Marfan Syndrome

Congenital Abdominal Aortic Aneurysm: Presentation, Etiology, Diagnosis and Management

Aortic aneurysms are common in adults due to atherosclerosis but are rare in children and young adults, often overlooked due to infrequent reporting. Acquired aneurysms are usually linked to factors like umbilical artery ligation, connective tissue diseases, or vasculitides. In contrast, the causes of congenital abdominal aortic aneurysms (AAA) remain unknown due to their extreme rarity. Only a few cases have been reported. Prompt diagnosis is essential when symptoms such as abdominal distention, vomiting, or abdominal pulsatility occur. Diagnosis is typically confirmed through ultrasonography and multi-slice spiral computed tomography angiographies (MCSTA). After detection, a comprehensive investigation is necessary to rule out acquired AAA causes. Managing congenital AAA requires a highly personalized approach, with early surgical repair using grafts as a recommended option. After an extensive analysis of numerous academic sources, we have comprehensively understood the epidemiology, clinical features, and diagnostic and treatment techniques for congenital abdominal aortic aneurysms.

Human DNA Mutations and their Impact on Genetic Disorders

DNA is a remarkably precise medium for copying and storing biological information. It serves as a design for cellular machinery that permits cells, organs, and even whole organisms to work. The fidelity of DNA replication results from the action of hundreds of genes involved in proofreading and damage repair. All human cells can acquire genetic changes in their DNA all over life. Genetic mutations are changes to the DNA sequence that happen during cell division when the cells make copies of themselves. Mutations in the DNA can cause genetic illnesses such as cancer, or they could help humans better adapt to their environment over time. The endogenous reactive metabolites, therapeutic medicines, and an excess of environmental mutagens, such as UV rays all continuously damage DNA, compromising its integrity. One or more chromosomal alterations and point mutations at a single site (monogenic mutation) including deletions, duplications, and inversions illustrate such DNA mutations. Genetic conditions can occur when an altered gene is inherited from parents, which increases the risk of developing that particular condition, or some gene alterations can happen randomly. Moreover, symptoms of genetic conditions depend on which gene has a mutation. There are many different diseases and conditions caused by mutations. Some of the most common genetic conditions are Alzheimer’s disease, some cancers, cystic fibrosis, Down syndrome, and sickle cell disease. Interestingly, scientists find that DNA mutations are more common than formerly thought. This review outlines the main DNA mutations that occur along the human genome and their influence on human health. The subject of patents pertaining to DNA mutations and genetic disorders has been brought up.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Promising Marine Natural Products for Tackling Viral Outbreaks: A Focus on Possible Targets and Structure-activity Relationship

Recently, people worldwide have experienced several outbreaks caused by viruses that have attracted much interest globally, such as HIV, Zika, Ebola, and the one being faced, SARSCoV- 2 viruses. Unfortunately, the availability of drugs giving satisfying outcomes in curing those diseases is limited. Therefore, it is necessary to dig deeper to provide compounds that can tackle the causative viruses. Meanwhile, the efforts to explore marine natural products have been gaining great interest as the products have consistently shown several promising biological activities, including antiviral activity. This review summarizes some products extracted from marine organisms, such as seaweeds, seagrasses, sponges, and marine bacteria, reported in recent years to have potential antiviral activities tested through several methods. The mechanisms by which those compounds exert their antiviral effects are also described here, with several main mechanisms closely associated with the ability of the products to block the entry of the viruses into the host cells, inhibiting replication or transcription of the viral genetic material, and disturbing the assembly of viral components. In addition, the structure-activity relationship of the compounds is also highlighted by focusing on six groups of marine compounds, namely sulfated polysaccharides, phlorotannins, terpenoids, lectins, alkaloids, and flavonoids. In conclusion, due to their uniqueness compared to substances extracted from terrestrial sources, marine organisms provide abundant products having promising activities as antiviral agents that can be explored to tackle virus-caused outbreaks.

Microhomology-Mediated Break-Induced Replication: A Possible Molecular Mechanism of the Formation of a Large CNV in FBN1 Gene in a Patient with Marfan Syndrome

Background: Marfan syndrome (MFS) is an autosomal dominant multisystem disorder caused by mutations in the fibrillin-1 gene (FBN1). A small portion of them is copy number variations (CNVs), which can occur through recombination-based, replication-based mechanisms or retrotransposition. Not many have been characterized precisely in MFS.

Methods: A female patient with suspected Marfan syndrome was referred for genetic testing at our institute. After systematic sequencing of FBN1, TGFBR1, and TGFBR2 genes, multiplex ligation-dependent probe amplification was applied. Long-range PCR, subsequent Sanger sequencing with designed primers, and preliminary in silico analysis were applied for the precise characterization of the breakpoints.

Results: Primary analysis displayed a de novo large deletion affecting exons 46 and 47 in the FBN1 gene, which resulted in the loss of the 31st and 32^nd calcium-binding EGFlike domains. Further examination of the breakpoints showed a 4916 nucleotide long deletion localized in intronic regions. Surprisingly a ‘TG’ dinucleotide insertion was detected at the junction. We hypothesize that the CNV formation was generated by a rare event based on the known microhomology-mediated break-induced replication (MMBIR).

Conclusion: An increasing number of CNVs are associated with Mendelian diseases and other traits. Approximately 2-7% of the cases in MFS are caused by CNVs. Up to date, hardly any model was proposed to demonstrate the formation of these genomic rearrangements in the FBN1 gene. Hereby, with the help of previous models and breakpoint analysis, we presented a potential mechanism (based on MMBIR) in the formation of this large deletion.

Mitral Valve Prolapse and Sudden Cardiac Death in Athletes at High Risk

Mitral valve prolapse (MVP) is the most frequent valvulopathy in the general population, with usually a favourable prognosis. Although it can be associated with some complications, ventricular arrhythmias (VA) and sudden cardiac death (SCD) are the most worrying. The estimated risk of SCD in MVP is between 0.2% to 1.9% per year, including MVP patients with and without severe mitral regurgitation (MR). The association between SCD and MVP is expressed by a phenotype called “malignant MVP” characterized by transthoracic echocardiography (TTE) findings such as bileaflet myxomatous prolapse and mitral annulus disjunction (MAD), ECG findings such as repolarization abnormalities, complex ventricular arrhythmias (c-VAs) and LV fibrosis of papillary muscles (PMs) and inferobasal wall visualized by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Therefore, attention is raised for patients with “arrhythmic MVP” characterized from an ECG point of view by frequent premature ventricular contractions (PVCs) arising from one or both PMs as well as by T-wave inversion in the inferolateral leads. In athletes, SCD is the most frequent medical cause of death and in young subjects (< 35 years) usually is due to electrical mechanism affecting who has a silent cardiovascular disease and are not considered per se a cause of increased mortality. In MVP, SCD was reported to happen during sports activity or immediately after and valve prolapse was the only pathological aspect detected.

The aim of the present paper is to explore the association between SCD and MVP in athletes, focusing attention on ECG, TTE in particular, and CMR findings that could help to identify subjects at high risk for complex arrhythmias and eventually SCD. In addition, it is also examined if sports activity might predispose patients with MVP to develop major arrhythmias.

Big Data for Treatment Planning: Pathways and Possibilities for Smart Healthcare Systems

Background: Treatment planning is one of the crucial stages of healthcare assessment and delivery. Moreover, it also has a significant impact on patient outcomes and system efficiency. With the evolution of transformative healthcare technologies, most areas of healthcare have started collecting data at different levels, as a result of which there is a splurge in the size and complexity of health data being generated every minute.

Introduction: This paper explores the different characteristics of health data with respect to big data. Besides this, it also classifies research efforts in treatment planning on the basis of the informatics domain being used, which includes medical informatics, imaging informatics and translational bioinformatics.

Methods: This is a survey paper that reviews existing literature on the use of big data technologies for treatment planning in the healthcare ecosystem. Therefore, a qualitative research methodology was adopted for this work.

Results: Review of existing literature has been analyzed to identify potential gaps in research, identifying and providing insights into high prospect areas for potential future research.

Conclusion: The use of big data for treatment planning is rapidly evolving, and findings of this research can head start and streamline specific research pathways in the field.

Acanthosis Nigricans: An Updated Review

Background: Early recognition of acanthosis nigricans is important because acanthosis nigricans can be a cutaneous manifestation of a variety of systemic disorders and, rarely, as a sign of internal malignancy.

Objective: The purpose of this article is to familiarize pediatricians with the clinical manifestations, evaluation, diagnosis, and management of acanthosis nigricans.

Methods: A search was conducted in November 2021in PubMed Clinical Queries using the key term \"acanthosis nigricans\". The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article.

Results: Acanthosis nigricans is characterized by symmetric, hyperpigmented, and velvety plaques with ill-defined borders, typically involving intertriginous areas. Obesity is the most common cause of acanthosis nigricans which is increasingly observed in obese children and adolescents and can serve as a cutaneous marker of insulin resistance. Early recognition of acanthosis nigricans is important because acanthosis nigricans can also be a cutaneous manifestation of a variety of systemic disorders and, rarely, as a sign of internal malignancy. This may consist of weight reduction, discontinuation of causative drugs, treatment of underlying endocrinopathy, or treatment of an underlying malignancy. For patients with isolated acanthosis nigricans and for those whose underlying cause is not amenable to treatment, treatment of the lesion may be considered for cosmetic reasons. Topical retinoids, vitamin D analogs, chemical peels, and other keratolytics are often used for the treatment of localized lesions. Seldom, systemic therapy such as oral retinoids may be considered for extensive or generalized acanthosis nigricans and acanthosis nigricans unresponsive to topical therapy. Other uncommon treatment modalities include dermabrasion, laser therapy, and surgical removal.

Conclusion: Although acanthosis nigricans is treatable, a complete cure is difficult to achieve. The underlying cause should be treated, if possible, to resolve and prevent the recurrence of acanthosis nigricans. The diagnosis is mainly clinical, based on the characteristic appearance (symmetrically distributed, hyperpigmented, velvety, papillomatous, hyperkeratotic plaques with ill-defined borders) and the typical sites (intertriginous areas, flexural area, and skin folds) of the lesions. The diagnosis might be difficult for lesions that have atypical morphology or are in an unusual location. Clinicians should be familiar with the clinical signs, evaluation, diagnosis, and therapy of acanthosis nigricans because of the link between it and underlying diseases.

