bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose‐induced cAMP elevation in β‐cells involves amplification of constitutive and glucagon‐activated GLP‐1 receptor signalling
Authors: Shuai Hongyan , Xu Yunjian , Ahooghalandari Parvin , Tengholm Anders 
Published: December 2020

AbstractAimcAMP typically signals downstream of Gs‐coupled receptors and regulates numerous cell functions. In β‐cells, cAMP amplifies Ca2+‐triggered exocytosis of insulin granules. Glucose‐induced insulin secretion is associated with Ca2+‐ and metabolism‐dependent increases of the sub‐plasma‐membrane cAMP concentration ([cAMP]pm) in β‐cells, but potential links to canonical receptor signalling are unclear. The aim of this study was to clarify the role of glucagon‐like peptide‐1 receptors (GLP1Rs) for glucose‐induced cAMP signalling in β‐cells.MethodsTotal internal reflection microscopy and fluorescent reporters were used to monitor changes in cAMP, Ca2+ and ATP concentrations as well as insulin secretion in MIN6 cells and mouse and human β‐cells. Insulin release from mouse and human islets was also measured with ELISA.ResultsThe GLP1R antagonist exendin‐(9‐39) (ex‐9) prevented both GLP1‐ and glucagon‐induced elevations of [cAMP]pm, consistent with GLP1Rs being involved in the action of glucagon. This conclusion was supported by lack of unspecific effects of the antagonist in a reporter cell‐line. Ex‐9 also suppressed IBMX‐ and glucose‐induced [cAMP]pm elevations. Depolarization with K+ triggered Ca2+‐dependent [cAMP]pm elevation, an effect that was amplified by high glucose. Ex‐9 inhibited both the Ca2+ and glucose‐metabolism‐dependent actions on [cAMP]pm. The drug remained effective after minimizing paracrine signalling by dispersing the islets and it reduced basal [cAMP]pm in a cell‐line heterologously expressing GLP1Rs, indicating that there is constitutive GLP1R signalling. The ex‐9‐induced reduction of [cAMP]pm in glucose‐stimulated β‐cells was paralleled by suppression of insulin secretion.ConclusionAgonist‐independent and glucagon‐stimulated GLP1R signalling in β‐cells contributes to basal and glucose‐induced cAMP production and insulin secretion.
Safety of clonidine used for long‐term sedation in paediatric intensive care: A systematic review
Authors: Eberl Sonja , Ahne Gabriele , Toni Irmgard , Standing Joseph , Neubert Antje 
Published: December 2020

AimAlthough not approved, the α‐adrenoceptor agonist clonidine is considered an option for long‐term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication.MethodsRelevant literature was systematically identified from PubMed and Embase. We included interventional and observational studies on paediatric patients admitted to intensive care units and systemically long‐term sedated with clonidine‐containing regimes. In duplicates, we conducted standardised and independent full‐text assessment and extraction of safety data.ResultsData from 11 studies with 909 patients were analysed. The studies were heterogeneous regarding patient characteristics (age groups, comorbidity, or comedication) and sedation regimes (dosage, route, duration, or concomitant sedatives). Just four randomised controlled trials (RCTs) and one observational study had comparison groups, using placebo or midazolam. For safety outcomes, our validity evaluation showed low risk of bias only in three studies. All studies focused on haemodynamic problems, particularly bradycardia and hypotension. Observed incidences or subsequent interventions never caused concerns. However, only two RCTs allowed meaningful comparisons with control groups. Odds ratios showed no significant difference between the groups, but small sample sizes (50 and 125 patients) must be considered; pooled analyses were not reasonable.ConclusionAll evaluated studies concluded that the use of clonidine in paediatric intensive care units is safe. However, a valid characterisation of the safety profile remains challenging due to limited, biased and heterogeneous data and missing investigation of long‐term effects. This evaluation demonstrates the lack of data, which prevents reliable conclusions on the safety of clonidine for long‐term sedation in critically ill children. For an evidence‐based use, further studies are needed.
Curcumin attenuates renal interstitial fibrosis by regulating autophagy and retaining mitochondrial function in unilateral ureteral obstruction rats
Authors: Lu Miaomiao , Li Hang , Liu Wenlin , Zhang Xuemei , Li Lili , Zhou Hongli 
Published: December 2020

