Journal of Clinical Medicine — Open Access Journal

Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice; however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders. Full article

Background: Interactions and early warning effects of non-hepatic alkaline phosphatase (NHALP) and high-sensitivity C-reactive protein (hs-CRP) on the progression of vertebral fractures (VFs) in patients with rheumatoid arthritis (RA) remain unclear. We aim to explore whether serum concentrations of NHALP and hs-CRP could serve as a promising dual biomarker for prognostic assessment of VF progression. Methods: Unadjusted and adjusted hazard ratios (aHRs) of VF progression were calculated for different categories of serum NHALP and hs-CRP using the Cox regression model in RA patients. The modification effect between serum NHALP and hs-CRP on VF progression was determined using an interaction product term. Results: During 4489 person-years of follow-up, higher NHALP (>125 U/L) and hs-CRP (>3.0 mg/L) were robustly associated with incremental risks of VF progression in RA patients (aHR: 2.2 (95% confidence intervals (CIs): 1.2–3.9) and 2.0 (95% CI: 1.3–3.3) compared to the lowest HR category, respectively). The interaction between NHALP and hs-CRP on VF progression was statistically significant (p < 0.05). In the stratified analysis, patients with combined highest NHALP and hs-CRP had the greatest risk of VF progression (aHR: 4.9 (95% CI: 2.5–9.6)) compared to the lowest HR group (NHALP < 90 U/L and hs-CRP < 1 mg/L). Conclusions: In light of underdiagnoses of VFs and misleading diagnosis by single test, NHALP and hs-CRP could serve as compensatory biomarkers to predict subclinical VF progression in RA patients. Full article

The aim of the presented research was to analyze the nutritional status of male subjects with ulcerative colitis in remission by using body composition that was assessed by bioelectrical impedance measurement against a gender-matched control group. Forty-four male patients in remission with ulcerative colitis were recruited for the case-control study and simultaneously, a matched control group of 44 male individuals without inflammatory bowel diseases was pair-matched (general community individuals). The body composition measurement was conducted by the bioelectrical impedance method using BodyComp MF Plus and Bodygram Pro 3.0 software. Parameters assessed include body cell mass (BCM), total body water (TBW), extracellular body water (EBW), intracellular body water (IBW), fat mass (FM), fat-free mass (FFM), muscle mass (MM), and the body cell mass (BCM) index. A significant between-group difference was observed only for EBW, where subjects with ulcerative colitis were characterized by a higher mass of extracellular water (p = 0.0405). Individuals with ulcerative colitis were characterized by a lower BCM share than the control group (p = 0.0192). A comparative analysis of the body composition of male patients with ulcerative colitis with those who did not have ulcerative colitis revealed only minor differences. The risk of malnutrition, assessed using both BMI and bioelectrical impedance, in men with ulcerative colitis in remission is the same as in healthy males in the matched general population. Full article

Circulating brain-derived neurotrophic factor (BDNF) predicts survival rate in patients with coronary artery disease (CAD). We examined the relationship between BDNF and renalase before and after percutaneous coronary intervention (PCI) and the role of renalase in patients with CAD. Serum BDNF and renalase levels were determined using blood samples collected before and after PCI. Incident myocardial infarction, stroke, and mortality were followed up longitudinally. A total of 152 patients completed the assessment. BDNF levels were not significantly changed after PCI compared to baseline levels (24.7 ± 11.0 vs. 23.5 ± 8.3 ng/mL, p = 0.175), although renalase levels were significantly reduced (47.5 ± 17.3 vs. 35.9 ± 11.3 ng/mL, p < 0.001). BDNF level before PCI was an independent predictor of reduction in renalase (95% confidence interval (CI): −1.371 to −0.319). During a median 4.1 years of follow-up, patients with serum renalase levels of ≥35 ng/mL had a higher risk of myocardial infarction, stroke, and death than those with renalase of <35 ng/mL (hazard ratio = 5.636, 95% CI: 1.444–21.998). In conclusion, our results show that serum BDNF levels before PCI were inversely correlated with the percentage change in renalase levels after PCI. Nevertheless, post-PCI renalase level was a strong predictor for myocardial infarction, stroke, and death. Full article

