bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-Transplantation of Bone Marrow-MSCs and Myogenic Stem/Progenitor Cells from Adult Donors Improves Muscle Function of Patients with Duchenne Muscular Dystrophy
Authors: Klimczak Aleksandra , Zimna Agnieszka , Malcher Agnieszka , Kozlowska Urszula , Futoma Katarzyna , Czarnota Jaroslaw , Kemnitz Pawel , Bryl Anna , Kurpisz Maciej
Published: May 2020

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with a progressive deficiency of dystrophin that leads to skeletal muscle degeneration. In this study, we tested the hypothesis that a co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle can improve the skeletal muscle function of DMD patients. Three patients diagnosed with DMD, confirmed by the dystrophin gene mutation, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015). Stem/progenitor cells collected from bone marrow and skeletal muscles of related healthy donors, based on HLA matched antigens, were expanded in a closed MC3 cell culture system. A simultaneous co-transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii (two patients) and gastrocnemius (one patient). During a six-month follow-up, the patients were examined with electromyography (EMG) and monitored for blood kinase creatine level. Muscle biopsies were examined with histology and assessed for dystrophin at the mRNA and protein level. A panel of 27 cytokines was analysed with multiplex ELISA. We did not observe any adverse effects after the intramuscular administration of cells. The efficacy of BM-MSC and SM-SPC application was confirmed through an EMG assessment by an increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index. The beneficial effect of cellular therapy was confirmed by a decrease in creatine kinase levels and a normalised profile of pro-inflammatory cytokines. BM-MSCs may support the pro-regenerative potential of SM-SPCs thanks to their trophic, paracrine, and immunomodulatory activity. Both applied cell populations may fuse with degenerating skeletal muscle fibres in situ, facilitating skeletal muscle recovery. However, further studies are required to optimise the dose and timing of stem/progenitor cell delivery.
Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site
Authors: Luddi Alice , Pavone Valentina , Semplici Bianca , Governini Laura , Criscuoli Mattia , Paccagnini Eugenio , Gentile Mariangela , Morgante Giuseppe , De Leo Vincenzo , Belmonte Giuseppe , Zarovni Natasa , Piomboni Paola
Published: May 2020

Embryo implantation has been defined as the “black box” of human reproduction. Most of the knowledge on mechanisms underlining this process derives from animal models, but they cannot always be translated to humans. Therefore, the development of an in vitro/ex vivo model recapitulating as closely and precisely as possible the fundamental functional features of the human endometrial tissue is very much desirable. Here, we have validated endometrial organoids as a suitable 3D-model to studying epithelial endometrial interface for embryo implantation. Transmission and scanning electron microscopy analyses showed that organoids preserve the glandular organization and cell ultrastructural characteristics. They also retain the responsiveness to hormonal treatment specific to the corresponding phase of the menstrual cycle, mimicking the in vivo glandular-like aspect and functions. Noteworthy, organoids mirroring the early secretive phase show the development of pinopodes, large cytoplasmic apical protrusions of the epithelial cells, traditionally considered as reliable key features of the implantation window. Moreover, organoids express glycodelin A (GdA), a cycle-dependent marker of the endometrial receptivity, with its quantitative and qualitative features accounting well for the profile detected in the endometrium in vivo. Accordingly, organoids deriving from the eutopic endometrium of women with endometriosis show a GdA glycosylation pattern significantly different from healthy organoids, confirming our prior data on endometrial tissues. The present results strongly support the idea that organoids may closely recapitulate the molecular and functional characteristics of their cells/tissue of origin.
Impairment of Proteasome and Autophagy Underlying the Pathogenesis of Leukodystrophy
Authors: Lin Dar-Shong , Ho Che-Sheng , Huang Yu-Wen , Wu Tsu-Yen , Lee Tsung-Han , Huang Zo-Darr , Wang Tuan-Jen , Yang Shun-Jie , Chiang Ming-Fu
Published: May 2020

Impairment of the ubiquitin-proteasome-system (UPS) and autophagy causing cytoplasmic aggregation of ubiquitin andp62 have been implicated in the pathogenesis of most neurodegenerative disorders, yet, they have not been fully elucidated in leukodystrophies. The relationship among impairment of UPS, autophagy, and globoid cell leukodystrophy (GLD), one of the most common demyelinating leukodystrophies, is clarified in this study. We examined the ubiquitin and autophagy markers in the brains of twitcher mice, a murine model of infantile GLD, and in human oligodendrocytes incubated with psychosine. Immunohistochemical examinations showed spatiotemporal accumulation of ubiquitin- and p62-aggregates mainly in the white matter of brain and spinal cord at disease progression. Western blot analysis demonstrated a significant accumulation of ubiquitin, p62, and LC3-II in insoluble fraction in parallel with progressive demyelination and neuroinflammation in twitcher brains. In vitro study validated a dose- and time-dependent cytotoxicity of psychosine upon autophagy and UPS machinery. Inhibition of autophagy and UPS exacerbated the accumulation of insoluble ubiquitin, p62, and LC3-II proteins mediated by psychosine cytotoxicity as well as increased cytoplasmic deposition of ubiquitin- and p62-aggregates, and accumulation of autophagosomes and autolysosomes. Further, the subsequent accumulation of reactive oxygen species and reduction of mitochondrial respiration led to cell death. Our studies validate the impairment of proteasome and autophagy underlying the pathogenesis of GLD. These findings provide a novel insight into pathogenesis of GLD and suggest a specific pathomechanism as an ideal target for therapeutic approaches.
The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription
Authors: Brandt Janine , Wendt Lisa , Bodmer Bianca S. , Mettenleiter Thomas C. , Hoenen Thomas
Published: May 2020

