Journal of Clinical Medicine

8 pages, 1076 KiB

Open AccessArticle

Thyroid Hormones and Spermatozoa: In Vitro Effects on Sperm Mitochondria, Viability and DNA Integrity

by Rosita A. Condorelli, Sandro La Vignera, Laura M. Mongioì, Angela Alamo, Filippo Giacone, Rossella Cannarella and Aldo E. Calogero

J. Clin. Med. 2019, 8(5), 756; https://doi.org/10.3390/jcm8050756 - 27 May 2019

Cited by 18 | Viewed by 3895

Abstract

The aim of this study wasto assess the in vitro effects of levothyroxine (LT4) on conventional and bio-functional sperm parameters and its implications on fertility. Patients with male idiopathic infertility were enrolled and subjected to examination of the seminal fluid and capacitation according [...] Read more.

The aim of this study wasto assess the in vitro effects of levothyroxine (LT4) on conventional and bio-functional sperm parameters and its implications on fertility. Patients with male idiopathic infertility were enrolled and subjected to examination of the seminal fluid and capacitation according to the WHO 2010 criteria and flow cytometric sperm analysis for the evaluation of bio-functional sperm parameters. LT4 significantly increased the percentage of spermatozoa with high mitochondrial membrane potential (MMP), decreased the percentage of spermatozoa with low MMP and increased sperm motility already at a concentration of 0.9 pmol L⁻¹. Therefore, LT4 significantly reduced sperm necrosis and lipid peroxidation ameliorating chromatin compactness. These effects of LT4 were evident at a concentration of 2.9 pmol L⁻¹, close to the physiological free-thyroxine (FT4) concentrations in the seminal fluid of euthyroid subjects. We showed a beneficial role of thyroid hormones on sperm mitochondrial function, oxidative stress and DNA integrity. The results of this in vitro study could have a clinical application in patients with idiopathic infertility, clarifying the role of thyroid function on male fertility. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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16 pages, 1310 KiB

Open AccessArticle

Effects of Variability in Blood Pressure, Glucose, and Cholesterol Concentrations, and Body Mass Index on End-Stage Renal Disease in the General Population of Korea

by Mee Kyoung Kim, Kyungdo Han, Hun-Sung Kim, Yong-Moon Park, Hyuk-Sang Kwon, Kun-Ho Yoon and Seung-Hwan Lee

J. Clin. Med. 2019, 8(5), 755; https://doi.org/10.3390/jcm8050755 - 27 May 2019

Cited by 18 | Viewed by 6110

Abstract

Aim: Metabolic parameters, such as blood pressure, glucose, lipid levels, and body weight, can interact with each other, and this clustering of metabolic risk factors is related to the progression to end-stage renal disease (ESRD). The effect of variability in metabolic parameters on [...] Read more.

Aim: Metabolic parameters, such as blood pressure, glucose, lipid levels, and body weight, can interact with each other, and this clustering of metabolic risk factors is related to the progression to end-stage renal disease (ESRD). The effect of variability in metabolic parameters on the risk of ESRD has not been studied previously. Methods: Using nationally representative data from the Korean National Health Insurance System, 8,199,135 participants who had undergone three or more health examinations between 2005 and 2012 were included in this analysis. Intraindividual variability in systolic blood pressure (SBP), fasting blood glucose (FBG), total cholesterol (TC), and body mass index (BMI) was assessed by examining the coefficient of variation, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability and low variability was defined as the lower three quartiles of variability. Results: Over a median (5–95%) of 7.1 (6.5–7.5) years of follow-up after the variability assessment period, 13,600 (1.7/1000 person-years) participants developed ESRD. For each metabolic parameter, an incrementally higher risk of ESRD was observed for higher variability quartiles compared with the lowest quartile. The risk of ESRD was 46% higher in the highest quartile of SBP variability, 47% higher in the highest quartile of FBG variability, 56% higher in the highest quartile of BMI variability, and 108% higher in the highest quartile of TC variability. Compared with the group with low variability for all four parameters, the group with high variability for all four parameters had a significantly higher risk for incident ESRD (hazard ratio (HR) 4.12; 95% CI 3.72–4.57). Conclusions: Variability in each metabolic parameter was an independent predictor of the development of ESRD among the general population. There was a composite effect of the variability in additional metabolic parameters on the risk of ESRD. Full article

(This article belongs to the Section Epidemiology & Public Health)

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Kaplan–Meier estimates of cumulative incidence of end-stage renal disease (ESRD) according to the number of high-variability metabolic parameters: Total population (A), population with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (B), and population with baseline eGFR <60 mL/min/1.73 m2 (C). High variability was defined as the highest quartile (Q4) of variability independent of the mean (VIM). Unadjusted Kaplan–Meier curves are presented because of the large sample size and relatively balanced distribution of baseline covariates. Full article ">Figure 2
Incidence rates, hazard ratios, and 95% confidence intervals of end-stage renal disease (ESRD), according to variability score (0–12): 0 points was assigned to Q1 (lowest quartile of variability), 1 point to Q2, 2 points to Q3, and 3 points to Q4 (highest quartile of variability) for each of the four parameters (fasting blood glucose, total cholesterol, systolic blood pressure, and body mass index). The incidence rates of ESRD are represented by gray bars. The hazard ratio and 95% confidence intervals are shown as circles and solid lines, respectively. The analysis was adjusted for age, sex, alcohol intake, smoking, regular exercise, income, fasting blood glucose level, total cholesterol, systolic blood pressure, body mass index, estimated glomerular filtration rate, and proteinuria. * p < 0.05. Full article ">Figure 3
Hazard ratios and 95% confidence intervals of end-stage renal disease (ESRD) according to number of high-variability metabolic parameters. Subgroup analyses were stratified by age (a), sex (b), BMI category (c), presence of renal impairment (d), diabetes mellitus (e), and hypertension (f). The analysis was adjusted for age, sex, alcohol intake, smoking, regular exercise, income, fasting blood glucose level, total cholesterol, systolic blood pressure, body mass index, estimated glomerular filtration rate, and proteinuria. Full article ">

10 pages, 1243 KiB

Open AccessArticle

Impact of Lymphocyte and Neutrophil Counts on Mortality Risk in Severe Community-Acquired Pneumonia with or without Septic Shock

by Estel Güell, Marta Martín-Fernandez, Mari C. De la Torre, Elisabet Palomera, Mateu Serra, Rafael Martinez, Manel Solsona, Gloria Miró, Jordi Vallès, Samuel Fernández, Edgar Cortés, Vanessa Ferrer, Marc Morales, Juan C. Yébenes, Jordi Almirall and Jesús F. Bermejo-Martin

J. Clin. Med. 2019, 8(5), 754; https://doi.org/10.3390/jcm8050754 - 27 May 2019

Cited by 21 | Viewed by 4445

Abstract

Background: Community-acquired pneumonia (CAP) is a frequent cause of death worldwide. As recently described, CAP shows different biological endotypes. Improving characterization of these endotypes is needed to optimize individualized treatment of this disease. The potential value of the leukogram to assist prognosis in [...] Read more.

Background: Community-acquired pneumonia (CAP) is a frequent cause of death worldwide. As recently described, CAP shows different biological endotypes. Improving characterization of these endotypes is needed to optimize individualized treatment of this disease. The potential value of the leukogram to assist prognosis in severe CAP has not been previously addressed. Methods: A cohort of 710 patients with CAP admitted to the intensive care units (ICUs) at Hospital of Mataró and Parc Taulí Hospital of Sabadell was retrospectively analyzed. Patients were split in those with septic shock (n = 304) and those with no septic shock (n = 406). A single blood sample was drawn from all the patients at the time of admission to the emergency room. ICU mortality was the main outcome. Results: Multivariate analysis demonstrated that lymphopenia <675 cells/mm³ or <501 cells/mm³ translated into 2.32- and 3.76-fold risk of mortality in patients with or without septic shock, respectively. In turn, neutrophil counts were associated with prognosis just in the group of patients with septic shock, where neutrophils <8850 cells/mm³ translated into 3.6-fold risk of mortality. Conclusion: lymphopenia is a preserved risk factor for mortality across the different clinical presentations of severe CAP (sCAP), while failing to expand circulating neutrophils counts beyond the upper limit of normality represents an incremental immunological failure observed just in those patients with the most severe form of CAP, septic shock. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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23 pages, 995 KiB

Open AccessReview

Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis?

by Elsa Sanchez-Lopez, Anyan Cheng and Monica Guma

J. Clin. Med. 2019, 8(5), 753; https://doi.org/10.3390/jcm8050753 - 27 May 2019

Cited by 39 | Viewed by 7611

Abstract

The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like [...] Read more.

The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like synoviocytes (FLS), and the synovial tissue macrophages (STM), toward an overproduction of enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration. Recent studies have shown metabolic changes in stromal and immune cells from RA patients. Metabolic disruption in the synovium provide the opportunity to use in vivo metabolism-based imaging techniques for patient stratification and to monitor treatment response. In addition, these metabolic changes may be therapeutically targetable. Thus, resetting metabolism of the synovial membrane offers additional opportunities for disease modulation and restoration of homeostasis in RA. In fact, rheumatologists already use the antimetabolite methotrexate, a chemotherapy agent, for the treatment of patients with inflammatory arthritis. Metabolic targets that do not compromise systemic homeostasis or corresponding metabolic functions in normal cells could increase the drug armamentarium in rheumatic diseases for combination therapy independent of systemic immunosuppression. This article summarizes what is known about metabolism in synovial tissue cells and highlights chemotherapies that target metabolism as potential future therapeutic strategies for RA. Full article

(This article belongs to the Section Endocrinology & Metabolism)

