bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of canagliflozin on human myocardial redox signalling: clinical implications
Authors: Kondo Hidekazu , Akoumianakis Ioannis , Badi Ileana , Akawi Nadia , Kotanidis Christos P , Polkinghorne Murray , Stadiotti Ilaria , Sommariva Elena , Antonopoulos Alexios S , Carena Maria C , Oikonomou Evangelos K , Reus Elsa Mauricio , Sayeed Rana , Krasopoulos George , Srivastava Vivek , Farid Shakil , Chuaiphichai Surawee , Shirodaria Cheerag , Channon Keith M , Casadei Barbara , Antoniades Charalambos 
Published: June 2021

Abstract

Aims
Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans.

Methods and results
Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.− production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM.

Conclusions
We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy
Authors: Lopes Luis R , Garcia-Hernández Soledad , Lorenzini Massimiliano , Futema Marta , Chumakova Olga , Zateyshchikov Dmitry , Isidoro-Garcia Maria , Villacorta Eduardo , Escobar-Lopez Luis , Garcia-Pavia Pablo , Bilbao Raquel , Dobarro David , Sandin-Fuentes Maria , Catalli Claudio , Gener Querol Blanca , Mezcua Ainhoa , Garcia Pinilla Jose , Bloch Rasmussen Torsten , Ferreira-Aguar Ana , Revilla-Martí Pablo , Basurte Elorz Maria Teresa , Bautista Paves Alicia , Ramon Gimeno Juan , Figueroa Ana Virginia , Franco-Gutierrez Raul , Fuentes-Cañamero Maria Eugenia , Martinez Moreno Marina , Ortiz-Genga Martin , Piqueras-Flores Jesus , Analia Ramos Karina , Rudzitis Ainars , Ruiz-Guerrero Luis , Stein Ricardo , Triguero-Bocharán Mayte , de la Higuera Luis , Ochoa Juan Pablo , Abu-Bonsrah Dad , Kwok Cecilia Y T , Smith Jacob B , Porrello Enzo R , Akhtar Mohammed M , Jager Joanna , Ashworth Michael , Syrris Petros , Elliott David A , Monserrat Lorenzo , Elliott Perry M 
Published: June 2021

AbstractAimsThe aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P &lt; 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P &lt; 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.Conclusions Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Evaluating the genetic basiss of anti-cancer property of Taxol in Saccharomyces cerevisiae model
Authors: Veerabhadrappa Bhavana , Subramanian Subasri , S. J. Sudharshan , Dyavaiah Madhu 
Published: June 2021

ABSTRACT
Taxol has been regarded as one of the most successful anti-cancer drugs identified from natural sources to date. Although Taxol is known to sensitize cells by stabilizing microtubules, its ability to cause DNA damage in peripheral blood lymphocytes and to induce oxidative stress and apoptosis indicates that Taxol may have other modes of cytotoxic action. This study focuses on identifying the additional targets of Taxol that may contribute to its multifaceted cell killing property, using Saccharomyces cerevisiae. We show that yeast oxidative stress response mutants (sod1Δ, tsa1Δ and cta1Δ) and DNA damage response mutants (mre11∆, sgs1∆ and sub1∆) are highly sensitive to Taxol. Our results also show that Taxol increases the level of reactive oxygen species (ROS) in yeast oxidative stress response mutant strains. Further, 4ʹ,6-Diamidino-2ʹ-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) staining show that Taxol induces apoptotic features such as nuclear fragmentation and chromatin condensation in DNA repair mutants. On the whole, our results suggest that Taxol's cytotoxic property is attributed to its multifaceted mechanism of action. Yeast S. cerevisiae anti-oxidant and DNA repair gene mutants are sensitive to Taxol compared to wild-type, suggesting yeast model can be used to identify the genetic targets of anti-cancer drugs.
Maternal Piwi regulates primordial germ cell development to ensure the fertility of female progeny in Drosophila
Authors: Gonzalez Lauren E , Tang Xiongzhuo , Lin Haifan 
Published: June 2021