MicroRNAs as Biomarkers for Birth Defects

It is estimated that 2-4% of live births will have a birth defect (BD). The availability of biomarkers for the prenatal detection of BDs will facilitate early risk assessment, prompt medical intervention and ameliorating disease severity. miRNA expression levels are often found to be altered in many diseases. There is, thus, a growing interest in determining whether miRNAs, particularly extracellular miRNAs, can predict, diagnose, or monitor BDs. These miRNAs, typically encapsulated in exosomes, are released by cells (including those of the fetus and placenta) into the extracellular milieu, such as blood, urine, saliva and cerebrospinal fluid, thereby enabling interaction with target cells. Exosomal miRNAs are stable, protected from degradation, and retain functionality. The observation that placental and fetal miRNAs can be detected in maternal serum, provides a strong rationale for adopting miRNAs as noninvasive prenatal biomarkers for BDs. In this mini-review, we examine the current state of research involving the use of miRNAs as prognostic and diagnostic biomarkers for BD.

Pediatrics for Disability: A Comprehensive Approach to Children with Syndromic Psychomotor Delay

Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that occurs in the pediatric age and is also described by the term “mental retardation”. Intellectual disability occurs in 3-28 % of the general population due to a genetic cause, including chromosome aberrations. Among people with intellectual disabilities, the cause of the disability was identified as a single gene disorder in up to 12 %, multifactorial disorders in up to 4 %, and genetic disorders in up to 8.5 %. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. A multidisciplinary team is essential to manage the patient, thereby controlling the complications of the syndrome and promoting the correct psychophysical development. This requires continuous follow-up of these children by the pediatrician, which is essential for both the clinical management of the syndrome and facilitating the social integration of these children.

Cardiovascular Diseases in Pregnancy - A Brief Overview

Even though, there have been many advances in maternal medical care and fertility treatments, the presence of cardiovascular disease has a significant impact on pregnancy. In pregnant women, several heart conditions, such as valvular heart disease, chronic hypertension, congenital heart defects and non-ischemic cardiomyopathies are linked to increased risk of fetal as well as maternal morbidity and mortality. To date, the management of the co-existing conditions of pregnancy and heart disease has been challenging. Therefore, in-depth information may be beneficial to tackle a difficult case scenario. Towards this end, this paper provides an overview of the recent updated knowledge of pregnancy-related cardiovascular diseases in women.

Drug Repositioning: A Unique Approach to Refurbish Drug Discovery

For a decade, it has been observed that there is a remarkable decrease in the quantum of novel clinically approved drugs, in spite of modernization in the research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions, which still need exploration for getting over the shortage of novel drugs reaching the market. This review focuses on an activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis that a single drug interacts with multiple targets. It also includes current research trends related to drug repositioning, which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights the importance of computational tools and databases of various forms for drug repositioning purposes, which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro, or animal models do not confirm in subsequent clinical trials. Hence, considering the positive outcomes of drug repositioning, it can be surmised that this approach can serve as a promising one that can develop into a robust drug discovery strategy.

Identification of Disease-specific Single Amino Acid Polymorphisms Using a Simple Random Forest at Protein-level

Background: The number of human genetic variants deposited into publicly available databases has been increasing exponentially. Among these variants, non-synonymous single nucleotide polymorphisms (nsSNPs), also known as single Amino Acid Polymorphisms (SAPs), have been demonstrated to be strongly correlated with phenotypic variations of traits/diseases.

Objective: However, the detailed mechanisms governing the disease association of SAPs remain unclear. Thus, further investigation of new attributes and improvement of the prediction becomes more and more urgent since amount of unknown disease-related SAPs need to be investigated.

Methods: Based on the principle of Random Forest (RF), we firstly constructed a new effective prediction model for SAPs associated with a particular disease from protein sequences. Four usual sequence signature extractions were separately performed to select the optimal features. Then SAP peptide lengths from 12 to 202 were also optimized.

Results: The optimal models achieve higher than 90% accuracy and Area Under the Curve (AUC) of over 0.9 on all 11 external testing datasets. Finally, the good performance on an independent test set with an accuracy higher than 95% proves the superiority of our method.

Conclusion: In this paper, based on Random Forest (RF), we constructed 11 disease-association prediction models for SAPs from the protein sequence level. All models yield prediction accuracy higher than 90% and Area Under the Curve (AUC) more than 0.9. Our method only using the information of protein sequences are more universal than those that depend on some additional information or predictions about the proteins.

Association of Viruses in the Development of Cardiovascular Diseases

Cardiovascular diseases (CVD), primarily inflammatory cardiomyopathy, are characterized by the infiltration of inflammatory cells into the myocardium. It has a relatively high risk of deteriorating heart function and has heterogeneous etiologies. Inflammatory cardiomyopathy is mainly mediated by viral infections but can also be mediated by protozoa, fungal or bacterial infections. Besides that, there are a wide variety of drugs, toxic substances, and systemic immune-mediated diseases that result in the development of cardiovascular diseases (CVDs). Despite broad research, inflammatory cardiomyopathy has a poor prognosis. The roles of the pathogens, host genomic counterparts and environmental triggers in the progression of disease are still under consideration, including the role of some viruses as active inducers and others as bystanders. In this review article, we review the available evidence on the types, pathogenesis and treatment of myocarditis, inflammatory cardiomyopathy, and atherosclerosis with a particular focus on virus-associated cardiac diseases.

Aortic Dissection: A Review of the Pathophysiology, Management and Prospective Advances

Aortic dissection is an emergent medical condition, generally affecting the elderly, characterized by a separation of the aortic wall layers and subsequent creation of a pseudolumen that may compress the true aortic lumen. Predisposing factors mediate their risk by either increasing tension on the wall or by causing structural degeneration. They include hypertension, atherosclerosis, and a number of connective tissue diseases. If it goes undetected, aortic dissection carries a significant mortality risk; therefore, a high degree of clinical suspicion and a prompt diagnosis are required to maximize survival chances. Imaging methods, most commonly a CT scan, are essential for diagnosis; however, several studies have also investigated the effect of several biomarkers to aid in the detection of the condition. The choice of intervention varies depending on the type of dissection, with open surgical repair remaining of choice in those with type. In dissections, however, the role of conventional open surgery has considerably diminished in complicated type B dissections, with endovascular repair, a much less invasive technique, proving to be more effective. In uncomplicated type B dissections, where medical choice reigned supreme as the optimal intervention, endovascular repair is being explored as a viable option which may reduce long- term mortality outcomes, although the ideal intervention in this situation is far from settled.

Infection, Infectious Agents and Vascular Disease

Background: Infectious agents may be involved in the pathogenesis of vascular disease and related complications. The aim of this review is to analyze the most relevant information on the common infections related to vascular disease, discussing the main pathophysiological mechanisms.

Methods: In the current review, the most important evidence on the issue of infections and vascular disease is searched on Medline, Scopus, and ScienceDirect database.

Results: Among infectious agents, herpesviruses, parvovirus B19, hepatitis viruses, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, treponema pallidum, mycobacterium tuberculosis, pseudomonas aeruginosa, staphylococcus aureus, and candida albicans seem to particularly related to vascular disease.

Conclusion: Infectious agents may affect vessel’s homeostasis and functionality, both on the arterial and venous side, by means of several pathophysiological mechanisms such as dysregulation in vasomotor function, thromboembolic complications, initiation and progression of atherosclerosis, alteration of perivascular adipose tissue, recruiting inflammatory cells and molecules.

Significance of Hemodynamics Biomarkers, Tissue Biomechanics and Numerical Simulations in the Pathogenesis of Ascending Thoracic Aortic Aneurysms

Guidelines for the treatment of aortic wall diseases are based on measurements of maximum aortic diameter. However, aortic rupture or dissections do occur for small aortic diameters. Growing scientific evidence underlines the importance of biomechanics and hemodynamics in aortic disease development and progression. Wall shear stress (WWS) is an important hemodynamics marker that depends on aortic wall morphology and on the aortic valve function. WSS could be helpful to interpret aortic wall remodeling and define personalized risk criteria. The complementarity of Computational Fluid Dynamics and 4D Magnetic Resonance Imaging as tools for WSS assessment is a promising reality. The potentiality of these innovative technologies will provide maps or atlases of hemodynamics biomarkers to predict aortic tissue dysfunction. Ongoing efforts should focus on the correlation between these non-invasive imaging biomarkers and clinico-pathologic situations for the implementation of personalized medicine in current clinical practice.

A Review of Selected Adult Congenital Heart Diseases Encountered in Daily Practice

The advancement in corrective surgical procedures and anaesthesia technology has resulted in the increased survival of patients with Congenital Heart Diseases (CHD). Most of the surviving CHD patients have successfully reached adulthood and those surviving adults now outnumber the infants born with the CHD. Unfortunately, the surviving adults with CHD do not get proper care due to either inconsistent follow-up or not getting care from a specialist in the field of CHD. It is imperative for general practicing clinicians to be aware of the congenital diseases as well as the current clinical recommendations. This manuscript reviews some of the common congenital diseases seen in adults such as cardiac shunts, left heart obstructive lesions, and aortopathies.

Molecular Diagnosis and Treatment of Multiple Endocrine Neoplasia Type 2B in Ethnic Han Chinese

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed.

Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported.

Results: All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B.

Discussion & Conclusion: The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis.

Management and Outcomes of Aortic Dissection in Pregnancy with Marfan Syndrome: A Systematic Review

Background: In Marfan Syndrome (MFS), aortic dilatation is one of the main cardiovascular manifestations which deteriorate due to the physiological changes during pregnancy. We aimed to assess the up-to-date management and outcomes of aortic root dilation and dissection (AoD) in pregnancy with MFS.

Patients and Methods: A systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Original studies published between January 1, 2001 and December 31, 2018 and which described the management and/or outcomes of AoD during or after pregnancy in women with MFS were included. Literature searches were conducted. The PubMed search was performed using terms "Marfan Syndrome" [Mesh] and "Pregnancy" [Mesh] whereas the Google Scholar search was for “Marfan” and “Pregnancy”, all words anywhere in the article.

