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

Open AccessFeature PaperArticle
Social Factors Determine the Emergency Medical Admission Workload
J. Clin. Med. 2017, 6(6), 59; doi:10.3390/jcm6060059 -
Abstract
We related social factors with the annual rate of emergency medical admissions using census small area statistics. All emergency medical admissions (70,543 episodes in 33,343 patients) within the catchment area of St. James’s Hospital, Dublin, were examined between 2002 and 2016. Deprivation Index,
[...] Read more.
We related social factors with the annual rate of emergency medical admissions using census small area statistics. All emergency medical admissions (70,543 episodes in 33,343 patients) within the catchment area of St. James’s Hospital, Dublin, were examined between 2002 and 2016. Deprivation Index, Single-Parent status, Educational level and Unemployment rates were regressed against admission rates. High deprivation areas had an approximately fourfold (Incidence Rate Ratio (IRR) 4.0 (3.96, 4.12)) increase in annual admission rate incidence/1000 population from Quintile 1(Q1), from 9.2/1000 (95% Confidence Interval (CI): 9.0, 9.4) to Q5 37.3 (37.0, 37.5)). Single-Parent families comprised 40.6% of households (95% CI: 32.4, 49.7); small areas with more Single Parents had a higher admission rate-IRR (Q1 vs. for Q5) of 2.92 (95% CI: 2.83, 3.01). The admission incidence rate was higher for Single-Parent status (IRR 1.50 (95% CI: 1.46, 1.52)) where the educational completion level was limited to primary level (Incidence Rate Ratio 1.45 (95% CI: 1.43, 1.47)). Small areas with higher educational quintiles predicted lower Admission Rates (IRR 0.85 (95% CI: 0.84, 0.86)). Social factors strongly predict the annual incidence rate of emergency medical admissions. Full article
Figures

Figure 1

Open AccessReview
Renin Inhibition with Aliskiren: A Decade of Clinical Experience
J. Clin. Med. 2017, 6(6), 61; doi:10.3390/jcm6060061 -
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of arterial hypertension as well as in more complex mechanisms of cardiovascular and renal diseases. RAAS-blocking agents like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have long been key components
[...] Read more.
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of arterial hypertension as well as in more complex mechanisms of cardiovascular and renal diseases. RAAS-blocking agents like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have long been key components in the treatment of essential hypertension, heart failure, diabetic nephropathy, and chronic kidney disease, showing benefits well beyond blood pressure reduction. Renin blockade as the first step of the RAAS cascade finally became possible in 2007 with the approval of aliskiren, the first orally active direct renin inhibitor available for clinical use and the newest antihypertensive agent on the market. In the last decade, many clinical trials and meta-analyses have been conducted concerning the efficacy and safety of aliskiren in comparison to other antihypertensive agents, as well as the efficacy and potential clinical use of various combinations. Large trials with cardiovascular and renal endpoints attempted to show potential benefits of aliskiren beyond blood pressure lowering, as well as morbidity and mortality outcomes in specific populations such as diabetics, heart failure patients, and post-myocardial infarction individuals. The purpose of this review is to present the currently available data regarding established and future potential clinical uses of aliskiren. Full article
Figures

Figure 1

Open AccessArticle
An Effective, Versatile, and Inexpensive Device for Oxygen Uptake Measurement
J. Clin. Med. 2017, 6(6), 58; doi:10.3390/jcm6060058 -
Abstract
In the last ten years, the use of fluorescent probes developed to measure oxygen has resulted in several marketed devices, some unreasonably expensive and with little flexibility. We have explored the use of the effective, versatile, and inexpensive Redflash technology to determine oxygen
[...] Read more.
In the last ten years, the use of fluorescent probes developed to measure oxygen has resulted in several marketed devices, some unreasonably expensive and with little flexibility. We have explored the use of the effective, versatile, and inexpensive Redflash technology to determine oxygen uptake by a number of different biological samples using various layouts. This technology relies on the use of an optic fiber equipped at its tip with a membrane coated with a fluorescent dye (www.pyro-science.com). This oxygen-sensitive dye uses red light excitation and lifetime detection in the near infrared. So far, the use of this technology has mostly been used to determine oxygen concentration in open spaces for environmental studies, especially in aquatic media. The oxygen uptake determined by the device can be easily assessed in small volumes of respiration medium and combined with the measurement of additional parameters, such as lactate excretion by intact cells or the membrane potential of purified mitochondria. We conclude that the performance of by this technology should make it a first choice in the context of both fundamental studies and investigations for respiratory chain deficiencies in human samples. Full article
Figures

