Open AccessFeature PaperArticle
Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice
J. Clin. Med. 2017, 6(8), 80; doi:10.3390/jcm6080080 (registering DOI) -
Abstract
Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other
[...] Read more.
Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway. Full article
Figures

Figure 1

Open AccessArticle
The Fragility Index in a Cohort of Pediatric Randomized Controlled Trials
J. Clin. Med. 2017, 6(8), 79; doi:10.3390/jcm6080079 -
Abstract
Data suggest inadequacy of common statistical techniques for reporting outcomes in clinical trials. The Fragility Index can measure how many events the statistical significance hinges on, and may facilitate better interpretation of trial results. This study aimed to assess the Fragility Index in
[...] Read more.
Data suggest inadequacy of common statistical techniques for reporting outcomes in clinical trials. The Fragility Index can measure how many events the statistical significance hinges on, and may facilitate better interpretation of trial results. This study aimed to assess the Fragility Index in pediatric randomized controlled trials (RCTs) with statistically significant findings published in high-quality medical journals. A Fragility Index was calculated on included trials with dichotomous positive outcomes. Analysis of the relationship between trial characteristics and the Fragility Index was performed. Of the 429 abstracts screened, 17 met the inclusion criteria and underwent analysis. The median Fragility Index was 7 with an interquartile range of 2–11. In 41% of the studies, the number of patients lost to follow-up or withdrawn prior to analysis was equal to or greater than the Fragility Index. There was no correlation between the RCT sample size and the Fragility Index (r = 0.249, p = 0.335) nor the event group size and the Fragility Index (r = 0.250, p = 0.334). There was a strong negative correlation between the original p-value and the Fragility Index (r = −0.700, p = 0.002). The Fragility Index is a calculated metric that may assist in applying clinical relevance to statistically significant outcomes in pediatric randomized controlled trials with dichotomous outcomes. Full article
Figures

Figure 1

Open AccessBrief Report
Impact of Larger Sputum Volume on Xpert® MTB/RIF Assay Detection of Mycobacterium tuberculosis in Smear-Negative Individuals with Suspected Tuberculosis
J. Clin. Med. 2017, 6(8), 78; doi:10.3390/jcm6080078 -
Abstract
As a strategy to improve the sensitivity of nucleic acid-based testing in acid-fast bacilli (AFB) negative samples, larger volumes of sputum (5–10 mL) were tested with Xpert® MTB/RIF from 176 individuals with smear-negative sputum undergoing tuberculosis evaluation. Despite larger volumes, this strategy
[...] Read more.
As a strategy to improve the sensitivity of nucleic acid-based testing in acid-fast bacilli (AFB) negative samples, larger volumes of sputum (5–10 mL) were tested with Xpert® MTB/RIF from 176 individuals with smear-negative sputum undergoing tuberculosis evaluation. Despite larger volumes, this strategy had a suboptimal sensitivity of 50% (4/8). Full article
Open AccessFeature PaperReview
Ultrasound for Early Detection of Joint Disease in Patients with Hemophilic Arthropathy
J. Clin. Med. 2017, 6(8), 77; doi:10.3390/jcm6080077 -
Abstract
Joint bleeding represents the most commonly reported type of hemorrhage in patients affected by hemophilia. Although the widespread use of prophylaxis has been able to significantly reduce the onset of arthropathy, it has been shown that a non-negligible percentage of patients develop degenerative
[...] Read more.
Joint bleeding represents the most commonly reported type of hemorrhage in patients affected by hemophilia. Although the widespread use of prophylaxis has been able to significantly reduce the onset of arthropathy, it has been shown that a non-negligible percentage of patients develop degenerative changes in their joints despite this type of treatment. Thus, periodic monitoring of the joint status in hemophilia patients has been recommended to identify early arthropathic changes and prevent the development or progression of hemophilic arthropathy. Ultrasound (US) has proven able to detect and quantify the most relevant biomarkers of disease activity (i.e., joint effusion and synovial hypertrophy) and degenerative damages (i.e., osteo-chondral changes) by means of scoring scales of increasing disease severity. In the present review, we have detailed major literature evidence about the use of US to assess joint status in hemophilia patients, focusing on signs of disease activity and degenerative damages. In particular, we have discussed recent evidence about “point-of-care” use patients with hemophilia. Full article
Figures