Abstract
In many animals, germline development is initiated by proteins and RNAs that are expressed maternally. PIWI proteins and their associated small noncoding PIWI-interacting RNAs (piRNAs), which guide PIWI to target RNAs by base-pairing, are among the maternal components deposited into the germline of the Drosophila early embryo. Piwi has been extensively studied in the adult ovary and testis, where it is required for transposon suppression, germline stem cell self-renewal, and fertility. Consequently, loss of Piwi in the adult ovary using piwi-null alleles or knockdown from early oogenesis results in complete sterility, limiting investigation into possible embryonic functions of maternal Piwi. In this study, we show that the maternal Piwi protein persists in the embryonic germline through gonad coalescence, suggesting that maternal Piwi can regulate germline development beyond early embryogenesis. Using a maternal knockdown strategy, we find that maternal Piwi is required for the fertility and normal gonad morphology of female, but not male, progeny. Following maternal piwi knockdown, transposons were mildly derepressed in the early embryo but were fully repressed in the ovaries of adult progeny. Furthermore, the maternal piRNA pool was diminished, reducing the capacity of the PIWI/piRNA complex to target zygotic genes during embryogenesis. Examination of embryonic germ cell proliferation and ovarian gene expression showed that the germline of female progeny was partially masculinized by maternal piwi knockdown. Our study reveals a novel role for maternal Piwi in the germline development of female progeny and suggests that the PIWI/piRNA pathway is involved in germline sex determination in Drosophila.
Sex differences in outcomes following coronary artery bypass grafting: a meta-analysis
Authors: Bryce Robinson N , Naik Ajita , Rahouma Mohamed , Morsi Mahmoud , Wright Drew , Hameed Irbaz , Di Franco Antonino , Girardi Leonard N , Gaudino Mario 
Published: June 2021

Abstract OBJECTIVESPrevious reports have found females are a higher risk of morbidity and mortality following isolated coronary artery bypass grafting (CABG). Here, we describe the differences in outcomes following isolated CABG between males and females.METHODSFollowing a systematic literature search, studies reporting sex-related outcomes following isolated CABG were pooled in a meta-analysis performed using the generic inverse variance method. The primary outcome was operative mortality. Secondary outcomes included rates of stroke, repeat revascularization, myocardial infarction, major adverse cardiac events, and late mortality. Subgroup analyses were performed for studies published before and after the year 2000 and for the type of risk adjustment.RESULTSEighty-four studies were included with a total of 903 346 patients. Females were at higher risk for operative mortality (odds ratio: 1.77, 95% confidence interval [CI]: 1.64–1.92, P &lt; 0.001). At subgroup analysis, there was no difference in operative or late mortality between studies published prior and after 2000 or between studies using risk adjustment. Females were at a higher risk of late mortality (incidence rate ratio [IRR]: 1.16, 95% CI: 1.06–1.26, P &lt; 0.001), major adverse cardiac events (IRR: 1.40, 95% CI: 1.19–1.66, P &lt; 0.001), myocardial infarction (IRR: 1.28, 95% CI: 1.13–1.45, P &lt; 0.001) and stroke (IRR: 1.31, 95% CI: 1.15–1.51, P &gt; 0.001) but not repeat revascularization (IRR: 0.99, 95% CI: 0.76–1.29, P = 0.95). The use of the off-pump technique or multiple arterial grafts was not associated with the primary outcome.CONCLUSIONSFemales undergoing CABG are at higher risk for operative and late mortality as well as postoperative events including major adverse cardiac events, myocardial infarction and stroke.PROSPERO registrationCRD42020187556
A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders
Authors: Romero-Miguel Diego , Casquero-Veiga Marta , MacDowell Karina S , Torres-Sanchez Sonia , Garcia-Partida José Antonio , Lamanna-Rama Nicolás , Romero-Miranda Ana , Berrocoso Esther , Leza Juan C , Desco Manuel , Soto-Montenegro María Luisa 
Published: June 2021

Abstract

Background
Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.

Methods
On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35–49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.

Results
MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).

Conclusions
MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2–ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
Smoking Affects the Patterns of Metabolic Disorders and Metabolic Syndrome in Patients With First-Episode Drug-Naive Schizophrenia: A Large Sample Study Based on the Chinese Han Population
Authors: Li Zezhi , Wang Shuning , Chen Yuping , Wu Xi , Gu Yinjun , Lang Xiaoe , Wu Fengchun , Zhang Xiang Yang 
Published: June 2021