Results: The literature search yielded 177 articles on PubMed and 13,900 articles on Google Scholar. Assessment of full-text articles for eligibility after removal of duplicates from both databases yielded 12 eligible studies to be included in the final review.

Conclusion: Women with MFS are at high risk of aortic dissection during pregnancy and women with aortic root 41-45 mm should consider avoiding pregnancy. Guideline-specific management of aortic aneurysms in pregnancy will reduce the risk of dissection. Diagnosis and Management of MFS need a multidisciplinary approach and team that should start working early in pregnancy. Further studies are needed to optimize medical and surgical approaches in addition to preconception counselling in highrisk subjects.

Volume Measurement in the Diagnosis of Mounier Kuhn Syndrome and an Unknown Accompanying Pathology: Pulmonary Artery Enlargement

Background: Mounier Kuhn Syndrome (MKS) is a rare congenital anomaly characterized by abnormal dilatation of the trachea and main bronchi. The aim of this study is to discuss tracheal volume measurement in MKS, and the pathologies accompanying MKS, especially pulmonary artery enlargement.

Materials and Methods: 38 patients, 18 of whom were diagnosed with MKS and 20 as control group, were included in the study. Trachea volume and pulmonary artery diameter were measured through thorax-computed tomography (CT) images of the patients. Accompanying pathologies were recorded.

Results: In the measurements done through the CT scans, the trachea volume was found to be 25.45 cm3 in the control group and 44.17 cm3 in the patient group. The most frequent accompanying pathologies were tracheal diverticulum, bronchiectasis and pulmonary artery enlargement.

Conclusion: In patients with MKS, there is a significant difference in volume calculation as in trachea diameter. Though bronchiectasis and tracheal diverticulum are known as pathologies most frequently accompanying MKS, to the knowledge of the researchers, pulmonary artery enlargement due to the increase in pulmonary truncus diameter was first emphasized in this article.

Role of Azoles in Cancer Prevention and Treatment: Present and Future Perspectives

Background: Cancer has gradually become one of the leading causes of death worldwide. The incidence of cancer among the population has increased alarmingly over the last two decades, primarily due to an increasing population of immune-compromised patients and the continuing rise in anti-cancer drug resistance. Azole found privileged structure in medicinal chemistry and pharmaceutical industry and also found to be showing antioxidant; antimicrobial, anthelmintic, anticancer, antiviral, anti-parasitic, anti-inflammatory, anti-HIV, and antihypertensive activities.

Objective: In this review, we highlight some areas of current interest in context to azoles and their derivatives as potential chemotherapeutic agents and inhibitors.

Method: A comprehensive literature search was performed for writing this review. An updated view on different derivatives of azoles and use in cancer management has been discussed.

Results: Here we have discussed the present scenario of azoles and their derivatives as potential chemotherapeutic agents and inhibitors. Along with, the future perspectives of azoles in cancer prevention and treatment are also discussed.

Conclusion: The information provided in this review might be useful to researchers in designing of novel and potent multifunctional azole analogues for the treatment of cancer and other multifactorial diseases.

Craniocervical Dissections: Radiologic Findings, Pitfalls, Mimicking Diseases: A Pictorial Review

Background: Craniocervical Dissections (CCD) are a crucial emergency state causing 20% of strokes in patients under the age of 45. Although DSA (digital substraction angiography) is regarded as the gold standard, noninvasive methods of CT, CTA and MRI, MRA are widely used for diagnosis.

Aim: Our aim is to illustrate noninvasive imaging findings in CCD.

Conclusion: Emphasizing on diagnostic pitfalls, limitations and mimicking diseases.

Statins in Aortic Disease

Background: Numerous studies indicate that statins have multiple beneficial actions (known as ‘pleiotropic actions') on cardiovascular system through the improvement of endothelial dysfunction, inflammation, oxidative stress, excessive arterial thrombosis, and stabilization of the atherosclerotic plaque. Aortic disease primarily consists of aortic valve stenosis, aortic valve regurgitation, aneurysm disease, and genetic disorders such as Marfan syndrome, bicuspid aortic valve and aortic coarctation. Many studies have revealed the cardioprotective actions of statins in aortic disease.

Objective: Our aim was to present current data concerning the value of treatment with statins in aortic diseases.

Methods: A thorough search of PubMed and the Cochrane Database was conducted to identify the studies and novel articles related to the use of statins in aortic disease.

Results: Numerous studies in animals and humans indicate a beneficial effect of treatment with statins in the previous conditions apart from a few conflicting data.

Conclusion: There is a need of further investigation in this field, especially for the estimation of the optimal type and dose of statins required in each clinical condition of aortic disease.

Big Data and Genome Editing Technology: A New Paradigm of Cardiovascular Genomics

Opinion Statements: Cardiovascular diseases (CVDs) encompass a range of conditions extending from congenital heart disease to acute coronary syndrome most of which are heterogenous in nature and some of them are multiple genetic loci. However, the pathogenesis of most CVDs remains incompletely understood. The advance in genome-editing technologies, an engineering process of DNA sequences at precise genomic locations, has enabled a new paradigm that human genome can be precisely modified to achieve a therapeutic effect. Genome-editing includes the correction of genetic variants that cause disease, the addition of therapeutic genes to specific sites in the genomic locations, and the removal of deleterious genes or genome sequences. Site-specific genome engineering can be used as nucleases (known as molecular scissors) including zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) systems to provide remarkable opportunities for developing novel therapies in cardiovascular clinical care. Here we discuss genetic polymorphisms and mechanistic insights in CVDs with an emphasis on the impact of genome-editing technologies. The current challenges and future prospects for genomeediting technologies in cardiovascular medicine are also discussed.

Novel Insights into Complex Cardiovascular Pathologies using 4D Flow Analysis by Cardiovascular Magnetic Resonance Imaging

Background: Blood flow assessment is essential to fully understand cardiovascular function in disease pathologies and for identification of individuals at long-term risk of cardiovascular disease development. Qualitative and quantitative assessments of blood flow by imaging modalities have been limited, and much of the accurate quantification has relied on invasive measures.

Methods: This review discusses how four-dimensional velocity cardiovascular magnetic resonance (4D flow CMR) offers increasing potential for the non-invasive assessment of blood flow in the heart and major blood vessels such as the aorta. 4D flow CMR refers to phase contrast CMR with flow encoding in all three spatial directions that is resolved relative to all three dimensions of space and to the dimension of time throughout the cardiac cycle.

Results: It has been demonstrated that 4D flow CMR can be used to assess parameters such as flow, pressure, velocity, wall shear stress and turbulent kinetic energy throughout the heart and major vessels of the cardiovascular system. It has been possible to gain new insights into cardiovascular pathologies such as, but not limited to, hypertrophic cardiomyopathy, dilated cardiomyopathy, Marfan syndrome and aortic bicuspid valve disease.

Conclusion: Future work to standardize 4D flow CMR scan acquisition parameters is required. Furthermore, the development of automated analysis tools and standardized reporting of quantitative metrics are needed to increase capacity for larger studies and for translation to clinical practice. In doing so, the potential for 4D flow CMR to disentangle complex questions related to cardiovascular function will be maximized.

Anatomical Approach to Clinical Problems of Popliteal Fossa

Background: Popliteal fossa, also known as the popliteal space, is located behind the knee joint. This region can develop many clinical complications in the vascular, nervous, lymphatics, adipose, as well as swelling and masses.

Objective: The objective of this review article is to give a detailed understanding of the popliteal fossa and the clinical pathology that may present itself.

Methods: MEDLINE® searches were conducted of literature published since 1950s for “popliteal fossa,” “diseases,” “anatomy,” “arterial,” “venous,” “nerves,” “entrapment syndrome,” “aneurysms,” “cysts,” “lymphatics,” “solid masses,” “tumors,” “inflammatory lesions,” and “swellings.” The references provide up-to-date literature for all the pathologies discussed.

Results: This review articles discusses the anatomy, clinical examination, including history, physical, and imaging modalities, and various diseases that present themselves in patients. Diseases relating to the arterial and venous systems, nervous system, musculature, adipose, lymphatics, cysts and other solid masses, including neoplasms, and abscesses. The differential diagnosis and symptoms of certain conditions are addressed to isolate the root of the manifestation.

Conclusion: Diseases of the popliteal fossa can use histology and electrophysiology to aid in diagnosis, as well as instrumentation. Surgical approaches are uses to treat varying pathologies as they are the best means of therapy.

Extracellular Matrix Scaffolds for Tissue Engineering and Regenerative Medicine

The extracellular matrix is produced by the resident cells in tissues and organs, and secreted into the surrounding medium to provide biophysical and biochemical support to the surrounding cells due to its content of diverse bioactive molecules. Recently, the extracellular matrix has been used as a promising approach for tissue engineering. Emerging studies demonstrate that extracellular matrix scaffolds are able to create a favorable regenerative microenvironment, promote tissue-specific remodeling, and act as an inductive template for the repair and functional reconstruction of skin, bone, nerve, heart, lung, liver, kidney, small intestine, and other organs. In the current review, we will provide a critical overview of the structure and function of various types of extracellular matrix, the construction of three-dimensional extracellular matrix scaffolds, and their tissue engineering applications, with a focus on translation of these novel tissue engineered products to the clinic. We will also present an outlook on future perspectives of the extracellular matrix in tissue engineering and regenerative medicine.

miR-29c-3p is an Effective Biomarker of Abdominal Aortic Aneurysm in Patients Undergoing Elective Surgery

Background: Abdominal aortic aneurysm (AAA) is usually asymptomatic and mostly diagnosed incidentally. Aortic dilatation progresses along with the wall weakening and eventually leads to a life-threatening rupture. Currently, there are no effective screening biomarkers for AAA. MicroRNAs, a class of small noncoding RNA molecules, offer great potential as biomarkers because of their stability in the bloodstream and expression profile specific for different diseases.

Objective: To assess the circulating miR-29c-3p as a potential biomarker of AAA and to elucidate the biological functions of miR-29c-3p in terms of pathogenesis of aneurysms.

Methods: Two groups of patients scheduled for elective surgery were studied: 52 patients with AAA, and 51 patients with peripheral artery disease who served as a control group (matched by age and gender). Serum miRNA was measured for circulating miR-29c-3p using quantitative real-time PCR. Functional tests of miR-29c-3p impact on the targeted transcripts were studied using its mimic or inhibitor and a cell culture of endothelial cells.

