Clinical pathologies draw us to envisage disease as either an independent entity or a diverse set of traits governed by common physiopathological mechanisms, prompted by environmental assaults throughout life. Autoimmune diseases are not an exception, given they represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. Although they are pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms, research generally focuses on a single disease. Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to decipher the nature of human biological systems. Once the currently costly omic-based technologies become universally accessible, the way will be paved for a cleaner picture to risk quantification, prevention, prognosis and diagnosis, allowing us to clearly define better phenotypes always ensuring the integrity of the individuals studied. However, making accurate predictions for most autoimmune diseases is an ambitious challenge, since the understanding of these pathologies is far from complete. Herein, some pitfalls and challenges of the genetics of autoimmune diseases are reviewed, and an approximation to the future of research in this field is presented.
Autoimmunity; Common; Genetics; Genomics; Personalized; Predictive medicine; Polyautoimmunity; Translational medicine
In this article, we give an overview of new technologies for the diagnosis of tuberculosis (TB) and drug resistance, consider their advantages over existing methodologies, broad issues of cost, cost-effectiveness and programmatic implementation, and their clinical as well as public health impact, focusing on the industrialized world. Molecular nucleic-acid amplification diagnostic systems have high specificity for TB diagnosis (and rifampicin resistance) but sensitivity for TB detection is more variable. Nevertheless, it is possible to diagnose TB and rifampicin resistance within a day and commercial automated systems make this possible with minimal training. Although studies are limited, these systems appear to be cost-effective. Most of these tools are of value clinically and for public health use. For example, whole genome sequencing of Mycobacterium tuberculosis offers a powerful new approach to the identification of drug resistance and to map transmission at a community and population level.
Diagnosis; Drug resistance; Tuberculosis; Public health; Whole genome sequencing
Following US Food and Drugs Administration approval in July 2012 of daily oral tenofovir and emtricitabine for pre-exposure prophylaxis (PrEP) to prevent HIV infection in high-risk individuals in the USA, there has been much controversy about the implementation of this PrEP regimen in other countries throughout the world, and in Europe in particular. In this review, we focus on the challenges and opportunities of a daily oral PrEP regimen to curb the rising incidence of HIV infection in high-risk groups, and particularly in men who have sex with men. A number of issues would need to be addressed before PrEP could be implemented, including assessing the real effectiveness and cost-effectiveness of daily PrEP, the sustainability of daily adherence, the risk of selecting resistance, the long-term safety, and the risk of change in sexual behavior that might offset the benefit of PrEP. Alternatives to a daily oral PrEP regimen are being explored.
HIV; Tenofovir; Emtricitabine; Men who have sex with men; Intermittent; PrEP; Adherence
Despite its high incidence and devastating outcomes, acute respiratory distress syndrome (ARDS) has no specific treatment, with effective therapy currently limited to minimizing potentially harmful ventilation and avoiding a positive fluid balance. Many pharmacological therapies have been investigated with limited success to date. In this review article we provide a state-of-the-art update on recent and ongoing trials, as well as reviewing promising future pharmacological therapies in ARDS.
Acute lung injury; Acute respiratory distress syndrome
Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.
Chronic obstructive pulmonary disease (COPD); Exacerbations; Frequent exacerbator phenotype; Comorbidities
Considerable variety in how patients respond to treatments, driven by differences in their geno- and/ or phenotypes, calls for a more tailored approach. This is already happening, and will accelerate with developments in personalized medicine. However, its promise has not always translated into improvements in patient care due to the complexities involved. There are also concerns that advice for tests has been reversed, current tests can be costly, there is fragmentation of funding of care, and companies may seek high prices for new targeted drugs. There is a need to integrate current knowledge from a payer’s perspective to provide future guidance. Multiple findings including general considerations; influence of pharmacogenomics on response and toxicity of drug therapies; value of biomarker tests; limitations and costs of tests; and potentially high acquisition costs of new targeted therapies help to give guidance on potential ways forward for all stakeholder groups. Overall, personalized medicine has the potential to revolutionize care. However, current challenges and concerns need to be addressed to enhance its uptake and funding to benefit patients.
Biomarkers; Drug development; Genomics; Genotyping; Healthcare policy; Pharmacogenetics precision medicine; Personalized medicine; Health authorities; Rational use of medicines; Reimbursement; Targeted treatments
Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting.
Biomarker; Diagnostics; Early detection; Epigenetics; Genetics; Lung cancer; Screening; Transcriptomics
The extra-cranial venous system is complex and not well studied in comparison to the peripheral venous system. A newly proposed vascular condition, named chronic cerebrospinal venous insufficiency (CCSVI), described initially in patients with multiple sclerosis (MS) has triggered intense interest in better understanding of the role of extra-cranial venous anomalies and developmental variants. So far, there is no established diagnostic imaging modality, non-invasive or invasive, that can serve as the “gold standard” for detection of these venous anomalies. However, consensus guidelines and standardized imaging protocols are emerging. Most likely, a multimodal imaging approach will ultimately be the most comprehensive means for screening, diagnostic and monitoring purposes. Further research is needed to determine the spectrum of extra-cranial venous pathology and to compare the imaging findings with pathological examinations. The ability to define and reliably detect noninvasively these anomalies is an essential step toward establishing their incidence and prevalence. The role for these anomalies in causing significant hemodynamic consequences for the intra-cranial venous drainage in MS patients and other neurologic disorders, and in aging, remains unproven.