AbstractObjectiveAlthough metabolic disorders and smoking are common in schizophrenia, few studies have investigated the effects of smoking on metabolic disorders or metabolic syndrome (MetS) in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. We sought to investigate the differences in metabolic disorders and MetS between smoking and nonsmoking FEDN schizophrenia patients.MethodsA total of 428 FEDN schizophrenia patients and 435 controls were recruited. Blood pressure, waist circumference, body mass index (BMI), lipid profiles, and glucose metabolism were measured. The psychopathology was evaluated by Positive and Negative Syndrome Scale.ResultsFEDN schizophrenia patients had a higher smoking rate than controls (23.8% vs 14.0%, P &lt; .001). After adjusting for confounding variables, the prevalence of MetS, overweight, hypertension, hypertriglyceridemia, elevated insulin, and insulin resistance in smoking patients was higher than those in nonsmoking patients, while overweight and hypertension were higher in the smoking controls than in nonsmoking controls (all P &lt; .05). In smoking patients, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS, while in nonsmoking patients, waist circumference, systolic blood pressure, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS. In smoking patients, BMI and homeostatic model assessment for insulin resistance were associated factors of MetS (both P &lt; .05). In nonsmoking patients, sex, BMI, insulin, and homeostatic model assessment for insulin resistance were associated factors of MetS (all P &lt; .05).ConclusionsOur study indicates that smoking schizophrenia patients have a higher prevalence of MetS and metabolic disorders than nonsmoking patients. Moreover, smoking and nonsmoking patients have different contributing components and associated factors for MetS.
The Limits of Static Interests: Appreciating Asylum Seekers’ Contributions to a Country’s Economy in Article 8 ECHR Adjudication on Expulsion
Authors: Reyhani Adel-Naim , Golmohammadi Gloria 
Published: June 2021

Abstract
This article critiques the European Court of Human Rights’ approach towards assessing asylum seekers’ right to respect for private and family life under article 8 of the European Convention on Human Rights in the context of their expulsion. In balancing the right of the individual against the public interest, it is argued that the court’s case law follows a static perspective. The rigidly defined assumption that the public interest lies in enforcing migration control and that the societal contributions of asylum seekers cannot influence the strength of the public interest is prevalent in jurisprudence yet underexplored in scholarship. The article uses the case of asylum seekers who contribute to a country’s economy to demonstrate that the court currently fails to appreciate the interdependence between these interests. It then suggests a path by which the court’s approach might be adjusted towards more nuance, ultimately allowing the contributions of asylum seekers to European communities to be appropriately reflected in legal determinations.
Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages
Authors: Liu Kaiwen , Sato Ryota , Shibata Takuma , Hiranuma Ryosuke , Reuter Tatjana , Fukui Ryutaro , Zhang Yun , Ichinohe Takeshi , Ozawa Manabu , Yoshida Nobuaki , Latz Eicke , Miyake Kensuke 
Published: June 2021

Abstract
RNase T2, a ubiquitously expressed RNase, degrades RNAs in the endosomal compartments. RNA sensors, double-stranded RNA (dsRNA)-sensing Toll-like receptor 3 (TLR3) and single-stranded RNA (ssRNA)-sensing TLR7, are localized in the endosomal compartment in mouse macrophages. We here studied the role of RNase T2 in TLR3 and TLR7 responses in macrophages. Macrophages expressed RNase T2 and a member of the RNase A family RNase 4. RNase T2 was also expressed in plasmacytoid and conventional dendritic cells. Treatment with dsRNAs or type I interferon (IFN) up-regulated expression of RNase T2 but not RNase 4. RNase T2-deficiency in macrophages up-regulated TLR3 responses but impaired TLR7 responses. Mechanistically, RNase T2 degraded both dsRNAs and ssRNAs in vitro, and its mutants showed a positive correlation between RNA degradation and the rescue of altered TLR3 and TLR7 responses. H122A and C188R RNase T2 mutations, not H69A and E118V mutations, impaired both RNA degradation and the rescue of altered TLR3 and TLR7 responses. RNase T2 in bone marrow-derived macrophages was broadly distributed from early endosomes to lysosomes, and colocalized with the internalized TLR3 ligand poly(I:C). These results suggest that RNase T2-dependent RNA degradation in endosomes/lysosomes negatively and positively regulates TLR3 and TLR7 responses, respectively, in macrophages.
Description of the Etiologies, Clinical Characteristics, and Outcomes in Patients with Hyperferritinemia in a Colombian Tertiary Hospital
Authors: Ruiz-Ordoñez Ingrid , Puerta-Sarmiento Germán , Muñoz-Patiño Valentina , Giraldo-Fernández Valentina , Nieto-Aristizábal Ivana , Vivas Álvaro J , Tobón Gabriel J 
Published: June 2021

Abstract

Background
This study analyzes the clinical characteristics, outcomes, and conditions associated with hyperferritinemia (≥5000 ng/mL) in a high-complexity center in Colombia.

Methods
This retrospective and descriptive study was performed between 2011 and 2020, at the Fundación Valle del Lili, Cali, Colombia, by reviewing medical charts from patients who had serum ferritin measurements equal to or greater than 5000 ng/mL.