Results: Serum miR-29c-3p was significantly elevated in AAA patients as compared with controls (RQ=8.73) and correlated with the diameter of the aneurysm. No association between well-known risk factors and level of circulating miR-29c-3p was found using a logistic regression. In vitro study revealed that miR-29c-3p suppressed transcripts of ELN, COL4A1, PTEN and VEGFA.

Conclusion: The results suggest that elevated miR-29c-3p is a potential serum biomarker for AAA. Causal involvement of miR-29c-3p in pathogenesis of the disease was found in human vascular endothelial cells, which extracellular matrix synthesis and integrity maintenance was inhibited.

Coronary Artery Ectasia-A Review of Current Literature

Coronary artery ectasia (CAE) is one of the uncommon cardiovascular disorders. Its incidence ranges from 1.2%-4.9%. Coronary artery ectasia likely represents an exaggerated form of expansive vascular remodeling (i.e. excessive expansive remodeling) in response to atherosclerotic plaque growth with atherosclerosis being the most common cause. Although, it has been described more than five decades ago, its management is still debated. We therefore reviewed the literature until date by searching PubMed and Google scholar using key words “coronary artery ectasia”, “coronary artery aneurysm”, “pathophysiology”, “diagnosis”, “management” either by itself or in combination. We reviewed the full articles and review articles and focused mainly on pathophysiology, diagnosis and management of CAE.

Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling

Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery.

Physical and Mechanical Therapies for Lower Limb Problems in Children with Joint Hypermobility Syndrome: A Systematic Review Protocol

Background: Joint hypermobility syndrome (JHS) is one of the most common heritable genetic disorders of connective tissue, characterised by excessive joint range of motion and the presence of musculoskeletal symptoms. Prevalence estimates of JHS range from 5% to 18% and vary with gender, age and ethnicity. JHS is associated with generalised joint laxity, joint instability, motion incoordination, decreased joint position sense, and musculoskeletal pain. The research evidence-base for treating lower limb symptoms in JHS is increasing. This paper outlines a protocol for a systematic review of the evidence for physical and mechanical treatments for lower limb problems in children with JHS.

Methods/Design: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PUBMED and CINAHL will be searched for randomised controlled trials and quasirandomised controlled trials investigating physical and mechanical interventions for lower limb problems in children with JHS. Two authors will independently screen studies for eligibility for inclusion and will assess risk of bias of included studies. One author will extract and analyse statistical data, which will be checked by the second author.

Discussion: The systematic review aims to establish the best-practice use of physical and mechanical interventions for lower limb complications of JHS in children and to highlight the areas of greatest need for future research.

Clinical Characteristics and Treatment of Cardiomyopathies in Children

Cardiomyopathies are diseases of the heart muscle, a term introduced in 1957 to identify a group of myocardial diseases not attributable to coronary artery disease. The definition has since been modified to refer to structural and or functional abnormalities of the myocardium where other known causes of myocardial dysfunction, such as systemic hypertension, valvular disease and ischemic heart disease, have been excluded. In this review, we discuss the pathophysiology, clinical assessment and therapeutic strategies for hypertrophic, dilated and hypertrophic cardiomyopathies, with a particular focus on aspects unique to children.

Novel Methods of Genetic Modification of Human Pluripotent Stem Cells

Genomic engineering has enormous potential along basic research, drug discovery and cell therapeutics. Many existing methods for targeted gene knockout mutagenesis or integration rely on homologous recombination. The low rate of spontaneous recombination in nearly all mammalian cell types, as well as the scale of screening, effort and time required to isolate the targeted events during genome modification, have hindered progress in this field. The present review has the objective to present latest improvements of technology to develop genetic modification to a clinical grade level so it can be used in human therapy.

Recent Advancement in the Treatment of Cardiovascular Diseases: Conventional Therapy to Nanotechnology

Cardiovascular disease (CVD), accounting around 30% of deaths worldwide, collectively comprised of disorders affecting the heart and blood vessels as well as their associated adverse conditions. Despite outstanding progress in the area of the treatments of CVDs, significant challenges remain in designing of efficient delivery systems for myocardial therapy. Moreover, current therapy for CVDs is limited due to various clinical complications such as systemic toxicity, stent thrombosis, etc. Molecular and nanotechnology approaches provide the tools to explore such frontiers of biomedical science at the cellular level and thus offer unique features for potential application in the field of cardiac therapy. In this review, recent advances in CVD related risk factors, chronic inflammation, and their therapeutic modalities such as stem cell therapy, gene delivery, tissue factor (TF) inhibitors, miRNAs, leukotriene modifiers, thrombolytic agents etc., in modern molecular aspects are discussed. Moreover, nanoparticle based drug delivery, nanocarriers as molecular imaging, and the various challenges of myocardial tissue engineering aspects have been summarized. All these aspects may provide additional therapeutic substitutes in clinical trials for the registration of new drugs.

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis.

Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

Evaluation of Anti-aging Compounds Using the Promoters of Elastin and Fibrillin-1 Genes Combined with a Secreted Alkaline Phosphatase Reporter in Normal Human Fibroblasts

Elastic fibers are major constituents of the extracellular matrix (ECM) in dynamic tissues in the human body, and regulation of elastin and fibrillin-1 expression mediates the formation of these fibers. Traditional assays for the measurement of elastin and fibrillin-1, such as western blotting, Luna staining and immunostaining, are relatively complex and time-consuming. Thus, a relatively simple assay system that also provides rational results is urgently needed. In the study, we aimed to develop a human cell-based assay system that can be used to analyze functional compounds using the promoters of elastin (ELN) and fibrillin-1 (FBN1) genes integrated with a secreted alkaline phosphatase (SEAP) reporter in normal human fibroblast cells. We used this system to assess anti-aging compounds. We used several regulators of elastinogenesis, including retinol, coenzyme Q10, deoxyArbutin and Elestan^TM (Manilkara multinervis leaf extract), to verify the efficacy of this assay system. Our results demonstrate that this assay system can be used as a fast and realistic method for identifying anti-aging components for future use in foods, cosmetics and drugs.

Editorial (Thematic Issue: Novel Insights on Aortic Aneurysm)

Novel Inflammatory Indices in Aortic Disease

Inflammation plays a critical role in the atherosclerotic process in various vascular beds, starting from endothelial dysfunction and counting all stages of plaque development. The significant contribution of inflammation in the initiation and progression of atherosclerosis has been documented over many years but its contribution to the development of other cardiovascular disease remains unclear. Inflammatory process constitutes a basic part of pathogenic cascade of aortic diseases including those of aortic valve stenosis and aortic aneurysms. Thus, both of these entities are related with high rates of morbidity and mortality. Therefore, the need to detect and investigate indices representative of inflammation that will be easily measured and may reflect the process of these diseases, is mandatory. However, such biomarkers for aortic diseases that could have a significant prognostic value on survival via the early identification of high risk patients, in general, remain few. Therefore, the illumination of role of such biomarkers, will facilitate the understanding of the mechanisms in molecular and/or cellular level that are responsible for the creation of aortic disease. Such an approach may provide a pathophysiological basis for early diagnosis.

The Location of Vascular Flap is Related with Daily Activity Patterns in Non-traumatic Acute Aortic Syndrome in a Chinese Population

Background: Acute aortic syndrome (AAS) is a group of serious and lethal aortic emergencies, which have so variable and non-specific clinical presentations and can be misdiagnosed as other diseases. AAS occurs frequently in daily life, but too little attention was paid on the location of its vascular flap according to different daily activity patterns.

Methods: The data of 160 cases hospitalized for non-traumatic acute aortic syndrome in Chinese PLA general hospital from January 1st, 2004 to December 31st, 2013 were analyzed retrospectively. Among the 160 patients enrolled, 155 (96.9%, of160) were finally diagnosed with acute aortic dissection (AAD) and the other 5 (3.1%, of 160) with ruptured aortic aneurysm (RAA). Of those155 patients with AAD, 45 (29.0%, of 155) were definitely diagnosed with type A and 110 (71.0%, of 155) for type B according to the Stanford classification system.

Results: (1) Flaps of aorta in AAS patients were found more commonly located in the thoracic descending aorta (68.1%, 109/160), and the other 24 cases (15.0%, 24/160) in the ascending aorta, 21 cases (21/160, 13.1 %) in aorta arch, and only 6 cases (6/160,3.8%) in the abdominal aorta. (2) There are 65 AAS patients (40.63%) with the body postural changes, 44 (27.50%) for body stretching, 25 (15.63%) for weighting, 17 (10.63%) for pound on the anterior body, 5 (3.13%) for turning the steering wheel and 4 (2.50%) for cycling during the onset of disease. (3) In the body postural changes group, the vessel flaps were dominantly found on thoracic descending aorta (76.92%, 50/65), which was significantly higher than the others (62.11%, 59/95; X²=3.902, P=0.040). (4) In the body stretching group, the vessel flaps on thoracic descending aorta were frequently (56.82%, 25/44), and on the ascending aorta was 31.82% (14/44), which significantly higher than the body postural change group (4.63%, 3/65; X²=15.028, P=0.0001) (5) The proportion of aortic arch flaps in the weighting group was 28.57% (6/21), which was significantly higher than the others (11.11%, 15/135; X²=3.073, P=0.081). (6) The frequency of the ascending aorta flap location in the pound on the anterior body group was significantly higher than the other activities (41.18%, 7/17 vs. 11.89%, 17/143; X²=10.222, P=0.001); and the abdominal aorta was also significantly higher than the other activities (16.65%, 3/17 vs. 20.98%, 3/143; X²=10.178, P=0.001). (7) There were 9 cases (5.63%, 9/160) with the twist movement(turning the steering wheel and cycling) had vascular flaps situated in thoracic descending aorta, which significantly higher than the others (100.00%, 9/9 vs. 65.56%, 99/151; X²=4.592, P=0.032).

Conclusions: These results showed the location of vascular flap is highly related with daily activity pattern in nontraumatic acute aortic syndrome, which might be useful for clinicians when they prevent and cure this disease more timely and effectively.