Ebola virus (EBOV) is a zoonotic pathogen causing severe hemorrhagic fevers in humans and non-human primates with high case fatality rates. In recent years, the number and extent of outbreaks has increased, highlighting the importance of better understanding the molecular aspects of EBOV infection and host cell interactions to control this virus more efficiently. Many viruses, including EBOV, have been shown to recruit host proteins for different viral processes. Based on a genome-wide siRNA screen, we recently identified the cellular host factor carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) as being involved in EBOV RNA synthesis. However, mechanistic details of how this host factor plays a role in the EBOV life cycle remain elusive. In this study, we analyzed the functional and molecular interactions between EBOV and CAD. To this end, we used siRNA knockdowns in combination with various reverse genetics-based life cycle modelling systems and additionally performed co-immunoprecipitation and co-immunofluorescence assays to investigate the influence of CAD on individual aspects of the EBOV life cycle and to characterize the interactions of CAD with viral proteins. Following this approach, we could demonstrate that CAD directly interacts with the EBOV nucleoprotein NP, and that NP is sufficient to recruit CAD into inclusion bodies dependent on the glutaminase (GLN) domain of CAD. Further, siRNA knockdown experiments indicated that CAD is important for both viral genome replication and transcription, while substrate rescue experiments showed that the function of CAD in pyrimidine synthesis is indeed required for those processes. Together, this suggests that NP recruits CAD into inclusion bodies via its GLN domain in order to provide pyrimidines for EBOV genome replication and transcription. These results define a novel mechanism by which EBOV hijacks host cell pathways in order to facilitate genome replication and transcription and provide a further basis for the development of host-directed broad-spectrum antivirals.
Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex
Authors: Solé Laura , Sastre Daniel , Colomer-Molera Magalí , Vallejo-Gracia Albert , Roig Sara R. , Pérez-Verdaguer Mireia , Lillo Pilar , Tamkun Michael M. , Felipe Antonio
Published: May 2020

The voltage-gated potassium channel Kv1.3 plays a crucial role during the immune response. The channel forms oligomeric complexes by associating with several modulatory subunits. KCNE4, one of the five members of the KCNE family, binds to Kv1.3, altering channel activity and membrane expression. The association of KCNEs with Kv channels is the subject of numerous studies, and the stoichiometry of such associations has led to an ongoing debate. The number of KCNE4 subunits that can interact and modulate Kv1.3 is unknown. KCNE4 transfers important elements to the Kv1.3 channelosome that negatively regulate channel function, thereby fine-tuning leukocyte physiology. The aim of this study was to determine the stoichiometry of the functional Kv1.3-KCNE4 complex. We demonstrate that as many as four KCNE4 subunits can bind to the same Kv1.3 channel, indicating a variable Kv1.3-KCNE4 stoichiometry. While increasing the number of KCNE4 subunits steadily slowed the activation of the channel and decreased the abundance of Kv1.3 at the cell surface, the presence of a single KCNE4 peptide was sufficient for the cooperative enhancement of the inactivating function of the channel. This variable architecture, which depends on KCNE4 availability, differentially affects Kv1.3 function. Therefore, our data indicate that the physiological remodeling of KCNE4 triggers functional consequences for Kv1.3, thus affecting cell physiology.
Investigation of Ultrasound-Mediated Intracellular Ca2+ Oscillations in HIT-T15 Pancreatic β-Cell Line
Authors: Yoon Chi Woo , Lee Nan Sook , Koo Kweon Mo , Moon Sunho , Goo Kyosuk , Jung Hayong , Yoon Changhan , Lim Hae Gyun , Shung K. Kirk
Published: May 2020

In glucose-stimulated insulin secretion (GSIS) of pancreatic β-cells, the rise of free cytosolic Ca2+ concentration through voltage-gated calcium channels (VGCCs) triggers the exocytosis of insulin-containing granules. Recently, mechanically induced insulin secretion pathways were also reported, which utilize free cytosolic Ca2+ ions as a direct regulator of exocytosis. In this study, we aimed to investigate intracellular Ca2+ responses on the HIT-T15 pancreatic β-cell line upon low-intensity pulsed ultrasound (LIPUS) stimulation and found that ultrasound induces two distinct types of intracellular Ca2+ oscillation, fast-irregular and slow-periodic, from otherwise resting cells. Both Ca2+ patterns depend on the purinergic signaling activated by the rise of extracellular ATP or ADP concentration upon ultrasound stimulation, which facilitates the release through mechanosensitive hemichannels on the plasma membrane. Further study demonstrated that two subtypes of purinergic receptors, P2X and P2Y, are working in a competitive manner depending on the level of glucose in the cell media. The findings can serve as an essential groundwork providing an underlying mechanism for the development of a new therapeutic approach for diabetic conditions with further validation.
PPAR Beta/Delta and the Hallmarks of Cancer
Authors: Wagner Nicole , Wagner Kay-Dietrich
Published: May 2020