AbstractRenal interstitial fibrosis (RIF) is the leading cause of end‐stage renal disease, partly because of the lack of effective treatments. Curcumin, the primary active ingredient in turmeric, reportedly exerts potent antifibrotic effects. This study investigated the effects of curcumin on RIF in unilateral ureteral obstruction (UUO) rats and characterized the underlying action mechanism. UUO rats were treated with curcumin for 7 and 14 d. Renal fibrosis was evaluated through haematoxylin‐eosin staining, Masson staining, and type I and III collagen expression. Autophagy and mitochondria were observed through scanning electron microscopy. NLRP3 inflammasomes, mitochondria, and autophagy‐related proteins were detected through Western blotting. Mitochondrial respiratory enzyme activity was assessed spectrophotometrically. Compared with UUO rats, renal fibrosis was attenuated and NLRP3 inflammasome activation was inhibited in curcumin‐treated rats. Furthermore, mitochondrial dysfunction was ameliorated and the LC3B/LC3A ratio and Beclin‐1 expression were increased in curcumin‐treated rats. Additionally, curcumin inhibited the PI3K/AKT/mTOR pathway. These results indicate that curcumin is a promising treatment agent for RIF, and its antifibrotic effects may be mediated by the inhibition of NLRP3 inflammasome activity through the regulation of autophagy and protection of mitochondrial function in UUO rats.
Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing
Authors: Hedberg‐Oldfors Carola , Lindgren Ulrika , Basu Swaraj , Visuttijai Kittichate , Lindberg Christopher , Falkenberg Maria , Larsson Lekholm Erik , Oldfors Anders 
Published: December 2020

AbstractMuscle pathology in inclusion body myositis (IBM) typically includes inflammatory cell infiltration, muscle fibers with rimmed vacuoles and cytochrome c oxidase (COX)‐deficient fibers. Previous studies have revealed clonal expansion of large mitochondrial DNA (mtDNA) deletions in the COX‐deficient muscle fibers. Technical limitations have prevented complete investigations of the mtDNA deletions and other mtDNA variants. Detailed characterization by deep sequencing of mtDNA in muscle samples from 21 IBM patients and 10 age‐matched controls was performed after whole genome sequencing with a mean depth of mtDNA coverage of 46,000x. Multiple large mtDNA deletions and duplications were identified in all IBM and control muscle samples. In general, the IBM muscles demonstrated a larger number of deletions and duplications with a mean heteroplasmy level of 10% (range 1%‐35%) compared to controls (1%, range 0.2%‐3%). There was also a small increase in the number of somatic single nucleotide variants in IBM muscle. More than 200 rearrangements were recurrent in at least two or more IBM muscles while 26 were found in both IBM and control muscles. The deletions and duplications, with a high recurrence rate, were mainly observed in three mtDNA regions, m.534‐4429, m.6330‐13993, and m.8636‐16072, where some were flanked by repetitive sequences. The mtDNA copy number in IBM muscle was reduced to 42% of controls. Immunohistochemical and western blot analyses of IBM muscle revealed combined complex I and complex IV deficiency affecting the COX‐deficient fibers. In conclusion, deep sequencing and quantitation of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age‐matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.
Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2‐related disorders
Authors: Lorca Rebeca , Pannone Luca , Cuesta‐Llavona Elías , Bocchinfuso Gianfranco , Rodríguez‐Reguero Julian , Carpentieri Giovanna , Hernando Inés , Flex Elisabetta , Tartaglia Marco , Coto Eliecer , Gómez Juan , Martinelli Simone 
Published: December 2020

