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J. Clin. Med., Volume 8, Issue 6 (June 2019)

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Open AccessArticle
Moderate and Stable Pain Reductions as a Result of Interdisciplinary Pain Rehabilitation—A Cohort Study from the Swedish Quality Registry for Pain Rehabilitation (SQRP)
J. Clin. Med. 2019, 8(6), 905; https://doi.org/10.3390/jcm8060905 (registering DOI)
Received: 10 June 2019 / Revised: 18 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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Abstract
Few studies have investigated the real-life outcomes of interdisciplinary multimodal pain rehabilitation programs (IMMRP) for chronic pain. This study has four aims: investigate effect sizes (ES); analyse correlation patterns of outcome changes; define a multivariate outcome measure; and investigate whether the clinical self-reported [...] Read more.
Few studies have investigated the real-life outcomes of interdisciplinary multimodal pain rehabilitation programs (IMMRP) for chronic pain. This study has four aims: investigate effect sizes (ES); analyse correlation patterns of outcome changes; define a multivariate outcome measure; and investigate whether the clinical self-reported presentation pre-IMMRP predicts the multivariate outcome. To this end, this study analysed chronic pain patients in specialist care included in the Swedish Quality Registry for Pain Rehabilitation for 22 outcomes (pain, psychological distress, participation, and health) on three occasions: pre-IMMRP, post-IMMRP, and 12-month follow-up. Moderate stable ES were demonstrated for pain intensity, interference in daily life, vitality, and health; most other outcomes showed small ES. Using a Multivariate Improvement Score (MIS), we identified three clusters. Cluster 1 had marked positive MIS and was associated with the overall worst situation pre-IMMRP. However, the pre-IMMRP situation could only predict 8% of the variation in MIS. Specialist care IMPRPs showed moderate ES for pain, interference, vitality, and health. Outcomes were best for patients with the worst clinical presentation pre-IMMRP. It was not possible to predict who would clinically benefit most from IMMRP. Full article
(This article belongs to the Special Issue Rehabilitation for Persistent Pain Across the Lifespan)
Open AccessArticle
Shared Decision-Making in Chronic Patients with Polypharmacy: An Interventional Study for Assessing Medication Appropriateness
J. Clin. Med. 2019, 8(6), 904; https://doi.org/10.3390/jcm8060904 (registering DOI)
Received: 12 May 2019 / Revised: 16 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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Abstract
Potentially inappropriate medications are associated with polypharmacy and polypathology. Some interventions such as pharmacotherapy reviews have been designed to reduce the prescribing of inappropriate medications. The objective of this study is to evaluate how effective a decision-making support tool is for determining medication [...] Read more.
Potentially inappropriate medications are associated with polypharmacy and polypathology. Some interventions such as pharmacotherapy reviews have been designed to reduce the prescribing of inappropriate medications. The objective of this study is to evaluate how effective a decision-making support tool is for determining medication appropriateness in patients with one or more chronic diseases (hypertension, dyslipidaemia, and/or diabetes) and polypharmacy in the primary care setting. For this, a quasi-experimental study (randomised, controlled and multicentre) has been developed. The study compares an intervention group, which assesses medication appropriateness by applying a decision support tool, with a control group that follows the usual clinical practice. The intervention included a decision support tool in paper format, where participants were informed about polypharmacy, inappropriate medications, associated problems and available alternatives, as well as shared decision-making. This is an informative guide aimed at helping patients with decision-making by providing them with information about the secondary risks associated with inappropriate medications in their treatment, according to the Beers and START/STOPP criteria. The outcome measure was the proportion of medication appropriateness. The proportion of patients who confirmed medication appropriateness after six months of follow-up is greater in the intervention group (32.5%) than in the control group (27.9%) p = 0.008. The probability of medication appropriateness, which was calculated by the proportion of drugs withdrawn or replaced according to the STOPP/Beers criteria and those initiated according to the START criteria, was 2.8 times higher in the intervention group than in the control group (OR = 2.8; 95% CI 1.3–6.1) p = 0.008. In patients with good adherence to the treatment, the percentage of appropriateness was 62.1% in the shared decision-making group versus 37.9% in the control group (p = 0.005). The use of a decision-making support tool in patients with potentially inappropriate medications increases the percentage of medication appropriateness when compared to the usual clinical practice. Full article
(This article belongs to the Special Issue The Future of Artificial Intelligence in Clinical Medicine)
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Open AccessReview
Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication
J. Clin. Med. 2019, 8(6), 903; https://doi.org/10.3390/jcm8060903 (registering DOI)
Received: 30 May 2019 / Revised: 15 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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Abstract
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms [...] Read more.
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease. Full article
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Open AccessReview
Congenital Heart Defects in Monochorionic Twins: A Systematic Review and Meta-Analysis
J. Clin. Med. 2019, 8(6), 902; https://doi.org/10.3390/jcm8060902 (registering DOI)
Received: 20 May 2019 / Revised: 14 June 2019 / Accepted: 18 June 2019 / Published: 24 June 2019
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Abstract
Monochorionic (MC) twins are at an increased risk of developing congenital heart defects (CHDs) compared to singletons and dichorionic twins. The development of acquired CHDs in this specific group of twins is associated with twin–twin transfusion syndrome (TTTS). We performed a systematic review [...] Read more.
Monochorionic (MC) twins are at an increased risk of developing congenital heart defects (CHDs) compared to singletons and dichorionic twins. The development of acquired CHDs in this specific group of twins is associated with twin–twin transfusion syndrome (TTTS). We performed a systematic review and meta-analysis to provide an overview of the reported birth prevalence of CHDs in liveborn MC twins with and without TTTS. Twelve studies were included in this review. Compared to the reference population, MC twins were 6.3 times more likely to be born with a CHD (59.3 per 1000 liveborn twins; relative risk (RR) 6.3; 95% confidence interval (CI): 4.4–9.1), and TTTS twins had a 12-fold increased risk of having a CHD at birth (87.3 per 1000 live births; RR 12.4, 95% CI: 8.6–17.8). The increased incidence of CHDs can mainly be attributed to the risk of right ventricular outflow tract obstruction (35/1000 TTTS twin live births vs. 0.5/1000 singleton live births). We recommend an expert fetal echocardiogram in all MC twins, follow-up scans in the event of TTTS, and a postnatal cardiac evaluation in all TTTS survivors. Full article
(This article belongs to the Special Issue Diagnosis, Treatment and Outcome in Complicated Monochorionic Twins)
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Open AccessArticle
Dysfunctional Coping Mechanisms Contribute to Dry Eye Symptoms
J. Clin. Med. 2019, 8(6), 901; https://doi.org/10.3390/jcm8060901 (registering DOI)
Received: 21 May 2019 / Revised: 16 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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Abstract
Dysfunctional coping behaviors, such as catastrophizing, have been implicated in pain severity and chronicity across several pain disorders. However, the impact of dysfunctional coping has not been examined under the context of dry eye (DE). This study evaluates relationships between catastrophizing and measures [...] Read more.