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. Three different isoforms, PPAR alpha, PPAR beta/delta and PPAR gamma have been identified. They all form heterodimers with retinoic X receptors to activate or repress downstream target genes dependent on the presence/absence of ligands and coactivators or corepressors. PPARs differ in their tissue expression profile, ligands and specific agonists and antagonists. PPARs attract attention as potential therapeutic targets for a variety of diseases. PPAR alpha and gamma agonists are in clinical use for the treatment of dyslipidemias and diabetes. For both receptors, several clinical trials as potential therapeutic targets for cancer are ongoing. In contrast, PPAR beta/delta has been suggested as a therapeutic target for metabolic syndrome. However, potential risks in the settings of cancer are less clear. A variety of studies have investigated PPAR beta/delta expression or activation/inhibition in different cancer cell models in vitro, but the relevance for cancer growth in vivo is less well documented and controversial. In this review, we summarize critically the knowledge of PPAR beta/delta functions for the different hallmarks of cancer biological capabilities, which interplay to determine cancer growth.
Vitamin D3 in High-Quality Cow Milk: An Italian Case Study
Authors: Mandrioli Mara , Boselli Emanuele , Fiori Federica , Rodriguez-Estrada Maria Teresa
Published: May 2020

The quality-labeling category of high-quality (HQ) milk defined by the Italian legislation must comply with specific requirements concerning rigorous breeder management, hygienic controls, fat and protein content, bacterial load, somatic cells, lactic acid content, and non-denatured soluble serum proteins. However, there is no specification for the vitamin D content of HQ milk. Moreover, the data on the vitamin D content of this milk category are very scarce. In the present study, the content of vitamin D3 was evaluated in HQ raw and pasteurized cow milk obtained from Italian cowsheds and supermarkets. The vitamin D3 content varied from not detected (less than 1 µg L−1) to 17.0 ± 2.0 µg L−1 milk and was not related to the milk fat content. These results represent a case study including a significant although not exhaustive part of the contemporary Italian market of HQ milk. It was shown for the first time that HQ raw milk does not necessarily contain more vitamin D3, even though non-expert consumers likely to buy milk labeled as HQ could expect it. The vitamin D3 content in HQ pasteurized whole milk should be reported on the label of the milk package as a best practice of consumer information policy.
Impact of a 25% Salt Reduction on the Microbial Load, Texture, and Sensory Attributes of a Traditional Dry-Cured Sausage
Authors: Elias Miguel , Laranjo Marta , Potes Maria Eduarda , Agulheiro-Santos Ana Cristina , Fernandes Maria José , Garcia Raquel , Fraqueza Maria João
Published: May 2020

Catalão is a Portuguese dry-cured traditional sausage, highly appreciated for its distinctive sensory properties. The aim of this study was to evaluate the impact of a 25% salt reduction on Catalão manufactured with either purebred Alentejano (Al) or crossbred Iberian × Duroc (IDr) pork meat, on its physicochemical and microbiological stability, texture parameters, and sensory attributes. No significant effect of salt reduction or genotype was observed for pH, aW, and microbiological parameters. PUFA content was significantly higher for Al Catalão, particularly due to the content in linoleic and linolenic fatty acids. IDr 3% NaCl samples had the highest mean n6/n3 PUFA ratio, and the highest mean values for the atherogenicity and thrombogenicity indices, showing that both genotype and salt content influence these nutritional indices. Texture profile of Catalão was significantly influenced by salt content and genotype. Al samples were less adhesive, cohesive, and easier to chew. Low-salt Catalão was harder, more adhesive, and less cohesive, with lower resilience and higher chewiness values. Regarding sensory attributes, salt content influenced the product aroma, with reduced-salt sausages being evaluated as significantly less aromatic. Overall, a 25% salt reduction did not have a significant impact on the quality, stability, and sensory evaluation of Catalão.
Impact of Acorn Flour on Gluten-Free Dough Rheology Properties
Authors: Beltrão Martins R. , Nunes M. C. , M. Ferreira L. M. , A. Peres J. , R. N. A. Barros A. I. , Raymundo A.
Published: May 2020

Gluten is a fundamental ingredient in breadmaking, since is responsible for the viscoelastic behaviour of the dough. The lack of gluten has a critical effect on gluten-free dough, leading to less cohesive and less elastic doughs, and its replacement represents a challenge for bakery industry. However, dough rheology can be improved combining different ingredients with structural capacity and taking advantage from their interactions. Although acorn flour was used to bake bread even before Romans, nowadays is an underexploited resource. It presents good nutritional characteristics, particularly high fibre content and is naturally gluten free. The aim of this study was to use acorn flour as a gluten-free ingredient to improve dough rheology, following also market trends of sustainability and fibre-rich ingredients. Doughs were prepared with buckwheat and rice flours, potato starch and hydroxypropylmethylcellulose. Two levels of acorn flour (23% and 35% w/w) were tested and compared with control formulation. Micro-doughLAB was used to study mixing and pasting properties. Doughs were characterised using small amplitude oscillatory measurements (SAOS), with a controlled stress rheometer, and regarding Texture Profile Analysis (TPA) by a texturometer. Dietary fibre content and its soluble and insoluble fractions were also evaluated on the developed breads. Acorn flour showed promising technological properties as food ingredient for gluten-free baking (improved firmness, cohesiveness and viscoelasticity of the fermented dough), being an important fibre source.
Survey of SNPs Associated with Total Number Born and Total Number Born Alive in Pig
Authors: Bakoev Siroj , Getmantseva Lyubov , Bakoev Faridun , Kolosova Maria , Gabova Valeria , Kolosov Anatoly , Kostyunina Olga
Published: May 2020

