to perform effective medication reviews for patients with complex polypharmacy, yet no specialist referral mechanism exists. To develop a structured framework for specialist review of primary care patients with complex polypharmacy.MethodsWe developed the clinical pharmacology structured review (CPSR) and stopping by indication tool (SBIT). We tested these in an age‐sex stratified sample of 100 people with polypharmacy aged 65–84 years from the Clinical Practice Research Datalink, an anonymised primary care database. Simulated medication reviews based on electronic records using the CPSR and SBIT were performed. We recommended medication changes or review to optimise treatment benefits, reduce risk of harm or reduce treatment burden.ResultsRecommendations were made for all patients, for almost half (4.8 ± 2.4) of existing medicines (9.8 ± 3.1), most commonly stopping a drug (1.7 ± 1.3/patient) or reviewing with the patient (1.4 ± 1.2/patient). At least 1 new medicine (0.7 ± 0.9) was recommended for 51% patients. Recommendations predominantly aimed to reduce harm (44%). There was no relationship between number of recommendations made and time since last primary care medication review. We identified a core set of clinical information and investigations (polypharmacy workup) that could inform a standard screen prior to specialist review.ConclusionThe CPSR, SBIT and polypharmacy workup could form the basis of a specialist review for patients with complex polypharmacy. Further research is needed to test this approach in patients in general practice.
Pharmacology and physiological function of the orphan GPRC6A receptor
Authors: Jørgensen Christinna V. , Bräuner‐Osborne Hans 
Published: February 2020

AbstractThe G protein‐coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) is a Gq/11‐coupled receptor widely expressed in human and rodent tissues. The proposed endogenous ligands are L‐amino acids, divalent cations, osteocalcin and testosterone. This MiniReview provides an updated overview of the literature including the latest in vitro and in vivo studies. GPRC6A forms homodimers, it undergoes constitutive internalization, and very interestingly, the reason for the intracellular retention of the human receptor has been revealed. Multiple physiological functions of GPRC6A have been suggested based on studies using three different global GPRC6A knockout (KO) mouse models where exon II, exon VI or the full locus has been deleted. The newest studies on the full locus GPRC6A KO model show intact glucose and bone homoeostasis with a minor reduction in serum osteocalcin levels. Unfortunately, the physiological function of the receptor remains elusive due to a general lack of consensus/validation of reported phenotypes of the different KO models, and more research is thus warranted to uncover the physiological function. Recent discoveries of human genetic variants that cause either a premature stop codon or an intracellular retention of the receptor point towards human population studies as the preferred approach to continue studies on the function of GPRC6A.
Interleukin‐1 receptor‐associated kinase 4 inhibitor interrupts toll‐like receptor signalling and sensitizes chronic lymphocytic leukaemia cells to apoptosis
Authors: Delvecchio Vincenza Simona , Sana Ilenia , Mantione Maria Elena , Vilia Maria Giovanna , Ranghetti Pamela , Rovida Alessandra , Angelillo Piera , Scarfò Lydia , Ghia Paolo , Muzio Marta 
Published: February 2020

SummaryChronic lymphocytic leukaemia (CLL) cells are strongly influenced by microenvironmental signals through the activation of distinct membrane receptors including the B‐cell receptor and toll‐like receptors (TLR). Recapitulating TLR stimulation in vitro by treating CLL cells with the TLR9 ligand CpG can induce metabolic activation and protection from apoptosis. We hypothesized that interfering with TLR signalling may be beneficial for treating CLL, and we tested in preclinical studies the effect of a specific interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitory small molecule on primary leukaemic cells isolated from the peripheral blood of patients. We observed that IRAK4, an upstream kinase of the TLR pathway, is expressed in patients with CLL, and lower IRAK4 mRNA levels associate with a better outcome. The specific IRAK4 inhibitor disrupted TLR signalling as assessed by reduction of the specific biomarkers NFKBIZ and interleukin‐6 mRNAs, and restrained the protective effect of in vitro TLR stimulation on cell viability. To note, IRAK4 inhibitor induced p53 and triggered apoptosis. Co‐treatment of CLL cells with increasing concentrations of IRAK4i and the Bruton tyrosine kinase inhibitor ibrutinib demonstrated a synergistic effect. Our results suggest that targetting IRAK4 may represent a novel approach in CLL and may be combined with other signalling inhibitors.
Prospective, real‐time monitoring of pegylated Escherichia coli and Erwinia asparaginase therapy in childhood acute lymphoblastic leukaemia and non‐Hodgkin lymphoma in Belgium
Authors: Mondelaers Veerle , Ferster Alina , Uyttebroeck Anne , Brichard Bénédicte , van der Werff ten Bosch Jutte , Norga Koenraad , Francotte Nadine , Piette Caroline , Vandemeulebroecke Katrien , Verbeke Charlotte , Schmidt Susanne , Benoit Yves , Lammens Tim , De Moerloose Barbara 
Published: February 2020