Heart failure (HF) is a complex clinical syndrome in which structural/functional myocardial abnormalities result in symptoms and signs of hypoperfusion and/or pulmonary or systemic congestion at rest or during exercise. More than 80% of deaths in patients with HF recognize a cardiovascular cause, with most being either sudden cardiac death (SCD) or death caused by progressive pump failure. Risk stratification of SCD in patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF) represents a clinical challenge. This review will give an update of current strategies for SCD risk stratification in both HFrEF and HFpEF. Full article

Background: Hypoalbuminemia is known to be associated with adverse outcomes in critical illness. In this study, we attempted to identify whether hypoalbuminemia on emergency department (ED) arrival is a reliable predictor for in-hospital mortality in necrotizing fasciitis (NF). patients. Method: A retrospective cohort study of hospitalized adult patients with NF was conducted in a tertiary teaching hospital in Taiwan between March 2010 and March 2018. Blood samples were collected in the ED upon arrival, and serum albumin levels were determined. We evaluated the predictive value of serum albumin level at ED presentation for in-hospital mortality. All collected data were statistically analyzed. Result: Of the 707 NF patients, 40 (5.66%) died in the hospital. The mean serum albumin level was 3.1 ± 0.9 g/dL and serum albumin levels were significantly lower in the non-survivor group than in the survivor group (2.8 ± 0.7 g/dL vs. 3.5 ± 0.8 g/dL). In the multivariable logistic regression model, albumin was significantly associated with in-hospital mortality (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.88–0.96, p < 0.001). The area under-the-receiver-operating-characteristic curve (AUC) for in-hospital survival was 0.77 (95% CI 0.72–0.82) and corresponding sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratio were 66%, 74%, 33%, 88%, 2.25, and 0.48, respectively. High sensitivity (96%) for survival was shown at albumin level of 4.0 g/dL and high specificity (91%) for mortality was shown at a level of 2.5 g/dL. Conclusion: Initial serum albumin levels strongly predicted in-hospital mortality among patients with necrotizing fasciitis. NF patients with hypoalbuminemia on ED arrival should be closely monitored for signs of deterioration and early and aggressive intervention should be considered to prevent mortality. Full article

Aromatherapy, the therapeutic use of essential oils, is often used to reduce pain in primary dysmenorrhea. Eleven databases, including four English (PubMed, AMED, EMBASE, and the Cochrane Library) and seven Korean medical databases, were searched from inception through August 2018 without restrictions on publication language. Randomized controlled trials (RCTs) testing aromatherapy for pain reduction in primary dysmenorrhea were considered. Data extraction and risk-of-bias assessments were performed by two independent reviewers. All of the trials reported superior effects of aromatherapy for pain reduction compared to placebo (n = 1787, standard mean difference (SMD): −0.91, 95% CI: −1.17 to −0.64, p < 0.00001) with high heterogeneity (I² = 88%). A sub-analysis for inhalational aromatherapy for the alleviation of pain also showed superior effects compared to placebo (n = 704, SMD: −1.02, 95% CI: −1.59 to −0.44, p = 0.0001, I² = 95%). With regard to aromatherapy massage, the pooled results of 11 studies showed favorable effects of aromatherapy massage on pain reduction compared to placebo aromatherapy massage (n = 793, SMD: −0.87, 95% CI: −1.14 to −0.60, p < 0.00001, I² = 70%). Oral aromatherapy had superior effects compared to placebo (n = 290, SMD: −0.61, 95% CI: −0.91 to −0.30, p < 0.0001, I² = 0%). In conclusion, our systemic review provides a moderate level of evidence on the superiority of aromatherapy (inhalational, massage, or oral use) for pain reduction over placebo in primary dysmenorrhea. Full article

This study evaluated the effects of exergaming on college students’ energy expenditure (EE), moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), rating of perceived exertion (RPE), and enjoyment compared to traditional treadmill exercise, and sex differences. Sixty college students (30 female; $\overline{\mathrm{X}}$_age = 23.6 ± 4.1 years) completed three 20-min exercise sessions on Xbox 360 Kinect Just Dance (Microsoft, Redmond, WA, USA), Xbox 360 Kinect Reflex Ridge (Microsoft, Redmond, WA, USA), and treadmill walking. Their EE and PA were assessed by ActiGraph accelerometers (ActiGraph Co.; Pensacola, FL, USA); RPE every four min; enjoyment via an established scale. Significant exercise-type by sex interaction effects were observed for RPE (p < 0.01): females reported significantly lower RPE during exergaming sessions but significantly higher RPE during treadmill walking. Results revealed significant main effects for all outcomes between exercise sessions (all p < 0.01): treadmill walking resulted in significantly higher metabolic equivalents (METs), MVPA, and EE (p < 0 .01), yet lower LPA (p < 0.01), compared to the two exergaming sessions. Participants’ RPE was significantly higher during treadmill walking than during exergaming sessions, with exergaming eliciting significantly higher enjoyment (all p < 0.01). College students find exergaming more enjoyable and report lower RPE compared to traditional treadmill exercise, though not yet matching the moderate physiological intensity level. Full article