Reproductive productivity depend on a complex set of characteristics. The number of piglets at birth (Total number born, Litter size, TNB) and the number of alive piglets at birth (Total number born alive, NBA) are the main indicators of the reproductive productivity of sows in pig breeding. Great hopes are pinned on GWAS (Genome-Wide Association Studies) to solve the problems associated with studying the genetic architecture of reproductive traits of pigs. This paper provides an overview of international studies on SNP (Single nucleotide polymorphism) associated with TNB and NBA in pigs presented in PigQTLdb as “Genome map association”. Currently on the base of Genome map association results 306 SNPs associated with TNB (218 SNPs) and NBA (88 SNPs) have been identified and presented in the Pig QTLdb database. The results are based on research of pigs such as Large White, Yorkshire, Landrace, Berkshire, Duroc and Erhualian. The presented review shows that most SNPs found in chromosome areas where candidate genes or QTLs (Quantitative trait locus) have been identified. Further research in the given direction will allow to obtain new data that will become an impulse for creating breakthrough breeding technologies and increase the production efficiency in pig farming.
Inhibition of Protein-Tyrosine Phosphatase PTP1B and LMPTP Promotes Palmitate/Oleate-Challenged HepG2 Cell Survival by Reducing Lipoapoptosis, Improving Mitochondrial Dynamics and Mitigating Oxidative and Endoplasmic Reticulum Stress
Authors: Bourebaba Lynda , Łyczko Jacek , Alicka Michalina , Bourebaba Nabila , Szumny Antoni , Fal Andrzej , Marycz Krzysztof
Published: May 2020

Objectives: Non-alcoholic fatty liver disease (NAFLD) is considered a well-known pathology that is determined without using alcohol and has emerged as a growing public health problem. Lipotoxicity is known to promote hepatocyte death, which, in the context of NAFLD, is termed lipoapoptosis. The severity of NAFLD correlates with the degree of hepatocyte lipoapoptosis. Protein–tyrosine phosphatases (PTP) including PTP1B and Low molecular weight PTP (LMPTP), are negative regulators of the insulin signaling pathway and are considered a promising therapeutic target in the treatment of diabetes. In this study, we hypothesized that the inhibition of PTP1B and LMPTP may potentially prevent hepatocyte apoptosis, mitochondrial dysfunction and endoplasmic reticulum (ER) stress onset, following lipotoxicity induced using a free fatty acid (FFA) mixture. Methods: HepG2 cells were cultured in the presence or absence of two PTP inhibitors, namely MSI-1436 and Compound 23, prior to palmitate/oleate overloading. Apoptosis, ER stress, oxidative stress, and mitochondrial dynamics were then evaluated by either MUSE or RT-qPCR analysis. Results: The obtained data demonstrate that the inhibition of PTP1B and LMPTP prevents apoptosis induced by palmitate and oleate in the HepG2 cell line. Moreover, mitochondrial dynamics were positively improved following inhibition of the enzyme, with concomitant oxidative stress reduction and ER stress abrogation. Conclusion: In conclusion, PTP’s inhibitory properties may be a promising therapeutic strategy for the treatment of FFA-induced lipotoxicity in the liver and ultimately in the management of the NAFLD condition.
Time from Symptom Onset to Hospitalisation of Coronavirus Disease 2019 (COVID-19) Cases: Implications for the Proportion of Transmissions from Infectors with Few Symptoms
Authors: Thompson Robin N. , Lovell-Read Francesca A. , Obolski Uri
Published: May 2020

Interventions targeting symptomatic hosts and their contacts were successful in bringing the 2003 SARS pandemic under control. In contrast, the COVID-19 pandemic has been harder to contain, partly because of its wide spectrum of symptoms in infectious hosts. Current evidence suggests that individuals can transmit the novel coronavirus while displaying few symptoms. Here, we show that the proportion of infections arising from hosts with few symptoms at the start of an outbreak can, in combination with the basic reproduction number, indicate whether or not interventions targeting symptomatic hosts are likely to be effective. However, as an outbreak continues, the proportion of infections arising from hosts with few symptoms changes in response to control measures. A high proportion of infections from hosts with few symptoms after the initial stages of an outbreak is only problematic if the rate of new infections remains high. Otherwise, it can simply indicate that symptomatic transmissions are being prevented successfully. This should be considered when interpreting estimates of the extent of transmission from hosts with few COVID-19 symptoms.
Antibiotic Resistance and Therapy for H. pylori Infection in Immigrant Patients Treated in Italy
Authors: Fiorini Giulia , Saracino Ilaria Maria , Zullo Angelo , Pavoni Matteo , Saccomanno Laura , Lazzarotto Tiziana , Cavallo Rossana , Antonelli Guido , Vaira Berardino
Published: May 2020