Figure 1

Open AccessFeature PaperReview
Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?
J. Clin. Med. 2017, 6(6), 57; doi:10.3390/jcm6060057 -
Abstract
Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of
[...] Read more.
Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia. Full article
Figures

Open AccessFeature PaperReview
Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders
J. Clin. Med. 2017, 6(6), 56; doi:10.3390/jcm6060056 -
Abstract
Mitochondrial disorders are a clinically heterogeneous group of disorders that are caused by defects in the respiratory chain, the metabolic pathway of the adenosine tri-phosphate (ATP) production system. Epilepsy is a common and important feature of these disorders and its management can be
[...] Read more.
Mitochondrial disorders are a clinically heterogeneous group of disorders that are caused by defects in the respiratory chain, the metabolic pathway of the adenosine tri-phosphate (ATP) production system. Epilepsy is a common and important feature of these disorders and its management can be challenging. Epileptic seizures in the context of mitochondrial disease are usually treated with conventional anti-epileptic medication, apart from valproic acid. However, in accordance with the treatment of intractable epilepsy where there are limited treatment options, the ketogenic diet (KD) has been considered as an alternative therapy. The use of the KD and its more palatable formulations has shown promising results. It is especially indicated and effective in the treatment of mitochondrial disorders due to complex I deficiency. Further research into the mechanism of action and the neuroprotective properties of the KD will allow more targeted therapeutic strategies and thus optimize the treatment of both epilepsy in the context of mitochondrial disorders but also in other neurodegenerative disorders. Full article
Figures

Open AccessFeature PaperReview
The Role of Interleukin-18, Oxidative Stress and Metabolic Syndrome in Alzheimer’s Disease
J. Clin. Med. 2017, 6(5), 55; doi:10.3390/jcm6050055 -
Abstract
The role of interleukins (ILs) and oxidative stress (OS) in precipitating neurodegenerative diseases including sporadic Alzheimer’s disease (AD), requires further clarification. In addition to neuropathological hallmarks—extracellular neuritic amyloid-β (Aβ) plaques, neurofibrillary tangles (NFT) containing hyperphosphorylated tau and neuronal loss—chronic inflammation, as well as
[...] Read more.
The role of interleukins (ILs) and oxidative stress (OS) in precipitating neurodegenerative diseases including sporadic Alzheimer’s disease (AD), requires further clarification. In addition to neuropathological hallmarks—extracellular neuritic amyloid-β (Aβ) plaques, neurofibrillary tangles (NFT) containing hyperphosphorylated tau and neuronal loss—chronic inflammation, as well as oxidative and excitotoxic damage, are present in the AD brain. The pathological sequelae and the interaction of these events during the course of AD need further investigation. The brain is particularly sensitive to OS, due to the richness of its peroxidation-sensitive fatty acids, coupled with its high oxygen demand. At the same time, the brain lack robust antioxidant systems. Among the multiple mechanisms and triggers by which OS can accumulate, inflammatory cytokines can sustain oxidative and nitrosative stress, leading eventually to cellular damage. Understanding the consequences of inflammation and OS may clarify the initial events underlying AD, including in interaction with genetic factors. Inflammatory cytokines are potential inducers of aberrant gene expression through transcription factors. Susceptibility disorders for AD, including obesity, type-2 diabetes, cardiovascular diseases and metabolic syndrome have been linked to increases in the proinflammatory cytokine, IL-18, which also regulates multiple AD related proteins. The association of IL-18 with AD and AD-linked medical conditions are reviewed in the article. Such data indicates that an active lifestyle, coupled to a healthy diet can ameliorate inflammation and reduce the risk of sporadic AD. Full article
Figures

Figure 1

Open AccessReview
The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart
J. Clin. Med. 2017, 6(5), 53; doi:10.3390/jcm6050053 -
Abstract
Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and
[...] Read more.
Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression. Full article
Figures

Open AccessFeature PaperReview
Hemophilia Care in the Pediatric Age
J. Clin. Med. 2017, 6(5), 54; doi:10.3390/jcm6050054 -
Abstract
Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should
[...] Read more.
Hemophilia is the most common of the severe bleeding disorders and if not properly managed since early infancy can lead to chronic disease and lifelong disabilities. However, it enjoys the most efficacious and safe treatment among the most prevalent monogenic disorders. Hemophilia should be considered in the neonatal period in the case of unusual bleeding or in the case of positive family history. Later, hemophilia should be suspected mainly in males because of abnormal bruising/bleeding or unusual bleeding following invasive procedures—for example, tonsillectomy or circumcision. Prophylactic treatment that is started early with clotting-factor concentrates has been shown to prevent hemophilic arthropathy and is, therefore, the gold standard of care for hemophilia A and B in most countries with adequate resources. Central venous access catheters and arterovenous fistulas play an important role in the management of hemophilia children requiring repeated and/or urgent administration of coagulation factor concentrates. During childhood and adolescence, personalized treatment strategies that suit the patient and his lifestyle are essential to ensure optimal outcomes. Physical activity is important and can contribute to better coordination, endurance, flexibility and strength. The present article focuses also on questions frequently posed to pediatric hematologists like vaccinations, day-care/school access and dental care. Full article
Open AccessFeature PaperReview
Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases
J. Clin. Med. 2017, 6(5), 52; doi:10.3390/jcm6050052 -
Abstract
Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on
[...] Read more.
Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment. Full article
Figures

