Journal of Clinical Medicine

9 pages, 668 KiB

Open AccessArticle

Background Glucocorticoid Therapy Has No Impact on Efficacy and Safety of Abatacept or Adalimumab in Patients with Rheumatoid Arthritis

by Yannick Degboé, Michael Schiff, Michael Weinblatt, Roy Fleischmann, Harris A. Ahmad and Arnaud Constantin

J. Clin. Med. 2020, 9(6), 2017; https://doi.org/10.3390/jcm9062017 - 26 Jun 2020

Cited by 1 | Viewed by 3047

Abstract

To date, the impact of background glucocorticoids (GC) on the efficacy and safety of abatacept or adalimumab in patients with active rheumatoid arthritis (RA) is not clearly established. This post hoc analysis of (AMPLE) trial (NCT00929864) compared efficacy and safety outcomes over 2 [...] Read more.

To date, the impact of background glucocorticoids (GC) on the efficacy and safety of abatacept or adalimumab in patients with active rheumatoid arthritis (RA) is not clearly established. This post hoc analysis of (AMPLE) trial (NCT00929864) compared efficacy and safety outcomes over 2 years in patients treated with abatacept or adalimumab plus background methotrexate (MTX), who continued GC (≤10 mg/day) versus those who were not receiving GC (no-GC). Of 646 randomized patients, 317 received abatacept + MTX (161 GC, 156 no-GC) and 326 received adalimumab + MTX (162 GC, 164 no-GC). At Year 2, the adjusted mean changes from baseline in Disease Activity Score (DAS28 C-reactive protein (CRP)) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were not significantly different in the GC versus no-GC subgroups receiving abatacept or adalimumab. A similar proportion of patients achieved remission, HAQ-DI score improvement ≥0.3 and radiographic progression rates. No clinically meaningful safety differences were observed between GC versus no-GC subgroups either with abatacept or adalimumab. In patients with active RA of similar baseline disease activity treated with abatacept or adalimumab plus background MTX, there was no additional value of background GC on clinical, functional or radiographic outcomes over two years. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis: Pathogenesis, Diagnosis and Therapies)

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9 pages, 737 KiB

Open AccessArticle

Association of Lower Plasma Homoarginine Concentrations with Greater Risk of All-Cause Mortality in the Community: The Framingham Offspring Study

by Edzard Schwedhelm, Rebecca J. Song, Ramachandran S. Vasan, Edwin R. van den Heuvel, Juliane Hannemann, Vanessa Xanthakis and Rainer Böger

J. Clin. Med. 2020, 9(6), 2016; https://doi.org/10.3390/jcm9062016 - 26 Jun 2020

Cited by 12 | Viewed by 2439

Abstract

Lower circulating homoarginine concentrations have been associated with morbidity and mortality in patients with established cardiovascular disease (CVD). We assayed plasma homoarginine concentrations in 3331 Framingham Offspring Study participants attending examination cycle six (mean age 58.6 years, 53% women). We evaluated correlates of [...] Read more.

Lower circulating homoarginine concentrations have been associated with morbidity and mortality in patients with established cardiovascular disease (CVD). We assayed plasma homoarginine concentrations in 3331 Framingham Offspring Study participants attending examination cycle six (mean age 58.6 years, 53% women). We evaluated correlates of plasma homoarginine and related homoarginine to incident CVD and death. We also classified participants as having higher (upper quartile) versus lower (lower three quartiles) homoarginine and previously assayed asymmetric dimethylarginine (ADMA) concentrations, and created cross-classification groups. We observed 630 incident CVD events and 940 deaths during a median follow-up of 18 years. In multivariable regression analysis, homoarginine was associated positively with male sex, body mass index, anti-hypertensive medication use and systolic blood pressure, but inversely with age and smoking. Higher homoarginine levels were associated with a lower mortality risk (hazard ratio (HR) per SD increment, 0.83, 95% CI: 0.74–0.93) adjusting for standard CVD risk factors, and ADMA. Among the cross-classification groups, participants with higher homoarginine and lower ADMA had a lower mortality risk (HR, 0.81, 95% CI: 0.67–0.98) compared to those with low levels of both. Further studies are needed to dissect the mechanisms of the association of homoarginine and mortality over decades in the community. Full article

(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)

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13 pages, 269 KiB

Open AccessArticle

Sleep Quality and Sleep Disturbance Perception in Dual Disorder Patients

by Gianina Luca and Lola Peris

J. Clin. Med. 2020, 9(6), 2015; https://doi.org/10.3390/jcm9062015 - 26 Jun 2020

Cited by 5 | Viewed by 2741

Abstract

Background: Sleep problems are particularly frequent in psychiatric disorders, but their bidirectional intersection is poorly clarified. An especial link between substance use and sleep seems to exist. While dual disorder patients are certainly at higher risk of experiencing sleep problems, very limited research [...] Read more.

Background: Sleep problems are particularly frequent in psychiatric disorders, but their bidirectional intersection is poorly clarified. An especial link between substance use and sleep seems to exist. While dual disorder patients are certainly at higher risk of experiencing sleep problems, very limited research is available today. Methods: Forty-seven dual disorder hospitalized patients were included in this first study. A complete psychiatric evaluation was performed, and sleep habits, patterns and potential disorders were evaluated with specific sleep scales, as well as anxiety. Results: The global prevalence of insomnia symptoms was considerably higher compared with the general population. Different abuse patterns as a function of concurrent psychiatric diagnosis were found, with no significant gender differences. The association between the investigated sleep parameters and any specific substance of abuse was minor. The addict behavior started in more than half of the patients prior to the main psychiatric diagnosis and close to the beginning of sleep problems. Men had a higher prevalence of insomnia symptoms, together with a higher incidence of anxiety. Overall, subjective daytime functioning was not altered as a consequence of poor sleep. Conclusion: Dual disorder patients face significant sleep disturbances, with low sleep quality. The role of sleep in addiction and dual disorders deserves greater research. Full article

(This article belongs to the Special Issue Diagnosis and Management of Addiction and Other Mental Disorders (Dual Disorders))

12 pages, 273 KiB

Open AccessArticle

Role of Exocrine and Endocrine Insufficiency in the Management of Patients with Chronic Pancreatitis

by Carmelo Diéguez-Castillo, Cristina Jiménez-Luna, Jose Luis Martín-Ruiz, Joaquina Martínez-Galán, José Prados, Carolina Torres, Amanda Rocío González-Ramírez and Octavio Caba

J. Clin. Med. 2020, 9(6), 2014; https://doi.org/10.3390/jcm9062014 - 26 Jun 2020

Cited by 4 | Viewed by 2461

Abstract

Background: Exocrine pancreatic insufficiency results from the destruction of the pancreatic parenchyma and is diagnosed by using direct or indirect tests, both of which have shortcomings. Chronic pancreatitis is the most frequent cause of this pathology in adults. Methods: Patients meeting radiological or [...] Read more.