Dysfunctional coping behaviors, such as catastrophizing, have been implicated in pain severity and chronicity across several pain disorders. However, the impact of dysfunctional coping has not been examined under the context of dry eye (DE). This study evaluates relationships between catastrophizing and measures of DE, including pain severity and pain-related daily interference. The population consisted of patients seen at Miami Veterans Affairs eye clinic between April 2016 and October 2017. Patients filled out standardized questionnaires assessing symptoms of DE and eye pain, non-ocular pain, mental health, coping behaviors (Pain Catastrophizing Scale, PCS), and pain-related daily interference as a perceived impact on quality of life (Multidimensional Pain Inventory, Interference Subscale, MPI-Interference), and all patients underwent an ocular surface examination. In total, 194 patients participated, with a mean age of 58.8 ± 9.6 years, the majority being male, non-Hispanic, and black. PCS (catastrophizing) was correlated with DE symptom severity, including Dry-Eye Questionnaire 5 (DEQ5; r = 0.41, p < 0.0005), Ocular Surface Disease Index (OSDI; r = 0.40, p < 0.0005), and neuropathic-like eye pain (Neuropathic Pain Symptom Inventory-Eye (NPSI-Eye; r = 0.48, p < 0.0005). Most tear metrics, on the other hand, did not correlate with PCS. Linear regressions showed that PCS, non-ocular pain intensity, and number of pain conditions were significant predictors of DEQ5 (overall DE symptoms), while PCS and non-ocular pain intensity were predictors of NPSI-Eye scores, as were insomnia scores and analgesic use. In a separate analysis, PCS and DE symptoms (OSDI) associated with pain-related interference (MPI-Interference) along with non-ocular pain intensity, post-traumatic stress disorder (PTSD), number of pain conditions, and non-Hispanic ethnicity. These findings suggest that catastrophizing is not significantly related to signs of DE, but is strongly associated to pain-related symptoms of DE and daily interference due to pain. Full article
(This article belongs to the Special Issue Dry Eye Syndrome: New Insights on Epidemiology and Management)
Open AccessArticle
Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo
J. Clin. Med. 2019, 8(6), 900; https://doi.org/10.3390/jcm8060900 (registering DOI)
Received: 13 May 2019 / Revised: 17 June 2019 / Accepted: 20 June 2019 / Published: 24 June 2019
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Abstract
Osteosarcoma is the most common type of bone cancer. Multimodality treatment involving chemotherapy, radiotherapy and surgery is not effective enough to control osteosarcoma. Regorafenib, the oral multi-kinase inhibitor, has been shown to have positive efficacy on disease progression delay in chemotherapy resistant osteosarcoma [...] Read more.
Osteosarcoma is the most common type of bone cancer. Multimodality treatment involving chemotherapy, radiotherapy and surgery is not effective enough to control osteosarcoma. Regorafenib, the oral multi-kinase inhibitor, has been shown to have positive efficacy on disease progression delay in chemotherapy resistant osteosarcoma patients. However anti-cancer effect and mechanism of regorafenib in osteosarcoma is ambiguous. Thus, the aim of this study is to investigate the efficacy and molecular mechanism of regorafenib on osteosarcoma in vitro and in vivo. Human osteosarcomas U-2 OS or MG-63 were treated with regorafenib, miltefosine (protein kinase B (AKT) inhibitor), or PD98059 (mitogen-activated protein/extracellular signal-regulated kinase (MEK) pathway inhibitor) for 24 or 48 h. Cell viability, apoptotic signaling transduction, tumor invasion, expression of tumor progression-associated proteins and tumor growth after regorafenib treatment were assayed by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, transwell assay, Western blotting assay and in vivo animal experiment, respectively. In these studies, we also indicated that regorafenib suppressed cell growth by prompting apoptosis of osteosarcoma cells, which is mediated through inactivation of ERK and AKT signaling pathways. After regorafenib treatment, downregulation of related genes in invasion (vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9)), proliferation (CyclinD1) and anti-apoptosis (X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia-1 (MCL-1), and cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP)) were found. Moreover, upregulation of caspase-3 and caspase-8 cleavage were also observed. In sum, we suggest that regorafenib has potential to suppress osteosarcoma progression via inactivation of AKT and ERK mediated signaling pathway. Full article
(This article belongs to the Section Cell Biology)
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Open AccessArticle
Pulmonary Embolism and Coexisting Deep Vein Thrombosis: A Detrimental Association?
J. Clin. Med. 2019, 8(6), 899; https://doi.org/10.3390/jcm8060899
Received: 24 May 2019 / Revised: 17 June 2019 / Accepted: 19 June 2019 / Published: 23 June 2019
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Abstract
Background: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with [...] Read more.
Background: The prognostic significance of coexisting deep vein thrombosis (DVT) in acute pulmonary embolism (PE) is controversial. This study aimed to provide routine patient care data on the impact of this association on PE severity and 3-month outcomes in a population presenting with symptomatic venous thromboembolism (VTE) from the REMOTEV registry. Methods and Results: REMOTEV is a prospective, non-interventional study of patients with acute symptomatic VTE, treated with direct oral anticoagulants (DOACs) or standard anticoagulation (vitamin K antagonists (VKA) or parenteral heparin/fondaparinux alone) for at least 3 months. From 1 November 2013 to 28 February 2018, among 1241 consecutive patients included, 1192 had a follow-up of at least 3 months and, among them, 1037 had PE with (727) or without DVT (310). The median age was 69 (55–80, 25th–75th percentiles). Patients with PE-associated DVT had more severe forms of PE (p < 0.0001) and, when DVT was present, proximal location was significantly correlated to PE severity (p < 0.01). However, no difference in all-cause mortality rate (hazard ratio (HR) 1.36 (CI 95% 0.69–2.92)), nor in the composite criterion of all-cause mortality and recurrence rate (HR 1.56 (CI 95% 0.83–3.10)) was noted at 3 months of follow-up. Conclusion: In REMOTEV, coexisting DVT was associated with a higher severity of PE, with no impact on short-term prognosis. Full article
(This article belongs to the Section Vascular Medicine)
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Open AccessArticle
High N-Terminal proB-Type Natriuretic Peptide Indicates Elevated Risk of Death after Percutaneous Coronary Intervention Compared to Coronary Artery Bypass Surgery in Patients with Left Ventricular Dysfunction
J. Clin. Med. 2019, 8(6), 898; https://doi.org/10.3390/jcm8060898
Received: 8 April 2019 / Revised: 12 June 2019 / Accepted: 20 June 2019 / Published: 23 June 2019
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Abstract
Background: Reduced left ventricular function (LVF) is a predictor for stent-thrombosis. In advanced heart failure (characterized by high NT-proBNP) with an activated coagulation system, coronary events clinically perceived as sudden death or death from heart failure may be more common in patients treated [...] Read more.