Figure 1

Open AccessFeature PaperReview
Role of Autoantibodies in the Diagnosis of Connective-Tissue Disease ILD (CTD-ILD) and Interstitial Pneumonia with Autoimmune Features (IPAF)
J. Clin. Med. 2017, 6(5), 51; doi:10.3390/jcm6050051 -
Abstract
The diagnosis of interstitial lung disease (ILD) requires meticulous evaluation for an underlying connective tissue disease (CTD), with major implications for prognosis and management. CTD associated ILD (CTD-ILD) occurs most commonly in the context of an established CTD, but can be the first
[...] Read more.
The diagnosis of interstitial lung disease (ILD) requires meticulous evaluation for an underlying connective tissue disease (CTD), with major implications for prognosis and management. CTD associated ILD (CTD-ILD) occurs most commonly in the context of an established CTD, but can be the first and/or only manifestation of an occult CTD or occur in patients who have features suggestive of an autoimmune process, but not meeting diagnostic criteria for a defined CTD—recently defined as “interstitial pneumonia with autoimmune features” (IPAF). The detection of specific autoantibodies serves a critical role in the diagnosis of CTD-ILD, but there remains a lack of data to guide clinical practice including which autoantibodies should be tested on initial assessment and when or in whom serial testing should be performed. The implications of detecting autoantibodies in patients with IPAF on disease behaviour and management remain unknown. The evaluation of CTD-ILD is challenging due to the heterogeneity of presentations and types of CTD and ILD that may be encountered, and thus it is imperative that immunologic tests are interpreted in conjunction with a detailed rheumatologic history and examination and multidisciplinary collaboration between respiratory physicians, rheumatologists, immunologists, radiologists and pathologists. Full article
Figures

Figure 1

Open AccessReview
Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy
J. Clin. Med. 2017, 6(5), 50; doi:10.3390/jcm6050050 -
Abstract
Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol,
[...] Read more.
Technical advances in the ability to measure mitochondrial dysfunction are providing new insights into mitochondrial disease pathogenesis, along with new tools to objectively evaluate the clinical status of mitochondrial disease patients. Glutathione (l-ϒ-glutamyl-l-cysteinylglycine) is the most abundant intracellular thiol, and the intracellular redox state, as reflected by levels of oxidized (GSSG) and reduced (GSH) glutathione, as well as the GSH/GSSG ratio, is considered to be an important indication of cellular health. The ability to quantify mitochondrial dysfunction in an affected patient will not only help with routine care, but also improve rational clinical trial design aimed at developing new therapies. Indeed, because multiple disorders have been associated with either primary or secondary deficiency of the mitochondrial electron transport chain and redox imbalance, developing mitochondrial therapies that have the potential to improve the intracellular glutathione status has been a focus of several clinical trials over the past few years. This review will also discuss potential therapies to increase intracellular glutathione with a focus on EPI-743 (α-tocotrienol quinone), a compound that appears to have the ability to modulate the activity of oxidoreductases, in particular NAD(P)H:quinone oxidoreductase 1. Full article
Open AccessArticle
Serum Profiles of Cytokines in Behcet’s Disease
J. Clin. Med. 2017, 6(5), 49; doi:10.3390/jcm6050049 -
Abstract
Introduction: Behcet’s disease (BD) is a chronic systemic autoinflammatory vasculitis which is handled by the variety of proteins like cytokines. Therefore, cytokines are considered as one of the prototypic factors during inflammatory responses of BD. Consequently, the present study was designed for evaluation
[...] Read more.
Introduction: Behcet’s disease (BD) is a chronic systemic autoinflammatory vasculitis which is handled by the variety of proteins like cytokines. Therefore, cytokines are considered as one of the prototypic factors during inflammatory responses of BD. Consequently, the present study was designed for evaluation of cytokine profiles in Iranian BD cases, including those with and without uveitis. Materials and Method: All cases were divided into three groups based on ophthalmologic exam results: BD with uveitis, BD without uveitis, and recovered uveitis BD. Cases with a history of BD recovery were placed in the group of recovered uveitis. The patients with infectious uveitis as well as other collagen vascular diseases and patients who have used biologics to treat ocular immune-mediated diseases were excluded. Finally, after venous blood sampling, levels of cytokines were quantified and statistical approaches were performed for measurements. Results: Enrolled cases were divided to 26 patients with active uveitis, 25 patients with recovered uveitis and 24 patients without uveitis and interestingly, just IL-2 was the only cytokine that showed statistical difference in patients with BD uveitis in comparison with other groups (pvalue = 0.02). The pair wise comparison showed a significant difference between the patients with and without uveitis groups (pvalue = 0.004) as well as patients with uveitis and recovered uveitis groups (pvalue = 0.002). Discussion: Significant elevation of IL-2 in patients with uveitis (in comparison with recovered or without uveitis cases) demonstrates that it may be one of the main proteins that enroll in the pathophysiology of BD uveitis and may be considered as a new target for refractory disease therapies. Studies with larger samples can help to obtain more accurate conclusions. Full article
Open AccessReview
Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension
J. Clin. Med. 2017, 6(5), 48; doi:10.3390/jcm6050048 -
Abstract
Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor
[...] Read more.
Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor tyrosine kinase inhibitor) -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of pulmonary arterial hypertension (PAH) and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for the treatment of PAH. Full article
Figures