Background: Exocrine pancreatic insufficiency results from the destruction of the pancreatic parenchyma and is diagnosed by using direct or indirect tests, both of which have shortcomings. Chronic pancreatitis is the most frequent cause of this pathology in adults. Methods: Patients meeting radiological or histological diagnostic criteria of chronic pancreatitis are enrolled and the stool elastase test is conducted, considering fecal elastase levels >200 µg/g to represent normal pancreatic function, and levels <200 μg/g to indicate the presence of exocrine pancreatic insufficiency. Additionally, we determine the body mass index of the patients and study their nutritional status and main biochemical and hematological variables, including their glucose and hemoglobin A1c (HbA1c) levels. Results: Exocrine pancreatic insufficiency is detected in 60% of the patients. Among these, 83.3% are severe cases, and 72% of the latter also are diagnosed with endocrine pancreatic insufficiency (diabetes mellitus). During the nutritional status study, HbA1c levels are significantly higher, and magnesium and prealbumin levels are significantly lower in patients with exocrine pancreatic insufficiency than in those without this disease. Conclusions: Exocrine and endocrine pancreatic insufficiency are highly prevalent among patients with chronic pancreatitis and an early diagnosis of these diseases is vital to improve the clinical management of these patients and reduce their risk of mortality. Full article

(This article belongs to the Section Gastroenterology & Hepatopancreatobiliary Medicine)

16 pages, 944 KiB

Open AccessArticle

Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis

by Eujin Park, Chung Lee, Nayoung K. D. Kim, Yo Han Ahn, Young Seo Park, Joo Hoon Lee, Seong Heon Kim, Min Hyun Cho, Heeyeon Cho, Kee Hwan Yoo, Jae Il Shin, Hee Gyung Kang, Il-Soo Ha, Woong-Yang Park and Hae Il Cheong

J. Clin. Med. 2020, 9(6), 2013; https://doi.org/10.3390/jcm9062013 - 26 Jun 2020

Cited by 28 | Viewed by 4291 | Correction

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate [...] Read more.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate in pediatric patients with SRNS has been reported to be approximately 30%. In this study, genotype-phenotype correlations in a cohort of 291 Korean pediatric patients with SRNS/FSGS were analyzed. The overall mutation detection rate was 43.6% (127 of 291 patients). WT1 was the most common causative gene (23.6%), followed by COQ6 (8.7%), NPHS1 (8.7%), NUP107 (7.1%), and COQ8B (6.3%). Mutations in COQ6, NUP107, and COQ8B were more frequently detected, and mutations in NPHS2 were less commonly detected in this cohort than in study cohorts from Western countries. The mutation detection rate was higher in patients with congenital onset, those who presented with proteinuria or chronic kidney disease/ESRD, and those who did not receive steroid treatment. Genetic diagnosis in patients with SRNS provides not only definitive diagnosis but also valuable information for decisions on treatment policy and prediction of prognosis. Therefore, further genotype-phenotype correlation studies are required. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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21 pages, 547 KiB

Open AccessArticle

Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

by Folke Brinkmann, Beatrice Hanusch, Manfred Ballmann, Sebene Mayorandan, Alexander Bollenbach, Kristine Chobanyan-Jürgens, Kathrin Jansen, Anjona Schmidt-Choudhury, Nico Derichs, Dimitrios Tsikas and Thomas Lücke

J. Clin. Med. 2020, 9(6), 2012; https://doi.org/10.3390/jcm9062012 - 26 Jun 2020

Cited by 8 | Viewed by 4365

Abstract

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. [...] Read more.

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients’ lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation. Full article

(This article belongs to the Special Issue Atherosclerosis: Endothelial Dysfunction and Beyond)

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15 pages, 2178 KiB

Open AccessArticle

Clinical and Psychological Impact of COVID-19 Infection in Adult Patients with Eosinophilic Gastrointestinal Disorders during the SARS-CoV-2 Outbreak

by Edoardo Vincenzo Savarino, Paola Iovino, Antonella Santonicola, Matteo Ghisa, Giorgio Laserra, Brigida Barberio, Daria Maniero, Greta Lorenzon, Carolina Ciacci, Vincenzo Savarino and Fabiana Zingone

J. Clin. Med. 2020, 9(6), 2011; https://doi.org/10.3390/jcm9062011 - 26 Jun 2020

Cited by 15 | Viewed by 4232

Abstract

Eosinophilic gastrointestinal diseases (EGIDs) are chronic gastrointestinal conditions requiring corticosteroid and immunosuppressive therapy for disease control. Patients with EGIDs usually report impaired quality of life. We aimed to report the clinical and psychological impact of COVID-19 infection in EGID patients. In this prospective [...] Read more.

Eosinophilic gastrointestinal diseases (EGIDs) are chronic gastrointestinal conditions requiring corticosteroid and immunosuppressive therapy for disease control. Patients with EGIDs usually report impaired quality of life. We aimed to report the clinical and psychological impact of COVID-19 infection in EGID patients. In this prospective web-based study we invited all consecutive EGID patients attending the University Hospital of Salerno (Campania) and Padua (Veneto) to fill an ad hoc COVID-19 survey. Moreover, a telemedicine service for direct consultation was organized. Data regarding the occurrence and perception of COVID-19 infection as well as clinical information were recorded. The study population included 102 EGID patients (mean age 36.6 years, 34 females), of whom 89 had eosinophilic esophagitis, nine had gastroenteritis, and four had colitis. No patient was diagnosed with COVID-19 or had recurrence of his/her primary disease. All of them were adherent to therapy and preventive measures adoption. Most patients were worried because of COVID-19 and social preventing measures but did not consider themselves at major risk or susceptible to COVID-19 or other infections due to their chronic condition or therapy. Female gender and low education level were associated to a higher psychological perception of COVID-19 compared to lockdown status or other demographic and clinical factors (p < 0.05). Overall, COVID-19 had a limited clinical impact on patients with EGIDs. The degree of education and sex, but not the fact of living in a lockdown area, influenced the perception of SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Gastrointestinal Disorders: Diagnosis, Treatments and Clinical Features)

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10 pages, 629 KiB

Open AccessArticle

Validation of IOTA-ADNEX Model in Discriminating Characteristics of Adnexal Masses: A Comparison with Subjective Assessment

by Soo Young Jeong, Byung Kwan Park, Yoo Young Lee and Tae-Joong Kim

J. Clin. Med. 2020, 9(6), 2010; https://doi.org/10.3390/jcm9062010 - 26 Jun 2020

Cited by 21 | Viewed by 3683

Abstract

(1) Background: The aim of this study is to compare the IOTA-ADNEX (international ovarian tumor analysis–assessment of different neoplasias in the adnexa) model with gynecologic experts in differentiating ovarian diseases. (2) Methods: All participants in this prospective study underwent ultrasonography (US) equipped with [...] Read more.

(1) Background: The aim of this study is to compare the IOTA-ADNEX (international ovarian tumor analysis–assessment of different neoplasias in the adnexa) model with gynecologic experts in differentiating ovarian diseases. (2) Methods: All participants in this prospective study underwent ultrasonography (US) equipped with the IOTA-ADNEX^TM model and subjective assessment by a sonographic expert. Receiver operating characteristic (ROC) curves were also generated to compare overall accuracies. The optimal cut-off value of the ADNEX model for excluding benign diseases was calculated. (3) Results: Fifty-nine participants were eligible: 54 and 5 underwent surgery and follow-up computed tomography (CT), respectively. Benign and malignant diseases were confirmed in 49 (83.1%) and 10 (16.9%) participants, respectively. The specificity of the ADNEX model was 0.816 (95% confidence interval (CI): 0.680–0.912) in all participants and 0.795 (95% CI, 0.647–0.902) in the surgical group. The area under the ROC curve of the ADNEX model (0.924) was not significantly different from that of subjective assessment (0.953 in all participants, 0.951 in the surgical group; p = 0.391 in all participants, p = 0.407 in the surgical group). The optimal cut-off point using the ADNEX model was 47.3%, with a specificity of 0.977 (95% CI: 0.880–0.999). (4) Conclusions: The IOTA-ADNEX model is equal to gynecologic US experts in excluding benign ovarian tumors. Subsequently, being familiar with this US software may help gynecologic beginners to reduce unnecessary surgery. Full article

(This article belongs to the Section Obstetrics & Gynecology)

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14 pages, 797 KiB

Open AccessArticle

Does the Use of the “Proseek^® Multiplex Oncology I Panel” on Peritoneal Fluid Allow a Better Insight in the Pathophysiology of Endometriosis, and in Particular Deep-Infiltrating Endometriosis?

by Alexandra Perricos, René Wenzl, Heinrich Husslein, Thomas Eiwegger, Manuela Gstoettner, Andreas Weinhaeusel, Gabriel Beikircher and Lorenz Kuessel

J. Clin. Med. 2020, 9(6), 2009; https://doi.org/10.3390/jcm9062009 - 26 Jun 2020

Cited by 13 | Viewed by 2975

Abstract

Endometriosis appears to share certain cancer-related processes, such as cell attachment, invasion, proliferation and neovascularization, some of which can also be found in other healthy tissues. In order to better understand the altered milieu of the peritoneal cavity, while acknowledging the reported similarities [...] Read more.