Background: Helicobacter pylori (H. pylori) infection is the leading cause of both peptic ulcers and gastric tumors, including low-grade MALT-lymphoma and adenocarcinoma. Although it is decreasing in developed countries, H. pylori prevalence remains high in developing areas, mainly due to low socio-economic levels, and the potential consumption of contaminated water. Moreover, a different pattern of primary antibiotic resistance is expected in their H. pylori isolates, potentially affecting the efficacy of standard eradication therapies. Indeed, a previous study showed the eradication rate following triple therapy was distinctly lower in dyspeptic H. pylori infected immigrants living in Italy as compared to Italian patients. Aims: to evaluate the resistance pattern in H. pylori isolates from immigrant patients in Italy, and the success rate of first-line therapy in these patients. Materials and Methods: This retrospective study evaluated data of consecutive immigrant patients, diagnosed with H. pylori infection in a single center (Bologna, Italy) between January 2009 and January 2019. Patients underwent first-line therapy with either sequential or Pylera® (Allergan USA, Inc. Madison, NJ, USA) therapy. Results: A total of 609 immigrants were diagnosed with H. pylori infection during the study period, but 264 previously received an eradication therapy. Therefore, the study was focused on 294 out of 345 naïve patients with a successful bacterial culture with antibiogram. Latin America immigrants had the highest overall resistance rate. Levofloxacin resistance rate was significantly higher in Latin Americans and Asians as compared with Europeans. Based on resistance patterns, sequential therapy showed a clear decreasing trend in eradication rates. Conclusions: while antibiotic resistance rates are generally increasing worldwide, Pylera® seems to achieve a good performance as first-line treatment in all naïve foreigner patients, except for Africans.
Shortening of Overall Orthodontic Treatment Duration with Low-Intensity Pulsed Ultrasound (LIPUS)
Authors: Kaur Harmanpreet , El-Bialy Tarek
Published: May 2020

The aim of this retrospective clinical study was to determine if there is a reduction in the overall treatment duration in orthodontic patients using low-intensity pulsed ultrasound (LIPUS) and Invisalign SmartTrack® clear aligners. Data were collected from the first thirty-four patients (9 males, 25 females; average age 41.37 ± 15.02) who finished their orthodontic treatment using an intraoral LIPUS device and Invisalign clear aligners in a private clinic. The LIPUS parameters used by patients at home for 20 min/day were: ultrasonic frequency 1.5 MHz, pulse duration 200µs, pulse repetition rate 1 kHz, and spatial average-temporal average intensity 30mW/cm2. A control group (11 males, 23 females; average age 31.36 ± 14.41) matching for the same malocclusions was randomly selected from finished treatment cases of the same clinician. The date of first Invisalign attachment placement and first use of LIPUS application was recorded as T0, and the date of retainer delivery was recorded as T1. The treatment duration (T1–T0) and treatment reduction percentage with LIPUS device were collected and analyzed using two-sample t-test in Microsoft Excel. Treatment duration was significantly reduced in the LIPUS group (541.44 ± 192.23 days) compared to control group (1061.05 ± 455.64 days) (p < 0.05). The LIPUS group showed on average 49% reduction in the overall treatment time as compared to the control group. The average compliance of the patients using LIPUS was 66.02%. Patients who used LIPUS showed a clinically significant reduction in the overall orthodontic treatment duration compared to the control group who used Invisalign clear aligners only.
Challenges to the Application of Integrated, Personalized Care for Patients with COPD—A Vision for the Role of Clinical Information
Authors: Vanfleteren Lowie E.G.W. , van ‘t Hul Alex J. , Kulbacka-Ortiz Katarzyna , Andersson Anders , Ullman Anders , Ingvar Martin
Published: May 2020

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease defined by airflow limitation and characterized by a spectrum of treatable and untreatable pulmonary and extra-pulmonary disease characteristics. Nonpharmacological management related to physical activity, physical capacity, body composition, breathing and energy-saving techniques, coping strategies, and self-management is as important as its pharmacological management. Most patients with COPD carry other chronic diagnoses and this poses a key challenge, as it lowers the quality of life, increases mortality, and impacts healthcare consumption. A personalized, multi-, and interprofessional approach is key. Today, healthcare is poorly organized to meet this complexity with the isolation between care levels, logic silos of the different healthcare professions, and lack of continuity of care along the patient’s journey with the healthcare system. In order to meet the criteria for integrated, personalized care for COPD, the structural capabilities of healthcare to support a comprehensive approach and continuity of care needs improvement. COPD is preeminently a disease that requires a transition from a reactive single-specialty approach to a proactive interprofessional approach. In this study, we discuss the issues that need to be addressed when moving from current health care practice to a person-centered model where the care processes and information are aligned to the individual personal needs of the patient.
Right Ventricular Free Wall Strain and Congestive Hepatopathy in Patients with Acute Worsening of Chronic Heart Failure: A CATSTAT-HF Echo Substudy
Authors: Borovac Josip A. , Glavas Duska , Susilovic Grabovac Zora , Supe Domic Daniela , Stanisic Lada , D’Amario Domenico , Duplancic Darko , Bozic Josko
Published: May 2020

Right ventricular (RV) function is an important predictor of prognosis in patients with heart failure. However, the relationship of the RV free wall longitudinal strain (RV FWS) and the degree of hepatic dysfunction during the acute worsening of heart failure (AWHF) is unknown. We sought to determine associations of RV FWS with laboratory liver function tests and parameters of RV function including tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (RV FAC), maximal tricuspid jet velocity (TR Vmax), RV S′ velocity, and estimated RV systolic pressure (RVSP). A total of 42 AWHF patients from the CATSTAT-HF study were stratified in two groups by the RV FWS median (−16.5%). Patients < RV FWS median had significantly prolonged international normalized ratio (INR; p = 0.002), increased total bilirubin (p < 0.001) and alkaline phosphatase (ALP; p = 0.020), and decreased albumin (p = 0.005) and thrombocytes (p = 0.017) compared to patients > RV FWS median. RV FWS independently correlated to total bilirubin (β = 0.457, p = 0.004), ALP (β = 0.556, p = 0.002), INR (β = 0.392, p = 0.022), albumin (β = −0.437, p = 0.013), and thrombocytes (β = −404, p = 0.038). Similarly, TAPSE, RV FAC, and RV S′ significantly correlated with RV FWS. In conclusion, RV impairment, reflected in reduced RV FWS, is independently associated with a higher degree of hepatic dysfunction among patients with AWHF (CATSTAT-HF ClinicalTrials gov number, NCT03389386).
Smoking and SARS-CoV-2 Disease (COVID-19): Dangerous Liaisons or Confusing Relationships?
Authors: Li Volti Giovanni , Caruso Massimo , Polosa Riccardo
Published: May 2020