Children are susceptible to a variety of respiratory infections. Wheezing is a common sign presented by children with respiratory infections. Asthma, bronchiolitis, and bronchitis are common causes of childhood wheezing disease (CWD) and are regarded as overlapping disease spectra. Macrolides are common antimicrobial agents with anti-inflammatory effects. We conducted a comprehensive literature search and a systematic review of studies that investigated the influences of macrolide treatment on CWD. The primary outcomes were the impact of macrolides on hospitalization courses of patients with CWD. Data pertaining to the study population, macrolide treatment, hospital courses, and recurrences were analyzed. Twenty-three studies with a combined study population of 2210 patients were included in the systematic review. Any kind of benefit from macrolide treatment was observed in approximately two-thirds of the studies (15/23). Eight studies were included in the meta-analysis to investigate the influence of macrolides on the length of stay (LOS), duration of oxygen demand (DOD), symptoms and signs of respiratory distress, and re-admission rates. Although the benefits of macrolide treatment were reported in several of the studies, no significant differences in LOS, DOD, symptoms and signs of respiratory distress, or re-admission rates were observed in patients undergoing macrolide treatment. In conclusion, any kind of benefit of macrolide treatment was observed in approximately two-thirds of the studies; however, no obvious benefits of macrolide treatment were observed in the hospitalization courses of children with CWD. The routine use of macrolides to improve the hospitalization course of children with CWD is not suggested. Full article

Background: Postoperative Acute Kidney Injury (AKI) is a common and serious complication associated with significant morbidity and mortality. While several pre- and intra-operative risk factors for AKI have been recognized in cardiac surgery patients, relatively few data are available regarding the incidence and risk factors for perioperative AKI in other surgical operations. The aim of the present study was to determine the risk factors for perioperative AKI in patients undergoing major abdominal surgery. Methods: This was a prospective, observational study of patients undergoing major abdominal surgery in a tertiary care center. Postoperative AKI was diagnosed according to the Acute Kidney Injury Network criteria within 48 h after surgery. Patients with chronic kidney disease stage IV or V were excluded. Logistic regression analysis was used to evaluate the association between perioperative factors and the risk of developing postoperative AKI. Results: Eleven out of 61 patients developed postoperative AKI. Four intra-operative variables were identified as predictors of AKI: intra-operative blood loss (p = 0.002), transfusion of fresh frozen plasma (p = 0.004) and red blood cells (p = 0.038), as well as high chloride load (p = 0.033, cut-off value > 500 mEq). Multivariate analysis demonstrated an independent association between AKI development and preoperative albuminuria, defined as a urinary Albumin to Creatinine ratio ≥ 30 mg·g⁻¹ (OR = 6.88, 95% CI: 1.43–33.04, p = 0.016) as well as perioperative chloride load > 500 mEq (OR = 6.87, 95% CI: 1.46–32.4, p = 0.015). Conclusion: Preoperative albuminuria, as well as a high intraoperative chloride load, were identified as predictors of postoperative AKI in patients undergoing major abdominal surgery. Full article

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by glomerular deposition of randomly arranged non-amyloid fibrils. FGN has a poor renal prognosis and its optimal treatment is a medical challenge. Rituximab therapy has recently emerged as a promising approach even though its mechanism of action remains hypothetical. We describe the case of a 55-year-old woman with FGN successfully treated by rituximab. During the 36-month follow-up, she had three relapses of FGN, occurring each time in the context of B cell recovery. Investigation of the distribution of B cell subpopulations at the time of the third relapse showed, as previously described for some immunological diseases, an increase in the proportion of switched memory B cells relative to healthy subjects, whereas global memory B cell pool was not yet recovered. This case suggests that B cell reconstitution should be carefully monitored in the management of FGN treated with rituximab. Full article