Endometriosis appears to share certain cancer-related processes, such as cell attachment, invasion, proliferation and neovascularization, some of which can also be found in other healthy tissues. In order to better understand the altered milieu of the peritoneal cavity, while acknowledging the reported similarities between endometriosis and neoplastic processes, we applied a multiplex oncology panel to search for specific biomarker signatures in the peritoneal fluid of women with endometriosis, women with deep-infiltrating endometriosis (DIE), as well as controls. In total, 84 patients were included in our study, 53 women with endometriosis and 31 controls. Ninety-two proteins were measured in prospectively collected peritoneal fluid (PF) samples, using the “Proseek^® Multiplex Oncology I Panel”. We first compared patients with endometriosis versus controls, and in a second step, DIE versus endometriosis patients without DIE. Out of the 92 analyzed proteins, few showed significant differences between the groups. In patients with endometriosis, ICOS ligand, Endothelial growth factor, E-selectin, Receptor tyrosine-protein kinase erbB-2, Interleukin-6 receptor alpha, Vascular endothelial growth factor receptor 2, Fms-related tyrosine kinase 3 ligand, C-X-C motif chemokine 10, Epididymal secretory protein E4 and Folate receptor-alpha were decreased, while Interleukin-6 and Interleukin-8 were increased compared to controls. Looking at patients with DIE, we found Chemokine ligand 19, Stem cell factor, Vascular endothelial growth factor D, Interleukin-6 receptor alpha and Melanoma inhibitory activity to be increased compared to endometriosis patients without DIE. We have shown a distinct regulation of the immune response, angiogenesis, cell proliferation, cell adhesion and inhibition of apoptosis in PF of patients with endometriosis compared to controls. The specific protein pattern in the PF of DIE patients provides new evidence that DIE represents a unique entity of extrauterine endometriosis with enhanced angiogenetic and pro-proliferative features. Full article

(This article belongs to the Section Obstetrics & Gynecology)

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5 pages, 178 KiB

Open AccessEditorial

Systemic Manifestations and Complications in Patients with Rheumatoid Arthritis

by Ji-Won Kim and Chang-Hee Suh

J. Clin. Med. 2020, 9(6), 2008; https://doi.org/10.3390/jcm9062008 - 26 Jun 2020

Cited by 24 | Viewed by 5196

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease with symmetrical peripheral polyarthritis, predominantly involving the small joints [...] Full article

(This article belongs to the Collection Systemic Manifestations and Complications of Rheumatoid Arthritis)

16 pages, 1934 KiB

Open AccessArticle

Early Predictors of Employment Status One Year Post Injury in Individuals with Traumatic Brain Injury in Europe

by Juan Carlos Arango-Lasprilla, Marina Zeldovich, Laiene Olabarrieta-Landa, Marit Vindal Forslund, Silvia Núñez-Fernández, Nicole von Steinbuechel, Emilie Isager Howe, Cecilie Røe, Nada Andelic and CENTER-TBI Participants and Investigators

J. Clin. Med. 2020, 9(6), 2007; https://doi.org/10.3390/jcm9062007 - 26 Jun 2020

Cited by 15 | Viewed by 4374

Abstract

Sustaining a traumatic brain injury (TBI) often affects the individual’s ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI [...] Read more.

Sustaining a traumatic brain injury (TBI) often affects the individual’s ability to work, reducing employment rates post-injury across all severities of TBI. The objective of this multi-country study was to assess the most relevant early predictors of employment status in individuals after TBI at one-year post-injury in European countries. Using a prospective longitudinal non-randomized observational cohort (The Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) project), data was collected between December 2014–2019 from 63 trauma centers in 18 European countries. The 1015 individuals who took part in this study were potential labor market participants, admitted to a hospital and enrolled within 24 h of injury with a clinical TBI diagnosis and indication for a computed tomography (CT) scan, and followed up at one year. Results from a binomial logistic regression showed that older age, status of part-time employment or unemployment at time of injury, premorbid psychiatric problems, and higher injury severity (as measured with higher Injury severity score (ISS), lower Glasgow Coma Scale (GCS), and longer length of stay (LOS) in hospital) were associated with higher unemployment probability at one-year after injury. The study strengthens evidence for age, employment at time of injury, premorbid psychiatric problems, ISS, GCS, and LOS as important predictors for employment status one-year post-TBI across Europe. Full article

(This article belongs to the Special Issue Traumatic Brain Injury: Recent Developments and Emerging Trends)

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19 pages, 7055 KiB

Open AccessArticle

Muscle Cell Morphogenesis, Structure, Development and Differentiation Processes Are Significantly Regulated during Human Ovarian Granulosa Cells In Vitro Cultivation

by Claudia Dompe, Wiesława Kranc, Karol Jopek, Katarzyna Kowalska, Sylwia Ciesiółka, Błażej Chermuła, Artur Bryja, Maurycy Jankowski, Joanna Perek, Małgorzata Józkowiak, Lisa Moncrieff, Greg Hutchings, Krzysztof Janowicz, Leszek Pawelczyk, Małgorzata Bruska, James Petitte, Paul Mozdziak, Magdalena Kulus, Hanna Piotrowska-Kempisty, Robert Z. Spaczyński, Michał Nowicki and Bartosz Kempisty Show full author list Hide full author list

J. Clin. Med. 2020, 9(6), 2006; https://doi.org/10.3390/jcm9062006 - 26 Jun 2020

Cited by 4 | Viewed by 3158

Abstract

Granulosa cells (GCs) have many functions and are fundamental for both folliculogenesis and oogenesis, releasing hormones and communicating directly with the oocyte. Long-term in vitro cultures of GCs show significant stem-like characteristics. In the current study, RNA of human ovarian granulosa cells was [...] Read more.

Granulosa cells (GCs) have many functions and are fundamental for both folliculogenesis and oogenesis, releasing hormones and communicating directly with the oocyte. Long-term in vitro cultures of GCs show significant stem-like characteristics. In the current study, RNA of human ovarian granulosa cells was collected at 1, 7, 15 and 30 days of long-term in vitro culture. Understanding the process of differentiation of GCs towards different cell lineages, as well as the molecular pathways underlying these mechanisms, is fundamental to revealing other possible stemness markers of this type of cell. Identifying new markers of GC plasticity may help to understand the aetiology and recurrence of a wide variety of diseases and health conditions and reveal possible clinical applications of the ovarian tissue cells, affecting not only the reproductive ability but also sex hormone production. Granulosa cells were the subject of this study, as they are readily available as remnant material leftover after in vitro fertilisation procedures and exhibit significant stem-like characteristics in culture. The change in gene expression was investigated through a range of molecular and bioinformatic analyses. Expression microarrays were used, allowing the identification of groups of genes typical of specific cellular pathways. This candidate gene study focused on ontological groups associated with muscle cell morphogenesis, structure, development and differentiation, namely, “muscle cell development”, “muscle cell differentiation”, “muscle contraction”, “muscle organ development”, “muscle organ morphogenesis”, “muscle structure development”, “muscle system process” and “muscle tissue development”. The results showed that the 10 most upregulated genes were keratin 19, oxytocin receptor, connective tissue growth factor, nexilin, myosin light chain kinase, cysteine and glycine-rich protein 3, caveolin 1, actin, activating transcription factor 3 and tropomyosin, while the 10 most downregulated consisted of epiregulin, prostaglandin-endoperoxide synthase 2, transforming growth factor, interleukin, collagen, 5-hydroxytryptmine, interleukin 4, phosphodiesterase, wingless-type MMTV integration site family and SRY-box 9. Moreover, ultrastructural observations showing heterogeneity of granulosa cell population are presented in the study. At least two morphologically different subpopulations were identified: large, light coloured and small, darker cells. The expression of genes belonging to the mentioned ontological groups suggest the potential ability of GCs to differentiate and proliferate toward muscle lineage, showing possible application in muscle regeneration and the treatment of different diseases. Full article