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Positron emission tomography (PET) methods that provide information on the underlying biochemical processes. PET imaging not only can improve clinical diagnostics but also potentially predict treatment effects. 18F-FDG, 2-deoxy-2-(fluorine-18)fluoro-D-glucose, provides information on glycolysis and glucose uptake; 11C-DASA23, a class of N, N-diarylsulfonamides, is able to measure PKM2 uptake; 18F-Gln, 18F-(2S,4R)4-fluoroglutamine, allows for the monitoring of glutamine metabolism. 11C-Met, 11C-methionine; 18F-FET, O-(2-[18F]fluoroethyl)-L-tyrosine; 18F-FAMT, L-3-(18F)-Fluoro-α-methyl tyrosine; radiolabeled methionine and tyrosine can provide data on amino acid uptake and protein synthesis. Finally, 11C-acetate is converted to acetyl-CoA and used in mitochondria in TCA cycle or incorporated into cell membranes. MCT4, monocarboxylate transporter 4; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; R-5-P, ribose-5-phosphate; PGD, phosphogluconate dehydrogenase; 6-PG, 6-phosphogluconate; G6PD, glucose-6-phosphate-dehydrogenase; HK, hexokinase; PFK1, phosphofructokinase 1; F2,6BP, fructose-2,6-bisphosphate; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; THF, tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; CK, choline kinase; PKM2, pyruvate kinase muscle isozyme M2; LDHα, lactate dehydrogenase A; CA, carbonic anhydrase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; PDK1, pyruvate dehydrogenase kinase 1; IDH, isocitrate dehydrogenase; α-KGDH, alpha-ketoglutarate dehydrogenase; GLS, glutaminase. Full article ">Figure 2
Anticancer agents targeting various metabolic pathways that are upregulated in activated cells. Since synovial tissue cells share many similar metabolic changes, these very same antimetabolites may also have potential uses in RA. MCT4, monocarboxylate transporter 4; GLUT1, glucose transporter 1; MCT1, monocarboxylate transporter 1; R-5-P, ribose-5-phosphate; PGD, phosphogluconate dehydrogenase; 6-PG, 6-phosphogluconate; G6PD, glucose-6-phosphate-dehydrogenase; HK, hexokinase; PFK1, phosphofructokinase 1; F2,6BP, fructose-2,6-bisphosphate; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; TS, thymidylate synthase; THF, tetrahydrofolate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; CK, choline kinase; PKM2, pyruvate kinase muscle isozyme M2; LDHα, lactate dehydrogenase A; CA, carbonic anhydrase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; PDK1, pyruvate dehydrogenase kinase 1; IDH, isocitrate dehydrogenase; α-KGDH, alpha-ketoglutarate dehydrogenase; GLS, glutaminase. Full article ">

14 pages, 1258 KiB

Open AccessArticle

Sleep after Heavy Alcohol Consumption and Physical Activity Levels during Alcohol Hangover

by Lydia E. Devenney, Kieran B. Coyle, Thomas Roth and Joris C. Verster

J. Clin. Med. 2019, 8(5), 752; https://doi.org/10.3390/jcm8050752 - 27 May 2019

Cited by 31 | Viewed by 14869

Abstract

Alcohol consumption can negatively affect sleep quality. The current study examined the impact of an evening of alcohol consumption on sleep, and next day activity levels and alcohol hangover. n = 25 healthy social drinkers participated in a naturalistic study, consisting of an [...] Read more.

Alcohol consumption can negatively affect sleep quality. The current study examined the impact of an evening of alcohol consumption on sleep, and next day activity levels and alcohol hangover. n = 25 healthy social drinkers participated in a naturalistic study, consisting of an alcohol and alcohol-free test day. On both days, a GENEactiv watch recorded sleep and wake, and corresponding activity levels. In addition, subjective assessments of sleep duration and quality were made, and hangover severity, and the amount of consumed alcoholic beverages were assessed. Alcohol consumption was also assessed in real-time during the drinking session, using smartphone technology. The results confirmed, by using both objective and subjective assessments, that consuming a large amount of alcohol has a negative impact on sleep, including a significant reduction in objective sleep efficiency and significantly lower self-reported sleep quality. Activity levels during the hangover day were significantly reduced compared to the alcohol-free control day. Of note, next-morning retrospective alcohol consumption assessments underestimated real-time beverage recordings. In conclusion, heavy alcohol consumption impairs sleep quality, which is associated with increased next day hangover severity and reduced activity levels. The outcome of this study underlines that, in addition to retrospectively reported data, real-time objective assessments are needed to fully understand the effects of heavy drinking. Full article

(This article belongs to the Special Issue The Alcohol Hangover: Causes, Consequences, and Treatment)

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14 pages, 1125 KiB

Open AccessArticle

Infliximab Induced a Dissociated Response of Severe Periodontal Biomarkers in Rheumatoid Arthritis Patients

by Mélanie Rinaudo-Gaujous, Vincent Blasco-Baque, Pierre Miossec, Philippe Gaudin, Pierre Farge, Xavier Roblin, Thierry Thomas, Stephane Paul and Hubert Marotte

J. Clin. Med. 2019, 8(5), 751; https://doi.org/10.3390/jcm8050751 - 26 May 2019

Cited by 21 | Viewed by 3836

Abstract

Objective: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease [...] Read more.

Objective: Rheumatoid arthritis and periodontal disease are associated together, but the effect of therapy provided for one disease to the second one remained under-investigated. This study investigated effect of infliximab therapy used to treat rheumatoid arthritis (RA) on various biomarkers of periodontal disease (PD) severity including serologies of Porphyromonas gingivalis and Prevotella intermedia and matrix metalloproteinase 3. Methods: Seventy nine RA patients were enrolled at the time to start infliximab therapy and the 28 joint disease activity score (DAS28), anti-cyclic citrullinated petides 2nd generation (anti-CCP2), anti-P. gingivalis antibody, and Matrix metalloproteinase 3 (MMP-3) were monitored before and at 6 months of infliximab therapy. Joint damage and severe periodontal disease were assessed at baseline. Anti-CCP2, anti-P. gingivalis antibody, and MMP-3 were determined by enzyme-linked immunosorbent assay (ELISA). Results: At baseline, anti-CCP2 titers were associated with anti-P. gingivalis lipopolysaccharide (LPS)-specific antibodies titers (p < 0.05). Anti-P. gingivalis antibodies were not significantly correlated with clinical, biological, or destruction parameters of RA disease. At 6 months of infliximab therapy, MMP-3 level decreased (from 119 ± 103 ng/mL to 62.44 ± 52 ng/mL; p < 0.0001), whereas P. gingivalis antibody levels remained at the same level. DAS28 and inflammation markers C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR) also decreased significantly during infliximab therapy (p < 0.05) as anti-CCP2 levels (p < 0.001). Only high MMP-3 level at baseline was associated with infliximab efficacy (p < 0.01). Conclusion: MMP-3 level can be a useful marker of the efficacy of infliximab in RA patients. The treatment did not affect anti-P. gingivalis antibodies. Full article

(This article belongs to the Special Issue Rheumatoid Arthritis Therapy Reappraisal: Strategies, Opportunities and Challenges)

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Evaluation of the measure of anti-P. gingivalis whole extract and LPS specific antibodies by ELISA. Anti-P. gingivalis and anti-P. intermedia (A) whole extract antibodies were measured in healthy blood donors and RA patients. Correlations between both anti-P. gingivalis LPS and whole extract (two ways to assess the same germ; (B); anti-P. intermedia and anti-P. gingivalis whole extract (assessment of two oral germs; (C) in RA patients. No correlation between anti-P. gingivalis and anti-E. coli LPS antibodies in RA patients (assessment of one oral germ and on commensal gut germ; (D). Anti-P. gingivalis (E) and anti-P. intermedia (F) whole extract antibodies were measured in SLE., IBD., and RA patients. From the bottom up, the bars indicate the interquartile range and the median. AU: arbitrary units; r: Spearman correlation coefficient; LPS: lipopolysaccharide; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; IBD: inflammatory bowel disease; ***: p < 0.001. Full article ">Figure 2
Correlation between clinical and biological parameters at baseline. Correlations between RF IgA and DAS28 (A); anti-CCP2 and anti-P. gingivalis whole extract antibodies (B); anti-CCP2 and anti-P. gingivalis LPS specific antibodies (C); and RF IgG and anti-P. intermedia antibodies (D). RF: rheumatoid factors; IU: international units; DAS28: disease activity score 28; AU: arbitrary units; anti-CCP2: anti-cyclic citrullinated petides 2nd generation; r: Spearman correlation coefficient; LPS: lipopolysaccharide; U: Unit; IU: International unit; NS: non-significant. Full article ">Figure 3
Effect of infliximab treatment on biological markers. Anti-CCP2 (A), RF IgM (B), anti-P. gingivalis antibodies (C), anti-P. intermedia antibodies (D), and MMP3 (E) were evaluated at baseline and after 6 months of infliximab therapy. Dots represent results for each patient, with values at baseline in round and at 6 months of infliximab therapy in square. From the bottom up, the bars indicate the interquartile range and the median. Anti-CCP2: anti-cyclic citrullinated petides 2nd generation; RF: rheumatoid factor; MMP-3: metalloproteinase 3; AU: arbitrary units; IU: International units; *: p < 0.05; ***: p < 0.001; ****: p < 0.0001. Full article ">Figure 4
Predictive factors for clinical response to infliximab therapy. Baseline values of MMP-3 (A) and anti-CCP2 (B) were represented. Delta MMP-3 (C) and delta anti-CCP2 (D) represent difference of MMP-3 and ACPA (baseline value minus 6 month value) and are shown according to clinical response to infliximab. Dots represent results for each patient, with responders in square (■) and non-responders in round (●). From the bottom up, the bars indicate the interquartile range and the median. Response to infliximab treatment was defined by an improvement > 1.2 of DAS28 at 6 months. MMP-3: matrix metalloproteinase-3; anti-CCP2: anti-cyclic citrullinated petides 2nd generation; *: p < 0.05; NS: non significant. Full article ">

19 pages, 1724 KiB

Open AccessArticle

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review

by Jessica Garau, Vanessa Cavallera, Marialuisa Valente, Davide Tonduti, Daisy Sproviero, Susanna Zucca, Domenica Battaglia, Roberta Battini, Enrico Bertini, Silvia Cappanera, Luisa Chiapparini, Camilla Crasà, Giovanni Crichiutti, Elvio Dalla Giustina, Stefano D’Arrigo, Valentina De Giorgis, Micaela De Simone, Jessica Galli, Roberta La Piana, Tullio Messana, Isabella Moroni, Nardo Nardocci, Celeste Panteghini, Cecilia Parazzini, Anna Pichiecchio, Antonella Pini, Federica Ricci, Veronica Saletti, Elisabetta Salvatici, Filippo M. Santorelli, Stefano Sartori, Francesca Tinelli, Carla Uggetti, Edvige Veneselli, Giovanna Zorzi, Barbara Garavaglia, Elisa Fazzi, Simona Orcesi and Cristina Cereda Show full author list Hide full author list

J. Clin. Med. 2019, 8(5), 750; https://doi.org/10.3390/jcm8050750 - 26 May 2019

Cited by 32 | Viewed by 6747

Abstract

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. [...] Read more.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes. Full article

(This article belongs to the Section Clinical Laboratory Medicine)

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Numbers and percentages of patients with Aicardi–Goutières syndrome with or without mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1 genes. Full article ">Figure 2
(A) Quantitative reverse transcription PCR of six ISGs IFI27, IFI44, IFIT1, ISG15, RSAD2 and SIGLEC1 in whole blood measured in 18 patients with Aicardi-Goutières syndrome and 31 controls. The threshold is calculated at 2.216: Higher values are considered positive, whereas lower scores are negative. (B) Interferon scores of 12 RNASEH2B mutated patients and 31 healthy controls. Scores above the threshold are positive whereas those below are negative. (C) Interferon signatures of 18 AGS patients. Full article ">Figure 2 Cont.
(A) Quantitative reverse transcription PCR of six ISGs IFI27, IFI44, IFIT1, ISG15, RSAD2 and SIGLEC1 in whole blood measured in 18 patients with Aicardi-Goutières syndrome and 31 controls. The threshold is calculated at 2.216: Higher values are considered positive, whereas lower scores are negative. (B) Interferon scores of 12 RNASEH2B mutated patients and 31 healthy controls. Scores above the threshold are positive whereas those below are negative. (C) Interferon signatures of 18 AGS patients. Full article ">Figure 3
Median fold expression of six interferon-stimulated genes ISGs IFI27, IFI44, IFIT1, ISG15, RSAD and SIGLEC1 according to the genotype of 18 AGS patients and controls. Full article ">

15 pages, 320 KiB

Open AccessArticle

How Gender Identity and Treatment Progress Impact Decision-Making, Psychotherapy and Aftercare Desires of Trans Persons

by Toby K. Mayer, Andreas Koehler, Jana Eyssel and Timo O. Nieder

J. Clin. Med. 2019, 8(5), 749; https://doi.org/10.3390/jcm8050749 - 26 May 2019

Cited by 16 | Viewed by 5064

Abstract

The gender identity of trans individuals influences their treatment preferences, and this in turn seems to affect their individual treatment progress. However, there has been no research which—next to the impact of gender identity on treatment desires—has also investigated the influence of treatment [...] Read more.