Role, Function and Therapeutic Potential of microRNAs in Vascular Aging

Due to increased life expectancy in a growing world population, the impact of ageing on the pathophysiology of cardiovascular diseases will increase. Therefore, a better understanding of agerelated biological changes is important and necessary to combat cardiovascular diseases in the future.

microRNAs (miRs) are small non coding RNAs emerging as key regulator in several vascular pathologies such as atherosclerosis or hypertension, which show a clear association with increasing age. This review discusses the involvement of miRs in several age-associated pathologies such as oxidative stress, vascular inflammation, vascular tension, endothelial cell senescence and impaired angiogenesis.

Management of Incidental Findings in the Era of Next-generation Sequencing

Next-generation sequencing (NGS) technologies allow for the generation of whole exome or whole genome sequencing data, which can be used to identify novel genetic alterations associated with defined phenotypes or to expedite discovery of functional variants for improved patient care. Because this robust technology has the ability to identify all mutations within a genome, incidental findings (IF)- genetic alterations associated with conditions or diseases unrelated to the patient’s present condition for which current tests are being performed- may have important clinical ramifications. The current debate among genetic scientists and clinicians focuses on the following questions: 1) should any IF be disclosed to patients, and 2) which IF should be disclosed – actionable mutations, variants of unknown significance, or all IF? Policies for disclosure of IF are being developed for when and how to convey these findings and whether adults, minors, or individuals unable to provide consent have the right to refuse receipt of IF. In this review, we detail current NGS technology platforms, discuss pressing issues regarding disclosure of IF, and how IF are currently being handled in prenatal, pediatric, and adult patients.

Forensic DNA Phenotyping in Criminal Investigations and Criminal Courts: Assessing and Mitigating the Dilemmas Inherent in the Science

Forensic DNA Phenotyping (“FDP”), estimating the externally visible characteristics (“EVCs”) of the source of human DNA left at a crime scene, is evolving from science fiction toward science fact. FDP can already identify a source’s gender with 100% accuracy, and likely hair color, iris color, adult height, and a number of other EVCs with accuracy rates approaching 70%. Patent applications have been filed for approaches to generating 3D likenesses of DNA sources based on the DNA alone. Nonetheless, criminal investigators, particularly in the United States, have been reticent to apply FDP in their casework. The reticence is likely related to a number of perceived and real dilemmas associated with FDP: is FDP racial profiling, should we test unknown and unseen physical conditions, does testing for behavioral characteristics impermissibly violate the source’s privacy, ought testing be permitted for samples from known sources or DNA databases, and should FDP be limited to use in investigations only or is FDP appropriate for use in a criminal court. As this article explains, although those dilemmas are substantive, they are not insurmountable, and can be quite easily managed with appropriate regulation and protocols. As FDP continues to develop, there will be less need for criminal investigators to shy away from FDP. Cold cases, missing persons, and victims in crimes without other evidence will one day soon all be well served by FDP.

Inflammaging and Proteases in Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is an age-related disease resulting in aortic wall weakening and dilatation which may progress to the fatal point of abrupt aortic wall rupture. Chronic inflammation is a driving force in the pathogenesis of AAA and extracellular matrix (ECM) proteases are considered central to aortic wall degradation. Considerable effort is dedicated to identifying the proteases responsible as well as the mechanism by which these proteases contribute to disease progression. As such, they are considered important molecular targets for pharmacological intervention. Along with smoking, male gender and family history, aging is a major risk factor for AAA. Examination of age-related changes of the immune system reveals an interwoven relationship between the processes of aging and chronic inflammation, collectively predisposing to AAA development. The present review explores current evidence as to the role of specific ECM proteases in AAA pathogenesis. The contribution of the aging process to disease pathogenesis is also explored to provide the relevant context and highlight key molecular pathways that should be considered while attempting to develop effective treatment approaches.

Chemistry and Pharmacology of Angiotensin-Converting Enzyme Inhibitors

The renin-angiotensin system has been established as an attractive target for pharmacological intervention since the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarily used in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism of action involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensin II and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinin degradation. Currently there are thirteen family members approved for use in humans. They differ in structure, chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic and toxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy. Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistent dry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximum safety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be an absolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially- used ACE-Is.

Giant Pulmonary Artery Aneurysm Secondary To Patent Ductus Arteriosus: A Case Report

Aneurysms involving the main pulmonary artery and its branches are rare. Clinical experience is limited, and their management is not well established. We present the case of a 35-year-old male patient with dyspnea and hemoptysis in whom subsequent imaging studies revealed a giant pulmonary artery aneurysm associated with an uncorrected patent ductus arteriosus and Eisenmenger’s syndrome. We chose to treat the patient conservatively with medical management due to the development of Eisenmenger’s physiology while waiting for heart-lung transplantation.

Halting Arterial Aging in Patients with Cardiovascular Disease: Hypolipidemic and Antihypertensive Therapy

Aging is associated with arterial stiffening and subsequent acceleration of pulse wave movement. Traditional cardiovascular risk factors such as hypertension and dyslipidemia are associated with increased arterial stiffness, a ‘premature’ arterial aging. Antihypertensive drugs exhibit beneficial effects on arterial stiffness, both at the central and peripheral level, and these effects are mainly attributed to blood pressure reduction per se. However, additional benefits of the renin-angiotensin system inhibitors have been recently suggested. Furthermore, a disparity in the effects of beta-blockers on arterial stiffness between conventional and vasodilatory agents has also been suggested. Statin treatment is an essential element of cardiovascular therapy and statins are frequently administered by patients with cardiovascular risk factors or established cardiovascular disease. The effects of statins on arterial stiffness are not yet well established. Moreover, the effects of combining statins with antihypertensive drugs or other strategies to attenuate arterial aging are not adequately studied. The aim of the current review is to present the effects of available therapeutic strategies on arterial stiffness with special emphasis on hypolipidemic and antihypertensive drugs, critically evaluate available information and provide future perspectives in this field.

Common Genetic Conditions of Ischemic Stroke to Keep in Mind

Stroke is a complex disease resulting from the interplay of genetics and environment. In some instances (mainly in young adults) stroke is the direct result of a monogenic disease. Among the monogenic causes of stroke, the diseases which are most frequently encountered in the adult general neurological practice are CADASIL, Fabry and mitochondrial diseases. Brain MRI and clinical features may frequently lead to a correct molecular diagnosis. Here we review the single-gene causes of ischemic stroke, with special regard to the associated features which may help in the diagnostic approach.

Mechanisms of Medial Arterial Calcification in Diabetes

Medial artery calcification (MAC) is a characteristic feature of diabetes. MAC represents a concentric calcification that proceeds via matrix vesicle-nucleated mineralization accompanied with apatitic calcium phosphate deposits in the arterial tunica media in the absence of atheroma and neointima. Multiple factors contribute to the induction and progression of diabetic MAC including inflammation, oxidative stress, adiposity, insulin resistance, advanced glycation end-products, and hyperphosphatemia. Osteoblast-like cells form in the vessel wall from vascular smooth muscle cells and multipotent vascular mesenchymal progenitors. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, Osterix, and RUNX2 are crucial in the programming of osteogenesis. Currently, no therapy is available to reverse vascular calcification. Available therapies can only reduce and slow the progression of vascular calcification. Targeting regulatory proteins and enzymes directly involved in osteochondrogenesis and hydroxyapatite accumulation in the vascular wall may be beneficial for generating new efficient anti-calcific drugs.

TGF-beta Signaling in Cancer Treatment

The transforming growth factor-beta (TGF-β) belongs to a superfamily of cytokines that act on protein kinase receptors at the plasma membrane to induce a plethora of biological signals that regulate cell growth and death, differentiation, immune response, angiogenesis and inflammation. Dysregulation of its pathway contributes to a broad variety of pathologies, including cancer. TGF-β is an important regulatory tumor suppressor factor in epithelial cells, where it early inhibits proliferation and induces apoptosis. However, tumor cells develop mechanisms to overcome the TGF-β-induced suppressor effects. Once this occurs, cells may respond to this cytokine inducing other effects that contribute to tumor progression. Indeed, TGF-β induces epithelial-mesenchymal transition (EMT), a process that is favored in tumor cells and facilitates migration and invasion. Furthermore, TGF-β mediates production of mitogenic growth factors, which stimulate tumor proliferation and survival. Finally, TGF-β is a well known immunosuppressor and pro-angiogenic factor. Many studies have identified the overexpression of TGF-β1 in various types of human cancer, which correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. For these reasons, different strategies to block TGF-β pathway in cancer have been developed and they can be classified in: (1) blocking antibodies and ligand traps; (2) antisense oligos; (3) TβRII and/or ALK5 inhibitors; (4) immune response-based strategies; (5) other inhibitors of the TGF-β pathway. In this review we will overview the two faces of TGF-β signaling in the regulation of tumorigenesis and we will dissect how targeting the TGF-β pathway may contribute to fight against cancer.

Medical Treatment of Aortic Aneurysms in Marfan Syndrome and other Heritable Conditions

Thoracic aortic aneurysms can be triggered by genetic disorders such as Marfan syndrome (MFS) and related aortic diseases as well as by inflammatory disorders such as giant cell arteritis or atherosclerosis. In all these conditions, cardiovascular risk factors, such as systemic arterial hypertension, may contribute to faster rate of aneurysm progression. Optimal medical management to prevent progressive aortic dilatation and aortic dissection is unknown. β-blockers have been the mainstay of medical treatment for many years despite limited evidence of beneficial effects. Recently, losartan, an angiotensin II type I receptor antagonist (ARB), has shown promising results in a mouse model of MFS and subsequently in humans with MFS and hence is increasingly used. Several ongoing trials comparing losartan to β -blockers and/or placebo will better define the role of ARBs in the near future. In addition, other medications, such as statins and tetracyclines have demonstrated potential benefit in experimental aortic aneurysm studies. Given the advances in our understanding of molecular mechanisms triggering aortic dilatation and dissection, individualized management tailored to the underlying genetic defect may be on the horizon of individualized medicine. We anticipate that ongoing research will address the question whether such genotype/pathogenesis-driven treatments can replace current phenotype/syndromedriven strategies and whether other forms of aortopathies should be treated similarly. In this work, we review currently used and promising medical treatment options for patients with heritable aortic aneurysmal disorders.