We read with great interest the article by Brake SJ and colleagues [...]
Serum Interleukin-6 and -8 as Predictors of Response to Vedolizumab in Inflammatory Bowel Diseases
Authors: Bertani Lorenzo , Caviglia Gian Paolo , Antonioli Luca , Pellicano Rinaldo , Fagoonee Sharmila , Astegiano Marco , Saracco Giorgio Maria , Bugianesi Elisabetta , Blandizzi Corrado , Costa Francesco , Ribaldone Davide Giuseppe
Published: May 2020

Vedolizumab, a monoclonal antibody directed against integrin α4β7, is an effective treatment for inflammatory bowel diseases. However, a significant number of patients do not achieve steroid-free clinical remission in the first year of treatment. An early identification of these patients is one of the most important challenges for clinicians and offers the possibility of therapeutic optimization in order to personalize biological therapy. The aim of our study was to test the prediction ability of interleukin (IL)-6 and -8 of clinical response after 12 months of therapy with vedolizumab (T2). We performed a prospective, multicentre study in patients affected by inflammatory bowel disease by analysing cytokines level before starting vedolizumab (T0) and after 10 weeks of therapy (T1). In the overall cohort (n = 54), IL-8 decrease > 2.6 pg/mL in the first 10 weeks of therapy was able to predict clinical response (area under the curve (AUC) = 0.70, sensitivity = 66%, specificity = 75%, p = 0.010), negative C-reactive protein (CRP) (AUC = 0.71, sensitivity = 64%, specificity = 80%, p = 0.009) and calprotectin < 250 mg/kg (AUC = 0.69, sensitivity = 64%, specificity = 78%, p = 0.030) after 44 weeks of therapy. In patients with ulcerative colitis (n = 40), baseline IL-8 values > 8.6 pg/mL and a decrease of IL-6 values > 0.4 pg/mL from T0 to T1 were significant and independent predictors of clinical response after 12 months of vedolizumab therapy (odds ratio (OR) = 6.96, 95% CI 1.27–38.22, p = 0.026 and OR = 7.29, 95% CI 1.42–37.50, p = 0.017, respectively). In patients with Crohn’s disease (n = 14), baseline IL-8 values > 8.6 pg/mL and baseline IL-6 values > 1.6 pg/mL allowed the identification of patients achieving negative CRP at T2 (AUC = 0.75, sensitivity = 74%, specificity = 76%, p < 0.001) and patients with faecal calprotectin values < 250 mg/kg at T2 (AUC = 0.71, sensitivity = 78%, specificity = 63%, p = 0.004). In conclusion, our study highlights a potential clinical role of serum cytokine levels for the prediction of clinical and biochemical steroid-free response in patients treated with vedolizumab.
The Influence of Bariatric Surgery on Pregnancy and Perinatal Outcomes—A Case-Control Study
Authors: Różańska-Walędziak Anna , Walędziak Maciej , Bartnik Paweł , Kacperczyk-Bartnik Joanna , Janik Michał , Kowalewski Piotr , Kwiatkowski Andrzej , Czajkowski Krzysztof
Published: May 2020

Introduction: Obesity in pregnant women increases the incidence of pregnancy-induced comorbidities and the rate of operative deliveries. Purpose of the Study: As bariatric surgery is the reference method of treatment of obesity, we wanted to evaluate its influence on the course of pregnancy and perinatal outcomes. Material and Methods: Data was collected from 627 female patients after bariatric surgery, of whom 107 had a history of pregnancy after the surgery, and 345 non-bariatric patients who had a delivery at a tertiary perinatal center. Sixty-one cases were matched (1:1) with controls for age, pre-pregnancy BMI and presence of pre-pregnancy comorbidities. The main endpoints were gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), small (SGA) and large for gestational age infants (LGA) and cesarean sections (CS). Results: Patients after bariatric procedures were significantly less likely to have GDM (19.67%/37.7%; p = 0.0433), PIH (11.47%/16.39%; p = 0.6072) and preterm delivery (13.11%/37.7%; p = 0.0026). The CS rate was higher (57.38%/40.98%; p = 0.0987). There was an increased risk of SGA (18.03%/13.11%; p = 0.6072) and a decreased risk of LGA (6.56%/16.39%; p = 0.146). Conclusions: Patients after bariatric surgery have a decreased risk of pregnancy-induced comorbidities, preterm deliveries and LGA infants, with an increase in rate of CS and SGA infants compared to general population matched for pre-pregnancy BMI, age and presence of pre-pregnancy comorbidities.
Age-Related Macular Degeneration Staging by Color Fundus Photography vs. Multimodal Imaging—Epidemiological Implications (The Coimbra Eye Study—Report 6)
Authors: Farinha Cláudia , Cachulo Maria Luz , Coimbra Rita , Alves Dalila , Nunes Sandrina , Pires Isabel , Marques João Pedro , Costa José , Martins Amélia , Sobral Isa , Barreto Patrícia , Laíns Inês , Figueira João , Ribeiro Luisa , Cunha-Vaz José , Silva Rufino
Published: May 2020