The gender identity of trans individuals influences their treatment preferences, and this in turn seems to affect their individual treatment progress. However, there has been no research which—next to the impact of gender identity on treatment desires—has also investigated the influence of treatment progress using a measure which assumes various possible transition pathways of trans persons.Therefore, an online community survey of trans people was conducted in Germany in 2015. Data were collected via an online survey from a non-clinical sample of n = 415 trans individuals (over half assigned female at birth), aged 16–76 (Mean (M) = 38.12). Almost one fifth of participants embraced non-binary or genderqueer (NBGQ) identities. Participants progressed 60.77% (standard deviation (SD) = 35.21) through treatment at point of data collection, as measured by the individual treatment progress score (ITPS). All participants, especially participants assigned male at birth, differed significantly in desire to participate in decision-making processes based on transition progress; individuals without treatment experience had less desire to decide treatment plans. NBGQ participants assigned male at birth in early stages of transition had significantly more desire for psychotherapy during transition than participants of the same identity in later transition stages. All participants, especially binary participants, significantly differed in desire for aftercare based on transition progress; individuals without treatment experience indicated more desire for aftercare. Results indicate health professionals should expect changing treatment desires in trans individuals at various stages of transition, particularly at treatment start, and based on gender identity. Full article

(This article belongs to the Special Issue Novel Research in Gender Incongruence)

8 pages, 1849 KiB

Open AccessArticle

Epidemiology and Burden of Diabetic Foot Ulcer and Peripheral Arterial Disease in Korea

by Dong-il Chun, Sangyoung Kim, Jahyung Kim, Hyeon-Jong Yang, Jae Heon Kim, Jae-ho Cho, Young Yi, Woo Jong Kim and Sung Hun Won

J. Clin. Med. 2019, 8(5), 748; https://doi.org/10.3390/jcm8050748 - 25 May 2019

Cited by 41 | Viewed by 5953

Abstract

Information about the epidemiology of diabetic foot ulcer (DFU) with peripheral arterial disease (PAD) is likely to be crucial for predicting future disease progression and establishing a health care budget. We investigated the incidence and prevalence of DFU and PAD in Korea. In [...] Read more.

Information about the epidemiology of diabetic foot ulcer (DFU) with peripheral arterial disease (PAD) is likely to be crucial for predicting future disease progression and establishing a health care budget. We investigated the incidence and prevalence of DFU and PAD in Korea. In addition, we examined costs of treatments for DFU and PAD. This study was conducted using data from Health Insurance Review and Assessment Service from 1 January 2011 to 31 December 2016. The incidence of DFU with PAD was 0.58% in 2012 and 0.49% in 2016. The prevalence of DFU with PAD was 1.7% in 2011 to 1.8% in 2016. The annual amputation rate of DFU with PAD was 0.95% in 2012 and 1.10% in 2016. Major amputation was decreased, while minor amputation was increased. The direct cost of each group was increased, especially the limb saving group. which was increased from 296 million dollars in 2011 to 441 million dollars in 2016. The overall incidence of DFU with PAD was about 0.5% of total population in Korea, from 2012 to 2016. Furthermore, costs for treatments of diabetic foot ulcer are increasing, especially those for the limb saving group. Full article

(This article belongs to the Special Issue Clinical Medicine for Healthcare and Sustainability)

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16 pages, 2558 KiB

Open AccessReview

Epithelial-Mesenchymal Plasticity in Organotropism Metastasis and Tumor Immune Escape

by Xiang Nan, Jiang Wang, Haowen Nikola Liu, Stephen T.C. Wong and Hong Zhao

J. Clin. Med. 2019, 8(5), 747; https://doi.org/10.3390/jcm8050747 - 25 May 2019

Cited by 20 | Viewed by 6154

Abstract

Most cancer deaths are due to metastasis, and almost all cancers have their preferential metastatic organs, known as “organotropism metastasis”. Epithelial-mesenchymal plasticity has been described as heterogeneous and dynamic cellular differentiation states, supported by emerging experimental evidence from both molecular and morphological levels. [...] Read more.

Most cancer deaths are due to metastasis, and almost all cancers have their preferential metastatic organs, known as “organotropism metastasis”. Epithelial-mesenchymal plasticity has been described as heterogeneous and dynamic cellular differentiation states, supported by emerging experimental evidence from both molecular and morphological levels. Many molecular factors regulating epithelial-mesenchymal plasticity have tissue-specific and non-redundant properties. Reciprocally, cellular epithelial-mesenchymal plasticity contributes to shaping organ-specific pre-metastatic niche (PMN) including distinct local immune landscapes, mainly through secreted bioactive molecular factors. Here, we summarize recent progress on the involvement of tumor epithelial-mesenchymal plasticity in driving organotropic metastasis and regulating the function of different immune cells in organ-specific metastasis. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Plasticity in Cancer Metastasis: Molecular Reprogramming, Cellular Adaptation, and Clinical Implications)

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17 pages, 3412 KiB

Open AccessArticle

Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer’s Pathology

by Amir Zeb, Donghwan Kim, Sayed Ibrar Alam, Minky Son, Raj Kumar, Shailima Rampogu, Saravanan Parameswaran, Rahul Mahadev Shelake, Rabia Mukhtar Rana, Shraddha Parate, Jae-Yean Kim and Keun Woo Lee

J. Clin. Med. 2019, 8(5), 746; https://doi.org/10.3390/jcm8050746 - 24 May 2019

Cited by 9 | Viewed by 4902

Abstract

Mechanistically, neurotoxic insults provoke Ca²⁺-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) and p25 forms hyperactivated Cdk5/p25 complex and causes severe neuropathological aberrations including hyperphosphorylated [...] Read more.

Mechanistically, neurotoxic insults provoke Ca²⁺-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) and p25 forms hyperactivated Cdk5/p25 complex and causes severe neuropathological aberrations including hyperphosphorylated tau-mediated neurofibrillary tangles formation, Alzheimer’s symptoms, and neuronal death. Therefore, the inhibition of Cdk5/p25 complex may relieve p-tau-mediated Alzheimer’s pathology. Herein, computational simulations have identified pyrrolidine-2,3-dione derivatives as novel inhibitors of Cdk5/p25 complex. A ligand-based pharmacophore was designed and employed as 3D query to retrieve drug-like molecules from chemical databases. By molecular docking, drug-like molecules obtaining dock score > 67.67 (Goldcore of the reference compound) were identified. Molecular dynamics simulation and binding free energy calculation retrieved four pyrrolidine-2,3-dione derivatives as novel candidate inhibitors of Cdk5/p25. The root means square deviation of Cdk5/p25 in complex with candidate inhibitors obtained an average value of ~2.15 Å during the 30 ns simulation period. Molecular interactions analysis suggested that each inhibitor occupied the ATP-binding site of Cdk5/p25 and formed stable interactions. Finally, the binding free energy estimation suggested that each inhibitor had lowest binding energy than the reference compound (−113.10 kJ/mol) to recapitulate their strong binding with Cdk5/p25. Overall, these inhibitors could mitigate tau-mediated Alzheimer’s phenotype. Full article

(This article belongs to the Section Clinical Laboratory Medicine)

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Training set compounds. The 2D chemical structures and IC50 (µM) values of the training set compounds for hypotheses generation. Full article ">Figure 2
Description of pharmacophore model (Hypo1). The chemical space of the selected pharmacophore is comprised of two hydrogen bond acceptors—HBA (green), one hydrogen bond donor—HBD (magenta), and one hydrophobic—HYP (cyan) feature. The inter-feature distance constraints are shown in angstrom (Å). Full article ">Figure 3
Drug-like database development and virtual screening. Chemical database are included NCI, Asinex, and Specs databases. Lipinski’s rule of five and ADMET descriptors tests filtered drug-like molecules. Pharmacophores-based virtual screening identified hit compounds against Cdk5/p25. Full article ">Figure 4
Root mean square deviation (RMSD) analyses.(A) RMSD of the Cα atoms of Cdk5/p25 in all the systems revealed their binding stability. (B) RMSD of backbone atoms of the Cdk5/p25 suggested their conformational stability in simulated environment. (C) RMSD of each simulated inhibitor (REF and hit molecules) suggested their stability during the simulation. (D) RMSD of the Cdk5/p25 in complex with ligand(s) advocated ligand(s) binding and stability during the entire simulation period. Red, green, orange, cyan, and blue colors represent REF, Hit1, Hit2, Hit3, and Hit4, respectively. Full article ">Figure 5
Binding mode analyses. All the hit molecules preferentially lodged in the ATP-binding site of Cdk5 with almost similar molecular orientation (A–E). The REF, Hit1, Hit2, Hit3, and Hit4 are depicted as red, green, orange, cyan, and blue, respectively. The three dimensional (3D) molecular interaction pattern of the REF and all the hit molecules with Cdk5/p25 has been illustrated (F–J). Interacting residues are displayed as thin sticks and labeled. REF, Hit1, Hit2, Hit3, and Hit4 are depicted as thick stick representation and colored as red, green, orange, cyan, and blue, respectively. Hydrogen bonds have been shown as black-dashed lines. Full article ">Figure 6
Evaluation of hydrogen bond formation between the Cdk5/25 and hit molecules. (A) The REF compound as well as all the hit molecules formed hydrogen bonds with Cdk5/p25. All the hit molecules showed slightly higher number of hydrogen bonds. (B) Hydrogen bonds remained persistent between the Cys83 of Cdk5 and each hit molecule. Red, green, orange, cyan, and blue colors represent REF, Hit1, Hit2, Hit3, and Hit4, respectively. Full article ">Figure 7
Binding free energy calculation. The GROMACS tool “g_mmpbsa” has calculated the binding free energy between the Cdk5/p25 and each hit molecule. All the hit molecules obtained lowest binding free energy values than the REF compound. Red, green, orange, cyan, and blue colors depict REF, Hit1, Hit2, Hit3, and Hit4, respectively. Full article ">

20 pages, 4376 KiB

Open AccessReview

Quantitative Measurements of Breast Density Using Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis

by Rooa Sindi, Cláudia Sá Dos Reis, Colleen Bennett, Gil Stevenson and Zhonghua Sun

J. Clin. Med. 2019, 8(5), 745; https://doi.org/10.3390/jcm8050745 - 24 May 2019

Cited by 11 | Viewed by 4534

Abstract

Breast density, a measure of dense fibroglandular tissue relative to non-dense fatty tissue, is confirmed as an independent risk factor of breast cancer. Although there has been an increasing interest in the quantitative assessment of breast density, no research has investigated the optimal [...] Read more.