Figure 1

Open AccessArticle
Predictors of Active Extravasation and Complications after Conventional Angiography for Acute Intraabdominal Bleeding
J. Clin. Med. 2017, 6(4), 47; doi:10.3390/jcm6040047 -
Abstract
Conventional angiography is used to evaluate and treat possible sources of intraabdominal bleeding, though it may cause complications such as contrast-induced nephropathy (CIN). The study’s purpose was to identify factors predicting active extravasation and complications during angiography for acute intraabdominal bleeding. All conventional
[...] Read more.
Conventional angiography is used to evaluate and treat possible sources of intraabdominal bleeding, though it may cause complications such as contrast-induced nephropathy (CIN). The study’s purpose was to identify factors predicting active extravasation and complications during angiography for acute intraabdominal bleeding. All conventional angiograms for acute bleeding (January 2013–June 2015) were reviewed retrospectively, including 75 angiograms for intraabdominal bleeding in 70 patients. Demographics, comorbidities, vital signs, complications within one month, and change in hematocrit (ΔHct) and fluids and blood products administered over the 24 h prior to angiography were recorded. Of 75 exams, 20 (27%) demonstrated extravasation. ΔHct was the only independent predictor of extravasation (p = 0.017), with larger ΔHct (−17%) in patients with versus those without extravasation (–1%) (p = 0.01). CIN was the most common complication, occurring in 10 of 66 angiograms (15%). Glomerular filtration rate (GFR) was the only independent predictor (p = 0.03); 67% of patients with GFR < 30, 29% of patients with GFR 30–60, and 8% of patients with GFR > 60 developed CIN. For patients with intraabdominal bleeding, greater ΔHct decrease over 24 h before angiography predicts active extravasation. Pre-existing renal impairment predicts CIN. Patients with large hematocrit declines should be triaged for rapid angiography, though benefits can be weighed with the risk of renal impairment. Full article
Open AccessFeature PaperReview
Treatment and Prevention of Bleeds in Haemophilia Patients with Inhibitors to Factor VIII/IX
J. Clin. Med. 2017, 6(4), 46; doi:10.3390/jcm6040046 -
Abstract
The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients’ management challenging. Indeed,
[...] Read more.
The development of alloantibodies neutralising therapeutically administered factor (F) VIII/IX (inhibitors) is currently the most severe complication of the treatment of haemophilia. When persistent and at a high titre, inhibitors preclude the standard replacement treatment with FVIII/FIX concentrates, making patients’ management challenging. Indeed, the efficacy of bypassing agents, i.e., activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIIa), needed to overcome the haemostatic interference of the inhibitor, is not comparable to that of factor concentrates. In addition, the therapeutical response is unpredictable, with a relevant inter-individual and even intra-individual variability, and no laboratory assay is validated to monitor the efficacy and safety of the treatment. As a result, inhibitor patients have a worse joint status and quality of life compared to inhibitor-free subjects and the eradication of the inhibitor by immune tolerance induction is the preeminent therapeutic goal, particularly in children. However, over the last decades, treatment with bypassing agents has been optimised, allowing home treatment and the individualisation of regimens aimed at improving clinical outcomes. In this respect, a growing body of evidence supports the efficacy of prophylaxis with both bypassing agents in reducing bleeding rates and improving the quality of life, although the impact on long-term outcomes (in particular on preventing/reducing joint deterioration) is still unknown. This review offers an update on the current knowledge and practice of the use of bypassing agents in haemophiliacs with inhibitors, as well as on debated issues and unmet needs in this challenging setting. Full article
Figures