(This article belongs to the Section Clinical Laboratory Medicine)

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12 pages, 1346 KiB

Open AccessArticle

¹⁸F-Fluorocholine PET and Multiphase CT Integrated in Dual Modality PET/4D-CT for Preoperative Evaluation of Primary Hyperparathyroidism

by Valentin Pretet, Marianela Rotania, Mehdi Helali, Mihaela Ignat, Michel Vix and Alessio Imperiale

J. Clin. Med. 2020, 9(6), 2005; https://doi.org/10.3390/jcm9062005 - 26 Jun 2020

Cited by 27 | Viewed by 2821

Abstract

The present retrospective study evaluates the diagnostic value of integrated ¹⁸F-Fluorocholine positron emission tomography/four-dimensional contrast-enhanced computed tomography (¹⁸F-FCH PET/4D-CT) as second-line imaging in preoperative work-up of primary hyperparathyroidism (pHPT), and compares ¹⁸F-FCH PET with 4D-CT. Patients with pHPT and [...] Read more.

The present retrospective study evaluates the diagnostic value of integrated ¹⁸F-Fluorocholine positron emission tomography/four-dimensional contrast-enhanced computed tomography (¹⁸F-FCH PET/4D-CT) as second-line imaging in preoperative work-up of primary hyperparathyroidism (pHPT), and compares ¹⁸F-FCH PET with 4D-CT. Patients with pHPT and negative/discordant first-line imaging addressed for integrated ¹⁸F-FCH PET/4D-CT were retrospectively selected. Sensitivity and detection rate (DR%) of ¹⁸F-FCH PET/CT, 4D-CT, and PET/4D-CT were calculated according to the per patient and per lesion analyses, and afterwards compared. Histology associated with a decrease more than 50% of perioperative parathyroid hormone (PTH) blood level was used as a gold standard. Persistent high serum PTH and calcium levels during a 6-month follow-up was considered as presence of pHPT in both operated and non-operated patients. 50 patients (55 glands) were included. 44/50 patients (88%) were surgically treated. On a per patient analysis, sensitivity was 93%, 80%, and 95%, and DR% was 82%, 68%, and 84%, respectively for PET/CT, 4D-CT, and PET/4D-CT. PET/CT was more sensitive than 4D-CT (p = 0.046). PET/4D-CT performed better than 4D-CT (p = 0.013) but was equivalent to PET/CT alone. On a per gland analysis, sensitivity PET/CT, 4D-CT, and PET/4D-CT was 88%, 66%, and 92%, and DR% was 79%, 57%, and 83%, respectively. PET/CT and PET/4D-CT were more sensitive than 4D-CT alone (p = 0.01, p < 0.001, respectively). However, PET/CT and PET/4D-CT performed similarly. In conclusion, ¹⁸F-FCH PET provides better identification of hyperfunctioning parathyroids than 4D-CT and the combination of both did not significantly improve diagnostic sensitivity. Further investigations involving larger populations are necessary to define the role of ¹⁸F-FCH PET/4D-CT as a “one-stop shop” second-line imaging in preoperative work-up of pHPT, especially considering the additional patient radiation exposure due to multi-phase CT. Full article

(This article belongs to the Section Nuclear Medicine & Radiology)

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24 pages, 2817 KiB

Open AccessReview

Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development

by Karishma Dhuri, Clara Bechtold, Elias Quijano, Ha Pham, Anisha Gupta, Ajit Vikram and Raman Bahal

J. Clin. Med. 2020, 9(6), 2004; https://doi.org/10.3390/jcm9062004 - 26 Jun 2020

Cited by 280 | Viewed by 21701

Abstract

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to [...] Read more.

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets the disease source at the RNA level and offers a promising alternative to therapies targeting downstream processes. To translate ASO-based therapies into a clinical success, it is crucial to overcome the challenges associated with off-target side effects and insufficient biological activity. In this regard, several chemical modifications and diverse delivery strategies have been explored. In this review, we systematically discuss the chemical modifications, mechanism of action, and optimized delivery strategies of several different classes of ASOs. Further, we highlight the recent advances made in development of ASO-based drugs with a focus on drugs that are approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical applications. We also discuss various promising ASO-based drug candidates in the clinical trials, and the outstanding opportunity of emerging microRNA as a viable therapeutic target for future ASO-based therapies. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 1363 KiB

Open AccessArticle

Pituitary Disease in AIP Mutation-Positive Familial Isolated Pituitary Adenoma (FIPA): A Kindred-Based Overview

by Ismene Bilbao Garay, Adrian F. Daly, Nerea Egaña Zunzunegi and Albert Beckers

J. Clin. Med. 2020, 9(6), 2003; https://doi.org/10.3390/jcm9062003 - 26 Jun 2020

Cited by 9 | Viewed by 3526

Abstract

Clinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one of the most important inherited settings for pituitary adenomas and the most frequent [...] Read more.

Clinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one of the most important inherited settings for pituitary adenomas and the most frequent genetic cause is a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene. AIP mutations lead to young-onset macroadenomas that are difficult to treat. Most are growth hormone secreting tumors, but all other secretory types can exist and the clinical profile of affected patients is variable. We present an overview of the current understanding of AIP mutation-related pituitary disease and illustrate various key clinical factors using examples from one of the largest AIP mutation-positive FIPA families identified to date, in which six mutation-affected members with pituitary disease have been diagnosed. We highlight various clinically significant features of FIPA and AIP mutations, including issues related to patients with acromegaly, prolactinoma, apoplexy and non-functioning pituitary adenomas. The challenges faced by these AIP mutation-positive patients due to their disease and the long-term outcomes in older patients are discussed. Similarly, the pitfalls encountered due to incomplete penetrance of pituitary adenomas in AIP-mutated kindreds are discussed. Full article

(This article belongs to the Special Issue Recent Advances in the Pathogenesis and Therapeutic Strategies of Pituitary Tumors)

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15 pages, 1809 KiB

Open AccessArticle

Impaired Fibrinolysis in Patients with Isolated Aortic Stenosis is Associated with Enhanced Oxidative Stress

by Jakub Siudut, Joanna Natorska, Ewa Wypasek, Łukasz Wiewiórka, Elżbieta Ostrowska-Kaim, Sylwia Wiśniowska-Śmiałek, Krzysztof Plens, Jacek Legutko and Anetta Undas

J. Clin. Med. 2020, 9(6), 2002; https://doi.org/10.3390/jcm9062002 - 25 Jun 2020

Cited by 18 | Viewed by 2286

Abstract

Aortic stenosis (AS) has been associated with impaired fibrinolysis and increased oxidative stress. This study aimed to investigate whether oxidative stress could alter fibrin clot properties in AS. We studied 173 non-diabetic patients, aged 51–79 years, with isolated AS. We measured plasma protein [...] Read more.