Breast density, a measure of dense fibroglandular tissue relative to non-dense fatty tissue, is confirmed as an independent risk factor of breast cancer. Although there has been an increasing interest in the quantitative assessment of breast density, no research has investigated the optimal technical approach of breast MRI in this aspect. Therefore, we performed a systematic review and meta-analysis to analyze the current studies on quantitative assessment of breast density using MRI and to determine the most appropriate technical/operational protocol. Databases (PubMed, EMBASE, ScienceDirect, and Web of Science) were searched systematically for eligible studies. Single arm meta-analysis was conducted to determine quantitative values of MRI in breast density assessments. Combined means with their 95% confidence interval (CI) were calculated using a fixed-effect model. In addition, subgroup meta-analyses were performed with stratification by breast density segmentation/measurement method. Furthermore, alternative groupings based on statistical similarities were identified via a cluster analysis employing study means and standard deviations in a Nearest Neighbor/Single Linkage. A total of 38 studies matched the inclusion criteria for this systematic review. Twenty-one of these studies were judged to be eligible for meta-analysis. The results indicated, generally, high levels of heterogeneity between study means within groups and high levels of heterogeneity between study variances within groups. The studies in two main clusters identified by the cluster analysis were also subjected to meta-analyses. The review confirmed high levels of heterogeneity within the breast density studies, considered to be due mainly to the applications of MR breast-imaging protocols and the use of breast density segmentation/measurement methods. Further research should be performed to determine the most appropriate protocol and method for quantifying breast density using MRI. Full article

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

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12 pages, 1171 KiB

Open AccessArticle

Perioperative Factors for Predicting the Need for Postoperative Intensive Care after Major Lung Resection

by Seung Hyun Kim, Sungwon Na, Seong Yong Park, Jinae Lee, Yhen-Seung Kang, Hwan-ho Jung and Jeongmin Kim

J. Clin. Med. 2019, 8(5), 744; https://doi.org/10.3390/jcm8050744 - 24 May 2019

Cited by 16 | Viewed by 3446

Abstract

Postoperative management after major lung surgery is critical. This study evaluates risk factors for predicting mandatory intensive care unit (ICU) admission immediately after major lung resection. We retrospectively reviewed patients for whom the surgeon requested an ICU bed before major lung resection surgery. [...] Read more.

Postoperative management after major lung surgery is critical. This study evaluates risk factors for predicting mandatory intensive care unit (ICU) admission immediately after major lung resection. We retrospectively reviewed patients for whom the surgeon requested an ICU bed before major lung resection surgery. Patients were classified into three groups. Univariable and multivariable logistic regression analyses were performed, and a clinical nomogram was constructed. Among 340 patients, 269, 50, and 21 were classified into the no need for ICU, mandatory ICU admission, and late-onset complication groups, respectively. Predictive postoperative diffusion capacity of the lung for carbon monoxide (47.2 (interquartile range (IQR) 43.3–65.7)% versus vs. 67.8 (57.1–79.7)%; p = 0.003, odds ratio (OR) 0.969, 95% confidence interval (CI) 0.95–0.99), intraoperative blood loss (400.00 (250.00–775.00) mL vs. 100.00 (50.00–250.00) mL; p = 0.040, OR 1.001, 95% CI 1.000–1.002), and open thoracotomy (p = 0.030, OR 2.794, 95% CI 1.11–7.07) were significant predictors for mandatory ICU admission. The risk estimation nomogram demonstrated good accuracy in estimating the risk of mandatory ICU admission (concordance index 83.53%). In order to predict the need for intensive care after major lung resection, preoperative and intraoperative factors need to be considered. Full article

(This article belongs to the Section Epidemiology & Public Health)

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16 pages, 2899 KiB

Open AccessArticle

Expression of PD-1 and CTLA-4 Are Negative Prognostic Markers in Renal Cell Carcinoma

by Andreas Kahlmeyer, Christine G. Stöhr, Arndt Hartmann, Peter J. Goebell, Bernd Wullich, Sven Wach, Helge Taubert and Franziska Erlmeier

J. Clin. Med. 2019, 8(5), 743; https://doi.org/10.3390/jcm8050743 - 24 May 2019

Cited by 34 | Viewed by 4512

Abstract

Immuno-oncological therapy with checkpoint inhibition (CI) has become a new standard treatment in metastatic renal cell carcinoma (RCC), but the prognostic value of the expression of CI therapy target molecules is still controversial. 342 unselected consecutive RCC tumor samples were analyzed regarding their [...] Read more.

Immuno-oncological therapy with checkpoint inhibition (CI) has become a new standard treatment in metastatic renal cell carcinoma (RCC), but the prognostic value of the expression of CI therapy target molecules is still controversial. 342 unselected consecutive RCC tumor samples were analyzed regarding their PD-1, PD-L1, and CTLA-4 expression by immunohistochemistry (IHC). The prognostic values for cancer-specific survival (CSS) and overall survival (OS) were analyzed for those not exposed to CI therapy. The expression of PD-1 in tumor-infiltrating mononuclear cells (TIMC) and PD-L1 in tumor cells was detected in 9.4% and 12.3%, respectively (Immune reactive score (IRS) > 0). Furthermore, PD-L1 expression in TIMC (IRS > 0) and CTLA-4 expression in TIMC (>1% positive cells) was detected in 4.8% and 6.3%. PD-1 expression and CTLA-4 expression were significantly associated with a worse OS and CSS in log rank survival analysis and univariate Cox regression analysis. CTLA-4 expression is a prognostic marker that is independently associated with a worse outcome in multivariate Cox regression analysis in the whole cohort (OS: p = 0.013; CSS: p = 0.048) as well as in a non-metastatic subgroup analysis (OS: p = 0.028; CSS: p = 0.022). Patients with combined CTLA-4 expression and PD-1-expression are at highest risk in OS and CSS. In RCC patients, PD-1 expression in TIMC and CTLA-4 expression in TIMC are associated with a worse OS and CSS. The combination of PD-1 expression in TIMC and CTLA-4 expression in TIMC might identify high risk patients. This is, to our knowledge, the first description of CTLA-4 expression to be a prognostic marker in RCC. Full article

(This article belongs to the Section Clinical Laboratory Medicine)

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11 pages, 238 KiB

Open AccessArticle

Effect of Lipid-Testing Interval on Stoke Risk among Newly Diagnosed Dyslipidemia Patients Initiated on Statins

by Ahryoung Ko, Seulggie Choi, Jooyoung Chang and Sang Min Park

J. Clin. Med. 2019, 8(5), 742; https://doi.org/10.3390/jcm8050742 - 24 May 2019

Cited by 1 | Viewed by 2718

Abstract

(1) Background: Although current guidelines recommend regular lipid testing for dyslipidemia patients, the effectiveness of regular lipid profile monitoring in clinical outcomes is unclear. (2) Methods: We assessed 64,664 newly diagnosed dyslipidemia patients from the Korean National Health Insurance Service Health Screening Cohort [...] Read more.

(1) Background: Although current guidelines recommend regular lipid testing for dyslipidemia patients, the effectiveness of regular lipid profile monitoring in clinical outcomes is unclear. (2) Methods: We assessed 64,664 newly diagnosed dyslipidemia patients from the Korean National Health Insurance Service Health Screening Cohort from 2003–2011 For lipid-testing frequency from all admission and outpatient records for 3 years after diagnosis. Participants were followed until 31 December 2015 for stroke. We used Cox regression analysis to determine the adjusted hazard ratio (aHR) for stroke according to lipid-testing interval. (3) Results: Compared to patients with lipid-testing intervals of ≤6 months, patients with >6 to ≤12 (aHR 1.32, 95% confidence interval (CI) 1.08–1.61), >12 to ≤18 (aHR 1.48, 95% CI 1.20–1.82), and >18 (aHR 1.54, 95% CI 1.25–1.90) month testing intervals had elevated risk of total stroke (p for trend <0.001). A significant association existed between lipid-testing interval and total and ischemic stroke risk in the >6 to ≤12 (aHR 1.62, 95% CI 1.19–2.21), >12 to ≤18 (aHR 1.87, 95% CI 1.36–2.58), and >18 (aHR 1.79, 95% CI 1.30–2.48) month interval groups, but no significant association existed between lipid-testing interval and hemorrhagic stroke risk. (4) Conclusions: Lipid-testing intervals of more than 6 months may lead to increased stroke risk among newly diagnosed dyslipidemia patients after initiation of statin treatment. Lipid testing every 6 months can lower stroke risk among dyslipidemia patients. Full article

(This article belongs to the Section Endocrinology & Metabolism)

18 pages, 2426 KiB

Open AccessArticle

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

by Foteinos-Ioannis D. Dimitrakopoulos, Anastasia E. Kottorou, Anna G. Antonacopoulou, Nikolaos Panagopoulos, Chrisoula Scopa, Melpomeni Kalofonou, Dimitrios Dougenis, Angelos Koutras, Thomas Makatsoris, Vassiliki Tzelepi and Haralabos P. Kalofonos

J. Clin. Med. 2019, 8(5), 741; https://doi.org/10.3390/jcm8050741 - 24 May 2019

Cited by 9 | Viewed by 4694

Abstract

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell [...] Read more.