Results
We found 350 reports of ferritin values ≥5000 ng/mL, corresponding to 317 patients, with a median ferritin value of 8789 (6001–15 373)  ng/mL. The most frequent etiologies were infection (n = 198, 56.57%), hematologic disorders (n = 104, 29.71%), and blood transfusion (n = 98, 28.00%). These last 2 etiologies cooccurred in 37 (10.57%) cases. The main clinical signs accompanying hyperferritinemia were fever in 199 (56.86%) cases, multiorgan involvement in 125 (35.71%), and hepatomegaly in 95 (27.14%) cases. Ninety-four (29.65%) patients died in the hospital, and 11 (3.47%) died within 30 days after medical discharge, mainly due to infection (n = 51, 48.57%). Intrahospital mortality was associated with significantly higher ferritin levels (10 846, IQR: 6425–23 459) than survival (8452, IQR: 5980–13 932) (P = 0.018).

Conclusions
Hyperferritinemia is related to many underlying causes, with infection being the principal cause in our cohort, followed by hematologic disorders. Additionally, in-hospital mortality was related to higher ferritin levels.
Smart about medications (SAM): a digital solution to enhance medication management following hospital discharge
Authors: Márquez Fosser Santiago , Mahmoud Nadar , Habib Bettina , Weir Daniala L , Chan Fiona , El Halabieh Rola , Vachon Jeanne , Thakur Manish , Tran Thai , Bustillo Melissa , Beauchamp Caroline , Bonnici André , Buckeridge David L , Tamblyn Robyn 
Published: June 2021

Abstract

Objective
To outline the development of a software solution to improve medication management after hospital discharge, including its design, data sources, intrinsic features, and to evaluate the usability and the perception of use by end-users.

Materials and Methods
Patients were directly involved in the development using a User Center Design (UCD) approach. We conducted usability interviews prior to hospital discharge, before a user started using the application. A technology acceptance questionnaire was administered to evaluate user self-perception after 2 weeks of use.

Results
The following features were developed; pill identification, patient-friendly drug information leaflet, side effect checker, and interaction checker, adherence monitoring and alerts, weekly medication schedule, daily pill reminders, messaging service, and patient medication reviews. The usability interviews show a 98.3% total success rate for all features, severity (on a scale of 1–4) 1.4 (SD 0.79). Regarding the self-perception of use (1–7 agreement scale) the 3 highest-rated domains were: (1) perceived ease of use 5.65 (SD 2.02), (2) output quality 5.44 (SD 1.65), and (3) perceived usefulness 5.29 (SD 2.11).

Discussion
Many medication management apps solutions have been created and most of them have not been properly evaluated. SAM (Smart About Medications) includes the user perspective, integration between a province drug database and the pharmacist workflow in real time. Its features are not limited to maintaining a medication list through manual entry.

Conclusion
We can conclude after evaluation that the application is usable and has been self-perceived as easy to use by end-users. Future studies are required to assess the health benefits associated with its use.
Buprenorphine-Related Deaths in North Carolina from 2010 to 2018
Authors: Bishop-Freeman Sandra C , Friederich Laura W , Feaster Marc S , Hudson Jason S 
Published: June 2021

Abstract
Buprenorphine (BUP) is a commonly prescribed medication for the treatment of opioid use disorder (OUD). As prescriptions increase in North Carolina, BUP is more frequently encountered statewide in routine postmortem casework. Between 2010 and 2018, there were 131 select cases investigated by the Office of the Chief Medical Examiner where BUP was detected in peripheral blood and considered a primary cause of death (COD), with no other opioids present and no other non-opioid substances found in the lethal range. The decedents ranged in age from 14 to 64 years, with 67% male. The mean/median peripheral blood concentrations were 4.1/2.1 ng/mL for BUP and 7.8/3.4 ng/mL for its metabolite, norbuprenorphine. These postmortem blood concentrations overlap antemortem therapeutic concentrations in plasma reported in the literature for opioid-dependent subjects receiving sublingual maintenance therapy. The pathologist considered scene findings, prescription history, autopsy findings, toxicological analysis and decedent behavior prior to death to conclude a drug-related COD. Many of the deaths were complicated by the presence of other central nervous system depressants along with contributory underlying cardiovascular and respiratory disease. The three most prevalent additive substances were alprazolam, ethanol and gabapentin, found in 67, 36 and 32 cases out of 131, respectively. Interpreting BUP involvement in a death is complex, and instances may be underestimated in epidemiological data because of the lack of a defined toxic or lethal range in postmortem blood along with its good safety profile. As expansion of access to OUD treatment becomes a priority, awareness of the challenges of postmortem interpretation is needed as increased use and diversion of BUP are inevitable.