Figure 1

Open AccessFeature PaperReview
Long-Term Effects of Pregnancy Complications on Maternal Health: A Review
J. Clin. Med. 2017, 6(8), 76; doi:10.3390/jcm6080076 -
Abstract
Background: Most pregnancy-related medical complications appear to resolve at delivery or shortly thereafter. Common examples are preterm labor, placental abruption, preeclampsia, and gestational diabetes. Women who developed such complications are known to be at increased risk of developing similar complications in future
[...] Read more.
Background: Most pregnancy-related medical complications appear to resolve at delivery or shortly thereafter. Common examples are preterm labor, placental abruption, preeclampsia, and gestational diabetes. Women who developed such complications are known to be at increased risk of developing similar complications in future pregnancies. It has recently become evident that these women are at an increased risk of long term medical complications. Methods: A search through scientific publications in English regarding the association of obstetric complications and long-term maternal illness. Results: There is a clear association between various obstetric complications and long-term effects on maternal health. Conclusions: Women with a history of adverse pregnancy outcomes are at increased risk of cardiovascular and metabolic diseases later in life. Data increasingly links maternal vascular, metabolic, and inflammatory complications of pregnancy with an increased risk of vascular disease in later life. Full article
Open AccessFeature PaperReview
Statins, Muscle Disease and Mitochondria
J. Clin. Med. 2017, 6(8), 75; doi:10.3390/jcm6080075 -
Abstract
Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal
[...] Read more.
Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction. Full article
Figures

Figure 1

Open AccessFeature PaperArticle
Effects of Assault Type on Cognitive Behaviour Therapy for Coexisting Depression and Alcohol Misuse
J. Clin. Med. 2017, 6(7), 72; doi:10.3390/jcm6070072 -
Abstract
Although assault exposure is common in mental health and substance misusing populations, screening for assaults in treatment settings is frequently overlooked. This secondary analysis explored the effects of past sexual (SA) and physical (PA) assault on depression, alcohol misuse, global functioning and attrition
[...] Read more.
Although assault exposure is common in mental health and substance misusing populations, screening for assaults in treatment settings is frequently overlooked. This secondary analysis explored the effects of past sexual (SA) and physical (PA) assault on depression, alcohol misuse, global functioning and attrition in the Depression and Alcohol Integrated and Single focussed Intervention (DAISI) project, whose participants (N = 278) received cognitive behaviour therapy (CBT) for their depression and/or alcohol misuse. Of the 278 DAISI participants, 220 consented to screening for past assault (either by a stranger or non-stranger) at baseline. Depression, alcohol, and global functioning assessments were administered at baseline and 3, 12, 24, and 36 months post baseline. A between-group analysis was used to assess differences between SA and No SA, and PA and No PA groupings, on adjusted mean treatment outcomes across all assessment periods. SA and PA participants had similar mean symptom reductions compared to No SA and No PA participants except for lower depression and global functioning change scores at the 12-month follow-up. People with coexisting depression and alcohol misuse reporting SA or PA can respond well to CBT for depression and alcohol misuse. However, follow-up is recommended in order to monitor fluctuations in outcomes. Full article
Open AccessFeature PaperReview
Th17 in Animal Models of Rheumatoid Arthritis
J. Clin. Med. 2017, 6(7), 73; doi:10.3390/jcm6070073 -
Abstract
IL-17-secreting helper CD4 T cells (Th17 cells) constitute a newly identified subset of helper CD4 T cells that play a key role in the development of rheumatoid arthritis (RA) in its animal models. Recently, several models of spontaneous RA, which elucidate the mechanism
[...] Read more.
IL-17-secreting helper CD4 T cells (Th17 cells) constitute a newly identified subset of helper CD4 T cells that play a key role in the development of rheumatoid arthritis (RA) in its animal models. Recently, several models of spontaneous RA, which elucidate the mechanism of RA onset, have been discovered. These animal models shed new light on the role of Th17 in the development of autoimmune arthritis. Th17 cells coordinate inflammation and promote joint destruction, acting on various cells, including neutrophils, macrophages, synovial fibroblasts, and osteoclasts. Regulatory T cells cannot control Th17 cells under conditions of inflammation. In this review, the pathogenic role of Th17 cells in arthritis development, which was revealed by the recent animal models of RA, is discussed. Full article
Figures