Potential Replication of Induced Pluripotent Stem Cells for Craniofacial Reconstruction

The craniofacial region contains many specified tissues, including bone, cartilage, muscle, blood vessels, fat, skin and neurons. A defect or dysfunction of the craniofacial tissue after post-cancer ablative surgery, trauma, congenital malformations and progressive deforming skeletal diseases has a huge influence on the patient’s life. Therefore, functional reconstruction of damaged tissues is highly sought. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound-healing. The recently acquired ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture may provide a powerful tool for in vitro disease modeling and an unlimited source for cell replacement therapy. This review focuses on the generation, biological characterization and discussion of the potential application of iPSCs for craniofacial tissue-engineering applications.

Intracranial Non-traumatic Aneurysms in Children and Adolescents

An intracranial aneurysm in a child or adolescent is a rare, but potentially devastating condition. As little as approximately 1200 cases are reported between 1939 and 2011, with many of the reports presenting diverting results. There is consensus, though, in that pediatric aneurysms represent a pathophysiological entity different from their adult counterparts. In children, there is a male predominance. About two-thirds of pediatric intracranial aneurysms become symptomatic with hemorrhage and the rate of re-hemorrhage is higher than in adults. The rate of hemorrhage from an intracranial aneurysm peaks in girls around menarche. The most common aneurysm site in children is the internal carotid artery, in particular at its terminal ending. Aneurysms in the posterior circulation are more common in children than adults. Children more often develop giant aneurysms, and may become symptomatic from the mass effect of the aneurysm (tumorlike symptoms). The more complex nature of pediatric aneurysms poses a larger challenge to treatment alongside with higher demands to the durability of treatment. Outcome and mortality are similar in children and adults, but long-term outcome in the pediatric population is influenced by the high rate of aneurysm recurrences and de novo formation of intracranial aneurysms. This urges the need for life-long follow-up and screening protocols.

Pathogenesis of Alcohol-Induced Osteoporosis and its Treatment: A Review

Osteoporosis is the most common bone disease in humans; it represents a major public health problem. This chronic disease is characterized by increase in bone fracture due to: reduced bone mass, deterioration of micro architectural and decreased bone strength, bone fragility; and bone mineral density 2.5 or more standard deviations below the normal mean. Secondary osteoporosis is a common cause of osteoporosis, and there are many underlying risk factors for osteoporosis. Chronic alcohol abuse is one of the modifiable risk factors in osteoporosis. There is evidence of correlation between chronic alcohol abuse and low bone mass. Alcohol is directly toxic to the bone; with increased incidence of fractures and complications. Although there is a paucity of studies regarding alcohol induced osteoporosis therapy, it can be classified into antiresorptive therapy and anabolic therapy. Bisphosphonates have been demonstrated to be clinically relevant to prevent bone damage associated with alcohol use while parathyroid hormone increased bone mineralization as well as bone formation in alcohol treated rats. Vitamin D supplementation could prevent bone toxicity in chronic drinkers. This review discussed the pathogenesis of alcohol-induced osteoporosis and the agents available for its treatment. Other potential therapies are also discussed.

Molecular Basis of Young Ischemic Stroke

Epidemiological and family studies have provided evidence on the role of genetic factors in stroke, particularly in stroke occurring at young age. However, despite its impact, young stroke continues to be understudied. This article reviews the existing literature on the most investigated monogenic disorders (CADASIL, Fabry disease, MELAS, RVCL, COL4A1, Marfan and Ehlers-Danlos syndromes) causing stroke in young and a number of candidate genes associated with stroke occurring in patients younger than 50 years. Although our study failed in identifying strong and reliable associations between specific genes and young stroke, our detailed literature revision on the field allowed us to compile a panel of genes possibly generating a susceptibility to stroke, which could be a starting point for future research. Since stroke is a potentially preventable disease, the identification of genes associated with young stroke may promote novel prevention strategies and allow the identification of therapeutic disease targets.

Therapeutic Approaches for Lysosomal Storage Diseases: A Patent Update

Lysosomal Storage Diseases (LSDs) are inherited metabolic disorders caused by specific lysosomal protein deficiencies, which lead to abnormal storage of macromolecular substrates. Most LSDs are characterized by central nervous system (CNS) pathology, intracellular deposition and protein aggregation, events also found in age-related neurodegenerative diseases. Over the past two decades, a few approaches for the cure of these disorders have been approved for clinical use, i.e. enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). However, these treatments are hampered by major limitations, such as the poor biodistribution in the CNS for ERT and severe side effects for SRT. Several additional therapeutic strategies have been proposed. In particular clinical trials are ongoing based on enzyme enhancement by pharmacological chaperones, i.e. small molecule compounds able to increases the residual activity of the lysosomal enzyme, and gene therapy approaches. In addition, recent patents in the field provide evidence that many efforts are currently dedicated to i) improve the properties of enzymes used for ERT, ii) find new pharmacological chaperones without inhibitory effects on enzyme activity and iii) combine gene therapy approaches with genome editing methods.

MicroRNAs in Aortic Disease

MicroRNAs (miRNAs) are non-coding RNAs of ~22 nucleotides which act as down regulators of gene expression in the post-transcription level and/or in the translation level. Several studies have shown that the process of their maturation is rather crucial for the development of cardiovascular system thus their regulation (up-,down-) is implicated with many cardiac pathologies. This is evaluated through their circulating levels which are reliable, stable and the changes in their serum profiles are representative of tissue alterations serum levels. Furthermore, they have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure cardiac arrhythmias and aortic stenosis. In the present review, we will first describe i) the process of miRNAs’ maturation ii) their role in the cardiovascular development, iii) their role as biomarkers of cardiac diseases, iv) the cardiac myo-miR families and the v) their role in cardiac remodeling and the development of cardiac diseases. Second we will review the miRNA families that participate in aortic stenosis separated according to its main pathways (imflammation, fibrosis, calcification). Finally, we will describe the miRNAs that participate in the development of aortic aneurysm and aortic dissection according to their serum levels.

The Multiple Aspects of Stroke and Stem Cell Therapy

Cumulative evidence shows that transplantation of stem cells (SC) derivatives can reduce the functional deficits induced by cerebral ischemia or hemorrhage in animals. Most SC sources have been applied to stroke models, with varying degrees of differentiation into neural derivatives and in varying number, timing and route of administration, with similar benefits on functional outcome. Pioneering clinical trials developed in parallel, and currently outnumber other applications of SC in neurological disorders. These trials reflect a paradigm shift from cell replacement therapy to disease-modeling effects, with increased used of nonneural SC. This shift stems in experimental demonstration of paracrine effects of SC that attenuate inflammation, limit cell death through neurotrophic effects, and enhance endogenous recovery processes. Due to its pathogenic characteristics, stroke can uniquely benefit from this variety of actions.

Redox Control of Cardiovascular Homeostasis by Angiotensin II

Covalent modification of sulfur-containing amino acids in proteins by reactive oxygen species (ROS) has been attracting attention as a major post-translational modification regulating intracellular signal transduction pathways. Angiotensin II (Ang II), a major physiologically active substrate in renin-angiotensin (RAS) system, plays a central role in the pathophysiology of cardiovascular systems. Many evidences show that Ang II activates several signaling pathways via an oxidative modification of proteins by Ang II-induced ROS. Ang II induced ROS production is predominantly regulated by three enzymes: NADPH oxidase, mitochondrial respiratory complex, and nitric oxide synthase (NOS), and each enzyme-generating ROS are found to activate appropriate signaling pathways via selective oxidation of specific proteins. These reactions are negatively regulated by ROS-scavenging enzymes or disulfide bridge reducing enzymes, and functional disorders of these enzymes are found to cause cardiovascular dysfunctions. Thus, the spatial and temporal regulation of oxidative modification of signaling proteins by ROS is essential to maintain cardiovascular homeostasis by Ang II. This review brings in the new aspect in understanding ROS-mediated regulation of cardiovascular homeostasis by Ang II, and provides the possible mechanisms underlying metamorphosis of cardiovascular homeostasis by ROS.

Biological, Geometric and Biomechanical Factors Influencing Abdominal Aortic Aneurysm Rupture Risk: A Comprehensive Review

The current clinical management of abdominal aortic aneurysm (AAA) disease is based to a great extent on measuring the aneurysm maximum diameter to decide when timely intervention is required. Decades of clinical evidence show that aneurysm diameter is positively associated with the probability of rupture, but that other parameters may also play a role in causing or predisposing the AAA to rupture. Biological factors associated with smooth muscle apoptosis are implicated in AAA expansion while geometric and biomechanical factors identified by means of computational modeling techniques have been positively correlated with rupture risk with a higher accuracy and sensitivity than maximum diameter alone. The objective of this review is to examine the factors found to influence AAA disease progression, clinical management and rupture, as well as a patent review that highlights developments in this arena in the past few years.

Climate Change, Climate Variability and Brucellosis

In addition to natural climate variability observed over comparable time periods, climate change is attributed directly or indirectly to human activity, altering the composition of global atmosphere. This phenomenon continues to be a significant and global threat for the humankind, and its impact compromises many aspects of the society at different levels, including health. The impact of climate change on zoonotic diseases has been largely ignored, particularly brucellosis. We here review some direct and indirect evidences of the impact of climate change and climate variability on brucellosis.

Inhibition of Matrix Metalloproteinases (MMPs) as a Potential Strategy to Ameliorate Hypertension-Induced Cardiovascular Alterations

A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins. Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling. Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy. Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction. It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications. Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs. Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system. This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors. Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed.

Current Genomics in Cardiovascular Medicine

Cardiovascular disease (CVD) is a heterogeneous, complex trait that has a major impact on human morbidity and mortality. Common genetic variation may predispose to common forms of CVD in the community, and rare genetic conditions provide unique pathogenetic insights into these diseases. With the advent of the Human Genome Project and the genomic era, new tools and methodologies have revolutionised the field of genetic research in cardiovascular medicine. In this review, we describe the rationale for the current emphasis on large-scale genomic studies, elaborate on genome wide association studies and summarise the impact of genomics on clinical cardiovascular medicine and how this may eventually lead to new therapeutics and personalised medicine.