Background: Reduced left ventricular function (LVF) is a predictor for stent-thrombosis. In advanced heart failure (characterized by high NT-proBNP) with an activated coagulation system, coronary events clinically perceived as sudden death or death from heart failure may be more common in patients treated by percutaneous coronary intervention (PCI) than in patients treated by coronary artery bypass grafting (CABG). Our study analyses (1) if patients with reduced LVF who require coronary revascularization will have a better survival benefit with CABG or PCI, and (2) if the survival benefit is predicted by NT-proBNP. Methods: This observational retrospective study included patients from the coronary catheter laboratory database of the Medical University of Vienna (CCLD-MUW). Multivariate Cox regression analyses were performed to test the hypothesis that there is an interaction in the risk of death between those with lower or elevated NT-proBNP levels and the revascularization procedure (PCI or CABG). The relative risk of PCI compared to CABG as reference was calculated for patients with low and elevated NT-proBNP levels. Results: In the entire study population with 398 patients (340 PCI and 58 CABG) the revascularization procedure had no predictive value. When the revascularization procedure*NTproBNP interaction was forced into the Cox regression model, this term was an independent predictor of death. The relative risk of PCI compared to CABG was similar in patients with lower NT-proBNP—1.01 (95% confidence interval (CI), 0.45–2.24), but was significantly increased in patients with elevated NT-proBNP—1.58 (95% CI, 1.07–2.33). Conclusion: Death is associated to the revascularization procedure, but only in those patients with elevated NT-proBNP levels. NT-proBNP is a predicting factor for the revascularization procedure: elevated levels showed an increased risk of death after PCI compared to CABG, whereas lower levels were associated with a similar risk after both revascularization procedures. Full article
(This article belongs to the Section Cardiology)
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Open AccessArticle
Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA) Concentrations in Patients with Obesity and the Risk of Obstructive Sleep Apnea (OSA)
J. Clin. Med. 2019, 8(6), 897; https://doi.org/10.3390/jcm8060897
Received: 27 May 2019 / Revised: 14 June 2019 / Accepted: 19 June 2019 / Published: 23 June 2019
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Abstract
Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of nitric oxide (NO) synthesis, and play a critical role in the process of endothelial dysfunction, and are considered markers of oxidative stress. The aim of the present study was to explore relationships [...] Read more.
Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of nitric oxide (NO) synthesis, and play a critical role in the process of endothelial dysfunction, and are considered markers of oxidative stress. The aim of the present study was to explore relationships between ADMA and/or SDMA and the occurrence of OSA in obese patients as well as the effect of the endothelial nitric oxide synthase (eNOS) gene polymorphism, which may modify the influence of ADMA or SDMA on NO production. A total of 518 unrelated obese subjects were included in this study. Body weight, height and blood pressure were measured and data on self-reported smoking status were collected. Obstructive sleep apnea (OSA) was assessed by the apnea hypopnea index (AHI). Blood samples were collected to measure serum concentrations of glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, creatinine, HbA1c (%), folic acid, vitamin B12, C-reactive protein (CRP), aspartate aminotransferase (ASP), alanine aminotransferase (ALT) and IL-6 by routine methods. The NOS3 gene G894T and 4a/4b polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. ADMA, SDMA and arginine concentrations were assessed simultaneously using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. Adjusted multivariate logistic regression analysis showed a significant association between the occurrence of OSA and high serum ADMA levels, BMI above 40, age > 43 years, hypertension and male sex. Heterozygotes for the G894T eNOS polymorphism have the lowest serum concentrations of ADMA and SDMA, while no effect of the 4a/4b variants was observed. The results indicate that OSA in obese individuals can coexist with high ADMA levels, which appear as a potential OSA predictor. Full article
(This article belongs to the Section Endocrinology & Metabolism)
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Open AccessArticle
Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury
J. Clin. Med. 2019, 8(6), 896; https://doi.org/10.3390/jcm8060896
Received: 23 April 2019 / Revised: 11 June 2019 / Accepted: 18 June 2019 / Published: 22 June 2019
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Abstract
Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course [...] Read more.
Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course during ALI is elusive. Ninety-six male CL57BL/6N mice underwent a double hit model of TxT and cecal ligation puncture (CLP, 24 h post-TxT). Shams underwent surgical procedures. CC16 was neutralized by the intratracheal application of an anti-CC16-antibody, either after TxT (early) or following CLP (late). Euthanasia was performed at 6 or 24 h post-CLP. Systemic and pulmonary levels of IL-6, IL-1β, and CXCL5 were determined, the neutrophils were quantified in the bronchoalveolar lavage fluid, and histomorphological lung damage was assessed. ALI induced a significant systemic IL-6 increase among all groups, while the local inflammatory response was most prominent after 24 h in the double-hit groups as compared to the shams. Significantly increased neutrophilic infiltration upon double hit was paralleled with the enhanced lung damage in all groups as compared to the sham, after 6 and 24 h. Neutralization of CC16 did not change the systemic inflammation. However, early CC16-neutralization increased the neutrophilic infiltration and lung injury at 6 h post-CLP, while 24 h later, the lung injury was reduced. Late CC16-neutralization increased neutrophilic infiltration, 24 h post-CLP, and was concurrent with an enhanced lung injury. The data confirmed the anti-inflammatory potential of endogenous CC16 in the murine double-hit model of ALI. Full article
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Open AccessArticle
25-Hydroxy Vitamin D Detection Using Different Analytic Methods in Patients with Migraine
J. Clin. Med. 2019, 8(6), 895; https://doi.org/10.3390/jcm8060895 (registering DOI)
Received: 3 May 2019 / Revised: 19 May 2019 / Accepted: 14 June 2019 / Published: 22 June 2019
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Abstract
Objectives: The aim of this study was to evaluate the performance of different analytic methods, such as liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography-ultraviolet (HPLC-UV), enzyme-linked immunosorbent assay (EIA), and chemiluminescence immunoassays (CLIA), in order to highlight whether or [...] Read more.
Objectives: The aim of this study was to evaluate the performance of different analytic methods, such as liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography-ultraviolet (HPLC-UV), enzyme-linked immunosorbent assay (EIA), and chemiluminescence immunoassays (CLIA), in order to highlight whether or not there is relative superiority amongst the assays. We analyzed two groups of subjects suffering from headache and two groups of healthy subjects. Design and Methods: We performed a prospective, single-blind single-center control-group study on 220 subjects with migraine. Subjects of both sexes >10 years old and with 12 months’ history of migraine were eligible for the study. As a control group, 120 healthy subjects were chosen by their family physician. Results: LC-MS/MS evaluation documented that in all enrolled subjects (migraine and control groups), the serum vitamin D3 levels were lower with respect to the normal range (30–100 ng/mL), with a mean value of 15.4 ng/mL, without difference between sex. The mean values measured using HPLC-UV, EIA, and CLIA tests such as Liaison® and Architect® did not show significant differences compared to the values obtained using LC-MS/MS. Conclusions: In conclusion, the population generally has low values of the vitamin D3 hormone, and the suggested range should probably be revised. HPLC-UV and CLIA were found to have appropriate analytical values compared to the reference method (LC-MS/MS), so it is possible to suggest their routine use to optimize care. Full article
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Open AccessArticle
Stabilizing Techniques and Guided Imagery for Traumatized Male Refugees in a German State Registration and Reception Center: A Qualitative Study on a Psychotherapeutic Group Intervention
J. Clin. Med. 2019, 8(6), 894; https://doi.org/10.3390/jcm8060894
Received: 6 May 2019 / Revised: 14 June 2019 / Accepted: 20 June 2019 / Published: 22 June 2019
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Abstract
Refugees have an increased risk of developing mental health problems. Due to the unstable setting in refugee state registration and reception centers, recommended trauma-focused treatment approaches are often not applicable. For this purpose, we devised a suitable therapeutic approach to treat traumatized refugees [...] Read more.