Epidemiology of age-related macular degeneration (AMD) is based on staging systems relying on color fundus photography (CFP). We aim to compare AMD staging using CFP to multimodal imaging with optical coherence tomography (OCT), infra-red (IR), and fundus autofluorescence (FAF), in a large cohort from the Epidemiologic AMD Coimbra Eye Study. All imaging exams from the participants of this population-based study were classified by a central reading center. CFP images were graded according to the International Classification and Grading System for AMD and staged with Rotterdam classification. Afterward, CFP images were reviewed with OCT, IR, and FAF and stage update was performed if necessary. Early and late AMD prevalence was compared in a total of 1616 included subjects. In CFP-based grading, the prevalence was 14.11% for early AMD (n = 228) and 1.05% (n = 17) for late AMD, nine cases (0.56%) had neovascular AMD (nAMD) and eight (0.50%) geographic atrophy (GA). Using multimodal grading, the prevalence increased to 14.60% for early AMD (n = 236) and 1.61% (n = 26) for late AMD, with 14 cases (0.87%) of nAMD and 12 (0.74%) of GA. AMD staging was more accurate with the multimodal approach and this was especially relevant for late AMD. We propose that multimodal imaging should be adopted in the future to better estimate and compare epidemiological data in different populations.
Eating Disorders, Heredity and Environmental Activation: Getting Epigenetic Concepts into Practice
Authors: Steiger Howard , Booij Linda
Published: May 2020

Epigenetic mechanisms are believed to link environmental exposures to alterations in gene expression, and in so doing, to provide a physical substrate for the activation of hereditary potentials by life experiences. In keeping with this idea, accumulating data suggest that epigenetic processes are implicated in eating-disorder (ED) etiology. This paper reviews literature on putative links between epigenetic factors and EDs, and examines ways in which epigenetic programming of gene expression could account for gene-environment interactions acting in the EDs. The paper also presents evidence suggesting that epigenetic processes link malnutrition and life stresses (gestational, perinatal, childhood, and adult) to risk of ED development. Drawing from empirical evidence and clinical experience, we propose that an epigenetically informed understanding of ED etiology can benefit patients, caregivers, and clinicians alike, in the sense that the perspective can reduce judgmental or blameful attitudes on the part of clinicians and caregivers, and increase self-acceptance and optimism about recovery on the part of those affected.
Macular Pigment Optical Density and Photoreceptor Outer Segment Length as Predisease Biomarkers for Age-Related Macular Degeneration
Authors: Nagai Norihiro , Minami Sakiko , Suzuki Misa , Shinoda Hajime , Kurihara Toshihide , Sonobe Hideki , Watanabe Kazuhiro , Uchida Atsuro , Ban Norimitsu , Tsubota Kazuo , Ozawa Yoko
Published: May 2020

To explore predisease biomarkers, which may help screen for the risk of age-related macular degeneration (AMD) at very early stages, macular pigment optical density (MPOD) and photoreceptor outer segment (PROS) length were analyzed. Thirty late AMD fellow eyes, which are at high risk and represent the predisease condition of AMD, were evaluated and compared with 30 age-matched control eyes without retinal diseases; there was no early AMD involvement in the AMD fellow eyes. MPOD was measured using MPS2® (M.E. Technica Co. Ltd., Tokyo, Japan), and PROS length was measured based on optical coherence tomography images. MPOD levels and PROS length in the AMD fellow eyes were significantly lower and shorter, respectively, than in control eyes. MPOD and PROS length were positively correlated in control eyes (R = 0.386; p = 0.035) but not in AMD fellow eyes. Twenty (67%) AMD fellow eyes met the criteria of MPOD < 0.65 and/or PROS length < 35 μm, while only five (17%) control eyes did. After adjusting for age and sex, AMD fellow eyes more frequently satisfied the definition (p < 0.001; 95% confidence interval, 3.50–60.4; odds ratio, 14.6). The combination of MPOD and PROS length may be a useful biomarker for screening predisease AMD patients, although further studies are required in this regard.
Pathway-Activity Likelihood Analysis and Metabolite Annotation for Untargeted Metabolomics Using Probabilistic Modeling
Authors: Hosseini Ramtin , Hassanpour Neda , Liu Li-Ping , Hassoun Soha
Published: May 2020

Motivation: Untargeted metabolomics comprehensively characterizes small molecules and elucidates activities of biochemical pathways within a biological sample. Despite computational advances, interpreting collected measurements and determining their biological role remains a challenge. Results: To interpret measurements, we present an inference-based approach, termed Probabilistic modeling for Untargeted Metabolomics Analysis (PUMA). Our approach captures metabolomics measurements and the biological network for the biological sample under study in a generative model and uses stochastic sampling to compute posterior probability distributions. PUMA predicts the likelihood of pathways being active, and then derives probabilistic annotations, which assign chemical identities to measurements. Unlike prior pathway analysis tools that analyze differentially active pathways, PUMA defines a pathway as active if the likelihood that the path generated the observed measurements is above a particular (user-defined) threshold. Due to the lack of “ground truth” metabolomics datasets, where all measurements are annotated and pathway activities are known, PUMA is validated on synthetic datasets that are designed to mimic cellular processes. PUMA, on average, outperforms pathway enrichment analysis by 8%. PUMA is applied to two case studies. PUMA suggests many biological meaningful pathways as active. Annotation results were in agreement to those obtained using other tools that utilize additional information in the form of spectral signatures. Importantly, PUMA annotates many measurements, suggesting 23 chemical identities for metabolites that were previously only identified as isomers, and a significant number of additional putative annotations over spectral database lookups. For an experimentally validated 50-compound dataset, annotations using PUMA yielded 0.833 precision and 0.676 recall.
PbS Nanoparticles Prepared Using 1, 10-Phenanthroline Adduct of Lead(II) Bis(N-alkyl-N-phenyl dithiocarbamate) as Single Source Precursors
Authors: Adeyemi Jerry O. , Onwudiwe Damian C.
Published: May 2020