Open AccessFeature PaperReview
Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders
J. Clin. Med. 2017, 6(4), 45; doi:10.3390/jcm6040045 -
Abstract
Along with haemophilia A and B, von Willebrand disease (VWD) and rare bleeding disorders (RBDs) cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality
[...] Read more.
Along with haemophilia A and B, von Willebrand disease (VWD) and rare bleeding disorders (RBDs) cover all inherited bleeding disorders of coagulation. Bleeding tendency, which can range from extremely severe to mild, is the common symptom. VWD, due to a deficiency and/or abnormality of von Willebrand factor (VWF), represents the most frequent bleeding disorder, mostly inherited as an autosomal dominant trait. The diagnosis may be difficult, based on a bleeding history and different diagnostic assays, which evaluate the pleiotropic functions of VWF. Different treatment options are available for optimal management of bleeding and their prevention, and long-term outcomes are generally good. RBDs are autosomal recessive disorders caused by a deficiency of any other clotting factor, apart from factor XII, and cover roughly 5% of all bleeding disorders. The prevalence of the severe forms can range from 1 case in 500,000 up to 1 in 2–3 million, according to the defect. Diagnosis is based on bleeding history, coagulation screening tests and specific factor assays. A crucial problem in RBDs diagnosis is represented by the non-linear relationship between clinical bleeding severity and residual clotting levels; genetic diagnosis may help in understanding the phenotype. Replacement therapies are differently available for patients with RBDs, allowing the successful treatment of the vast majority of bleeding symptoms. Full article
Figures

Figure 1

Open AccessArticle
Hip Arthropathy in Haemophilia
J. Clin. Med. 2017, 6(4), 44; doi:10.3390/jcm6040044 -
Abstract
Hip arthropathy in haemophilic patients is disabling for hip and other common target joints. Even if bleedings in the hip are not frequent, femoroacetabular alterations may affect the functional ability of patients at a very young age. A haematologic prophylaxis combined with an
[...] Read more.
Hip arthropathy in haemophilic patients is disabling for hip and other common target joints. Even if bleedings in the hip are not frequent, femoroacetabular alterations may affect the functional ability of patients at a very young age. A haematologic prophylaxis combined with an adequate lifestyle and regular and low-traumatic physical activity are the keys to preventing such arthropathy. In the early stages of arthropathy, anti-inflammatory drugs and physical therapy may be sufficient to limit its progression. In cases of recurrent symptoms, viscosupplementation with hyaluronic acid, and chemical synoviorthesis are useful options. In more advanced stages, hip arthroscopy may be treated by synovectomy or loose body removal. For late stages, total hip arthroplasty (THA) is mandatory. Until a few decades ago, the clinical outcomes after hip arthroplasty were variable, due to the different management of patients and the use of old generation implants and couplings. In the last decade, the introduction of the multidisciplinary management and the use of modern cementless implants with high performing materials and less invasive surgical techniques have dramatically improved the functional results. Nowadays, as is the case for other target joints, the purpose of the management in haemophilia centers is the early detection of any hip alterations—by clinical and ultrasound (US) evaluations of patients in childhood—to reveal any early articular damage and to provide adequate treatment in case of symptoms. The present paper represents an updated review of the several approaches to hip arthropathy in haemophilia. Full article
Figures

Figure 1

Open AccessCase Report
Severe Adenoviral Pneumonia in an Immunocompetent Host with Persistent Fevers Treated with Multiple Empiric Antibiotics for Presumed Bacterial Co-Infection: An Antibiotic Stewardship Perspective on De-Escalation Derailed
J. Clin. Med. 2017, 6(4), 42; doi:10.3390/jcm6040042 -
Abstract
We present a case of severe adenoviral pneumonia in a 20-year-old immunocompetent host with persistently high fevers. The patient was needlessly given multiple empiric antibiotics for non-existent bacterial co-infection. This case has important antibiotic stewardship lessons for practitioners in approaching fevers in the
[...] Read more.
We present a case of severe adenoviral pneumonia in a 20-year-old immunocompetent host with persistently high fevers. The patient was needlessly given multiple empiric antibiotics for non-existent bacterial co-infection. This case has important antibiotic stewardship lessons for practitioners in approaching fevers in the ICU. Full article
Figures

Figure 1