An increasing number of studies implicates the NF-κB (Nuclear Factor of kappa light chain gene enhancer in B cells) alternative pathway in non-small-cell lung cancer (NSCLC). We assessed the clinical significance of CD40 (Tumor necrosis factor receptor superfamily member 5, TNFRSF5), BAFFR (B-cell activating factor receptor), RANK (Receptor activator of NF-κB) and LTβR (lymphotoxin β receptor) receptors, which activate the alternative pathway of NF-κB, in NSCLC. Evaluation of CD40, BAFFR, RANK and LTβR expression was performed based on the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, while protein expression was assessed by immunohistochemistry in specimens from 119 operated NSCLC patients. CD40 gene overexpression was correlated with improved five-year overall survival (OS) (p < 0.001), while increased BAFFR and LTβR mRNA levels were associated with worse OS in patients with adenocarcinomas (p < 0.001 and p < 0.001, respectively). Similarly, patients with adenocarcinomas exhibited a negative correlation between membranous BAFFR protein expression in carcinoma cells and three- and five-year survival (p = 0.021; HR, 4.977 and p = 0.030; HR, 3.358, respectively) as well as between BAFFR protein overexpression in cancer-associated fibroblasts (CAFs) and two-year survival (p = 0.036; HR, 1.983). Patients with increased LTβR nuclear protein staining or stage II patients with lower cytoplasmic LTβR protein expression had worse five-year OS (p = 0.039 and p = 0.008, respectively). Moreover, CD40 protein expression in tumor infiltrating lymphocytes (TILs) and CAFs was positively associated with metastatic spread while BAFFR protein expression in CAFs was negatively associated with bone metastasis (p = 0.041). Our data suggests that CD40, BAFFR, RANK and LTβR play an important role in NSCLC and further supports the role of NF-κB alternative pathway in NSCLC. Full article

(This article belongs to the Special Issue Personalized Therapy in Non-Small Cell Lung Cancer: The Role of Biological Agents and Immunotherapy)

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11 pages, 1559 KiB

Open AccessArticle

Effects of Positive End-Expiratory Pressure on Pulmonary Oxygenation and Biventricular Function during One-Lung Ventilation: A Randomized Crossover Study

by Namo Kim, Su Hyun Lee, Kwan Woong Choi, Haeyeon Lee and Young Jun Oh

J. Clin. Med. 2019, 8(5), 740; https://doi.org/10.3390/jcm8050740 - 23 May 2019

Cited by 6 | Viewed by 3096

Abstract

Although the application of positive end-expiratory pressure (PEEP) can alter cardiopulmonary physiology during one-lung ventilation (OLV), these changes have not been clearly elucidated. This study assessed the effects of different levels of PEEP on biventricular function, as well as pulmonary oxygenation during OLV. [...] Read more.

Although the application of positive end-expiratory pressure (PEEP) can alter cardiopulmonary physiology during one-lung ventilation (OLV), these changes have not been clearly elucidated. This study assessed the effects of different levels of PEEP on biventricular function, as well as pulmonary oxygenation during OLV. Thirty-six lung cancer patients received one PEEP combination of six sequences, consisting of 0 (PEEP_0), 5 (PEEP_5), and 10 cmH₂O (PEEP_10), using a crossover design during OLV. The ratio of arterial oxygen partial pressure to inspired oxygen fraction (P/F ratio), systolic and diastolic echocardiographic parameters were measured at 20 min after the first, second, and third PEEP. P/F ratio at PEEP_5 was significantly higher compared to PEEP_0 (p = 0.014), whereas the P/F ratio at PEEP_10 did not show significant differences compared to PEEP_0 or PEEP_5. Left ventricular ejection fraction (LV EF) and right ventricular fractional area change (RV FAC) at PEEP_10 (EF, p < 0.001; FAC, p = 0.001) were significantly lower compared to PEEP_0 or PEEP_5. RV E/E’ (p = 0.048) and RV myocardial performance index (p < 0.001) at PEEP_10 were significantly higher than those at PEEP_0 or PEEP_5. In conclusion, increasing PEEP to 10 cmH₂O decreased biventricular function, especially on RV function, with no further improvement on oxygenation compared to PEEP 5 cmH₂O during OLV. Full article

(This article belongs to the Section Anesthesiology)

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10 pages, 6164 KiB

Open AccessBrief Report

Magnetic Resonance Elastography of Liver in Light Chain Amyloidosis

by Sudhakar K. Venkatesh, Safa Hoodeshenas, Sandeep H. Venkatesh, Angela Dispenzieri, Morie A. Gertz, Michael S. Torbenson and Richard L. Ehman

J. Clin. Med. 2019, 8(5), 739; https://doi.org/10.3390/jcm8050739 - 23 May 2019

Cited by 13 | Viewed by 3915

Abstract

In this paper, we present our preliminary findings regarding magnetic resonance elastography (MRE) on the livers of 10 patients with systemic amyloidosis. Mean liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) were obtained. Magnetic resonance imaging (MRI) images were analyzed for the [...] Read more.

In this paper, we present our preliminary findings regarding magnetic resonance elastography (MRE) on the livers of 10 patients with systemic amyloidosis. Mean liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) were obtained. Magnetic resonance imaging (MRI) images were analyzed for the distribution pattern of amyloid deposition. Pearson correlation analysis was performed in order to study the correlation between LSM, SSM, liver span, liver volume, spleen span, spleen volume, serum alkaline phosphatase (ALP), N-terminal pro b-type natriuretic peptide (NT pro BNP), and the kappa and lambda free light chains. An increase in mean LSM was seen in all patients. Pearson correlation analysis showed a statistically significant correlation between LSM and liver volume (r = 0.78, p = 0.007) and kappa chain level (r = 0.65, p = 0.04). Interestingly, LSM did not correlate significantly with SSM (r = 0.45, p = 0.18), liver span (r = 0.57, p = 0.08), or serum ALP (r = 0.60, p = 0.07). However, LSM correlated significantly with serum ALP when corrected for liver volume (partial correlation, r = 0.71, p = 0.03) and NT pro BNP levels (partial correlation, r = 0.68, p = 0.04). MRI review revealed that amyloid deposition in the liver can be diffuse, lobar, or focal. MRE is useful for the evaluation of hepatic amyloidosis and shows increased stiffness in hepatic amyloidosis. MRE has the potential to be a non-invasive quantitative imaging marker for hepatic amyloidosis. Full article

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

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(a) Scatter plots showing excellent correlation between two independent readers for liver stiffness (r = 0.99) and spleen stiffness (r = 0.94). (b) Bland–Altman plots for liver stiffness and spleen stiffness. (LSM = liver stiffness measurement; SSM = spleen stiffness measurement) Full article ">Figure 2
A 49-year-old female with systemic amyloidosis and hepatosplenomegaly on follow up. The axial computed tomography (CT) image (a), coronal T2-weighted image (b), and axial T1-weighted image (c) show hepatomegaly (craniocaudal span in (b), 30 cm) and splenomegaly (16 cm). Axial magnitude resonance elastography (MRE) image (d), color wave image (e), and color stiffness maps (f–h) in the upper abdomen. The liver is outlined with a continuous line, and the spleen is outlined with a dotted line on the color wave image (e). The color stiffness map (f) shows stiffness distribution on the routinely used scale of 0–8 kPa. Note that the entire liver shows an increase in stiffness. The color stiffness map (g) is the same, with a 95% confidence overlay. The regions that are not crossed out are regions with reliable measurements. Note that both the liver and spleen are almost completely outlined by the overlay. The color stiffness map (h) has a wider scale of 0–20 kPa, and one can see the heterogeneity in the distribution of stiffness. This scale is rarely used in the clinical evaluation of liver fibrosis. The mean ± SD for LSM is 18.1 ± 3.4 kPa, and for SSM, it is 16 ± 2.1 kPa. Full article ">Figure 3
A 68-year-old male with known systemic amyloidosis and post autologous stem cell transplant on follow up. The axial non-contrast enhanced CT image (a) shows hypodense in the right lobe (arrow). The axial T2-weighted image (b) shows hyperintensity in the right lobe corresponding to the hypodensity in that lobe. In-phase (c) and opposed-phase (d) images show no significant signal loss (<5%) in the right lobe, confirming that there is no increase in fat. Note the small subcapsular area of sparing in the right lobe (arrowhead, (c)). The non-contrast enhanced (e), arterial phase (f), and portal venous phase (g) images show no significant enhancement in the right lobe but do show normal enhancement in the left lobe. The subcapsular focal area in the right lobe (arrow heads) shows similar enhancement to the left lobe, suggesting a spared region of normal liver parenchyma. The MRE stiffness map with a scale of 0–8 kPa (h) shows increased stiffness in the right lobe, corresponding to the abnormality seen on CT and magnetic resonance imaging (MRI), and normal stiffness in the left lobe. The mean ± SD LSM is 6.7 ± 1.2 kPa. Full article ">Figure 4
A 64-year-old male with known pulmonary amyloidosis on follow up. A follow-up CT (not shown) revealed hypodense lesions in the liver. An MRI with MRE was performed. The coronal T2-weighted image (a) shows borderline hepatomegaly (15.5 cm). The spleen was also borderline enlarged (12 cm). Multifocal lesions (arrow heads) were found in both lobes of the liver, which appeared hyperintense on the axial T2-weighted image (b) and diffusion weighted image (c), hypointense on the T1-weighted image (d), and hypoenhancing on the post contrast image (e). The MRE stiffness map (f) with a scale of 0–8 kPa shows moderately elevated liver stiffness (mean ± SD, 4.6 ± 0.8 kPa) with focal increased stiffness regions corresponding to the focal lesions. A percutaneous biopsy performed on the right lobe lesions confirmed hepatic amyloidosis. Full article ">

11 pages, 378 KiB

Open AccessArticle

Association between Serum Urate and Risk of Hypertension in Menopausal Women with XDH Gene

by Jong-Han Lee, Tae Hwa Go, San-Hui Lee, Juwon Kim, Ji Hye Huh, Jang Young Kim, Dae Ryong Kang, Seongmun Jeong, Sang-Baek Koh and Jung Ran Choi

J. Clin. Med. 2019, 8(5), 738; https://doi.org/10.3390/jcm8050738 - 23 May 2019

Cited by 8 | Viewed by 3871

Abstract

Elevated serum urate (sUA) concentrations have been associated with an increased risk of hypertension. We aimed to examine the association of sUA concentration on the risk of hypertension in pre- and post-menopausal women and investigated the association between the polymorphism of the xanthine [...] Read more.