Aortic stenosis (AS) has been associated with impaired fibrinolysis and increased oxidative stress. This study aimed to investigate whether oxidative stress could alter fibrin clot properties in AS. We studied 173 non-diabetic patients, aged 51–79 years, with isolated AS. We measured plasma protein carbonylation (PC) and thiobarbituric acid reactive substances (TBARS), along with plasma clot permeability (K_s), thrombin generation, and fibrinolytic efficiency, which were evaluated by two assays: clot lysis time (CLT) and lysis time (Lys50). Coagulation factors and fibrinolytic proteins were also determined. Plasma PC showed an association with AS severity, reflected by the aortic valve area and the mean and maximum aortic gradients. Plasma PC was positively correlated with CLT, Lys50, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) antigens. TBARS were positively correlated with maximum aortic gradient, Lys50, and TF antigen. Regression analysis showed that PC predicted prolonged CLT (>104 min; odds ratio (OR) 6.41, 95% confidence interval (CI) 2.58–17.83, p < 0.001) and Lys50 (>565 s; OR 5.83, 95% CI 2.23–15.21, p < 0.001). Multivariate regression analysis showed that mean aortic gradient, PC, α2-antiplasmin, PAI-1, and triglycerides were predictors of prolonged CLT, while PC, α2-antiplasmin, and fibrinogen were predictors of Lys50. Our findings suggest that elevated oxidative stress contributes to impaired fibrinolysis in AS and is associated with AS severity. Full article

(This article belongs to the Section Vascular Medicine)

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11 pages, 1033 KiB

Open AccessArticle

Uterus Transplantation with Live Donors: Screening Candidates in One French Center

by Marie Carbonnel, Aurelie Revaux, Elena Menzhulina, Lea Karpel, Renaud Snanoudj, Morgan Le Guen, Dominique De Ziegler and Jean Marc Ayoubi

J. Clin. Med. 2020, 9(6), 2001; https://doi.org/10.3390/jcm9062001 - 25 Jun 2020

Cited by 22 | Viewed by 2674

Abstract

We report our experience regarding the profile and screening process of potential recipients (R) and their live donors (D) in our Uterus transplantation (UTx) trial from 2014 to 2020. The initial screening was performed using medical questionnaires and consultations. The second step of [...] Read more.

We report our experience regarding the profile and screening process of potential recipients (R) and their live donors (D) in our Uterus transplantation (UTx) trial from 2014 to 2020. The initial screening was performed using medical questionnaires and consultations. The second step of the screening consisted of two individual interviews with an independent multidisciplinary committee. Then, a complete medical, biological and imaging assessment of the directed living D, the R, and her partner was performed over a two-day hospitalization. A total of 239 women contacted our department: 165 potentials R and 74 potentials D. During the first step of screening, 141 R and 45 D were excluded. Only 12 R/D pairs were pursued. During inclusion, 10 R/D pairs were excluded. One R/D pair is still under evaluation. Finally, only 1 R/D pair was definitively included (0.6%), which led us to perform the first French UTx in March 2019 with a successful graft. The primary limiting factors of inclusion were due to very strict criteria and difficulty of having a suitable directed living D. The International Society of UTx (ISUTx) guidelines based on worldwide results of trials can help ease our inclusion criteria in the future while remaining safe for patients. Full article

(This article belongs to the Special Issue Uterus Transplantation)

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10 pages, 1184 KiB

Open AccessArticle

Abnormalities on Perfusion CT and Intervention for Intracranial Hypertension in Severe Traumatic Brain Injury

by Shannon Cooper, Cino Bendinelli, Andrew Bivard, Mark Parsons and Zsolt J. Balogh

J. Clin. Med. 2020, 9(6), 2000; https://doi.org/10.3390/jcm9062000 - 25 Jun 2020

Cited by 3 | Viewed by 2558

Abstract

The role of invasive intracranial pressure (ICP) monitoring in patients with severe traumatic brain injury (STBI) remain unclear. Perfusion computed tomography (CTP) provides crucial information about the cerebral perfusion status in these patients. We hypothesised that CTP abnormalities would be associated with the [...] Read more.

The role of invasive intracranial pressure (ICP) monitoring in patients with severe traumatic brain injury (STBI) remain unclear. Perfusion computed tomography (CTP) provides crucial information about the cerebral perfusion status in these patients. We hypothesised that CTP abnormalities would be associated with the severity of intracranial hypertension (ICH). To investigate this hypothesis, twenty-eight patients with STBI and ICP monitors were investigated with CTP within 48 h from admission. Treating teams were blind to these results. Patients were divided into five groups based on increasing intervention required to control ICH and were compared. Group I required no intervention above routine sedation, group II required a single first tier intervention, group III required multiple different first-tier interventions, group IV required second-tier medical therapy and group V required second-tier surgical therapy. Analysis of the results showed demographics and injury severity did not differ among groups. In group I no patients showed CTP abnormality, while patients in all other groups had abnormal CTP (p = 0.003). Severe ischaemia observed on CTP was associated with increasing intervention for ICH. This study, although limited by small sample size, suggests that CTP abnormalities are associated with the need to intervene for ICH. Larger scale assessment of our results is warranted to potentially avoid unnecessary invasive procedures in head injury patients. Full article

(This article belongs to the Section Clinical Neurology)

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10 pages, 919 KiB

Open AccessArticle

Low-Volume Nodal Metastasis in Endometrial Cancer: Risk Factors and Prognostic Significance

by Virginia García Pineda, Alicia Hernández Gutiérrez, Myriam Gracia Segovia, Jaime Siegrist Ridruejo, María Dolores Diestro Tejeda and Ignacio Zapardiel

J. Clin. Med. 2020, 9(6), 1999; https://doi.org/10.3390/jcm9061999 - 25 Jun 2020

Cited by 18 | Viewed by 3016

Abstract

Objective: To evaluate the oncological outcomes of patients with low-volume metastasis compared to those with macrometastasis and negative nodes in endometrial cancer. Methods: A single institutional retrospective study was carried out, which included all patients with endometrial cancer who underwent surgical treatment between [...] Read more.

Objective: To evaluate the oncological outcomes of patients with low-volume metastasis compared to those with macrometastasis and negative nodes in endometrial cancer. Methods: A single institutional retrospective study was carried out, which included all patients with endometrial cancer who underwent surgical treatment between January 2007 and December 2016. We analyzed the progression-free survival (PFS) and overall survival (OS) of all patients after sentinel node biopsy and full nodal surgical staging according to their final pathological nodal status, focusing on the impact of the size of nodal metastasis. Results: A total of 270 patients were operated on during the study period; among them, 230 (85.2%) patients underwent nodal staging. On final pathology, 196 (85.2%) patients had negative lymph nodes; low-volume metastasis (LVM) was present in 14 (6.1%) patients: 6 (2.6%) patients had isolated tumor cells (ITCs) and 8 (3.5%) patients presented just micrometastasis; additionally, 20 (8.7%) patients presented macrometastasis. After a median (range) follow-up of 60 (0–146) months, patients with macrometastasis showed a significantly worse PFS compared to LVM and node-negative patients (61.1% vs. 71.4% vs. 83.2%, respectively; p = 0.018), and similar results were obtained for 5-year OS (50% vs. 78.6% vs. 81.5%, respectively; p < 0.001). Half of the patients presenting LVM did not receive adjuvant treatment. Moreover, LVM had a moderate nonsignificant decrease in 5-year PFS compared to node-negative patients. Conclusions: Patients with endometrial cancer and low-volume nodal metastasis demonstrated a better prognosis than those presenting macrometastasis. Low-volume metastasis did not show worse oncological outcomes than node-negative patients, although there was a slight decrease in progression-free survival. Full article

(This article belongs to the Special Issue Endometrial Cancer: Latest Advances and Prospects)