Figure 1

Open AccessFeature PaperReview
The Role of Th17 Cells in the Pathogenesis of Behcet’s Disease
J. Clin. Med. 2017, 6(7), 74; doi:10.3390/jcm6070074 -
Abstract
Behcet’s disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. The pathogenesis of BD has not been fully elucidated; however, BD has been considered to be a typical Th1-mediated inflammatory disease, characterized by elevated levels of
[...] Read more.
Behcet’s disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. The pathogenesis of BD has not been fully elucidated; however, BD has been considered to be a typical Th1-mediated inflammatory disease, characterized by elevated levels of Th1 cytokines such as IFN-γ, IL-2, and TNF-α. Recently, some studies reported that Th17-associated cytokines were increased in BD; thus, Th17 cells and the IL17/IL23 pathway may play important roles in the pathogenesis of BD. In this chapter, we focus on the pathogenic role of Th17 cells in BD. Full article
Open AccessFeature PaperReview
Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders
J. Clin. Med. 2017, 6(7), 71; doi:10.3390/jcm6070071 -
Abstract
Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of a number of diseases and conditions. Oxidative stress occurs once the antioxidant defenses of the body become overwhelmed and are no longer able to detoxify reactive oxygen species (ROS). The ROS
[...] Read more.
Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of a number of diseases and conditions. Oxidative stress occurs once the antioxidant defenses of the body become overwhelmed and are no longer able to detoxify reactive oxygen species (ROS). The ROS can then go unchallenged and are able to cause oxidative damage to cellular lipids, DNA and proteins, which will eventually result in cellular and organ dysfunction. Although not always the primary cause of disease, mitochondrial dysfunction as a secondary consequence disease of pathophysiology can result in increased ROS generation together with an impairment in cellular energy status. Mitochondrial dysfunction may result from either free radical-induced oxidative damage or direct impairment by the toxic metabolites which accumulate in certain metabolic diseases. In view of the importance of cellular antioxidant status, a number of therapeutic strategies have been employed in disorders associated with oxidative stress with a view to neutralising the ROS and reactive nitrogen species implicated in disease pathophysiology. Although successful in some cases, these adjunct therapies have yet to be incorporated into the clinical management of patients. The purpose of this review is to highlight the emerging evidence of oxidative stress, secondary mitochondrial dysfunction and antioxidant treatment efficacy in metabolic and non-metabolic diseases in which there is a current interest in these parameters. Full article
Figures

Figure 1

Open AccessReview
Omega-3 Polyunsaturated Fatty Acids for the Treatment of IgA Nephropathy
J. Clin. Med. 2017, 6(7), 70; doi:10.3390/jcm6070070 -
Abstract
IgA nephropathy is a common disease that causes end-stage renal failure and requires renal replacement therapy. The main purpose of therapeutic intervention in this disease is not limited to improvement of prognosis and prevention of transition to end-stage renal failure, but also prevention
[...] Read more.
IgA nephropathy is a common disease that causes end-stage renal failure and requires renal replacement therapy. The main purpose of therapeutic intervention in this disease is not limited to improvement of prognosis and prevention of transition to end-stage renal failure, but also prevention of the occurrence of cardiovascular lesions, which increases risk in patients with chronic kidney disease. Steroids and immunosuppressants have been widely used as remission induction therapies; however, the balance between their therapeutic benefits and detrimental side-effects are controversial. In this regard, it is critical to identify alternative therapies which would provide holistic life-long benefits. Currently, the potential of ω-3 fatty acids as anti-inflammatory and inflammation-convergent drugs—especially the remarkable progress of the multifunctional ω-3 polyunsaturated fatty acids (PUFAs)—has garnered attention. In this section, we outline the background and current status of ω-3 PUFA-based treatment in IgA nephropathy. Full article
Figures

Figure 1

Open AccessFeature PaperReview
An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation
J. Clin. Med. 2017, 6(7), 69; doi:10.3390/jcm6070069 -
Abstract
Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be
[...] Read more.
Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field. Full article
Figures