Elevated serum urate (sUA) concentrations have been associated with an increased risk of hypertension. We aimed to examine the association of sUA concentration on the risk of hypertension in pre- and post-menopausal women and investigated the association between the polymorphism of the xanthine dehydrogenase gene and the risk of hypertension. Among 7294 women, 1415 premenopausal and 5879 postmenopausal women were recruited. Anthropometric parameters as risk factors of hypertension were identify by logistic regression models. In addition, we investigated an association between xanthine dehydrogenase gene and sUA and their combined associations on the risk of hypertension. Body mass index (BMI) and waist circumference (WC) were significantly increased in accordance to the increase of sUA levels (p < 0.001). Multivariate logistic regression analysis showed postmenopausal women with a high sUA and high BMI were 3.18 times more likely to have hypertension than in those with normal and lower sUA (Odds ratio: 3.18, 95% confidence interval: 2.54–3.96). Postmenopausal women with a high WC were 1.62 times more likely to have hypertension than in those with normal and lower sUA. Subjects with the AG genotype of rs206860 was found to be at lower risk of hypertension (odd ratio: 0.287, 95% confidence interval: 0.091–0.905, p = 0.033). This cross-sectional study indicated a high sUA is associated with a higher risk of hypertension in postmenopausal women. Further well-designed prospective studies in other populations are warranted to validate our results. Full article

(This article belongs to the Special Issue Clinical Medicine for Healthcare and Sustainability)

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16 pages, 2091 KiB

Open AccessArticle

Treatment Outcomes of Novel Targeted Agents in Relapse/Refractory Chronic Lymphocytic Leukemia: A Systematic Review and Network Meta-Analysis

by Po-Huang Chen, Ching-Liang Ho, Chin Lin, Yi-Ying Wu, Tzu-Chuan Huang, Yu-Kang Tu and Cho-Hao Lee

J. Clin. Med. 2019, 8(5), 737; https://doi.org/10.3390/jcm8050737 - 23 May 2019

Cited by 8 | Viewed by 6962

Abstract

Most chronic lymphocytic leukemia patients experience a relapse or become refractory to treatment with conventional chemotherapeutic agents. The network meta-analysis assesses the relative efficacy of novel targeted agents for the treatment of a relapse or refractory chronic lymphocytic leukemia. A systematic literature search [...] Read more.

Most chronic lymphocytic leukemia patients experience a relapse or become refractory to treatment with conventional chemotherapeutic agents. The network meta-analysis assesses the relative efficacy of novel targeted agents for the treatment of a relapse or refractory chronic lymphocytic leukemia. A systematic literature search included seven phase III randomized controlled trials, including a total of 2512 patients treated with nine regimens. Data were extracted and evidence synthesized using network meta-analysis. All novel targeted therapies were significantly more effective than ofatumumab and demonstrated promising prolongation of progression free survival (PFS), with a hazard ratio (HR) ranging from 0.10 to 0.52. Two novel targeted agent regimens, venetoclax plus rituximab and ibrutinib monotherapy, resulted in greater overall survival (HR, 0.335 and 0.361, respectively). Venetoclax plus rituximab and ibrutinib monotherapy were most favorable based on (1) HR for PFS compared with ofatumumab (Ibrutinib: HR, 0.10; 95% CI, 0.07–0.14; Venetoclax plus rituximab: HR, 0.10; 95% CI, 0.05–0.21) and SUCRA value (probability of being best) (Ibrutinib SUCRA, 0.92; Venetoclax rituximab SUCRA, 0.90) (2) HR for overall survival compared with ofatumumab (Ibrutinib: HR, 0.361; 95% CI, 0.208–0.627; Venetoclax rituximab: HR, 0.335; 95% CI, 0.112–0.997) and SUCRA value (Ibrutinib SUCRA, 0.84; Venetoclax rituximab SUCRA, 0.85) Both treatments reduced the risk of progression or death by 90% versus conventional ofatumumab. Both ibrutinib monotherapy and venetoclax rituximab have a high probability of being the most effective treatments for a relapse or refractory chronic lymphocytic leukemia with respect to long-term progression-free survival and overall survival. Full article

(This article belongs to the Section Oncology)

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Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of refractory/relapse chronic lymphocytic leukemia. Full article ">Figure 2
Schematic diagram of the network of evidence used in network meta-analysis (NMA). The black line indicates a direct comparison from RCT. The name of the trial and the published year are noted in black. The hazard ratio of PFS is noted in orange. The red dotted line indicates the individualized indirect comparison data published by Hillmen et al. HR: Hazard ratio, BR: Bendamustine + Rituximab, R: Rituximab, P: P-value. Full article ">Figure 3
Network meta-analysis results of treatment efficacy in refractory/relapse (R/R) chronic lymphocytic leukemia (CLL): Forest plot of PFS in R/R CLL. HR: Hazard ratio; CI: Confidence interval, SUCRA: Surface under the cumulative ranking curve, BR: Bendamustine + Rituximab, R: Rituximab. Full article ">Figure 4
Network meta-analysis results of treatment efficacy in refractory/relapse (R/R) chronic lymphocytic leukemia (CLL): Forest plot of OS in R/R CLL. HR: Hazard ratio, CI: Confidence interval, SUCRA: Surface under the cumulative ranking curve, BR: Bendamustine + Rituximab, R: Rituximab. Full article ">Figure 5
Network meta-analysis results of treatment efficacy in refractory/relapse (R/R) chronic lymphocytic leukemia (CLL): Forest plot of PFS in R/R CLL patients without del(17p) mutation. HR: Hazard ratio, CI: Confidence interval, SUCRA: Surface under the cumulative ranking curve, BR: Bendamustine + Rituximab, R: Rituximab. Full article ">Figure 6
Efficacy outcomes for progression-free survival (PFS) and overall survival (OS) in network meta-analysis: Scatter plot. Data are reported by SUCRA values from the results of our network meta-analysis. X-axis, SUCRA values for PFS. Y-axis, SUCRA values for OS. Red nodes indicate the most effective treatment options. Green nodes indicate treatment options more effective than conventional regimens. Navy blue nodes indicate treatment options as effective as conventional regimens. PFS: Progression-free survival, OS: Overall survival, B: Bendamustine, R: Rituximab, Ofa: Ofatumumab, SUCRA: Surface under the cumulative ranking curve. Full article ">

12 pages, 1181 KiB

Open AccessArticle

The Clinical Significance of Programmed Death-1, Regulatory T Cells and Myeloid Derived Suppressor Cells in Patients with Nontuberculous Mycobacteria-Lung Disease

by Chin-Chung Shu, Sheng-Wei Pan, Jia-Yih Feng, Jann-Yuan Wang, Yu-Jiun Chan, Chong-Jen Yu and Wei-Juin Su

J. Clin. Med. 2019, 8(5), 736; https://doi.org/10.3390/jcm8050736 - 23 May 2019

Cited by 22 | Viewed by 3360

Abstract

Background: Increasing expression of programmed death-1 (PD-1) in patients with nontuberculous mycobacteria lung disease (NTM-LD) has been reported, but its role in clinical characteristics and outcomes remains unclear. Methods: We enrolled 96 participants, including 46 with Mycobacterium avium complex (MAC)-LD, 23 with M. [...] Read more.

Background: Increasing expression of programmed death-1 (PD-1) in patients with nontuberculous mycobacteria lung disease (NTM-LD) has been reported, but its role in clinical characteristics and outcomes remains unclear. Methods: We enrolled 96 participants, including 46 with Mycobacterium avium complex (MAC)-LD, 23 with M. abscessus (MAB)-LD, and 27 controls. We measured expressions of PD-1, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and regulatory T (Treg) cells on CD4⁺ lymphocytes and myeloid-derived suppressor cells (MDSCs) and analyzed their association with clinical features and radiographic outcomes. Results: The percentage of PD-1 on CD4⁺(PD-1⁺CD4⁺) lymphocytes and MDSCs were higher in the MAC-LD group than the controls. There were no intergroup differences regarding CTLA-4⁺CD4⁺ lymphocytes. Higher PD-1⁺CD4⁺ lymphocytes were found in M. intracellulare- and M. avium-LD than in other MAC-LD. Positive sputum acid-fast stains and fibrocavitary radiographic lesions were correlated with elevated PD-1⁺CD4⁺ lymphocytes and Treg cells. The percentage of PD-1⁺CD4⁺ lymphocytes at the initial and 2 months of follow-up significantly predicted subsequent radiographic progression. Conclusion: As markers of immune tolerance, PD-1⁺CD4⁺ lymphocytes and MDSCs were higher in MAC-LD patients. The levels of PD-1⁺CD4⁺ and Treg cells were correlated with high mycobacteria bacilli burden in NTM-LD. Monitoring the expressions of PD-1⁺CD4⁺ lymphocytes may predict radiographic progression. Full article

(This article belongs to the Special Issue Tuberculosis: Clinical Applications in the Diagnosis and Treatment)

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The proportion of (A) programmed death-1 (PD-1), (B) cytotoxic T-lymphocyte antigen-4 (CTLA-4), and (C) regulatory lymphocytes (Treg) in CD4 lymphocytes; (D) myeloid derived suppressor cells (MDSCs) according to the status of mycobacterial lung disease. The results shown are case demonstration and bar charts between the controls and patients with Mycobacterium avium complex-lung disease (MAC-LD) and those with Mycobacterium abscessus-LD (MAB-LD). We discriminated the lymphocytes and monocytes by forward scatter (FSC) and side scatter (SSC). We first gated the lymphocyte marker CD4, and then gated PD-1, CTLA-4, and CD25+/Foxp3+ in the CD4-positive lymphocytes. In <a href="#jcm-08-00736-f001" class="html-fig">Figure 1</a>D, we gated CD3-/CD14-/HLA-DR- cells in peripheral blood mononuclear cells and then gated the CD11b+/CD33+ population. The data in the bar charts are mean values, and error bars are standard errors. The data were compared using the Mann Whitney U test. ns, not statistically significant (p > 0.05). Full article ">Figure 2
The proportion of programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on CD4+ lymphocytes in Mycobacterium avium complex-lung disease according to different causative subspecies. The data in the bar charts are mean values, and error bars are standard errors. The data were compared using the Mann Whitney U test. M., mycobacterium; ns, not statistically significant (p > 0.05). Full article ">Figure 3
The percentages of regulatory T cells (Treg), programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on CD4 lymphocytes, and myeloid derived suppressor cells (MDSCs) among the patients with nontuberculous mycobacteria-lung disease (NTM-LD) according to (A) positive or negative acid-fast bacilli staining for sputum, and (B) initial radiographic findings. The data in the bar charts are mean values and error bars are standard errors. The data were compared using the Mann Whitney U test. Y axis means percentage in (1) lymphocyte population for Treg, PD-1+CD4+, and CTLA4+CD4+ cells, and in (2) peripheral blood mononuclear cells for MDSCs. NTM-LD includes Mycobacterium avium complex and M. abscessus lung disease. FC, fibro-cavitary; NB, nodular bronchiectasis. ns, not statistically significant (p > 0.05). Full article ">Figure 4
The percentages of programmed death-1+ (PD-1+) CD4 lymphocytes, myeloid derived suppressor cells (MDSCs), and regulatory T cells (Treg) between the patients with or without radiographic progression. (A) Initial data and (B) after 2 months of follow-up. Y axis means percentage in (1) lymphocyte population for Treg, PD-1+CD4+, and CTLA4+CD4+ cells, and in (2) peripheral blood mononuclear cells for MDSCs. The data in the bar charts and error bars are mean and standard errors, respectively. The data were compared using the Mann Whitney U test. ns, not statistically significant (p > 0.05). Full article ">

19 pages, 632 KiB

Open AccessReview

Circulating miRNAs as Biomarkers for Endometriosis and Endometriosis-Related Ovarian Cancer—An Overview

by Marius Alexandru Moga, Andreea Bălan, Oana Gabriela Dimienescu, Victoria Burtea, Roxana Maria Dragomir and Costin Vlad Anastasiu

J. Clin. Med. 2019, 8(5), 735; https://doi.org/10.3390/jcm8050735 - 23 May 2019

Cited by 56 | Viewed by 10757

Abstract

Early detection and accurate diagnosis are pivotal in the management of endometriosis and endometriosis-related ovarian neoplasms (ERONs), yet there is no clear common ground regarding their pathogenesis. Endometriosis is a debilitating pathology that profoundly impairs the quality of life. Although the spontaneous resolution [...] Read more.