AbstractThe RASopathies are a family of clinically related disorders caused by mutations affecting genes participating in the RAS‐MAPK signaling cascade. Among them, Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are allelic conditions principally associated with dominant mutations in PTPN11, which encodes the nonreceptor SH2 domain‐containing protein tyrosine phosphatase SHP2. Individual PTPN11 mutations are specific to each syndrome and have opposite consequences on catalysis, but all favor SHP2's interaction with signaling partners. Here, we report on a subject with NS harboring biallelic variants in PTPN11. While the former (p.Leu261Phe) had previously been reported in NS, the latter (p.Thr357Met) is a novel change impairing catalysis. Members of the family carrying p.Thr357Met, however, did not show any obvious feature fitting NSML or within the RASopathy phenotypic spectrum. A major impact of this change on transcript processing and protein stability was excluded. These findings further support the view that NSML cannot be ascribed merely to impaired SHP2's catalytic activity and suggest that PTPN11 mutations causing this condition act through an alternative dominant mechanism.
Costs of elephant crop depredation exceed the benefits of trophy hunting in a community‐based conservation area of Namibia
Authors: Drake Michael D. , Salerno Jonathan , Langendorf Ryan E. , Cassidy Lin , Gaughan Andrea E. , Stevens Forrest R. , Pricope Narcisa G. , Hartter Joel 
Published: December 2020

AbstractThe Kazavango‐Zambezi Transfrontier Conservation Area is home to the largest remaining elephant population in Africa but is also the site of high levels of human‐elephant conflict through crop depredation. Offsetting the costs of coexisting with elephants in this area is critical to incentivizing elephant conservation within community‐based conservation (CBC) areas, and trophy hunting has long been touted as a method for generating revenue for communities from wildlife. However, the idea that sustainable elephant hunting can offset the costs of crop depredation remains largely untested. We combined household survey data, financial records, and elephant population data to compare the potential benefits of sustainable hunting with the costs of crop depredation in a CBC area in northeastern Namibia. We determined that sustainable trophy hunting only returns ~30% of the value of crops lost to the community and cannot alone offset the current costs of coexistence with elephants. As core institutions supporting the practice of conservation, CBC efforts must promote community management capacity to combine multiple wildlife‐based income streams and build partnerships at multiple scales of governance to address the challenges of elephant management.
Is the theory of collectivity of drinking cultures valid across educational groups?
Authors: Landberg Jonas , Trolldal Björn , Norström Thor 
Published: December 2020

AbstractIntroductionTo explore whether Skog's theory of collectivity of drinking cultures is valid across groups with different socioeconomic position (SEP).MethodsIndividual‐level information on alcohol consumption and SEP for the years 2004–2014 were retrieved from the Monitoring Project; a nationally representative monthly alcohol use survey. The analytical sample consisted of 162 369 respondents aged 25–79 years. SEP was measured by education level. Alcohol use was measured by yearly volume of consumption and frequency of heavy episodic drinking (HED). Respondents were divided into six SEP‐groups based on their education level and sex. Mean yearly volume consumption and prevalence of monthly HED was calculated for each group and graphically plotted against the overall mean volume of consumption.ResultsThe yearly changes in overall mean consumption during the study period reflected a collective shift in drinking across groups with basic, intermediate and high education. There were also indications that changes in overall mean consumption reflected collective shifts in the prevalence of HED across the SEP‐groups. Moreover, while the magnitude of the associations for both average volume and HED differed somewhat in strength across the SEP‐groups, they were clearly in the same, positive, direction.Discussion and ConclusionsOur findings add support for including a socioeconomic dimension to Skog's theory of collectivity of drinking cultures. Future studies should replicate our analyses on cases and periods with more tangible changes in the price and availability of alcohol.
Factors associated with potential over‐ and undertreatment of hyperglycaemia and annual measurement of HbA1c in type 2 diabetes in norwegian general practice
Authors: Tran Anh T. , Berg Tore J. , Mdala Ibrahimu , Gjelsvik Bjørn , Cooper John G. , Sandberg Sverre , Claudi Tor , Jenum Anne K. 
Published: December 2020