The applications of the 16S rRNA gene pyrosequencing has expanded our knowledge of the respiratory tract microbiome originally obtained using conventional, culture-based methods. In this study, we employed DNA-based molecular techniques for examining the sputum microbiome in bronchiectasis patients, in relation to disease severity. Of the sixty-three study subjects, forty-two had mild and twenty-one had moderate or severe bronchiectasis, which was classified by calculating the FACED score, based on the FEV₁ (forced expiratory volume in 1 s, %) (F, 0–2 points), age (A, 0–2 points), chronic colonization by Pseudomonas aeruginosa (C, 0–1 point), radiographic extension (E, 0–1 point), and dyspnoea (D, 0–1 point). Bronchiectasis was defined as mild, at 0–2 points, moderate at 3–4 points, and severe at 5–7 points. The mean age was 68.0 ± 9.3 years; thirty-three patients were women. Haemophilus (p = 0.005) and Rothia (p = 0.043) were significantly more abundant in the mild bronchiectasis group, whereas Pseudomonas (p = 0.031) was significantly more abundant in the moderate or severe group. However, in terms of the alpha and beta diversity, the sputum microbiota of the two groups did not significantly differ, i.e., the same dominant genera were found in all samples. Further large-scale studies are needed to investigate the sputum microbiome in bronchiectasis. Full article

Acute kidney injury (AKI) after liver transplantation has been reported to be associated with increased mortality. Recently, machine learning approaches were reported to have better predictive ability than the classic statistical analysis. We compared the performance of machine learning approaches with that of logistic regression analysis to predict AKI after liver transplantation. We reviewed 1211 patients and preoperative and intraoperative anesthesia and surgery-related variables were obtained. The primary outcome was postoperative AKI defined by acute kidney injury network criteria. The following machine learning techniques were used: decision tree, random forest, gradient boosting machine, support vector machine, naïve Bayes, multilayer perceptron, and deep belief networks. These techniques were compared with logistic regression analysis regarding the area under the receiver-operating characteristic curve (AUROC). AKI developed in 365 patients (30.1%). The performance in terms of AUROC was best in gradient boosting machine among all analyses to predict AKI of all stages (0.90, 95% confidence interval [CI] 0.86–0.93) or stage 2 or 3 AKI. The AUROC of logistic regression analysis was 0.61 (95% CI 0.56–0.66). Decision tree and random forest techniques showed moderate performance (AUROC 0.86 and 0.85, respectively). The AUROC of support the vector machine, naïve Bayes, neural network, and deep belief network was smaller than that of the other models. In our comparison of seven machine learning approaches with logistic regression analysis, the gradient boosting machine showed the best performance with the highest AUROC. An internet-based risk estimator was developed based on our model of gradient boosting. However, prospective studies are required to validate our results. Full article

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by heart failure symptoms and structural change (including fibrosis). The relationship between novel biomarkers and the above components remains unclear. Methods: Seventy-seven HFpEF patients were recruited. All patients underwent echocardiography with tissue doppler imaging, cardiac magnetic resonance imaging (CMRI), and measurement of plasma inflammatory, remodelling, endothelial function, and heart failure biomarker levels. Myocardial fibrosis was defined by CMRI-extracellular volume. Forward conditional logistic regression was applied to demonstrate the determinants of myocardial fibrosis or heart failure symptoms. Results: The levels of growth differentiation factor, tissue inhibitor of metalloproteinase (TIMP)-1, galectin-3, and N-terminal pro b-type natriuretic peptide (NT-proBNP) were significantly higher in patients with more myocardial fibrosis. Matrix metalloproteinase-2 (MMP-2) and galectin-3 were independent markers of ECV. After adjusting for confounding factors, plasma galectin-3 and MMP-2 levels were correlated with myocardial fibrosis levels (odds ratio (OR): 1.05, 95% confidence interval (CI): 1.02 to 1.09, p = 0.005 and OR: 2.11, 95% CI: 1.35–3.28, respectively), while NT-proBNP level only was associated with heart failure symptoms. We developed a score system consisted of biomarkers and clinical parameters. The area under the curve of the scoring system receiver operating characteristic curve is 0.838 to predict the degree of myocardial diffuse fibrosis. Conclusions: In conclusion, we found that galectin-3 and MMP-2 were significantly associated with global cardiac fibrosis in HFpEF patients. We also combined plasma biomarkers and clinical data to identify HFpEF patients with more severe cardiac fibrosis. Full article