Refugees have an increased risk of developing mental health problems. Due to the unstable setting in refugee state registration and reception centers, recommended trauma-focused treatment approaches are often not applicable. For this purpose, we devised a suitable therapeutic approach to treat traumatized refugees in a German state registration and reception center: Group therapy, focusing on stabilizing techniques and guided imagery according to Reddemann (2017). From May 2017 to April 2018, we conducted semi-structured interviews with n = 30 traumatized refugees to assess their experiences with the stabilizing techniques and guided imagery in group sessions and self-practice. Participants mainly reported that they had more pleasant feelings, felt increasingly relaxed, and could better handle recurrent thoughts. Additionally, the participants noticed that their psychosocial functioning had improved. The main difficulties that participants encountered were feeling stressed, having difficulties staying focused, or concentrating on the techniques. During self-practice, the participants found it most challenging that they did not have any verbal guidance, were often distracted by the surroundings in the accommodation, and had recurrent thoughts about post-migratory stressors, such as insecurity concerning the future or the application for asylum. Our results show that stabilizing techniques and guided imagery according to Reddemann (2017) are a suitable approach to treat traumatized refugees living in volatile conditions. Full article
(This article belongs to the Section Pathergasiology & Psychology)
Open AccessArticle
Interrogation of Phenotypic Plasticity between Epithelial and Mesenchymal States in Breast Cancer
J. Clin. Med. 2019, 8(6), 893; https://doi.org/10.3390/jcm8060893
Received: 28 May 2019 / Revised: 19 June 2019 / Accepted: 20 June 2019 / Published: 21 June 2019
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Abstract
Dynamic interconversions between transitional epithelial and mesenchymal states underpin the epithelial mesenchymal plasticity (EMP) seen in some carcinoma cell systems. We have delineated epithelial and mesenchymal subpopulations existing within the PMC42-LA breast cancer cell line by their EpCAM expression. These purified but phenotypically [...] Read more.
Dynamic interconversions between transitional epithelial and mesenchymal states underpin the epithelial mesenchymal plasticity (EMP) seen in some carcinoma cell systems. We have delineated epithelial and mesenchymal subpopulations existing within the PMC42-LA breast cancer cell line by their EpCAM expression. These purified but phenotypically plastic states, EpCAMHigh (epithelial) and EpCAMLow (mesenchymal), have the ability to regain the phenotypic equilibrium of the parental population (i.e., 80% epithelial and 20% mesenchymal) over time, although the rate of reversion in the mesenchymal direction (epithelial-mesenchymal transition; EMT) is higher than that in the epithelial direction (mesenchymal-epithelial transition; MET). Single-cell clonal propagation was implemented to delineate the molecular and cellular features of this intrinsic heterogeneity with respect to EMP flux. The dynamics of the phenotypic proportions of epithelial and mesenchymal states in single-cell generated clones revealed clonal diversity and intrinsic plasticity. Single cell-derived clonal progenies displayed differences in their functional attributes of proliferation, stemness marker (CD44/CD24), migration, invasion and chemo-sensitivity. Interrogation of genomic copy number variations (CNV) with whole exome sequencing (WES) in the context of chromosome count from metaphase spread indicated that chromosomal instability was not influential in driving intrinsic phenotypic plasticity. Overall, these findings reveal the stochastic nature of both the epithelial and mesenchymal subpopulations, and the single cell-derived clones for differential functional attributes. Full article
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Open AccessArticle
Optical Quality Assessment in Patients with Macular Diseases Using Optical Quality Analysis System
J. Clin. Med. 2019, 8(6), 892; https://doi.org/10.3390/jcm8060892
Received: 20 May 2019 / Revised: 13 June 2019 / Accepted: 17 June 2019 / Published: 21 June 2019
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Abstract
Macular diseases cause vision loss, as the macula is the functional center for vision. In this study we assessed optical quality in eyes with macular diseases and evaluated the effectiveness of the Optical Quality Analysis System (OQAS) to detect macular diseases. We analyzed [...] Read more.
Macular diseases cause vision loss, as the macula is the functional center for vision. In this study we assessed optical quality in eyes with macular diseases and evaluated the effectiveness of the Optical Quality Analysis System (OQAS) to detect macular diseases. We analyzed 88 eyes of 88 patients with macular diseases (51 men and 37 women; mean age: 65.24 ± 12.96 years) and 43 eyes of 43 control subjects (11 men and 32 women; mean age: 54.70 ± 15.03 years). The macular diseases included age-related macular disease (n = 62), diabetic macular edema (n = 19), and retinal vein occlusion (n = 7). We measured the objective scattering index (OSI), modulation transfer function (MTF), Strehl ratio, and predicted visual acuities (PVAs) at 100, 20, and 10% contrast levels in both groups using OQAS. We measured the retinal thickness in the macular disease group on optical coherence tomography. The macular disease and control groups significantly differed in OSI, MTF, Strehl ratio, and PVAs at 20 and 10% contrast levels (p < 0.05). In the macular disease group, retinal thickness correlated with OSI (r = 0.370, p < 0.001) and MTF (r = −0.264, p = 0.014). In conclusion, optical quality was worse in the patients with macular diseases compared to the control subjects, and retinal thickness affected optical quality. Therefore, the distortion of macular shape may contribute to vision disturbance in patients with macular diseases. Full article
(This article belongs to the Special Issue Application of Retinal and Optic Nerve Imaging in Clinical Medicine)
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Open AccessArticle
Fully Automated Support System for Diagnosis of Breast Cancer in Contrast-Enhanced Spectral Mammography Images
J. Clin. Med. 2019, 8(6), 891; https://doi.org/10.3390/jcm8060891
Received: 30 April 2019 / Revised: 8 June 2019 / Accepted: 17 June 2019 / Published: 21 June 2019
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Abstract
Contrast-Enhanced Spectral Mammography (CESM) is a novelty instrumentation for diagnosing of breast cancer, but it can still be considered operator dependent. In this paper, we proposed a fully automatic system as a diagnostic support tool for the clinicians. For each Region Of Interest [...] Read more.
Contrast-Enhanced Spectral Mammography (CESM) is a novelty instrumentation for diagnosing of breast cancer, but it can still be considered operator dependent. In this paper, we proposed a fully automatic system as a diagnostic support tool for the clinicians. For each Region Of Interest (ROI), a features set was extracted from low-energy and recombined images by using different techniques. A Random Forest classifier was trained on a selected subset of significant features by a sequential feature selection algorithm. The proposed Computer-Automated Diagnosis system is tested on 48 ROIs extracted from 53 patients referred to Istituto Tumori “Giovanni Paolo II” of Bari (Italy) from the breast cancer screening phase between March 2017 and June 2018. The present method resulted highly performing in the prediction of benign/malignant ROIs with median values of sensitivity and specificity of 87 . 5 % and 91 . 7 % , respectively. The performance was high compared to the state-of-the-art, even with a moderate/marked level of parenchymal background. Our classification model outperformed the human reader, by increasing the specificity over 8 % . Therefore, our system could represent a valid support tool for radiologists for interpreting CESM images, both reducing the false positive rate and limiting biopsies and surgeries. Full article
(This article belongs to the Section Oncology)
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Open AccessArticle
Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation
J. Clin. Med. 2019, 8(6), 890; https://doi.org/10.3390/jcm8060890
Received: 26 May 2019 / Revised: 12 June 2019 / Accepted: 15 June 2019 / Published: 21 June 2019
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Abstract
Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of [...] Read more.
Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain. Full article
(This article belongs to the Special Issue Glial Cells in Central Nervous System (CNS) Pathology and Repair)
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Open AccessArticle
Saliva and Serum Immune Responses in Apical Periodontitis
J. Clin. Med. 2019, 8(6), 889; https://doi.org/10.3390/jcm8060889
Received: 10 June 2019 / Revised: 14 June 2019 / Accepted: 17 June 2019 / Published: 21 June 2019
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Abstract
Apical periodontitis is an inflammatory reaction at the apex of an infected tooth. Its microbiota resembles that of marginal periodontitis and may induce local and systemic antibodies binding to bacteria- and host-derived epitopes. Our aim was to investigate the features of the adaptive [...] Read more.
Apical periodontitis is an inflammatory reaction at the apex of an infected tooth. Its microbiota resembles that of marginal periodontitis and may induce local and systemic antibodies binding to bacteria- and host-derived epitopes. Our aim was to investigate the features of the adaptive immune response in apical periodontitis. The present Parogene cohort (n = 453) comprises patients with cardiac symptoms. Clinical and radiographic oral examination was performed to diagnose apical and marginal periodontitis. A three-category endodontic lesion score was designed. Antibodies binding to the bacteria- and host-derived epitopes were determined from saliva and serum, and bacterial compositions were examined from saliva and subgingival samples. The significant ORs (95% CI) for the highest endodontic scores were observed for saliva IgA and IgG to bacterial antigens (2.90 (1.01–8.33) and 4.91 (2.48–9.71)/log10 unit), saliva cross-reacting IgG (2.10 (1.48–2.97)), serum IgG to bacterial antigens (4.66 (1.22–10.1)), and Gram-negative subgingival species (1.98 (1.16–3.37)). In a subgroup without marginal periodontitis, only saliva IgG against bacterial antigens associated with untreated apical periodontitis (4.77 (1.05–21.7)). Apical periodontitis associates with versatile adaptive immune responses against both bacterial- and host-derived epitopes independently of marginal periodontitis. Saliva immunoglobulins could be useful biomarkers of oral infections including apical periodontitis—a putative risk factor for systemic diseases. Full article
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Open AccessArticle
Prediction of Titanium Implant Success by Analysis of microRNA Expression in Peri-Implant Tissue. A 5-Year Follow-Up Study
J. Clin. Med. 2019, 8(6), 888; https://doi.org/10.3390/jcm8060888
Received: 12 June 2019 / Revised: 17 June 2019 / Accepted: 18 June 2019 / Published: 21 June 2019
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Abstract
The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained [...] Read more.
The aim of the present study is to evaluate the expression of microRNA (miRNA) in peri-implant soft tissue and to correlate epigenetic information with the clinical outcomes of the implants up to the five-year follow-up. Seven patients have been rehabilitated with fixed screw-retained bridges each supported by implants. Peri-implant bone resorption and soft tissue health parameters have been recorded over time with a five-year follow-up. Mini-invasive samples of soft peri-implant tissue have been taken three months after implant insertion. miRNA have been extracted from cells of the soft tissue samples to evaluate gene-expression at the implant sites by microarray analysis. The epigenomic data obtained by microarray technology has been statistically analyzed by dedicated software and compared with measured clinical parameters. Specific miRNA expression profiles predictive of specific clinical outcomes were found. In particular, some specific miRNA signatures appeared to be “protective” from bone resorption despite the presence of plaque accumulation. miRNA may be predictors of dental implant clinical outcomes and may be used as biomarkers for diagnostic and prognostic purposes in the field of implant dentistry. Full article
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Open AccessArticle
Association of Low Serum Adiponectin Levels with Aortic Arterial Stiffness in Patients with Type 2 Diabetes
J. Clin. Med. 2019, 8(6), 887; https://doi.org/10.3390/jcm8060887
Received: 22 May 2019 / Revised: 7 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
Adiponectin, an anti-inflammatory and anti-atherogenic protein, affects glucose metabolism. High serum adiponectin levels are associated with decreased diabetes mellitus (DM) risks. Aortic arterial stiffness (AS) is associated with cardiovascular disease and mortality in type 2 DM patients. We assessed the association between adiponectin [...] Read more.
Adiponectin, an anti-inflammatory and anti-atherogenic protein, affects glucose metabolism. High serum adiponectin levels are associated with decreased diabetes mellitus (DM) risks. Aortic arterial stiffness (AS) is associated with cardiovascular disease and mortality in type 2 DM patients. We assessed the association between adiponectin levels and aortic AS in type 2 DM patients. We measured serum adiponectin levels in 140 volunteers with type 2 DM and assigned patients with carotid–femoral pulse wave velocity (cfPWV) >10 m/s to the aortic AS group (n = 54, 38.6%). These patients had higher systolic (p = 0.001) and diastolic (p = 0.010) blood pressures; body fat masses (p = 0.041); serum triglyceride (p = 0.026), phosphorus (p = 0.037), and insulin (p = 0.040) levels; and homeostasis model assessment of insulin resistance values (p = 0.029) and lower estimated glomerular filtration rates (p = 0.009) and serum adiponectin levels (p = 0.001) than controls. Multivariable logistic regression analysis adjusted for confounders showed serum adiponectin levels (OR 0.922; 95% CI, 0.876–0.970; p = 0.002) as an independent predictor of aortic AS. Multivariable forward stepwise linear regression analyses showed that serum adiponectin levels (β = −0.283, adjusted R2 change: 0.054, p < 0.001) were negatively associated with cfPWV. Thus, serum adiponectin level is an independent predictor of aortic AS in type 2 DM patients. Full article
(This article belongs to the Special Issue Pathogenetic and Therapeutic Significance of Adipokines in Diabetes)
Open AccessArticle
Sex Moderates the Effect of Aerobic Exercise on Some Aspects of Cognition in Cognitively Intact Younger and Middle-Age Adults
J. Clin. Med. 2019, 8(6), 886; https://doi.org/10.3390/jcm8060886
Received: 29 April 2019 / Revised: 17 June 2019 / Accepted: 18 June 2019 / Published: 21 June 2019
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Abstract
We recently reported the results of a randomized, parallel-group, observer-masked, community-based clinical trial of 132 cognitively normal individuals aged 20–67 with below median aerobic capacity who were randomly assigned to one of two 6-month, four-times-weekly conditions: aerobic exercise and stretching/toning. We now assessed [...] Read more.