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12 pages, 486 KiB

Open AccessArticle

Antiplatelet Antibodies Do Not Predict the Response to Intravenous Immunoglobulins during Immune Thrombocytopenia

by Thomas Rogier, Maxime Samson, Guillaume Mourey, Nicolas Falvo, Nadine Magy-Bertrand, Sethi Ouandji, Jean-Baptiste Picque, Hélène Greigert, Christelle Mausservey, Arthur Imbach, Thibault Ghesquière, Laurent Voillat, Denis Caillot, Eric Deconinck, Bernard Bonnotte and Sylvain Audia

J. Clin. Med. 2020, 9(6), 1998; https://doi.org/10.3390/jcm9061998 - 25 Jun 2020

Cited by 12 | Viewed by 3001

Abstract

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to autoantibodies targeting platelet glycoproteins (GP). The mechanism of platelet destruction could differ depending on the specificity of antiplatelet antibodies: anti-GPIIb/IIIa antibodies lead to phagocytosis by splenic macrophages, in a Fcγ receptor (FcγR)-dependent manner [...] Read more.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to autoantibodies targeting platelet glycoproteins (GP). The mechanism of platelet destruction could differ depending on the specificity of antiplatelet antibodies: anti-GPIIb/IIIa antibodies lead to phagocytosis by splenic macrophages, in a Fcγ receptor (FcγR)-dependent manner while anti-GPIb/IX antibodies induce platelet desialylation leading to their destruction by hepatocytes after binding to the Ashwell–Morell receptor, in a FcγR-independent manner. Considering the FcγR-dependent mechanism of action of intravenous immunoglobulins (IVIg), we assumed that the response to IVIg could be less efficient in the presence of anti-GPIb/IX antibodies. We conducted a multicentric, retrospective study including all adult ITP patients treated with IVIg who had antiplatelet antibodies detected between January 2013 and October 2017. Among the 609 identified, 69 patients were included: 17 had anti-GPIb/IX antibodies and 33 had anti-GPIIb/IIIa antibodies. The response to IVIg was not different between the patients with or without anti-GPIb/IX (88.2% vs. 73.1%). The response to IVIg was better in the case of newly diagnosed ITP (odds ratio (OR) = 5.4 (1.2–24.7)) and in presence of anti-GPIIb/IIIa (OR = 4.82 (1.08–21.5)), while secondary ITP had a poor response (OR = 0.1 (0.02–0.64)). In clinical practice, the determination of antiplatelet antibodies is therefore of little value to predict the response to IVIg. Full article

(This article belongs to the Section Hematology)

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15 pages, 1921 KiB

Open AccessArticle

Left Ventricular Geometry and Replacement Fibrosis Detected by cMRI Are Associated with Major Adverse Cardiovascular Events in Nonischemic Dilated Cardiomyopathy

by Bianca Olivia Cojan-Minzat, Alexandru Zlibut, Ioana Danuta Muresan, Carmen Cionca, Dalma Horvat, Eva Kiss, Radu Revnic, Mira Florea, Razvan Ciortea and Lucia Agoston-Coldea

J. Clin. Med. 2020, 9(6), 1997; https://doi.org/10.3390/jcm9061997 - 25 Jun 2020

Cited by 11 | Viewed by 3545

Abstract

To investigate the relationship between left ventricular (LV) long-axis strain (LAS) and LV sphericity index (LVSI) and outcomes in patients with nonischemic dilated cardiomyopathy (NIDCM) and myocardial replacement fibrosis confirmed by late gadolinium enhancement (LGE) using cardiac magnetic resonance imaging (cMRI), we conducted [...] Read more.

To investigate the relationship between left ventricular (LV) long-axis strain (LAS) and LV sphericity index (LVSI) and outcomes in patients with nonischemic dilated cardiomyopathy (NIDCM) and myocardial replacement fibrosis confirmed by late gadolinium enhancement (LGE) using cardiac magnetic resonance imaging (cMRI), we conducted a prospective study on 178 patients (48 ± 14.4 years; 25.2% women) with first NIDCM diagnosis. The evaluation protocol included ECG monitoring, echocardiography and cMRI. LAS and LVSI were cMRI-determined. Major adverse cardiovascular events (MACEs) were defined as a composite outcome including heart failure (HF), ventricular arrhythmias (VAs) and sudden cardiac death (SCD). After a median follow-up of 17 months, patients with LGE+ had increased risk of MACEs. Kaplan-Meier curves showed significantly higher rate of MACEs in patients with LGE+ (p < 0.001), increased LVSI (p < 0.01) and decreased LAS (p < 0.001). In Cox analysis, LAS (HR = 1.32, 95%CI (1.54–9.14), p = 0.001), LVSI [HR = 1.17, 95%CI (1.45–7.19), p < 0.01] and LGE+ (HR = 1.77, 95%CI (2.79–12.51), p < 0.0001) were independent predictors for MACEs. In a 4-point risk scoring system based on LV ejection fraction (LVEF) < 30%, LGE+, LAS > −7.8% and LVSI > 0.48%, patients with 3 and 4 points had a significantly higher risk for MACEs. LAS and LVSI are independent predictors of MACEs and provide incremental value beyond LVEF and LGE+ in patients with NIDCM and myocardial fibrosis. Full article

(This article belongs to the Special Issue Characterization and Clinical Management of Dilated Cardiomyopathy)

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20 pages, 2024 KiB

Open AccessReview

Optimal Timing of External Ventricular Drainage after Severe Traumatic Brain Injury: A Systematic Review

by Charlene Y. C. Chau, Saniya Mediratta, Mikel A. McKie, Barbara Gregson, Selma Tulu, Ari Ercole, Davi J. F. Solla, Wellingson S. Paiva, Peter J. Hutchinson and Angelos G. Kolias

J. Clin. Med. 2020, 9(6), 1996; https://doi.org/10.3390/jcm9061996 - 25 Jun 2020

Cited by 18 | Viewed by 6049

Abstract

External ventricular drainage (EVD) may be used for therapeutic cerebrospinal fluid (CSF) drainage to control intracranial pressure (ICP) after traumatic brain injury (TBI). However, there is currently uncertainty regarding the optimal timing for EVD insertion. This study aims to compare patient outcomes for [...] Read more.

External ventricular drainage (EVD) may be used for therapeutic cerebrospinal fluid (CSF) drainage to control intracranial pressure (ICP) after traumatic brain injury (TBI). However, there is currently uncertainty regarding the optimal timing for EVD insertion. This study aims to compare patient outcomes for patients with early and late EVD insertion. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, MEDLINE/EMBASE/Scopus/Web of Science/Cochrane Central Register of Controlled Trials were searched for published literature involving at least 10 severe TBI (sTBI) patients from their inception date to December 2019. Outcomes assessed were mortality, functional outcome, ICP control, length of stay, therapy intensity level, and complications. Twenty-one studies comprising 4542 sTBI patients with an EVD were included; 19 of the studies included patients with an early EVD, and two studies had late EVD placements. The limited number of studies, small sample sizes, imbalance in baseline characteristics between the groups and poor methodological quality have limited the scope of our analysis. We present the descriptive statistics highlighting the current conflicting data and the overall lack of reliable research into the optimal timing of EVD. There is a clear need for high quality comparisons of early vs. late EVD insertion on patient outcomes in sTBI. Full article

(This article belongs to the Special Issue Traumatic Brain Injury: Recent Developments and Emerging Trends)

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39 pages, 730 KiB

Open AccessReview

Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

by Maria Giovanna Scioli, Gabriele Storti, Federico D’Amico, Roger Rodríguez Guzmán, Federica Centofanti, Elena Doldo, Ela María Céspedes Miranda and Augusto Orlandi

J. Clin. Med. 2020, 9(6), 1995; https://doi.org/10.3390/jcm9061995 - 25 Jun 2020

Cited by 112 | Viewed by 9711

Abstract

Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world’s leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of [...] Read more.

Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world’s leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of nitric oxide, with or without an imbalance between endothelium-derived contracting, and relaxing factors associated with a pro-inflammatory and prothrombotic status. Endothelial dysfunction-induced phenotypic changes include up-regulated expression of adhesion molecules and increased chemokine secretion, leukocyte adherence, cell permeability, low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. Inflammation-induced oxidative stress results in an increased accumulation of reactive oxygen species (ROS), mainly derived from mitochondria. Excessive ROS production causes oxidation of macromolecules inducing cell apoptosis mediated by cytochrome-c release. Oxidation of mitochondrial cardiolipin loosens cytochrome-c binding, thus, favoring its cytosolic release and activation of the apoptotic cascade. Oxidative stress increases vascular permeability, promotes leukocyte adhesion, and induces alterations in endothelial signal transduction and redox-regulated transcription factors. Identification of new endothelial dysfunction-related oxidative stress markers represents a research goal for better prevention and therapy of CVD. New-generation therapeutic approaches based on carriers, gene therapy, cardiolipin stabilizer, and enzyme inhibitors have proved useful in clinical practice to counteract endothelial dysfunction. Experimental studies are in continuous development to discover new personalized treatments. Gene regulatory mechanisms, implicated in endothelial dysfunction, represent potential new targets for developing drugs able to prevent and counteract CVD-related endothelial dysfunction. Nevertheless, many challenges remain to overcome before these technologies and personalized therapeutic strategies can be used in CVD management. Full article

(This article belongs to the Section Vascular Medicine)

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14 pages, 496 KiB

Open AccessArticle

Outcome of Root Canal Treatments Provided by Endodontic Postgraduate Students. A Retrospective Study

by Carmen Llena, Teodora Nicolescu, Salvadora Perez, Silvia Gonzalez de Pereda, Ana Gonzalez, Iris Alarcon, Angela Monzo, José Luis Sanz, Maria Melo and Leopoldo Forner

J. Clin. Med. 2020, 9(6), 1994; https://doi.org/10.3390/jcm9061994 - 25 Jun 2020

Cited by 9 | Viewed by 4255

Abstract

The aim of this study was to assess the preoperative, intraoperative, and postoperative factors that influenced complete periapical healing in teeth that underwent primary root canal treatment (RCT), in patients treated by postgraduate students in endodontics. Factors were retrieved and compared with the [...] Read more.

The aim of this study was to assess the preoperative, intraoperative, and postoperative factors that influenced complete periapical healing in teeth that underwent primary root canal treatment (RCT), in patients treated by postgraduate students in endodontics. Factors were retrieved and compared with the periapical status during the follow-up visit. Healing was considered as the absence of clinical and radiological symptoms. Variables significantly associated by the chi-squared test were included in a logistic regression model (LRM). Preoperative factors associated with healing were: American Society of Anesthesiology (ASA) status (p = 0.01); the absence of preoperative pain (p = 0.04); positive response to pulp tests; when the RCT cause was caries, pain, abscess, or sinus tract; probing depth <4 mm; the absence of mobility; absence or <4 mm periapical lesion (p < 0.01). In the LRM, the factors included were: absence or <4 mm periapical lesion; probing depths <4 mm; RCT caused by caries, pain, abscess, or sinus tract; the tooth was not a bridge abutment. Postoperative factors were: teeth with direct restoration; teeth that did not act as a support for a fixed prosthetic restoration; the favorable condition of the coronal restoration (p < 0.01). In the LRM, only the status of the coronal restoration was included. Preoperative conditions and the adequate fit of the coronal restoration influenced the outcome of RCT. Full article

(This article belongs to the Section Dentistry, Oral Surgery and Oral Medicine)

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11 pages, 2189 KiB

Open AccessArticle

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

by Canay Caliskan, Benjamin Seeliger, Benedikt Jäger, Jan Fuge, Tobias Welte, Oliver Terwolbeck, Julia Freise, Coline H. M. van Moorsel, Yingze Zhang and Antje Prasse

J. Clin. Med. 2020, 9(6), 1993; https://doi.org/10.3390/jcm9061993 - 25 Jun 2020

Cited by 6 | Viewed by 2708

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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13 pages, 625 KiB

Open AccessArticle

Automated Nociceptive Withdrawal Reflex Measurements Reveal Normal Reflex Thresholds and Augmented Pain Ratings in Patients with Fibromyalgia

by Johannes Ydrefors, Tomas Karlsson, Ulrika Wentzel Olausson, Bijar Ghafouri, Ann-Charlotte Johansson, Håkan Olausson, Björn Gerdle and Saad S. Nagi

J. Clin. Med. 2020, 9(6), 1992; https://doi.org/10.3390/jcm9061992 - 25 Jun 2020

Cited by 6 | Viewed by 3436

Abstract

The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of [...] Read more.

The nociceptive withdrawal reflex (NWR) is used to probe spinal cord excitability in chronic pain states. Here, we used an automated and unbiased procedure for determining the NWR threshold and compared the reflex thresholds and corresponding pain ratings in a well-characterized cohort of fibromyalgia (n = 29) and matched healthy controls (n = 21). Surface electrical stimuli were delivered to the foot in a stepwise incremental and decremental manner. The surface electromyographic activity was recorded from the ipsilateral tibialis anterior muscle. Fibromyalgia patients reported significantly higher scores for psychological distress and pain-related disability and a significantly lower score for perceived state of health compared to the matched controls. The subjective pain ratings were significantly higher in patients. The NWR thresholds were similar to the controls. In the patients, but not in controls, the NWR thresholds and subjective pain ratings were significantly correlated. Our results showed an increased subjective pain sensitivity in fibromyalgia, but we found no evidence for spinal sensitization based on the reflex measures. Full article

(This article belongs to the Special Issue New Frontiers in the Diagnosis, Prediction, Prevention, and Management of Fibromyalgia)

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14 pages, 303 KiB

Open AccessReview

Erectile Dysfunction after Kidney Transplantation

by Anna Perri, Giulia Izzo, Danilo Lofaro, Sandro La Vignera, Antonio Brunetti, Aldo Eugenio Calogero and Antonio Aversa

J. Clin. Med. 2020, 9(6), 1991; https://doi.org/10.3390/jcm9061991 - 25 Jun 2020

Cited by 16 | Viewed by 6191

Abstract

Patients with kidney transplantation often have a worse quality of life than the general population. One of the reasons for this, in male patients, is the high prevalence of erectile dysfunction. This is mainly due to the presence of comorbidities, surgery for kidney [...] Read more.

Patients with kidney transplantation often have a worse quality of life than the general population. One of the reasons for this, in male patients, is the high prevalence of erectile dysfunction. This is mainly due to the presence of comorbidities, surgery for kidney transplantation, adverse drug effects, psychological changes related to chronic disease, as well as hyperprolactinemia and hypogonadism. Whenever these endocrine dysfunctions occur after kidney transplantation, they must be corrected with appropriate treatment, i.e., testosterone replacement therapy. Administration of the phosphodiesterase-5 inhibitor (PDE5i) sildenafil at the recommended posology does not significantly alter the pharmacokinetics of the calcineurin inhibitors cyclosporin A or tacrolimus and does not impair kidney allograft function. Tacrolimus increases the peak concentration and prolongs the half-life of PDE5i in kidney transplant patients and, therefore, daily administration cannot be recommended due to the significant drop in blood pressure. Intracavernous injection or topical application of alprostadil can be a second-line option for the treatment of erectile dysfunction after kidney transplantation, which does not alter cyclosporine concentrations and does not deteriorate kidney function. Finally, penile prostheses can be successfully implanted following pelvic organ transplantation after eliminating the risk of infection associated with surgery. Full article

(This article belongs to the Special Issue Erectile Dysfunction in Men with Chronic Diseases: From Pathophysiology to Clinical Management)

11 pages, 1795 KiB

Open AccessArticle

Low Galectin-3 Expression Level in Primary Tumors Is Associated with Metastasis in T1 Lung Adenocarcinoma

by Ming-Wei Kao, Yue-Chiu Su, Peir-In Liang, Yi-Ying Wu and Tse-Ming Hong

J. Clin. Med. 2020, 9(6), 1990; https://doi.org/10.3390/jcm9061990 - 25 Jun 2020

Cited by 4 | Viewed by 2671

Abstract

Background and objective: Although nodal and distant metastasis is rare in T1 lung adenocarcinoma, it is related to poor clinical prognosis. Association between galectin-3 (Gal-3) expression level, and clinical outcome of T1 lung adenocarcinoma has not been clarified. Methods: From January 2009 to [...] Read more.