Cerebral Aneurysm as an Exacerbating Factor in Stroke Pathology and a Therapeutic Target for Neuroprotection

Stroke remains a major cause of death in the US and around the world. Despite major scientific advances in our understanding of stroke pathology, the only FDA-approved drug for ischemic stroke is tissue plasminogen activator (tPA). Moreover, the therapeutic window for tPA is confined to the acute phase of stroke, thereby greatly limiting its benefits to less than 3% of ischemic stroke patients. Many treatment strategies for stroke have targeted the subacute or chronic phase in an effort to abrogate the secondary cell death that ensues after the initial stroke insult. Here, we advance the hypothesis that blood vessel disruption, or aneurysm, in the brain is an exacerbating factor for stroke, especially in the evolution of the penumbra or peri-infarct area. A better understanding of aneurysm, specifically its dynamic onset and juxtaposition to the ischemic brain tissue should facilitate the development of novel strategies for attenuating the secondary cell death associated with stroke. To this end, we discuss the laboratory and clinical evidence implicating aneurysm formation in stroke and also provide insights on how stem cell therapy may prove efficacious in combating aneurysm and stroke.

Spontaneous Pneumothorax

The management of spontaneous pneumothorax in the non-ventilated patient is determined by whether or not there is marked underlying lung pathology (secondary) or not (primary). Primary pneumothorax is generally managed initially by simple tube drainage, although the success of operative approaches suggests that earlier intervention may be beneficial. In contrast, patients with severe underlying lung disease have both increased operative risk, as well as failure of both operative and non-operative management. In either setting, early surgical consultation is ideal and particularly in the setting of secondary pneumothorax a multi-modality approach is optimal.

Screening, Evaluation, and Early Management of Acute Aortic Dissection in the ED

Acute aortic dissection (AAD) is a rare and lethal disease with presenting signs and symptoms that can often be seen with other high risk conditions; diagnosis is therefore often delayed or missed. Pain is present in up to 90% of cases and is typically severe at onset. Many patients present with acute on chronic hypertension, but hypotension is an ominous sign, often reflecting hemorrhage or cardiac tamponade. The chest x-ray can be normal in 10-20% of patients with AAD, and though transthoracic echocardiography is useful if suggestive findings are seen, and should be used to identify pericardial effusion, TTE cannot be used to exclude AAD. Transesophageal echocardiography, however, reliably confirms or excludes the diagnosis, where such equipment and expertise is available. CT scan with IV contrast is the most common imaging modality used to diagnose and classify AAD, and MRI can be used in patients in whom the use of CT or IV contrast is undesirable. Recent specialty guidelines have helped define high-risk features and a diagnostic pathway that can be used the emergency department setting. Initial management of diagnosed or highly suspected acute aortic dissection focuses on pain control, heart rate and then blood pressure management, and immediate surgical consultation.

Evolution and Analysis of Heterogeneity in the Clinical Expression of Aortic Diseases Similar to Marfan’s Syndrome: Challenge and Art in Clinical Diagnosis

Introduction: Marfan’s syndrome (MFS) is a dominant autosomal connective tissue disease that affects eyes, musculo-skeletal and cardiovascular systems. The initial evaluation must be meticulous. Because there are discrete clinical data only in aortic diseases similar to MFS. Objective: To conduct a retrospective evaluation of the diagnostic criteria applied upon admission of patients with MFS, the evolution of aortic deterioration, surgery, and survival over a period from 1983 to 2008. Material and Methods: Clinical, surgical and pathological records of patients diagnosed with Marfan’s syndrome were examined. Clinical findings, classification, established diagnoses, initial manifestations, duration of the disease, pathological findings, therapy, and survival were all re-evaluated. Results: A total of 166 patient files were studied. Seventy-eight had family histories of MFS. Seven did not fulfill the criteria for MFS, two might correspond to Shprintzen-Goldberg syndrome, three to Ehlers-Danlos syndrome, and two to Loeys-Dietz syndrome. Surgeries were performed in 63 adults. The survival rate of patients with aortic dilatation was 70% at 12 years. Survival diminished with aortic dissection. The mortality of the entire population was 14%. Conclusions: The evolution of MFS and other aortic diseases is variable. Cardiovascular damage is the factor that most commonly has an adverse effect on prognoses and must be under constant observation. Adding the Ghent criteria to clinical evaluation and attention to specific clinical findings can improve the classification of cases. Delays in diagnosis generally occur during the transition from adolescence to adulthood.

Repair of Dilated Aortic Root and Sinotubular Junction Using a Stabilizer Ring

Aortic root aneurysm and dissection are potentially life-threatening conditions that involve a structural weakness of the aortic wall. Management of aortic root aneurysm (with or without aortic insufficiency) has recently been the subject of much scholarly discussion which resulted in some modifications. The current trend is a valve-sparing root repair or replacement as well as preserving or restoring the diameter of the aortic annulus and sinutubular junction. This manuscript reviews the etiology and diagnosis of aortic root aneurysm or dilated aortic annulus as well as a novel treatment approach. A newly patented apparatus that restores and repairs the aortic annulus and sinotubular junction is reviewed.

Molecular Cloning of a Novel PPEF-1 Gene Variant from a T-Cell Lymphoblastic Lymphoma Cell Line

To determine if there is a gene variant of protein serine-threonine phosphatase with EF hand (PPEF-1) in T-cell lymphoblastic lymphoma SUP-T1 cell line, both in silico and in vitro approaches were conducted. In silico, a cDNA clone showing similar sequence to PPEF-1 was isolated from the SUP-T1 cDNA library and named PPEF-1V. The full-length of the PPEF-1V cDNA clone is a 2135bp containing a 1503bp open reading frame extending from 188bp to 1690bp, which corresponds to an encoded protein of 501 amino acid residues with a predicted molecular mass of 57.8 kDa. Alignment on both PPEF-1V and PPEF-1 sequences showed that PPEF-1V is a 350bp deletion in the nucleotide sequence of PPEF-1 from 128-477bp and a 152-amino-acid N-terminal deletion in the amino acid sequence of PPEF-1. In vitro, PPEF-1V transcript fragment was only highly expressed in T-cell lymphoblastic lymphoma cell line. In conclusion, the present patent showed that PPEF-1V could be a potential target for diagnosis or treatment of T-cell lymphoblastic lymphoma.

Novel Biomarkers Assessing the Calcium Deposition in Coronary Artery Disease

Coronary atherosclerosis is the pathophysiologic background of coronary artery disease. Vascular calcification is an actively regulated form of calcified tissue metabolism and a common feature of coronary atherosclerotic plaques. Interestingly, systematic research has revealed that vascular mineralization, is also a strong and independent predictor of cardiovascular morbidity and mortality. Recently, several biomarkers, including osteopontin, fetuin-A, matrix-carboxyglutamic acid protein, pyrophosphates, bone morphogenetic proteins, leptin, osteoprotegerin have emerged as surrogate markers of coronary calcification. Furthermore, biomarkers of vascular calcification can be used as prognostic markers of coronary artery disease and can predict future cardiovascular events and mortality. Nevertheless, there is little knowledge on the usefulness of these biomarkers in evaluating the results of treatments targeting coronary artery disease. Within this context, the present review sets out to discuss the role of new biomarkers assessing calcium deposition in coronary arteries and their role in the prognosis, progression, and treatment of cardiovascular disease.

Transforming Growth Factor β Signaling Perturbation in the Loeys-Dietz Syndrome

The transforming growth factor β (TGFβ) superfamily consists of multipotential secreting cytokines that mediate many key events in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act as ligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) and type 2 (TGFβRII), and TGFβRIII receptors which include an ubiquitous extracellular β-glycan and the membrane glycoprotein endoglin (CD105). Binding of TGFβs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, which then translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFβ signaling has been implicated in various human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes have been found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity is represented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/or cleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysms and dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologic hallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS, as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβ activity in disease management.

Antibody Targeting of TGF-β in Cancer Patients

The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-βs inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.

The Shock of the New: Progress in Schizophrenia Genomics

A growing list of common and rare genetic risk variants are being implicated in schizophrenia susceptibility. As with other complex genetic disorders most of the variance in genetic risk is still to be attributed. What can be learned from progress to date? The available data challenges how we conceptualize schizophrenia and suggests strong aetiological links with other psychiatric and developmental disorders. With the identification of rare copy number risk variants implicating specific genes (e.g. VIPR2 and NRXN1) it is increasingly possible to investigate molecular aetiology in patient subgroups to establish whether schizophrenia represents one or many different disease processes. This review summarizes recent research progress and suggests how the tools of modern genomics and neuroscience can be applied to best understand this devastating disorder.

Aptamers Against Cell Surface Receptors: Selection, Modification and Application

Aptamers are synthetic oligonucleotides selected from pools of random-sequence oligonucleotides which bind to a wide range of biomolecular targets with high affinity and specificity. Compared with antibodies, aptamers exhibit significant advantages including small size, easy synthesis and modification, as well as low immunogenicity. Many of the aptamers also show inhibition of their targets, making them potential therapeutic and targeting reagents in clinical applications. Compared with aptamers against intracellular proteins and molecules, however, the identification of aptamers against cell-surface receptors and receptor-related antigens is more difficult, due to the complex cellular environment in which receptors are located, and also the unique conformations and compositions of receptors to keep their activity. In this review, we will introduce the identification, modification and working mechanism of aptamers against cellsurface receptors. Based on the different characteristics of target receptors and selection strategies used, the identified aptamers show distinct binding affinity with recombinant targets or specific cell lines which express receptors on the surface in vitro. Some of the in vivo experiments also indicate that aptamers have the capability of inhibiting the overexpressing receptor-related tumor growth, working as potential anti-tumor therapeutic drugs. Despite of the difficulties during the selection of receptor aptamers and the study of their working mechanism during the present time, it is possible that in the future aptamers will increasingly exhibit therapeutic and diagnostic utility.

Anti-Inflammatory Activity of Tetracyclines: Applications to Human Disease

Tetracyclines possess anti-inflammatory characteristics which are largely independent of their antibacterial activity. A variety of in vitro biologic effects have been reported for tetracyclines in both immune and non-immune cells. The in vivo therapeutic efficacy of tetracyclines in diseases such as rheumatoid arthritis, multiple sclerosis, and stroke has also been demonstrated in both animal models and clinical studies. This review describes the experimental evidence which demonstrates the various non-antibacterial anti-inflammatory activities of tetracyclines and discusses possible mechanisms of action of these drugs.