AbstractAimsTo identify individual and general practitioner (GP) characteristics associated with potential over‐ and undertreatment of hyperglycaemia in type 2 diabetes and with HbA1c not being measured.MethodsA cross‐sectional study that included 10233 individuals with type 2 diabetes attending 282 GPs. Individuals with an HbA1c measurement during the last 15 months were categorized as potentially overtreated if they were prescribed a sulphonylurea and/or insulin when the HbA1c was less than 53 mmol/mol (7%) when aged over 75 years or less than 48 mmol/mol (6.5%) when aged between 65 and 75 years. Potential undertreatment was defined as age less than 60 years and HbA1c > 64 mmol/mol (8.0%) or HbA1c > 69 mmol/mol (8.5%) and treated with lifestyle modification and/or monotherapy. We used multilevel binary and multinominal logistic regression models to examine associations.ResultsOverall, 4.1% were potentially overtreated, 7.8% were potentially undertreated and 11% did not have HbA1c measured. Characteristics associated with potential overtreatment were as follows: long diabetes duration, prescribed antihypertensive medication, cardiovascular disease and renal failure. Potential undertreatment was associated with male gender, non‐western origin and low educational level. Characteristics associated with not having an HbA1c measurement performed were male gender, age < 50 years and cardiovascular diseases. GP specialist status and GPs’ use of a Noklus diabetes application reduced the risk of not having an HbA1c measurement performed.ConclusionPotential overtreatment in elderly individuals with type 2 diabetes was relatively low. Nevertheless, appropriate de‐intensification or intensification of treatment and regular HbA1c measurement in identified subgroups is warranted.
Group therapy via videoconferencing for individuals with early psychosis: A pilot study
Authors: Lecomte Tania , Abdel‐Baki Amal , Francoeur Audrey , Cloutier Briana , Leboeuf Amélie , Abadie Pascale , Villeneuve Marie , Guay Stephane 
Published: December 2020

AbstractAimThe COVID‐19 pandemic has introduced many mental health professionals to therapy via videoconferencing. Mostly individual teletherapy has been offered and studied, although group therapy is often offered in clinics. In fact, little is known regarding group therapy's acceptability, feasibility, and potential impact when offered via videoconferencing.MethodsThis pilot study offered group cognitive‐behavioural therapy for psychosis via videoconferencing to 14 individuals with early psychosis either living in remote areas or confined during the pandemic.ResultsThe rate of consenting to the study (79%) and actual participation rates were acceptable (18.5 sessions out of 24). Although some technological obstacles were encountered, solutions offered allowed the videoconferencing group to be considered feasible for most participants and therapists. Prepost results on symptoms and self‐esteem were comparable to those of other studies using the same group treatment but in‐person. Alliance scores seemed similar as well.ConclusionsMore studies are warranted on the efficacy of group therapy via videoconferencing. This pilot study does offer promising results, suggesting that a wider range of people with early psychosis can be reached and benefit from the advantages of receiving an evidence‐based group intervention.
Development and characterization of a 3D in vitro model mimicking acneic skin
Authors: Laclaverie Marine , Rouaud‐Tinguely Pauline , Grimaldi Christine , Jugé Romain , Marchand Laëtitia , Aymard Elodie , Closs Brigitte 
Published: December 2020

AbstractAcne is an inflammatory skin disease of the pilosebaceous unit, involving four essential factors: hyperseborrhoea combined to a modification of sebum composition, colonization by Cutibacterium (C.) acnes, hyperkeratinization and secreted inflammation. Understanding and mimicking compromised skin is essential to further develop appropriate therapeutic solutions. This study aimed to develop new in vitro 3D models mimicking acneic skin, by combining two main factors involved in the physiopathology, namely, altered sebum composition and C. acnes invasion. Normal human keratinocytes were first used to generate reconstructed human epidermis (RHE) that were then left untreated (control) or treated topically with a combination of both peroxidized squalene and C. acnes cultures. Once validated, this model considered relevant to mimic acneic skin, was further improved by using different phylotypes of C. acnes strains specifically isolated from healthy and acneic patients. While both phylotypes IB and II did not significantly alter RHE, C. acnes IA1 strains induce major acneic skin hallmarks such as hyperkeratinization, secreted inflammation and altered barrier function. Interestingly, these results are obtained independently of the origin of IA1 phylotypes (acneic vs. healthy patient), thus suggesting a role of the ecosystem in controlling C. acnes virulence in healthy skin. In conclusion, by combining two major factors involved in the physiopathology of acne, we (1) succeeded to design in vitro 3D models mimicking this skin disorder and (2) highlighted how C. acnes phylotypes can have an impact on epidermal physiology. These relevant models will be suitable for the substantiation of therapeutic molecules dedicated to acne treatment.
Risk of short‐term biodiversity loss under more persistent precipitation regimes
Authors: Reynaert Simon , De Boeck Hans J. , Verbruggen Erik , Verlinden Maya , Flowers Nina , Nijs Ivan 
Published: December 2020