Background and objective: Although nodal and distant metastasis is rare in T1 lung adenocarcinoma, it is related to poor clinical prognosis. Association between galectin-3 (Gal-3) expression level, and clinical outcome of T1 lung adenocarcinoma has not been clarified. Methods: From January 2009 to December 2014, 74 patients with surgically resected T1 lung adenocarcinoma were enrolled in this retrospective cohort study. Patient outcomes were followed up until December 2019. Gal-3 expression level in primary tumors was assessed immunohistochemically and evaluated based on the staining intensity and percentage. Patient characteristics and correlation between Gal-3 expression level and clinical outcomes were reviewed. Results: Low Gal-3 expression was associated with increased metastatic events (p = 0.03), especially distant metastasis (p = 0.007), and mortality rate (p = 0.04). Kaplan–Meier analysis revealed that high Gal-3 expression level was associated with favorable recurrence-free survival in T1 lung adenocarcinoma (log-rank p = 0.048) and T1a (≤ 2 cm, American Joint Committee on Cancer (AJCC) 7th edition) lung adenocarcinoma (log-rank p = 0.043). Gal-3 expression along with tumor size showed a larger area under curve (AUC) than tumor size alone for predicting metastatic events (AUC = 0.747 vs. 0.681) and recurrence (AUC = 0.813 vs. 0.766) in T1a lung adenocarcinoma in the receiver-operating characteristic curve. Conclusion: Low Gal-3 expression level in primary tumors was remarkably associated with increased metastatic events and reduced recurrence-free survival in T1 lung adenocarcinoma. We suggest that Gal-3 expression level in addition to tumor size may potentially be stronger than tumor size alone in predicting metastasis in T1a lung adenocarcinoma patients. Full article

(This article belongs to the Section Oncology)

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12 pages, 1550 KiB

Open AccessArticle

The Efficacy of Rotary, Reciprocating, and Combined Non-Surgical Endodontic Retreatment Techniques in Removing a Carrier-Based Root Canal Filling Material from Straight Root Canal Systems: A Micro-Computed Tomography Analysis

by Tarek-Fahed Alakabani, Vicente Faus-Llácer, Ignacio Faus-Matoses, Celia Ruiz-Sánchez, Álvaro Zubizarreta-Macho, Salvatore Sauro and Vicente Faus-Matoses

J. Clin. Med. 2020, 9(6), 1989; https://doi.org/10.3390/jcm9061989 - 25 Jun 2020

Cited by 13 | Viewed by 4289

Abstract

The aim of this study is to analyze and compare the efficacy of three non-surgical endodontic retreatment techniques in removing a carrier-based root canal filling material from straight root canal systems. The study was performed on 99 single-rooted extracted teeth using the ProTaper [...] Read more.

The aim of this study is to analyze and compare the efficacy of three non-surgical endodontic retreatment techniques in removing a carrier-based root canal filling material from straight root canal systems. The study was performed on 99 single-rooted extracted teeth using the ProTaper Gold endodontic rotary system up to the F2 file (Dentsply Maillefer, Baillagues, Switzerland), which were sealed with GuttaCore (Dentsply Maillefer, Ballaigues, Switzerland) and AH plus epoxy resin sealer (Dentsply DeTrey, Konstanz, Germany) and randomly assigned to the following non-surgical retreatment techniques: ProTaper Retreatment endodontic rotary instruments (D1–D3 files, Dentsply Maillefer, Ballaigues, Switzerland; n = 33, PTR), Reciproc Blue endodontic reciprocating instrument (R50, VDW, Munich, Germany; n = 33, RCB50), and a combined root canal retreatment technique between Gates-Glidden drills (sizes #3 and #2, Dentsply Maillefer, Ballaigues, Switzerland) and Hedstrom files (file size 35, 30, and 25, Dentsply Maillefer, Ballaigues, Switzerland; n = 33; H-GG). All of the teeth were submitted twice to a micro-computed tomography (micro-CT) scan, before and after non-surgical endodontic retreatment procedures. The volume of root canal filling material (mm³), volume of remaining root canal filling material (mm³), non-surgical endodontic retreatment working time (min), proportion of remaining root canal filling material (%), and efficacy of root canal filling material removal between the non-surgical endodontic retreatment techniques were analyzed using ANOVA one-way statistical analysis. Statistically significant differences were observed between the proportions of remaining root canal filling material of PTR and H-GG (p = 0.018), between the non-surgical endodontic retreatment working times (min; p < 0.001), and between the efficacies of root canal filling material removal by the non-surgical endodontic retreatment techniques (p = 0.009). However, the non-surgical endodontic retreatment systems allow for similar carrier-based root canal filling material removal. Full article

(This article belongs to the Special Issue Clinical Research of Endodontic Dentistry)

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11 pages, 541 KiB

Open AccessArticle

Supportive Implant Therapy (SIT): A Prospective 10-Year Study of Patient Compliance Rates and Impacting Factors

by Julia Mitschke, Stefanie Anna Peikert, Kirstin Vach and Eberhard Frisch

J. Clin. Med. 2020, 9(6), 1988; https://doi.org/10.3390/jcm9061988 - 25 Jun 2020

Cited by 1 | Viewed by 2576

Abstract

The main objective of this study is to present patient compliance rates and influential factors for regular attendance in a systematic implant aftercare program (Supportive Implant Therapy; SIT) within a 10-year observation period. From 2005 to 2008, we identified 233 patients with 524 [...] Read more.

The main objective of this study is to present patient compliance rates and influential factors for regular attendance in a systematic implant aftercare program (Supportive Implant Therapy; SIT) within a 10-year observation period. From 2005 to 2008, we identified 233 patients with 524 implants and implant-supported restorations at the study center. They had been instructed to attend an SIT program with 3-month recall intervals. A 2019 clinical prospective cohort study on 10-year compliance rates was performed. Data were assessed yearly in regression analyses to identify influential factors. Noncompliance rates increased during the period (4.8%, year 1; 39.7%, year 10). Total noncompliance was observed in four patients (1.7%) with 10 implants. “Age,” “Gender,” “Diabetes”, and “Surgical case complexity” showed no correlation with patient compliance. “Smoking” and “Cardiovascular diseases” significantly influenced patients in one of ten years, while “Number of implants per patient”, “Type of implant-supported prostheses”, and “Pre-existing experience in a prophylaxis program” reached significance after several years. When patients with implant-supported restorations are strongly recommended and frequently remotivated to comply with an SIT program with 3-month recall, an approximately 60% compliance rate after 10 years is achievable. Previous prophylaxis program experience, increased number of implants per patient, and removable implant-supported prostheses may be strong influential factors for increased patient compliance. Full article

(This article belongs to the Section Dentistry, Oral Surgery and Oral Medicine)

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J. Clin. Med., Volume 9, Issue 6 (June 2020) – 413 articles

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