Open AccessReview
Pathogenic Role of IL-17-Producing Immune Cells in Obesity, and Related Inflammatory Diseases
J. Clin. Med. 2017, 6(7), 68; doi:10.3390/jcm6070068 -
Abstract
Obesity is associated with low-grade chronic inflammation. Indeed, adipose tissues (AT) in obese individuals are the former site of progressive infiltration by pro-inflammatory immune cells, which together with increased inflammatory adipokine secretion induce adipocyte insulin resistance. IL-17-producing T (Th17) cells are part of
[...] Read more.
Obesity is associated with low-grade chronic inflammation. Indeed, adipose tissues (AT) in obese individuals are the former site of progressive infiltration by pro-inflammatory immune cells, which together with increased inflammatory adipokine secretion induce adipocyte insulin resistance. IL-17-producing T (Th17) cells are part of obese AT infiltrating cells, and are likely to be promoted by adipose tissue-derived mesenchymal stem cells, as previously reported by our team. Whereas Th17 cell are physiologically implicated in the neutralization of fungal and bacterial pathogens through activation of neutrophils, they may also play a pivotal role in the onset and/or progression of chronic inflammatory diseases, or cancer, in which obesity is recognized as a risk factor. In this review, we will highlight the pathogenic role of IL-17A producing cells in the mechanisms leading to inflammation in obesity and to progression of obesity-related inflammatory diseases. Full article
Figures

Figure 1

Open AccessFeature PaperReview
The Plasticity of Th17 Cells in the Pathogenesis of Rheumatoid Arthritis
J. Clin. Med. 2017, 6(7), 67; doi:10.3390/jcm6070067 -
Abstract
Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., “nonclassic Th1 cells”), which are reported to be more pathogenic than Th17
[...] Read more.
Helper T (Th) cells play an important role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). It has been revealed that Th17 cells can shift to Th1 cells (i.e., “nonclassic Th1 cells”), which are reported to be more pathogenic than Th17 cells per se. Thus, the association of Th cells in the pathogenesis of autoimmune disease has become more complicated. We recently reported using peripheral blood from untreated and early-onset RA patients that the ratio of CD161+Th1 cells (i.e., Th17-derived Th1 cells to CD161+Th17 cells) is elevated and that levels of interferon-γ (IFNγ)+Th17 cells are inversely correlated with levels of anti-CCP antibodies. Here, we review the plasticity of Th17 cells in the pathogenesis of RA, suggesting possible implications for novel therapies. Full article
Figures

Figure 1

Open AccessReview
When Less Is Good, Is None Better? The Prognostic and Therapeutic Significance of Peri-Transplant Minimal Residual Disease Assessment in Pediatric Acute Lymphoblastic Leukemia
J. Clin. Med. 2017, 6(7), 66; doi:10.3390/jcm6070066 -
Abstract
The measurement of minimal residual disease (MRD) in pediatric acute lymphoblastic leukemia (ALL) has become the most important prognostic tool of, and the backbone to, upfront risk stratification. While MRD assessment is the standard of care for assessing response and predicting outcomes for
[...] Read more.
The measurement of minimal residual disease (MRD) in pediatric acute lymphoblastic leukemia (ALL) has become the most important prognostic tool of, and the backbone to, upfront risk stratification. While MRD assessment is the standard of care for assessing response and predicting outcomes for pediatric patients with ALL receiving chemotherapy, its use in allogeneic hematopoietic stem cell transplant (HSCT) has been less clearly defined. Herein, we discuss the importance of MRD assessment during the peri-HSCT period and its role in prognostication and management. Full article
Open AccessFeature PaperReview
T Helper 17 Cells in Primary Sjögren’s Syndrome
J. Clin. Med. 2017, 6(7), 65; doi:10.3390/jcm6070065 -
Abstract
Primary Sjögren’s syndrome is an autoimmune disease characterized by diffuse infiltration of lymphocytes into exocrine glands and other tissues. The infiltrating lymphocytes have been identified as subsets of B cells and T cells, including T helper 17 cells, T regulatory cells and follicular
[...] Read more.
Primary Sjögren’s syndrome is an autoimmune disease characterized by diffuse infiltration of lymphocytes into exocrine glands and other tissues. The infiltrating lymphocytes have been identified as subsets of B cells and T cells, including T helper 17 cells, T regulatory cells and follicular helper T cells. The role of these cells in the development of the syndrome is now known, as is their impact on the production of proinflammatory cytokines such as IL-6, IL-17, IL-22 and IL-23. In particular, experimental animal models and patients suggest that a shift in Th17/Treg balance toward the proinflammatory Th17 axis exacerbates primary Sjögren’s syndrome and other autoimmune disorders. Nevertheless, the pathogenesis of the disorder is not yet fully elucidated. This review summarizes the recent advances in therapeutic control of the Treg/Th17 balance, as well as the efficacy of candidate therapeutics against primary Sjögren’s syndrome. Full article
Figures