AbstractRecent findings indicate that atmospheric warming increases the persistence of weather patterns in the mid‐latitudes, resulting in sequences of longer dry and wet periods compared to historic averages. The alternation of progressively longer dry and wet extremes could increasingly select for species with a broad environmental tolerance. As a consequence, biodiversity may decline. Here we explore the relationship between the persistence of summer precipitation regimes and plant diversity by subjecting experimental grassland mesocosms to a gradient of dry–wet alternation frequencies whilst keeping the total precipitation constant. The gradient varied the duration of consecutive wet and dry periods, from 1 up to 60 days with or without precipitation, over a total of 120 days. An alternation of longer dry and wet spells led to a severe loss of species richness (up to –75% relative to the current rainfall pattern in W‐Europe) and functional diversity (enhanced dominance of grasses relative to nitrogen (N)‐fixers and non‐N‐fixing forbs). Loss of N‐fixers and non‐N‐fixing forbs in severe treatments was linked to lower baseline competitive success and higher physiological sensitivity to changes in soil moisture compared to grasses. The extent of diversity losses also strongly depended on the timing of the dry and wet periods. Regimes in which long droughts (≥20 days) coincided with above‐average temperatures showed significantly more physiological plant stress over the experimental period, greater plant mortality, and impoverished communities by the end of the season. Across all regimes, the duration of the longest period below permanent wilting point was an accurate predictor of mortality across the communities, indicating that increasingly persistent precipitation regimes may reduce opportunities for drought stress alleviation. We conclude that without recruitment, which was precluded in this experiment, summer precipitation regimes with longer dry and wet spells will likely diminish plant diversity, at least in the short term.
Adherence to Maastricht V/Florence consensus report for the management ofHelicobacter pyloriinfection among primary care physicians and medical students in Croatia: A cross‐sectional study
Authors: Jukic Ivana , Vukovic Jonatan , Rusic Doris , Bozic Josko , Bukic Josipa , Leskur Dario , Seselja Perisin Ana , Modun Darko 
Published: December 2020

AbstractBackgroundHelicobacter pylori(H pylori) eradication is becoming increasingly difficult. The aim of our study was to determine the knowledge of current guidelines and attitude in the diagnosis and treatment ofH pyloriinfection in primary care physicians (PCPs) and medical students in Croatia.Materials and MethodsA study was conducted among PCPs and medical students to evaluate adherence to Maastricht V consensus guidelines. Questionnaire was distributed by e‐mail to 2338 PCPs offices in Croatia and to the medical students from the University of Split School of Medicine. Responses were collected electronically from June 22 to August 22, 2020.ResultsTwo hundred forty‐nine PCPs and 169 medical students were included in the study. Bismuth or non‐bismuth‐based quadruple therapy as first‐line treatment forH pyloriwas the choice of 4.8% of PCPs and 13% of students, while 66.3% PCPs and 79.9% students would choose clarithromycin‐based triple therapy. Bismuth‐based quadruple therapy was the most preferred second line of treatment for 45.4% of PCPs and 34.9% of students. Only 2.8% PCPs and 7.1% of students would correctly recommend first and second line of treatment for H. pylori infection. A larger proportion of students than PCPs would prefer C13‐urea breath test (50.3% vs 6.4%). Only 59.0% PCPs would treat forH pyloriin all patients including the asymptomatic ones. Students more frequently recognized the link betweenH pyloriand gastric cancer compared with PCPs (92.9% vs 73.5%).ConclusionsPrimary care physicians and medical students’ knowledge ofH pyloriguidelines are insufficient in Croatia and ask for additional training.