Dithiocarbamate complexes have remained prominent as single source precursors for the synthesis of clean metal sulfide nanoparticles. This study reports the synthesis of lead sulfide (PbS) nanoparticles using some novel complexes of 1, 10-phenanthroline lead(II) bis(N-alkyl-N-phenyl dithiocarbamate), represented as [Pb(L1)2phen] (1) and [Pb(L2)2phen] (2) (where L1 = bis(N-ethyl-N-phenyldithiocarbamate; L2 = bis(N-butyl-N-phenyldithiocarbamate); phen = 1, 10 phenanthroline) as a single source precursors. The complexes (1 and 2) were synthesized and characterized using various spectroscopic techniques and elemental analysis. The nanoparticles were synthesized via a solvothermal approach in oleylamine, used as a capping agent, and were given as PbS(1) and PbS(2) from [Pb(L1)2phen] (1) and [Pb(L2)2phen] (2), respectively, which were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), and absorption spectroscopy. The diffraction patterns confirmed the formation of face-centered cubic phase PbS nanoparticles with a preferential growth orientation along the (200) plane. The TEM images showed that PbS(1) were of a spherical morphology, while the morphology of PbS(2) tended to produce short rods. This was due to variation in the functional group on the precursor compounds. This variation also resulted in the different band gap energies found such as 1.148 and 1.107 eV for PbS(1) and PbS(2), respectively, indicating a blue shift from the bulk.
Antiviral, Antibacterial, Antifungal, and Cytotoxic Silver(I) BioMOF Assembled from 1,3,5-Triaza-7-Phoshaadamantane and Pyromellitic Acid
Authors: Jaros Sabina W. , Król Jarosław , Bażanów Barbara , Poradowski Dominik , Chrószcz Aleksander , Nesterov Dmytro S. , Kirillov Alexander M. , Smoleński Piotr
Published: May 2020

The present study reports the synthesis, characterization, and crystal structure of a novel bioactive metal-organic framework, [Ag4(µ-PTA)2(µ3-PTA)2(µ4-pma)(H2O)2]n·6nH2O (bioMOF 1), which was assembled from silver(I) oxide, 1,3,5-triaza-7-phosphaadamantane (PTA), and pyromellitic acid (H4pma). This product was isolated as a stable microcrystalline solid and characterized by standard methods, including elemental analysis, 1H and 31P{1H} NMR and FTIR spectroscopy, and single crystal X-ray diffraction. The crystal structure of 1 disclosed a very complex ribbon-pillared 3D metal-organic framework driven by three different types of bridging ligands (µ-PTA, µ3-PTA, and µ4-pma4−). Various bioactivity characteristics of bioMOF 1 were investigated, revealing that this compound acts as a potent antimicrobial against pathogenic strains of standard Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria, as well as a yeast (Candida albicans). Further, 1 showed significant antiviral activity against human adenovirus 36 (HAdV-36). Finally, bioMOF 1 revealed high cytotoxicity toward an abnormal epithelioid cervix carcinoma (HeLa) cell line with low toxicity toward a normal human dermal fibroblast (NHDF) cell line. This study not only broadens the family of PTA-based coordination polymers but also highlights their promising multifaceted bioactivity.
Advancing Target Identification of Nitrated Phospholipids in Biological Systems by HCD Specific Fragmentation Fingerprinting in Orbitrap Platforms
Authors: Neves Bruna , Duarte Sofia , Domingues Pedro , Pérez-Sala Dolores , Oliveira Maria Manuel , Domingues Maria do Rosário , Melo Tânia
Published: May 2020

Nitrated phospholipids have recently been detected in vitro and in vivo and associated with beneficial health effects. They were identified and quantified in biological samples by lipidomics methodologies using liquid chromatography-collision-induced dissociation (CID) tandem mass spectrometry (MS/MS) acquired with the linear ion trap mass spectrometer. Only a few studies have used higher-energy collision dissociation (HCD)-MS/MS in high-resolution Orbitraps to characterize nitrated phosphatidylserines and nitrated cardiolipins, highlighting the marked differences in the fragmentation patterns when using CID or HCD fragmentation methods. In this study, we aimed to evaluate the fragmentation of nitrated phosphatidylcholine and nitrated phosphatidylethanolamine species under HCD-MS/MS. We studied the effect of normalized collision energy (NCE) in the fragmentation pattern to identify the best acquisition conditions and reporter ions to detect nitrated phospholipids. The results showed that the intensity of the typical neutral loss of nitrous acid (HNO2) diminishes with increasing NCE, becoming non-detectable for a higher NCE. Thus, the loss of HNO2 could not be the most suitable ion/fragment for the characterization of nitrated phospholipids under HCD. In HCD-MS/MS new fragment ions were identified, corresponding to the nitrated fatty acyl chains, NO2-RCOO−, (NO2-RCOOH-H2O + H)+, and (NO2-RCOOH + H)+, suggested as potential reporter ions to detect nitrated phospholipids when using the HCD-MS/MS lipidomics analysis.