Open AccessFeature PaperReview
Myopathology of Adult and Paediatric Mitochondrial Diseases
J. Clin. Med. 2017, 6(7), 64; doi:10.3390/jcm6070064 -
Abstract
Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible
[...] Read more.
Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible phenotypic and genetic diversity of mtD can be attributed at least in part to the RC dual genetic control (nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)) and the complex interaction between the two genomes. Despite the increasing use of next-generation-sequencing (NGS) and various omics platforms in unravelling novel mtD genes and pathomechanisms, current clinical practice for investigating mtD essentially involves a multipronged approach including clinical assessment, metabolic screening, imaging, pathological, biochemical and functional testing to guide molecular genetic analysis. This review addresses the broad muscle pathology landscape including genotype–phenotype correlations in adult and paediatric mtD, the role of immunodiagnostics in understanding some of the pathomechanisms underpinning the canonical features of mtD, and recent diagnostic advances in the field. Full article
Open AccessReview
Pathophysiology of Hemophilic Arthropathy
J. Clin. Med. 2017, 6(7), 63; doi:10.3390/jcm6070063 -
Abstract
Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the
[...] Read more.
Spontaneous joint bleeding and repeated hemarthroses lead to hemophilic arthropathy—a debilitating disease with a significant negative impact on mobility and quality of life. Iron, cytokines, and angiogenic growth factors play a pivotal role in the onset of the inflammatory process that involves the synovial tissue, articular cartilage, and subchondral bone, with early damages and molecular changes determining the perpetuation of a chronic inflammatory condition. Synovitis is one of the earliest complications of hemarthrosis, and is characterized by synovial hypertrophy, migration of inflammatory cells, and a high degree of neo-angiogenesis with subsequent bleeding. The pathogenic mechanisms and molecular pathways by which blood in the joint cavity causes articular cartilage and subchondral bone destruction have yet to be fully elucidated. Both cytokines and matrix metalloproteinases and hydroxyl radicals may induce chondrocyte apoptosis. Members of the tumor necrosis factor receptor superfamily (such as the molecular triad: osteoprotegerin—OPG; receptor activator of nuclear factor κB—RANK; RANK ligand—RANKL) seem instead to play a major role in the inflammatory process. These pathogenic processes interact with each other and ultimately lead to a fibrotic joint and the disabling condition characteristic of hemophilic arthropathy. Full article
Figures

Figure 1

Open AccessReview
Fibrotic Hypersensitivity Pneumonitis: Key Issues in Diagnosis and Management
J. Clin. Med. 2017, 6(6), 62; doi:10.3390/jcm6060062 -
Abstract
The diagnosis of hypersensitivity pneumonitis (HP) relies on the clinical evaluation of a number of features, including a history of significant exposure to potentially causative antigens, physical examination, chest CT scan appearances, bronchoalveolar lavage lymphocytosis, and, in selected cases, histology. The presence of
[...] Read more.
The diagnosis of hypersensitivity pneumonitis (HP) relies on the clinical evaluation of a number of features, including a history of significant exposure to potentially causative antigens, physical examination, chest CT scan appearances, bronchoalveolar lavage lymphocytosis, and, in selected cases, histology. The presence of fibrosis is associated with higher morbidity and mortality. Differentiating fibrotic HP from the idiopathic interstitial pneumonias can be a challenge. Furthermore, even in the context of a clear diagnosis of fibrotic HP, the disease behaviour can parallel that of idiopathic pulmonary fibrosis in a subgroup, with inexorable progression despite treatment. We review the current knowledge on the diagnosis, management, and prognosis of HP with particular focus on the fibrotic phenotype. Full article
Figures

Figure 1a

Open AccessReview
Role of Gut Microbiota in Rheumatoid Arthritis
J. Clin. Med. 2017, 6(6), 60; doi:10.3390/jcm6060060 -
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease, caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental agent affecting the development of RA. Here we review the evidence from animal
[...] Read more.
Rheumatoid arthritis (RA) is a systemic autoimmune disease, caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental agent affecting the development of RA. Here we review the evidence from animal and human studies that supports the role of the gut microbiota in RA. We and others have demonstrated that the abundance of Prevotella copri is increased in some early RA. We have also used gnotobiotic experiments to show that dysbiosis in RA patients contributed to the development of Th17 cell-dependent arthritis in intestinal microbiota-humanized SKG mice. On the other hand, Prevotella histicola from human gut microbiota suppressed the development of arthritis. In summary, Prevotella species are involved in the pathogenesis of arthritis. Full article
Figures

Figure 1