Early detection and accurate diagnosis are pivotal in the management of endometriosis and endometriosis-related ovarian neoplasms (ERONs), yet there is no clear common ground regarding their pathogenesis. Endometriosis is a debilitating pathology that profoundly impairs the quality of life. Although the spontaneous resolution of endometriosis is possible, studies suggest that it can be a progressive condition, and ERONs can develop. The gold standard for diagnosis remains as the invasive method of laparoscopy followed by histological confirmation. In recent years, novel biomarkers have been discovered. MicroRNAs (miRNA) represent important epigenetic modulators of gene expression and are very attractive as biomarkers due to their lower complexity, tissue specificity, and stability in bodily fluids. Several studies have advanced the possibility of miRNAs becoming potential biomarkers in endometriosis and ERONs. Our aim is to bring these studies together in order to have a better understanding of whether, how, and when miRNAs might be used as biomarkers for these pathologies. Methods: We selected the reviewed papers from Google Academic, PubMed, and CrossRef. A total of eight studies met the inclusion criteria. Results: MiR-200 family, miR-143, 145, miR-20a, and miR199a were the most commonly dysregulated miRNAs in endometriosis, and miR-200 family was found to be dysregulated in both ERONs and endometriosis. Conclusions: No single miRNA was considered as a sole biomarker for this pathology. However, since the prognostic value of biomarkers is generally enhanced if more are assessed at the same time, a panel of miRNAs could be a better indicator of the disease. Full article

(This article belongs to the Special Issue Advanced Analytical Methods in Clinical Diagnosis and Therapy)

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27 pages, 471 KiB

Open AccessReview

A Systematic Review on the Cognitive Benefits and Neurophysiological Correlates of Exergaming in Healthy Older Adults

by Robert Stojan and Claudia Voelcker-Rehage

J. Clin. Med. 2019, 8(5), 734; https://doi.org/10.3390/jcm8050734 - 23 May 2019

Cited by 87 | Viewed by 8769

Abstract

Human aging is associated with structural and functional brain deteriorations and a corresponding cognitive decline. Exergaming (i.e., physically active video-gaming) has been supposed to attenuate age-related brain deteriorations and may even improve cognitive functions in healthy older adults. Effects of exergaming, however, vary [...] Read more.

Human aging is associated with structural and functional brain deteriorations and a corresponding cognitive decline. Exergaming (i.e., physically active video-gaming) has been supposed to attenuate age-related brain deteriorations and may even improve cognitive functions in healthy older adults. Effects of exergaming, however, vary largely across studies. Moreover, the underlying neurophysiological mechanisms by which exergaming may affect cognitive and brain function are still poorly understood. Therefore, we systematically reviewed the effects of exergame interventions on cognitive outcomes and neurophysiological correlates in healthy older adults (>60 years). After screening 2709 studies (Cochrane Library, PsycINFO, Pubmed, Scopus), we found 15 eligible studies, four of which comprised neurophysiological measures. Most studies reported within group improvements in exergamers and favorable interaction effects compared to passive controls. Fewer studies found superior effects of exergaming over physically active control groups and, if so, solely for executive functions. Regarding individual cognitive domains, results showed no consistence. Positive effects on neurophysiological outcomes were present in all respective studies. In summary, exergaming seems to be equally or slightly more effective than other physical interventions on cognitive functions in healthy older adults. Tailored interventions using well-considered exergames and intervention designs, however, may result in more distinct effects on cognitive functions. Full article

(This article belongs to the Special Issue The Effects of Exercise on Cognitive Function)

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12 pages, 1108 KiB

Open AccessArticle

Cardiovascular Safety and Possible Benefit of a 5-Alpha Reductase Inhibitor among Benign Prostatic Hyperplasia Patients, A Nationally Representative Cohort of Korean Men

by Jooyoung Chang, Seulggie Choi, Kyuwoong Kim and Sang Min Park

J. Clin. Med. 2019, 8(5), 733; https://doi.org/10.3390/jcm8050733 - 22 May 2019

Cited by 3 | Viewed by 7507

Abstract

Several studies suggest that 5-alpha reductase inhibitors (5ARIs) may be associated with elevated risk of cardiovascular disease (CVD). We investigated the association of 5ARI exposure and CVD incidence using the National Health Insurance Service-Health Screening Cohort, a nationally representative population-based sample of Koreans. [...] Read more.

Several studies suggest that 5-alpha reductase inhibitors (5ARIs) may be associated with elevated risk of cardiovascular disease (CVD). We investigated the association of 5ARI exposure and CVD incidence using the National Health Insurance Service-Health Screening Cohort, a nationally representative population-based sample of Koreans. We calculated the 4-year cumulative exposure to 5ARI for 215,003 men without prior 5ARI use. Participants were followed from January 1st, 2008 to December 31st, 2015. A subcohort of newly diagnosed benign prostatic hyperplasia (BPH) patients during 2004–2010 was also analyzed. The primary study outcome was CVD and secondary outcomes were myocardial infarction (MI) or stroke. Hazard ratios (HRs) were estimated using Cox proportional hazards models adjusted for conventional risk factors. In both the main cohort and BPH subcohort, the use of any 5ARI did not increase the risk of cardiovascular disease (HR = 1.06; 95% CI = 0.91–1.23; HR = 0.95; 95% CI = 0.88–1.03; respectively). Furthermore, as an unexpected finding, a dose-analysis among the BPH subcohort showed that the highest tertile of 5ARI exposure reduced the risk of CVD (HR = 0.82; 95% CI = 0.72–0.92; p-trend = 0.001), MI (HR = 0.69; 95% CI = 0.50–0.95), and stroke (HR = 0.84; 95% CI = 0.72–0.98) compared to non-users. Among men and BPH patients, 5ARI did not increase the risk of CVD. Among BPH patients, 5ARI use may reduce the risk CVD. Full article

(This article belongs to the Section Epidemiology & Public Health)

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26 pages, 806 KiB

Open AccessReview

Substance Abuse and Male Hypogonadism

by Ylenia Duca, Antonio Aversa, Rosita Angela Condorelli, Aldo Eugenio Calogero and Sandro La Vignera

J. Clin. Med. 2019, 8(5), 732; https://doi.org/10.3390/jcm8050732 - 22 May 2019

Cited by 45 | Viewed by 25812

Abstract

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a [...] Read more.

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production. Full article

(This article belongs to the Special Issue Disorders of Puberty: The Causes and the Endocrine Medical Treatment)

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16 pages, 1317 KiB

Open AccessArticle

Inflammatory Immune Responses in the Pathogenesis of Tick-Borne Encephalitis

by Petra Bogovič, Lara Lusa, Miša Korva, Miša Pavletič, Katarina Resman Rus, Stanka Lotrič-Furlan, Tatjana Avšič-Županc, Klemen Strle and Franc Strle

J. Clin. Med. 2019, 8(5), 731; https://doi.org/10.3390/jcm8050731 - 22 May 2019

Cited by 24 | Viewed by 5944

Abstract

Clinical manifestations of tick-borne encephalitis (TBE) are thought to result from the host immune responses to infection, but knowledge of such responses is incomplete. We performed a detailed clinical evaluation and characterization of innate and adaptive inflammatory immune responses in matched serum and [...] Read more.

Clinical manifestations of tick-borne encephalitis (TBE) are thought to result from the host immune responses to infection, but knowledge of such responses is incomplete. We performed a detailed clinical evaluation and characterization of innate and adaptive inflammatory immune responses in matched serum and cerebrospinal fluid (CSF) samples from 81 adult patients with TBE. Immune responses were then correlated with laboratory and clinical findings. The inflammatory immune responses were generally site-specific. Cytokines and chemokines associated with innate and Th1 adaptive immune responses were significantly higher in CSF, while mediators associated with Th17 and B-cell responses were generally higher in serum. Furthermore, mediators associated with innate and Th1 adaptive immune responses were positively associated with disease severity, whereas Th17 and B cell immune responses were not. During the meningoencephalitic phase of TBE, innate and Th1 adaptive inflammatory mediators were highly concentrated in CSF, the site of the disease. The consequence of this robust immune response was more severe acute illness. In contrast, inflammatory mediators associated with B cell and particularly Th17 responses were concentrated in serum. These findings provide new insights into the immunopathogenesis of TBE and implicate innate and Th1 adaptive responses in severity and clinical presentation of acute illness. Full article

(This article belongs to the Section Clinical Neurology)

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12 pages, 1756 KiB

Open AccessReview

Options for Fertility Treatments for Trans Women in Germany

by Florian Schneider, Bettina Scheffer, Jennifer Dabel, Laura Heckmann, Stefan Schlatt, Sabine Kliesch and Nina Neuhaus

J. Clin. Med. 2019, 8(5), 730; https://doi.org/10.3390/jcm8050730 - 22 May 2019

Cited by 19 | Viewed by 4967

Abstract

Fertility preservation in trans women is a crucial but thus far neglected component in the gender confirming treatment in Germany. It is difficult for trans women to access reproductive health care because centers offering treatment, psychological guidance, gender confirming surgery, as well as [...] Read more.

Fertility preservation in trans women is a crucial but thus far neglected component in the gender confirming treatment in Germany. It is difficult for trans women to access reproductive health care because centers offering treatment, psychological guidance, gender confirming surgery, as well as reproductive health services are scarce in Germany. Legal, social, or financial issues as well as individual patient comorbidities prevent trans women from receiving appropriate counselling. This review provides an overview on options of fertility preservation in trans women. We consider recent publications on testicular regression at the time of gender confirming surgery demonstrating presence of sperm or at least spermatogonia in the majority of tissues. This may open options for cryopreservation of sperm or testicular stem cells in trans women even at the final stage of transition. Hence, standardized urological procedures (i.e., sperm cryopreservation after masturbation or sperm extraction from the testicular tissue) and experimental approaches (cryopreservation of testicular tissue with undifferentiated spermatogonia) can be offered best at the initiation but also during the gender confirming process. However, counselling early in the gender confirming process increases the chances of fertility preservation because gender confirming hormone therapy has an impact on spermatogenesis. Full article

(This article belongs to the Special Issue Novel Research in Gender Incongruence)

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15 pages, 1754 KiB

Open AccessArticle

Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

by Matteo Bordoni, Orietta Pansarasa, Michela Dell’Orco, Valeria Crippa, Stella Gagliardi, Daisy Sproviero, Stefano Bernuzzi, Luca Diamanti, Mauro Ceroni, Gabriella Tedeschi, Angelo Poletti and Cristina Cereda

J. Clin. Med. 2019, 8(5), 729; https://doi.org/10.3390/jcm8050729 - 22 May 2019

Cited by 29 | Viewed by 5238

Abstract

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its [...] Read more.