Multiple Sclerosis; CCSVI; Jugular Vein Reflux; Doppler Sonography; Magnetic Resonance Venography; Computed Tomography Venography; Catheter Venography; Intravascular Ultrasound; Plethismography; Multimodal Imaging
Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition.
Embryo Selection; Epidemiology; Genetics; Immunology; Miscarriage; Recurrent Miscarriage; Sperm DNA Integrity
Sexual development in humans is only partly understood at the molecular level. It is dependent on genetic control primarily induced by the sex chromosomal differences between males and females. This leads to the development of the gonads, whereby afterwards the differentiation of the apparent phenotype is controlled by hormone action. Sex steroids may exert permanent and temporary effects. Their organizational features of inducing permanent changes in phenotype occur through genetic control of downstream genes. In this, androgens are the key elements for the differentiation of male internal and external genitalia as well as other sexual organs and general body composition, acting through a single androgen receptor. The androgen receptor is a nuclear transcription factor modulating DNA transcription of respective target genes and thereby driving development and growth in a stringent manner. The specificity of androgen action seems to be a strictly time-controlled process with the androgen receptor acting in concert with different metabolites and an array of cofactors modulating the cellular response and thereby permanently altering the phenotype of any given individual. For every cell programmed by androgens, a specific ‘androgen response index’ must be proposed.
Androgen insensitivity; Androgen receptor; Androgens; Disorders of sex development; Genetics; Sex development
More women die from breast cancer across the world today than from any other type of malignancy. The clinical course of breast cancer varies tremendously between patients. While some of this variability is explained by traditional clinico-pathological factors (including patient age, tumor stage, histological grade and estrogen receptor status), molecular profiling studies have defined breast cancer subtypes with distinct clinical outcomes. This mini-review considers recent studies which have used genomics technologies in an attempt to identify new biomarkers of prognosis and treatment response. These studies highlight the genetic heterogeneity that exists within breast cancers in space and time.
Breast cancer; Next-generation sequencing; Whole-genome sequencing; Molecular profiling; Personalized medicine; Heterogeneity
Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer.
Genetic models; Genetic polymorphisms; Genetic prognostic factors; Genotypes; Prognostic research; Tumor DNA
Asthma is characterized by both chronic inflammation and airway remodeling. Remodeling - the structural changes seen in asthmatic airways - is pivotal in the pathogenesis of the disease. Although significant advances have been made recently in understanding the different aspects of airway remodeling, the exact biology governing these changes remains poorly understood. There is broad agreement that, in asthma, increased airway smooth muscle mass, in part due to smooth muscle hyperplasia, is a very significant component of airway remodeling. However, significant debate persists on the origins of these airway smooth muscle cells. In this review article we will explore the natural history of airway remodeling in asthma and we will discuss the possible contribution of progenitors, stem cells and epithelial cells in mesenchymal cell changes, namely airway smooth muscle hyperplasia seen in the asthmatic airways.
Airway remodeling; Airway smooth muscle; Asthma; Fibrocytes; Mesenchymal stem cells
The coronary arteries have been regarded as end arteries for decades. However, there are functionally relevant anastomotic vessels, known as collateral arteries, which interconnect epicardial coronary arteries. These vessels provide an alternative source of blood supply to the myocardium in cases of occlusive coronary artery disease. The relevance of these collateral arteries is a matter of ongoing debate, but increasing evidence indicates a relevant protective role in patients with coronary artery disease. The collateral circulation can be assessed by different methods; the gold standard involves intracoronary pressure measurements. While the first clinical trials to therapeutically induce growth of collateral arteries have been unavailing, recent pilot studies using external counterpulsation or growth factors such as granulocyte colony stimulating factor (G-CSF) have shown promising results.
Angiogenesis; Arteriogenesis; Coronary artery disease; Coronary collateral circulation
Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.
CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.
Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.
CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear.
Venous hypertension; CCSVI; Multiple sclerosis; Leukoaraiosis; Normal-pressure hydrocephalus; Cerebral blood flow; Cerebrospinal fluid
The central theme of personalized medicine is the premise that an individual’s unique physiologic characteristics play a significant role in both disease vulnerability and in response to specific therapies. The major goals of personalized medicine are therefore to predict an individual’s susceptibility to developing an illness, achieve accurate diagnosis, and optimize the most efficient and favorable response to treatment. The goal of achieving personalized medicine in psychiatry is a laudable one, because its attainment should be associated with a marked reduction in morbidity and mortality. In this review, we summarize an illustrative selection of studies that are laying the foundation towards personalizing medicine in major depressive disorder, bipolar disorder, and schizophrenia. In addition, we present emerging applications that are likely to advance personalized medicine in psychiatry, with an emphasis on novel biomarkers and neuroimaging.