SummaryAsparaginase (ASNase) is an important anti‐leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non‐Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti‐ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real‐time therapeutic drug monitoring of pegylated Escherichia coli (PEG‐)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second‐line after hypersensitivity to PEG‐ASNase. In total, 286 children were enrolled in the PEG‐ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG‐ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2‐day interval of IM administrations.
Gene expression profiling of primary vitreoretinal lymphoma
Authors: Arai Ayako , Takase Hiroshi , Yoshimori Mayumi , Yamamoto Kouhei , Mochizuki Manabu , Miura Osamu 
Published: February 2020

AbstractThe characteristics of tumor cells of primary vitreoretinal lymphoma (PVRL) have not been defined, although researches have shown that most cases are of diffuse large B‐cell lymphoma (DLBCL). To determine the subtype and biological characteristics of tumor cells of PVRL, we performed a gene expression profiling analysis. RNA was extracted from the vitreous fluid of 7 PVRL patients and from nodal samples of 10 DLBCL patients: 6 of germinal center B‐cell (GCB) type and 4 of activated B‐cell (ABC) type determined by Hans’ criteria. Six PVRL samples showed gene expression profiles that were similar to each other. The patterns were different from those of the ABC‐type nodular DLBCL but relatively close to those of the GCB‐type nodular DLBCL. Interestingly, all of the 6 examined PVRL samples had either MYD88L265P or mutation in the immunoreceptor tyrosine‐based activation motif (ITAM) region of CD79B. Five PVRL patients with similar gene expression profiles were treated with a standardized regimen: intravitreal administration of methotrexate (MTX) followed by six courses of systemic high doses of MTX. As a result, 2 patients had CD79B mutations and showed early central nervous system (CNS) progression. Patients without CNS progression did not have this mutation. In conclusion, PVRL had unique genetic features: an expression pattern different from ABC‐type and relatively close to GCB‐type DLBCL. CD79B mutations showed potential to serve as prognostic markers for CNS progression.
STIM1 knock-down decreases the affinity of obinutuzumab for CD20 by altering CD20 localization to Triton-soluble membrane
Authors: Heo W , Jin N , Park M S , Kim H-Y , Yoon S M , Lee J , Kim J Y 
Published: February 2020

SummaryObinutuzumab is thought to exert its effects through its high antibody-dependent cellular cytotoxicity (ADCC) via glyco-engineering of the Fc region. In addition, obinutuzumab causes direct binding-induced cell death (DCD) only by specifically binding to its target CD20, a Ca2+ channel. However, the specific features of CD20 related to obinutuzumab binding-induction of cell death are not clearly understood. In this study, we evaluated the relationship between the Ca2+ channel features of CD20 as a store-operated Ca2+ channel (SOC) and obinutuzumab binding-induced cell death. Ca2+ channel function and biochemical analysis revealed that CD20 is an Orai1- and stromal interaction molecule (STIM1)-dependent Ca2+ pore. However, binding of obinutuzumab on CD20 did not have any effect on Ca2+ influx activity of CD20; the direct cell death rate mediated by obinutuzumab binding was almost equivalent with or without the extracellular Ca2+ condition. Given the apparent interaction between STIM1 and CD20, we observed Triton-X solubilized obinutuzumab-bound CD20 accompanied by STIM1. Subsequently, obinutuzumab binding and cell death were decreased by STIM1 knock-down in Ramos B cells. Thus, STIM1 directly contributes to cell death by increasing the affinity of cells for obinutuzumab by transferring CD20 to the Triton-soluble membrane region.
The nature and culture of social work with children and families in long‐term casework: Findings from a qualitative longitudinal study
Authors: Ferguson Harry , Warwick Lisa , Cooner Tarsem Singh , Leigh Jadwiga , Beddoe Liz , Disney Tom , Plumridge Gillian 
Published: February 2020

AbstractSocial work in the United Kingdom is preoccupied with what social workers cannot do due to having limited time to spend with service users. Yet remarkably little research has examined what social workers actually do, especially in long‐term relationships. This paper draws from an ethnographic study of two social work departments in England that spent 15 months observing practice and organizational life. Our findings show that social work some of the time has a significant amount of involvement with some service users and the dominant view that relationship‐based practice is rarely achieved is in need of some revision. However, families at one research site received a much more substantial, reliable overall service due to the additional input of family support workers and having a stable workforce who had their own desks and were co‐located with managers in small team offices. This generated a much more supportive, reflective culture for social workers and service users than at the second site, a large open plan “hot‐desking” office. Drawing on relational, systemic, and complexity theories, the paper shows how the nature of what social workers do and culture of practice are shaped by the interaction between available services, office designs, and practitioners', managers', and service users' experiences of relating together.