We recently reported the results of a randomized, parallel-group, observer-masked, community-based clinical trial of 132 cognitively normal individuals aged 20–67 with below median aerobic capacity who were randomly assigned to one of two 6-month, four-times-weekly conditions: aerobic exercise and stretching/toning. We now assessed potential sex moderation on exercise-related changes in aerobic capacity, BMI and cognitive function. There was no sex moderation of the effect of aerobic exercise on aerobic capacity or BMI. We had previously reported an effect of aerobic exercise on executive function that was moderated by age. We found additional moderation by sex, such that in any age range men improved more than women. Processing speed showed significant sex moderation but not significant age moderation. In men, processing speed significantly improved by week 12 (b = 0.35, p = 0.0051), but the effect was diminished relative to week 12 at week 24 (b = 0.24, p = 0.0578). In women, there was no exercise effect at either time point (week 12: b = −0.06, p = 0.4156; week 24: b = −0.11, p = 0.1841). Men benefited cognitively more than women from aerobic exercise. This study highlights the importance of using sex-disaggregated analyses when assessing the impact of physical exercise intervention, and the need to ascertain the underlying mechanisms for differential cognitive benefit by sex. Full article
(This article belongs to the Special Issue The Effects of Exercise on Cognitive Function)
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Open AccessReview
Non-Invasive Biomarkers for Celiac Disease
J. Clin. Med. 2019, 8(6), 885; https://doi.org/10.3390/jcm8060885
Received: 12 May 2019 / Revised: 30 May 2019 / Accepted: 2 June 2019 / Published: 21 June 2019
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Abstract
Once thought to be uncommon, celiac disease has now become a common disease globally. While avoidance of the gluten-containing diet is the only effective treatment so far, many new targets are being explored for the development of new drugs for its treatment. The [...] Read more.
Once thought to be uncommon, celiac disease has now become a common disease globally. While avoidance of the gluten-containing diet is the only effective treatment so far, many new targets are being explored for the development of new drugs for its treatment. The endpoints of therapy include not only reversal of symptoms, normalization of immunological abnormalities and healing of mucosa, but also maintenance of remission of the disease by strict adherence of the gluten-free diet (GFD). There is no single gold standard test for the diagnosis of celiac disease and the diagnosis is based on the presence of a combination of characteristics including the presence of a celiac-specific antibody (anti-tissue transglutaminase antibody, anti-endomysial antibody or anti-deamidated gliadin peptide antibody) and demonstration of villous abnormalities. While the demonstration of enteropathy is an important criterion for a definite diagnosis of celiac disease, it requires endoscopic examination which is perceived as an invasive procedure. The capability of prediction of enteropathy by the presence of the high titer of anti-tissue transglutaminase antibody led to an option of making a diagnosis even without obtaining mucosal biopsies. While present day diagnostic tests are great, they, however, have certain limitations. Therefore, there is a need for biomarkers for screening of patients, prediction of enteropathy, and monitoring of patients for adherence of the gluten-free diet. Efforts are now being made to explore various biomarkers which reflect different changes that occur in the intestinal mucosa using modern day tools including transcriptomics, proteomics, and metabolomics. In the present review, we have discussed comprehensively the pros and cons of available biomarkers and also summarized the current status of emerging biomarkers for the screening, diagnosis, and monitoring of celiac disease. Full article
(This article belongs to the Special Issue Diagnosis and Treatment of Small Bowel Disorders)
Open AccessReview
Clinical Approach to the Patient in Critical State Following Immunotherapy and/or Stem Cell Transplantation: Guideline for the On-Call Physician
J. Clin. Med. 2019, 8(6), 884; https://doi.org/10.3390/jcm8060884
Received: 2 May 2019 / Revised: 17 June 2019 / Accepted: 18 June 2019 / Published: 20 June 2019
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Abstract
: The initial management of the hematology patient in a critical state is crucial and poses a great challenge both for the hematologist and the intensive care unit (ICU) physician. After years of clinical practice, there is still a delay in the proper [...] Read more.
: The initial management of the hematology patient in a critical state is crucial and poses a great challenge both for the hematologist and the intensive care unit (ICU) physician. After years of clinical practice, there is still a delay in the proper recognition and treatment of critical situations, which leads to late admission to the ICU. There is a much-needed systematic ABC (Airway, Breathing, Circulation) approach for the patients being treated on the wards as well as in the high dependency units because the underlying hematological disorder, as well as disease-related complications, have an increasing frequency. Focusing on score-based decision-making on the wards (Modified Early Warning Score (MEWS), together with Quick Sofa score), active sepsis screening with inflammation markers (C-reactive protein, procalcitonin, and presepsin), and assessment of microcirculation, organ perfusion, and oxygen supply by using paraclinical parameters from the ICU setting (lactate, central venous oxygen saturation (ScVO2), and venous-to-arterial carbon dioxide difference), hematologists can manage the immediate critical patient and improve the overall outcome. Full article
(This article belongs to the Special Issue Hematopoietic Stem Cell Transplant for Blood Cancer)
Open AccessArticle
The Effect of Donors’ Demographic Characteristics in Renal Function Post-Living Kidney Donation. Analysis of a UK Single Centre Cohort
J. Clin. Med. 2019, 8(6), 883; https://doi.org/10.3390/jcm8060883
Received: 23 May 2019 / Revised: 17 June 2019 / Accepted: 18 June 2019 / Published: 20 June 2019
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Abstract
Introduction: There is a great need to increase the organ donor pool, particularly for living donors. This study analyses the difference in post-living donation kidney function according to pre-donation characteristics of age, genetic relationship with the recipient, sex, ethnicity, and Body Mass Index [...] Read more.
Introduction: There is a great need to increase the organ donor pool, particularly for living donors. This study analyses the difference in post-living donation kidney function according to pre-donation characteristics of age, genetic relationship with the recipient, sex, ethnicity, and Body Mass Index (BMI). Methods: Retrospective single centre analysis of the trajectory of estimated Glomerular Filtration Rate (eGFR) post-living kidney donation, as a measure of kidney function. Mean eGFR of the different groups was compared at 6 months and during the 60 months follow up. Results: Mean age was 46 ± 13 years, 57% were female, and 60% Caucasian. Mean BMI was 27 ± 5 kg/m2, with more than a quarter of the cohort having a BMI > 30 (26%), and the majority of the donors genetically related to their recipients (56%). The higher decline rate in eGFR was at 6 months after donation, with female sex, non-Caucasian ethnicity, and age lower than 60 years being independently associated with higher recovery in kidney function (p < 0.05). In the 60 months follow up, older age, genetic relationship with the recipient, and male sex led to higher percentual difference in eGFR post-donation. Conclusion: In this study, with a high proportion of high BMI living kidney donors, female sex, age lower than 60 years, and non-genetic relationship with recipient were persistently associated with higher increase in post-donation kidney function. Ethnicity and BMI, per se, should not be a barrier to increasing the living donor kidney pool. Full article
(This article belongs to the Special Issue Recent Advances and Clinical Outcomes of Kidney Transplantation)
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Open AccessArticle
The SAMe-TT2R2 Score Predicts Warfarin Control in an Australian Population with Atrial Fibrillation
J. Clin. Med. 2019, 8(6), 882; https://doi.org/10.3390/jcm8060882
Received: 30 May 2019 / Revised: 10 June 2019 / Accepted: 15 June 2019 / Published: 20 June 2019
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Abstract
Background: Warfarin requires regular monitoring with the time in therapeutic range (TTR), a common indicator of control and TTR > 70% is indicative of efficient anticoagulation. The SAMe-TT2R2 (sex, age, medical history, treatment, tobacco use, race) model has been utilised [...] Read more.