RANKL signalization is implicated in the morphogenesis of various organs, including the skeleton. Mice invalidated for Rankl present an osteopetrotic phenotype that was less severe than anticipated, depending on RANKL’s implication in morphogenesis. The hypothesis of an attenuated phenotype, as a result of compensation during gestation by RANKL of maternal origin, was thus brought into question. In order to answer this question, Rankl null mutant pups from null mutant parents were generated, and the phenotype analyzed. The results validated the presence of a more severe osteopetrotic phenotype in the second-generation null mutant with perinatal lethality. The experiments also confirmed that RANKL signalization plays a part in the morphogenesis of skeletal elements through its involvement in cell-to-cell communication, such as in control of osteoclast differentiation. To conclude, we have demonstrated that the phenotype associated with Rankl invalidation is attenuated through compensation by RANKL of maternal origin. Full article

Aim: The livers from DCD (donation after cardiac death) donations are often envisaged as a possible option to bridge the gap between the availability and increasing demand of organs for liver transplantation. However, DCD livers possess a heightened risk for complications and represent a formidable management challenge. The aim of this study was to evaluate the effects of thrombolytic flush in DCD liver transplantation. Methods: An extensive search of the literature database was made on MEDLINE, EMBASE, Cochrane, Crossref, Scopus databases, and clinical trial registry on 20 September 2018 to assess the role of thrombolytic tissue plasminogen activator (tPA) flush in DCD liver transplantation. Results: A total of four studies with 249 patients in the tPA group and 178 patients in the non-tPA group were included. The pooled data revealed a significant decrease in ischemic-type biliary lesions (ITBLs) (P = 0.04), re-transplantation rate (P = 0.0001), and no increased requirement of blood transfusion (P = 0.16) with a better one year graft survival (P = 0.02). Conclusions: To recapitulate, tPA in DCD liver transplantation decreased the incidence of ITBLs, re-transplantation and markedly improved 1-year graft survival, without any increased risk for blood transfusion, hence it has potential to expand the boundaries of DCD liver transplantation. Full article

We compared radiotherapy outcomes between 241 elderly patients aged ≥75 years and 867 younger controls (age <75 years) with clinically localized prostate cancer. The elderly group showed an equivalent actuarial seven-year biochemical failure-free survival rate (7y-bNED) (94.9%) to the younger control group (96.4%, p = 0.593). The incidence of late genitourinary (GU) and gastrointestinal (GI) toxicities grade ≥2 was also similar between the elderly and younger cohorts, while no grade ≥4 adverse events occurred. We also examined the role of brachytherapy (BT) in the elderly group, in comparison with image-guided intensity-modulated radiotherapy (IG-IMRT). BT showed superior 7y-bNED (94.1%) than IG-IMRT (84.6%, p = 0.0183) in elderly patients, which was 100% (100% for BT and 100% for IG-IMRT, p > 0.999) for the low-risk group, 94.6% (92.8% and 100%, p = 0.203) for the intermediate-risk group, and 80.5% (91.2% and 73.6%, p = 0.0195) for the high-risk group. BT showed higher GU toxicity and equivalent GI toxicity to IG-IMRT. In conclusion, elderly patients showed bNED and toxicity that were equivalent to those observed in younger controls, and BT is a plausible option also for healthy elderly with potential to improve bNED, with higher but acceptable GU toxicity. Full article

Background: Sarcoplasmic reticulum Ca²⁺ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. Objective: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. Methods: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca²⁺ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. Results: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca²⁺ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. Conclusion: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband’s resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms. Full article

Exergaming, or active video gaming, has become an emerging trend in fitness, education and health sectors. It is defined as digital games that require bodily movements to play, stimulating an active gaming experience to function as a form of physical activity (PA). Since exergaming is becoming more popular, claims have been made on the usefulness of exergaming. It has, for example, been entitled as being “the future of fitness” by the American College of Sports Medicine, promoting PA and health in children and adolescents. However, research also suggests that long-term engagement in exergaming is difficult to achieve, and there is a noticeable reservation towards exergaming by parents, teachers and caregivers. To provide an overview and to outline the future directions of exergaming, the aim of this review was to critically illustrate the strengths, weaknesses, opportunities and threats of exergaming to promote PA and health in children and youth. The available evidence indicates that exergaming has the potential to improve health via an increase in PA. However, it seems that this potential is frequently underexploited, and further developments such as customized exergames are needed. Full article