Major depressive disorder; Schizophrenia; Personalized medicine; Psychiatric hereditability; Epigenetics; Environmental factors; Endophenotypes; Pharmacogenomics; Neuroimaging genetics
Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline.
Depression; Metabolic syndrome; Inflammation; Cortisol; Autonomic Tone; Cardiovascular; Obesity; Symptom profile; Treatment
A precise understanding of the genomic and epigenomic features of chronic lymphocytic leukemia (CLL) may benefit the study of the disease’s staging and treatment. While recent reports have shed some light on these aspects, several challenges need to be addressed before translating this research into clinical practice. Thus, even the best candidate driver genes display low mutational rates compared to other tumors. This means that a large percentage of cases do not display clear tumor-driving point mutations, or show candidate driving point mutations with no obvious biochemical relationship to the more frequently mutated genes. This genomic landscape probably reflects either an unknown underlying biochemical mechanism playing a key role in CLL or multiple biochemical pathways independently driving the development of this tumor. The elucidation of either scenario will have important consequences on the clinical management of CLL. Herein, we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterize the underlying biochemical events that drive this disease.
Chronic lymphocytic leukemia; Genomics; Epigenomics; Driver mutations; Personalized medicine
Conventional immunosuppressive therapies have radically transformed patient survival in systemic lupus erythematosus (SLE), but their use is associated with considerable toxicity and a substantial proportion of patients remain refractory to treatment. A more comprehensive understanding of the complexity of SLE immunopathogenesis has evolved over the past decade and has led to the testing of several biologic agents in clinical trials. There is a clear need for new therapeutic agents that overcome these issues, and biologic agents offer exciting prospects as future SLE therapies.
An array of promising new therapies are currently emerging or are under development including B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonal antibodies against interleukin-6 and interferon-α.
Lupus nephritis; B-cell depletion; BLys; T-cell co-stimulation; Interferon-α, SLE
Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic inflammatory condition with immune competent cells in lesions producing mainly pro-inflammatory cytokines. Dead cells and oxidized forms of low density lipoproteins (oxLDL) are abundant. The major direct cause of CVD appears to be rupture of atherosclerotic plaques. oxLDL has proinflammatory and immune-stimulatory properties, causes cell death at higher concentrations and contains inflammatory phospholipids with phosphorylcholine (PC) as an interesting epitope. Antibodies against PC (anti-PC) may be atheroprotective, one mechanism being anti-inflammatory. Bacteria and virus have been discussed, but it has been difficult to find direct evidence, and antibiotic trials have not been successful. Heat shock proteins could be one major target for atherogenic immune reactions. More direct causes of plaque rupture include pro-inflammatory cytokines, chemokines, and lipid mediators. To prove that inflammation is a cause of atherosclerosis and CVD, clinical studies with anti-inflammatory and/or immune-modulatory treatment are needed. The potential causes of immune reactions and inflammation in atherosclerosis and how inflammation can be targeted therapeutically to provide novel treatments for CVD are reviewed.
Immunity; Atherosclerosis; Cardiovascular disease; Phosholipids; Natural antibodies; T-cells; B-cells; Inflammation
The purpose of this article is to review the imaging techniques that have changed and are anticipated to change bladder cancer evaluation. The use of multidetector 64-slice computed tomography (CT) and magnetic resonance imaging (MRI) remain standard staging modalities. The development of functional imaging such as dynamic contrast-enhanced MRI, diffusion-weighted MRI and positron emission tomography (PET)-CT allows characterization of tumor physiology and potential genotypic activity, to help stratify and inform future patient management. They open up the possibility of tumor mapping and individualized treatment solutions, permitting early identification of response and allowing timely change in treatment. Further validation of these methods is required however, and at present they are used in conjunction with, rather than as an alternative to, conventional imaging techniques.
Bladder cancer; Diffusion-weighted MRI; Multidetector computed tomography; PET-CT; Staging; Ultrasound; Virtual cystoscopy
Advancements in phosphodiesterase (PDE)-targeted therapies have shown promise in recent years for treating patients with a variety of autoimmune diseases. This review summarizes the development of PDE4 inhibitors and the associated literature with a focus on treatments for autoimmune diseases. After the initial investigations of the prototypic PDE inhibitor, rolipram, more selective inhibitors targeting the PDE4 isozyme have been developed. With phase II and phase III clinical trials currently underway to evaluate the safety and efficacy of the latest generation of PDE4 inhibitors, namely apremilast, a new class of treatments may be around the corner for patients suffering from chronic, autoimmune diseases.
Autoimmune; Apremilast; Crohn’s; Dermatitis; PDE4; Psoriasis; SLE
Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that.
In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA.
In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions.
Renal involvement; Connective tissue diseases; Sjögren syndrome; Scleroderma renal crisis, Dermatomyositis/polymyositis; Systemic lupus erythematosus; Antiphospholipid syndrome; Rheumatoid arthritis