Background: Warfarin requires regular monitoring with the time in therapeutic range (TTR), a common indicator of control and TTR > 70% is indicative of efficient anticoagulation. The SAMe-TT2R2 (sex, age, medical history, treatment, tobacco use, race) model has been utilised as a predictor of warfarin control, with a score ≥ 2 indicative of poor control. However, it has been suggested that race may be over-represented in this model. To date, no Australian studies have applied this model, possibly because race is not routinely recorded. Therefore, the aim of this study was to apply the SAMe-TT2R2 model in an Australian population on warfarin managed by both a warfarin care program (WCP) and general practitioner (GP). Methods: Retrospective data was collected for patients receiving warfarin via a WCP in Queensland and whilst being managed by a GP. Patient data was used to calculate the SAMe-TT2R2 score and the TTR for each patient. Mean TTR was used for analysis and comparison with the categorised SAMe-TT2R2 score. Results: Of the 3911 patients managed by a WCP, there was a significantly lower mean TTR for patients with a SAMe-TT2R2 score ≥ 2 compared to 0–1 (78.6 ± 10.7% vs. 80.9 ± 9.5%, p < 0.0001). Of these patients, 200 were analysed whilst managed by a GP and the categorised SAMe-TT2R2 score did not result in a statistically different mean TTR (69.3 ± 16.3% with 0–1 vs. 63.6 ± 15.0% with ≥2, p = 0.089), but a score ≥2 differentiated patients with a TTR less than 65%. Conclusions: The SAMe-TT2R2 model differentiated Australian patients with reduced warfarin control, despite the exclusion of race. In Australia, the SAMe-TT2R2 score could assist clinicians in identifying Australian patients who may obtain reduced warfarin control and benefit from additional interventions such as a dedicated WCP. Full article
Open AccessArticle
Very Low-Density Lipoproteins of Metabolic Syndrome Modulates STIM1, Suppresses Store-Operated Calcium Entry, and Deranges Myofilament Proteins in Atrial Myocytes
J. Clin. Med. 2019, 8(6), 881; https://doi.org/10.3390/jcm8060881
Received: 31 May 2019 / Revised: 14 June 2019 / Accepted: 15 June 2019 / Published: 20 June 2019
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Abstract
Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin–nuclear factor of activated T-cells (NFAT) pathway, which is regulated [...] Read more.
Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin–nuclear factor of activated T-cells (NFAT) pathway, which is regulated by stromal interaction molecule 1 (STIM1)/ calcium release-activated calcium channel protein 1 (Orai1)–mediated store-operated Ca2+ entry (SOCE), is a pivotal mediator of adaptive cardiac hypertrophy. We hypothesized that MetS-VLDLs could affect SOCE and the calcineurin–NFAT pathway. Normal-VLDL and MetS-VLDL samples were isolated from the peripheral blood of healthy volunteers and individuals with MetS. VLDLs were applied to HL-1 atrial myocytes for 18 h and were also injected into wild-type C57BL/6 male mouse tails three times per week for six weeks. After the sarcoplasmic reticulum (SR) Ca2+ store was depleted, SOCE was triggered upon reperfusion with 1.8 mM of Ca2+. SOCE was attenuated by MetS-VLDLs, along with reduced transcriptional and membranous expression of STIM1 (P = 0.025), and enhanced modification of O-GlcNAcylation on STIM1 protein, while Orai1 was unaltered. The nuclear translocation and activity of calcineurin were both reduced (P < 0.05), along with the alteration of myofilament proteins in atrial tissues. These changes were absent in normal-VLDL-treated cells. Our results demonstrated that MetS-VLDLs suppressed SOCE by modulating STIM1 at the transcriptional, translational, and post-translational levels, resulting in the inhibition of the calcineurin–NFAT pathway, which resulted in the alteration of myofilament protein expression and sarcomere derangement in atrial tissues. These findings may help explain atrial myopathy in MetS. We suggest a therapeutic target on VLDLs to prevent atrial fibrillation, especially for individuals with MetS. Full article
(This article belongs to the Special Issue Novel Biomarkers for Heart Disease)
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Open AccessArticle
Haemotherapy with Fibrinogen for Perioperative Bleeding Prevention—A view on Arterial Thrombogenesis and Myocardial Infarction in the Rat In Vivo
J. Clin. Med. 2019, 8(6), 880; https://doi.org/10.3390/jcm8060880
Received: 20 May 2019 / Revised: 13 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Major blood loss during cardiac surgery is associated with increased morbidity and mortality. Clinical pilot studies indicated that preoperative fibrinogen supplementation reduces postoperative blood loss without increasing thrombotic complications. However, an increase in fibrinogen concentration might rather aggravate pre-existing thrombosis than increase the [...] Read more.
Major blood loss during cardiac surgery is associated with increased morbidity and mortality. Clinical pilot studies indicated that preoperative fibrinogen supplementation reduces postoperative blood loss without increasing thrombotic complications. However, an increase in fibrinogen concentration might rather aggravate pre-existing thrombosis than increase the incidence of thrombotic events. Therefore, we investigated, in the present study, whether fibrinogen supplementation influences (1) arterial thrombus formation, (2) the extent of myocardial infarction and (3) the cardioprotective effect of ischaemic preconditioning. Arterial thrombogenesis of the femoral artery was induced by topic FeCl3 treatment in anaesthetised Wistar rats after pretreatment with 60 mg/kg (Fiblow), 120 mg/kg (Fibhigh) or vehicle (Con). Vessel blood flow was monitored, and time to vessel occlusion was analysed as a marker for arterial thrombogenesis. In addition, regional myocardial I/R injury was induced by temporary left coronary artery occlusion in rats pretreated with or without fibrinogen supplementation. In additional groups, ischaemic preconditioning (IPC) was induced by 3 cycles of 5 min of ischaemia/reperfusion. In all groups, myocardial infarct size was determined by triphenyltetrazoliumchlorid staining. Arterial thrombogenesis was not affected by fibrinogen pretreatment. No differences in time until vessel occlusion between Con, Fiblow and Fibhigh groups were observed. In addition, fibrinogen supplementation in low and high concentrations had no effect on infarct size after regional myocardial ischaemia and reperfusion (Fiblow: 66 ± 10%, Fibhigh: 62 ± 9%; each ns vs. Con). IPC reduced infarct size from 62 ± 14% to 34 ± 12% (p < 0.05 vs. Con). Furthermore, both fibrinogen concentrations did not affect cardioprotection by ischaemic preconditioning (Fiblow + IPC: 34 ± 11%, Fibhigh + IPC: 31 ± 13%; each ns vs. IPC). Haemotherapy with fibrinogen did not affect arterial thrombogenesis, myocardial infarction and the cardioprotective effect of ischaemic preconditioning. Full article
(This article belongs to the Section Anesthesiology)
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Open AccessArticle
Distinct Chemokine Dynamics in Early Postoperative Period after Open and Robotic Colorectal Surgery
J. Clin. Med. 2019, 8(6), 879; https://doi.org/10.3390/jcm8060879
Received: 6 May 2019 / Revised: 29 May 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Stress response to robot-assisted colorectal surgery is largely unknown. Therefore, we conducted a prospective comparative nonrandomized study evaluating the perioperative dynamics of chemokines: IL-8/CXCL8, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, and eotaxin-1/CCL11 in 61 colorectal cancer patients following open colorectal surgery (OCS) or robot-assisted surgery [...] Read more.