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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(A) Frequency Distribution of SOD1 in healthy controls (CTRL) (n = 40) and sporadic Amyotrophic Lateral Sclerosis (sALS) patients (n = 39). We found a bell-shaped distribution of the normalized values corresponding to SOD1 concentration for healthy controls, while a bimodal distribution was described for sALS patients confirming the presence of two sub-group. (B) Aggregation of cytoplasmic SOD1 in a subgroup of sALS patients observed by immunofluorescence. (C) Analysis of DNA damage in Peripheral Blood Mononuclear Cells (PBMCs) of control and patients with normal SOD1 and aggregated SOD1. Patients with normal SOD1 showed low damaged DNA (very weak Comet tail) similar to that observed in healthy CTRL; on the other hand, a very bright tail was observed in sALS patients characterized by cytoplasmic SOD1 aggregates. (D–F) Comet assay quantification by three different parameters: Tail length, % tail DNA and tail moment. Data were analyzed by ANOVA (n = 3), followed by Newman-Keuls Multiple Comparison Test; * p < 0.05; ** p < 0.01 and *** p < 0.001. Full article ">Figure 2
RT-qPCR in SH-SY5Y treated with 1 mM H2O2 for 30 and 60 min showed that ATM/Chk2 and ATR/Chk1 are actively transcribed after 60 min of oxidative stress, suggesting that SOD1 localization in the nuclear compartment is involved in DNA damage response. Data were analyzed by ANOVA (n = 3), followed by Newman-Keuls Multiple Comparison Test; * p < 0.05; ** p < 0.01 and *** p < 0.001. Full article ">Figure 3
(A,B) Representative immunoblotting of cytoplasmic and nuclear Chk2 and quantification of Chk2 levels in the cytoplasmic compartment in SH-SY5Y at T0, T30 and T60. (C,D) Immunoprecipitation of Chk2 and quantification of cytoplasmic and nuclear SOD1 after oxidative stress. (E,F) The binding between Chk2 and SOD1 was further confirmed by immunoprecipitation also using AZD7762, a Chk1 and Chk2 inhibitor, to SH-SY5Y cells. After AZD7762 treatment no differences were observed in both nuclear and cytoplasm compartment. Data were analyzed by ANOVA (n = 3), followed by Newman-Keuls Multiple Comparison Test; * p < 0.05; ** p < 0.01 and *** p < 0.001. Full article ">Figure 4
(A,B) 1 mM H2O2 treatment determines significant phosphorylation at Ser residue at T60 in the nuclear compartment. SOD1 was immunoprecipitated and representative immunoblotting for pSer was reported for the nucleus. (C,D) 1 mM H2O2 treatment induces significant phosphorylation also at Thr residue at T60 in the nuclear compartment. SOD1 was immunoprecipitated and representative immunoblotting for pThr was reported for the nucleus. Data were analyzed by ANOVA (n = 3), followed by Newman-Keuls Multiple Comparison Test; * p < 0.05. PBMCs from healthy controls and from a subgroup of sALS patients were analyzed for pThr, pSer and SOD1 by immunofluorescence followed by confocal microscopy analysis. (E,F) In healthy controls both pThr and pSer were not observed in the nuclear fraction; (G,H) in PBMCs of sALS patients we observed a bright signal of SOD1 and pThr in the nuclear compartment, while SOD1 and pSer co-localization showed a slight signal. Nuclei were visualized using the fluorescent nuclear dye DAPI (blue). Full article ">Figure 5
(A) Cytoplasmic and nuclear localization of SOD1; chimeric fluorescent-tagged proteins bearing either a nuclear export signal (NES; YFP-NES-wtSOD1) or a nuclear localization signal (NLS NLS; YFP-NLS-wtSOD1) in SH-SY5Y cells were used. (B) Protective role of nuclear SOD1 against DNA damage in SH-SY5Y cells; 60 min of 1 mM H2O2 Treatment induced marked DNA damage in both NT SOD1 and SOD1-NES in SH-SY5Y cells. In SOD1-NLS cells, instead, no comets were observed, indicating that minor or no DNA fragmentation occurred. (C–E) Comet assay quantification by means tail length, % tail DNA and tail moment were carried out. Data were analyzed by ANOVA (n = 3), followed by Newman-Keuls Multiple Comparison Test; * p < 0.05; ** p < 0.01 and **** p < 0.0001. Full article ">

16 pages, 1151 KiB

Open AccessReview

Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

by Toshiaki Iba, Jerrold H. Levy, Aditya Raj and Theodore E. Warkentin

J. Clin. Med. 2019, 8(5), 728; https://doi.org/10.3390/jcm8050728 - 22 May 2019

Cited by 124 | Viewed by 19753

Abstract

Coagulopathy commonly occurs in sepsis as a critical host response to infection that can progress to disseminated intravascular coagulation (DIC) with an increased mortality. Recent studies have further defined factors responsible for the thromboinflammatory response and intravascular thrombosis, including neutrophil extracellular traps, extracellular [...] Read more.

Coagulopathy commonly occurs in sepsis as a critical host response to infection that can progress to disseminated intravascular coagulation (DIC) with an increased mortality. Recent studies have further defined factors responsible for the thromboinflammatory response and intravascular thrombosis, including neutrophil extracellular traps, extracellular vesicles, damage-associated molecular patterns, and endothelial glycocalyx shedding. Diagnosing DIC facilitates sepsis management, and is associated with improved outcomes. Although the International Society on Thrombosis and Haemostasis (ISTH) has proposed criteria for diagnosing overt DIC, these criteria are not suitable for early detection. Accordingly, the ISTH DIC Scientific Standardization Committee has proposed a new category termed “sepsis-induced coagulopathy (SIC)” to facilitate earlier diagnosis of DIC and potentially more rapid interventions in these critically ill patients. Therapy of SIC includes both treatment of the underlying infection and correcting the coagulopathy, with most therapeutic approaches focusing on anticoagulant therapy. Recently, a phase III trial of recombinant thrombomodulin was performed in coagulopathic patients. Although the 28-day mortality was improved by 2.6% (absolute difference), it did not reach statistical significance. However, in patients who met entry criteria for SIC at baseline, the mortality difference was approximately 5% without increased risk of bleeding. In this review, we discuss current advances in managing SIC and DIC. Full article

(This article belongs to the Special Issue Sepsis: Immunopathology, Patient Classification and Clinical Management)

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Three major factors contribute to DIC that include coagulation activation, platelet aggregation, and endothelial damage. Tissue factor expressed on the leukocytes and phosphatidylserine on the damaged cell membrane activate coagulation, decreased physiologic anticoagulant systems accelerate clot formation, and platelet aggregation is stimulated by thrombin and other inflammatory mediators. Endothelial damage reduces the antithrombotic milieu of the vascular lumen. PAMPs: pathogen-associated molecular patterns, NETs: neutrophil extracellular traps, DAMPs: damage-associated molecular patterns, ADAMTS13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, NO: nitric oxide, PGI2: prostagrandin I2, DIC: disseminated intravascular coagulation. Full article ">Figure 2
The coagulation, fibrinolytic, and natural anticoagulant systems. Both the extrinsic pathway and contact pathway are activated in sepsis. Tissue factor, expressed on the monocytes, endothelial cells, and extracellular vesicles triggers the extrinsic pathway, while the phosphatidylserine residue present in various cell membranes initiates the contact pathway of coagulation. Antithrombin/heparin, thrombomodulin/protein C, and tissue factor pathway inhibitor (TFPI) are the three major physiologic anticoagulant systems. FDP: fibrin/fibrinogen degradation products. Full article ">Figure 3
The sequential change from sepsis-induced coagulopathy to disseminated intravascular coagulation. Sepsis-induced coagulopathy progresses to disseminated intravascular coagulation (DIC) if the infection/inflammation is severe enough. Transient activation of fibrinolysis is observed initially, due to the release of tissue-type plasminogen activator (t-PA) from the vascular endothelial cells. Subsequently, the fibrinolytic system is suppressed by the production of plasminogen activator inhibitor-1. The imbalance between coagulation and fibrinolysis leads to a hypercoagulable state and organ dysfunction in sepsis. Full article ">

10 pages, 236 KiB

Open AccessArticle

Transthoracic Needle Biopsy of Pulmonary Nodules: Meteorological Conditions and the Risk of Pneumothorax and Chest Tube Placement

by Bedros Taslakian, Varshaa Koneru, James S. Babb and Divya Sridhar

J. Clin. Med. 2019, 8(5), 727; https://doi.org/10.3390/jcm8050727 - 22 May 2019

Cited by 6 | Viewed by 3160

Abstract

The purpose of this paper is to evaluate whether meteorological variables influence rates of pneumothorax and chest tube placement after percutaneous transthoracic needle biopsy (PTNB) of pulmonary nodules. A retrospective review of 338 consecutive PTNBs of pulmonary nodules at a single institution was [...] Read more.

The purpose of this paper is to evaluate whether meteorological variables influence rates of pneumothorax and chest tube placement after percutaneous transthoracic needle biopsy (PTNB) of pulmonary nodules. A retrospective review of 338 consecutive PTNBs of pulmonary nodules at a single institution was performed. All procedures implemented a coaxial approach, using a 19-gauge outer guide needle for access and a 20-gauge core biopsy gun with or without a small-gauge aspiration needle for tissue sampling. Correlation between age, sex, smoking history, lesion size, meteorological variables, and frequency of complications were evaluated. Fisher exact, trend and t tests were used to evaluate the relationship between each factor and rates of pneumothorax and chest tube placement. A p value of less than 0.05 was considered to indicate a statistically significant difference. Pneumothorax occurred in 115 of 338 patients (34%). Chest tube placement was required in 30 patients (8.9%). No significant relationship was found between pneumothorax rate and age (p = 0.172), sex (p = 0.909), smoking history (p = 0.819), or lesion location (p = 0.765). The presence or absence of special weather conditions did not correlate with the rate of pneumothorax (p = 0.241) or chest tube placement (p = 0.213). The mean atmospheric temperature (p = 0.619) and degree of humidity (p = 0.858) also did not correlate with differences in the rate of pneumothorax. Finally, mean atmospheric pressure on the day of the procedure demonstrated no correlation with the rate of pneumothorax (p = 0.277) or chest tube placement (p = 0.767). In conclusion, no correlation is demonstrated between the occurrence of pneumothorax after PTNB of pulmonary nodules and the studied meteorological variables. Full article

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

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