Stress response to robot-assisted colorectal surgery is largely unknown. Therefore, we conducted a prospective comparative nonrandomized study evaluating the perioperative dynamics of chemokines: IL-8/CXCL8, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, and eotaxin-1/CCL11 in 61 colorectal cancer patients following open colorectal surgery (OCS) or robot-assisted surgery (RACS) in reference to clinical data. Postoperative IL-8 and MCP-1 increase was reduced in RACS with a magnitude of blood loss, length of surgery, and concomitant up-regulation of IL-6 and TNFα as its independent predictors. RANTES at 8 h dropped in RACS and RANTES, and MIP1α/β at 24 h were more elevated in RACS than OCS. IL-8 and MCP-1 at 72 h remained higher in patients subsequently developing surgical site infections, in whom a 2.6- and 2.5-fold increase was observed. IL-8 up-regulation at 24 h in patients undergoing open procedure was predictive of anastomotic leak (AL; 94% accuracy). Changes in MCP-1 and RANTES were predictive of delayed restoration of bowel function. Chemokines behave differently depending on procedure. A robot-assisted approach may be beneficial in terms of chemokine dynamics by favoring Th1 immunity and attenuated angiogenic potential and postoperative ileus. Monitoring chemokine dynamics may prove useful for predicting adverse clinical events. Attenuated chemokine up-regulation results from less severe blood loss and diminished inflammatory response. Full article
(This article belongs to the Special Issue Robotic Surgery)
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Open AccessArticle
Circulating Concentrations of GDF11 are Positively Associated with TSH Levels in Humans
J. Clin. Med. 2019, 8(6), 878; https://doi.org/10.3390/jcm8060878
Received: 16 May 2019 / Revised: 12 June 2019 / Accepted: 18 June 2019 / Published: 19 June 2019
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Abstract
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily which declines with age and has been proposed as an anti-aging factor with regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are [...] Read more.
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily which declines with age and has been proposed as an anti-aging factor with regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are conflicting, casting doubts about its true functional actions. The aim of the present study was to analyze the potential involvement of GFD11 in energy homeostasis in particular in relation with thyroid hormones. Serum concentrations of GDF11 were measured by enzyme-linked immunosorbent assay (ELISA) in 287 subjects. A highly significant positive correlation was found between GDF11 and thyroid-stimulating hormone (TSH) concentrations (r = 0.40, p < 0.001). Neither resting energy expenditure (REE) nor REE per unit of fat-free mass (REE/FFM) were significantly correlated (p > 0.05 for both) with GDF11 levels. In a multiple linear regression analysis, the model that best predicted logGDF11 included logTSH, leptin, body mass index (BMI), age, and C-reactive protein (logCRP). This model explained 37% of the total variability of logGDF11 concentrations (p < 0.001), with only logTSH being a significant predictor of logGDF11. After segregating subjects by TSH levels, those within the low TSH group exhibited significantly decreased (p < 0.05) GDF11 concentrations as compared to the normal TSH group or the high TSH group. A significant correlation of GDF11 levels with logCRP (r = 0.19, p = 0.025) was found. GDF11 levels were not related to the presence of hypertension or cardiopathy. In conclusion, our results show that circulating concentrations of GDF11 are closely associated with TSH concentrations and reduced in subjects with low TSH levels. However, GDF11 is not related to the regulation of energy expenditure. Our data also suggest that GDF11 may be involved in the regulation of inflammation, without relation to cardiac function. Further research is needed to elucidate the role of GDF11 in metabolism and its potential involvement in thyroid pathophysiology. Full article
(This article belongs to the Section Endocrinology & Metabolism)
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Open AccessArticle
Feasibility, Tolerability and Efficacy of Carfilzomib in Combination with Lenalidomide and Dexamethasone in Relapsed Refractory Myeloma Patients: A Retrospective Real-Life Survey of the Sicilian Myeloma Network
J. Clin. Med. 2019, 8(6), 877; https://doi.org/10.3390/jcm8060877
Received: 17 May 2019 / Revised: 3 June 2019 / Accepted: 12 June 2019 / Published: 19 June 2019
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Abstract
Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report [...] Read more.
Background: The ASPIRE (NCT01080391) phase 3 trial showed the efficacy of carfilzomib, lenalidomide and dexamethasone (KRd) triplet for relapse and refractory multiple myeloma (RRMM). However, little is known about safety and efficacy of KRd outside a clinical trial context. Methods: Herein we report real life results of KRd given to 130 RRMM patients from 12 Sicilian Centers. Results: Median age was 62 years; patients had received a median of two previous lines of treatment (range 1–10) and 52% were refractory to previous treatment. Median number of KRd cycles was 12 (2–29), with a mean duration of treatment of 12 months; 21 patients had received at least 18 cycles. Overall response rate was 61%, including 18% complete response. Median PFS was 22.9 months, median OS was not reached. Creatinine clearance >30 mL/min, quality of the best achieved response and standard Fluorescence In Situ Hybridization (FISH) risk were independent predictors of favorable outcome. Patients who received the full-dosage of carfilzomib in the first two cycles had a better outcome. Conclusions: KRd was effective and well tolerated and in a considerable proportion of patients, therapy continued beyond the 18th cycle. The finding of a better outcome in patients with the higher cumulative dose of carfilzomib in the first two cycle encourages to maintain the maximum tolerated dose. Full article
(This article belongs to the Section Hematology)
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Open AccessArticle
Effects of a Lifestyle Intervention in Routine Care on Short- and Long-Term Maternal Weight Retention and Breastfeeding Behavior—12 Months Follow-up of the Cluster-Randomized GeliS Trial
J. Clin. Med. 2019, 8(6), 876; https://doi.org/10.3390/jcm8060876
Received: 30 April 2019 / Revised: 3 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Postpartum weight retention (PPWR) is associated with an increased risk for maternal obesity and is discussed to be influenced by breastfeeding. The objective was to evaluate the effect of a lifestyle intervention delivered three times during pregnancy and once in the postpartum period [...] Read more.
Postpartum weight retention (PPWR) is associated with an increased risk for maternal obesity and is discussed to be influenced by breastfeeding. The objective was to evaluate the effect of a lifestyle intervention delivered three times during pregnancy and once in the postpartum period on PPWR and on maternal breastfeeding behavior. In total, 1998 participants of the cluster-randomized “healthy living in pregnancy” (GeliS) trial were followed up until the 12th month postpartum (T2pp). Data were collected using maternity records and questionnaires. Data on breastfeeding behavior were collected at T2pp. At T2pp, mean PPWR was lower in women receiving counseling (IV) compared to the control group (C) (−0.2 ± 4.8 kg vs. 0.6 ± 5.2 kg), but there was no significant evidence of between-group differences (adjusted p = 0.123). In the IV, women lost more weight from delivery until T2pp compared to the C (adjusted p = 0.008) and showed a slightly higher rate of exclusive breastfeeding (IV: 87.4%; C: 84.4%; adjusted p < 0.001). In conclusion, we found evidence for slight improvements of maternal postpartum weight characteristics and the rate of exclusive breastfeeding in women receiving a lifestyle intervention embedded in routine care, although the clinical meaning of these findings is unclear. Full article
(This article belongs to the Special Issue Health in Preconception Pregnancy and Postpartum)
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