Complications of the Chest Wall and the Respiratory System After Surgery and Functional Performance

In a population of patients after successful heart surgery for congenital heart defects (CHD) might emerge noncardiac morbidities. Malfunction of the respiratory system (RS) including chest wall deformities (CWD) may represent risk for a long-term functional performance and QoL of these subjects. This review aims for the long-term (abnormal pulmonary hemodynamics prior to surgery) or short-term (e.g. thoracotomy) harmful impacts on the developing RS. CHD with redundant lung recoil may induce dramatic worsening of the mechanical properties of the RS. Despite successful repair of CHD harmful and successive adaptive processes may affect future development of the RS. Surgical treatment of CHD requires thoracic wall incision (median sternotomy or lateral thoracotomy), which currently with other perioperative impacts may represent unfavourable formation of CWD. Surprisingly, heart surgery itself does not lead either to an improvement or marked change in the severity or frequency of preoperative lung abnormalities (mostly lung volume restriction, hyperinflation, stiff lung or airway obstruction). Causes of RS dysfunction and CWD in patients after surgical repair of CHD are multifactorial. Therefore, a management of these abnormalities especially in adult and aged CHD is difficult. The early primary repair of CHD and recent interventional approaches (e.g., superior ministernotomy or usage of Amplatz occluder) may provide advantages regarding developing organ systems and prevent secondary changes of the heart and the RS. Further research should focus on individual factors in the development of CWD and postoperative respiratory changes. Long-term and/or probably permanent follow up of subjects after CHD repair is a must.

Pleiotropic Effects of ARB in Vascular Metabolism - Focusing on Atherosclerosis-Based Cardiovascular Disease

The renin-angiotensin system (RAS) plays an essential role in fluid and electrolyte homeostasis and the regulation of vascular tone; however, dysregulation and over-activation of the RAS lead to the pathogenesis of various cardiovascular diseases. The RAS is closely associated with NADPH oxidase, a major enzymatic source of reactive oxygen species (ROS) in vasculature, and angiotensin II, the final effecter of the RAS, is a potent stimulator of this oxidase. There are accumulating evidences to support the significance of NADPH oxidase in the pathogenesis of atherosclerosis. We demonstrated that the expression of NADPH oxidase is markedly enhanced in human atherosclerotic coronary arteries, and the distribution of oxidized oxidized low-density lipoprotein (LDL) in vasculature is closely associated with NAPDH oxidase and ROS. Our series of observations indicate there is a vicious circle consisting of vascular NADPH oxidase, the RAS, ROS, and oxidized LDL. Furthermore, we demonstrated that angiotensin II type 1 receptor blockers (ARBs) significantly suppressed the expression of NADPH oxidase p22phox in the aortic walls of patients with thoracic aortic aneurysm. ARBs, widely used for treatment of hypertension and hypertension-related organ damage, have succeeded in reducing the onset of cardiovascular diseases, preventing organ damage, and cardiac death. These beneficial effects of ARBs are largely dependent upon their primary effects of blood pressure lowering. However, this group of agents exerts a wide variety of biological effects on vascular metabolism, including antioxidative and anti-inflammatory actions. These pleiotropic actions play a role in cardiovascular protection. From a viewpoint of oxidative stress, we discuss pleiotropic effects of ARBs on vascular metabolism focusing on pathogenesis of atherosclerosis-based cardiovascular diseases.

Transforming Growth Factor-β Signaling in Motor Neuron Diseases

Transforming growth factor β (TGF-β), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. The TGF-β1, -β2, and -β3 isoforms are expressed by neurons and glial cells, and their receptors are expressed throughout the central nervous system. Several lines of evidence demonstrate that TGF-β signaling protects neurons from glutamate mediated excitotoxicity, a putative mechanism underlying the pathogenesis of various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Recent studies indicate that the TGF-β-Smad2/3 pathway restores motor function in a mouse model of ALS, and that disruption of TGF-β signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, the TGF-β-Smad2/3 pathway regulates the function of glial cells, although the implication of this regulation in neurodegeneration remains elusive. Conversely, myostatin, a member of the TGF-β superfamily, has gained attention as a potential therapeutic target for neuromuscular disorders because genetic deletion of this factor results in increased muscle volume. Signal transduction by BMP, a member of the TGF-β super family, regulates the function and growth of the neuromuscular junction, while the disruption of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-β signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.

Clinical Implications of Non-Invasive Measurement of Central Aortic Blood Pressure

Central arterial systolic blood pressure is a very important factor in the pathophysiology of cardiovascular diseases. Central arterial pressure is a better predictor of cardiovascular risk than peripheral brachial blood pressure. Measurement of central blood pressure is useful for a diagnosis of spurious systolic hypertension in young people. Antihypertensive drugs have a different impact on central blood pressure, for example angiotensin converting enzyme inhibitors, antagonists of angiotensin II receptors, calcium channel blockers more effectively lower central blood pressure than betablockers, despite all of those drugs (including beta-blockers) having a similar impact on peripheral pressure. This mechanism may be responsible for the beneficial effect of some antihypertensive drugs on cardiovascular end points observed in clinical trials, despite a low peripheral hypotensive effect. However, further clinical trials are required to provide more evidence for the prognostic and therapeutic implications of the measurement of central blood pressure before adopting its routine application in clinical practice.

Somatic Genome Variations in Health and Disease

It is hard to imagine that all the cells of the human organism (about 1014) share identical genome. Moreover, the number of mitoses (about 1016) required for the organisms development and maturation during ontogeny suggests that at least a proportion of them could be abnormal leading, thereby, to large-scale genomic alterations in somatic cells. Experimental data do demonstrate such genomic variations to exist and to be involved in human development and interindividual genetic variability in health and disease. However, since current genomic technologies are mainly based on methods, which analyze genomes from a large pool of cells, intercellular or somatic genome variations are significantly less appreciated in modern bioscience. Here, a review of somatic genome variations occurring at all levels of genome organization (i.e. DNA sequence, subchromosomal and chromosomal) in health and disease is presented. Looking through the available literature, it was possible to show that the somatic cell genome is extremely variable. Additionally, being mainly associated with chromosome or genome instability (most commonly manifesting as aneuploidy), somatic genome variations are involved in pathogenesis of numerous human diseases. The latter mainly concerns diseases of the brain (i.e. autism, schizophrenia, Alzheimers disease) and immune system (autoimmune diseases), chromosomal and some monogenic syndromes, cancers, infertility and prenatal mortality. Taking into account data on somatic genome variations and chromosome instability, it becomes possible to show that related processes can underlie non-malignant pathology such as (neuro)degeneration or other local tissue dysfunctions. Together, we suggest that detection and characterization of somatic genome behavior and variations can provide new opportunities for human genome research and genetics.

Arrhythmias and Left Ventricular Hypertrabeculation/Noncompaction

Arrhythmias in left ventricular hypertrabeculation/noncompaction (LVHT) comprise sustained or non-sustained ventricular tachycardia (VT) (n=135), atrial fibrillation (AF) (n=96) AV block (n=55) and QT prolongation (n=47). The prevalence differs between children and adults. In children most frequent are WPW-syndrome (n=24), AV block (n=24), VT (n=17) and bradycardia (n=15). In adults most frequent arrhythmias are VT (n=118), AF (n=95), QT prolongation (n=42) and AV block (n=31). Some arrhythmias are more frequently reported in children than in adults like WPW-syndrome (24 vs. 17 patients), second-degree AV block (4 vs. 0 patients), bradycardia (15 vs. 3 patients) and ventricular fibrillation (VF) (9 vs. 5 patients). There are nearly no pediatric cases with AF (1 vs. 95 patients). In 120 patients implantable cardioverters/defibrillators have been implanted for primary or secondary prevention of sudden cardiac death. The pathomechanisms of arrhythmias in LVHT are largely unknown, especially if patients with LVHT and neuromuscular disorders are more prone to arrhythmias than patients without. There is a need to clarify risk factors for VT or VF because 19% of LVHT patients with VT or VF have a normal systolic function and demonstration of systolic dysfunction is no reliable risk marker. Data about long-term follow- up of LVHT patients with implanted cardioverters/defibrillators are necessary since the indication for prophylactic implantation is still unclear. AF in LVHT increases the embolic risk, thus it would be useful to know which LVHT patients who have sinusrhythm at baseline are prone to develop AF in order to start early with anticoagulant therapy.

Neurological Involvement in Rheumatoid Arthritis

Joints but specifically the synovial is the most important target in rheumatoid arthritis (RA) yet the disease is a systemic inflammatory disorder where extraarticular manifestations are common. Among extraarticular organs and systems affected by RA, central and peripheral nervous system involvement is frequent and associated with significant morbidity and, in some cases, reduced life span. It may produce a myriad of symptoms and signs ranging from subtle numbness in a hand, to quadriparesis and sudden death. Central and peripheral neurologic damage may arise from structural damage produced by RA in diarthroidal joints, by the systemic inflammatory process of the disease itself or by the drugs used to treat it. Neurologic syndromes in these patients may appear suddenly or developed slowly through months, and emerge early or after years of having RA. Neurologic manifestations may be easily overlooked or incorrectly assigned to peripheral arthritis unless the attending physician is aware of these complications. In this article, we review neurologic involvement in RA patients with emphasis on clinical approach for early detection.

Treatment of Choroidal Neovascularization in High Myopia

High myopia affects approximately 2% of general population, and is a major cause of legal blindness in many developed countries. Choroidal neovascularization (CNV) is the most common vision-threatening complication of high myopia. Different therapeutic approaches have been attempted such as thermal laser photocoagulation, surgery and photodynamic therapy with verteporfin (PDT). The visual outcome of these therapies has been reported to be better than the natural history of the condition. However, the limited visual acuity improvement after PDT monotherapy and the appearance of subretinal fibrosis and chorioretinal atrophy prompted the association of other therapies. In the past few years a tremendous advance in the knowledge of the mechanisms underling CNV secondary to high myopia and age related macular degeneration has been achieved, leading to new therapeutic targets and novel drugs and combined therapies. These new therapeutic weapons have been designed to achieve a selective shut down of choroidal new vessels. Recent reviews have been published on the natural history and therapies for myopic CNV. Ohno-Matsui reported on the natural history of the condition as well as the outcome of laser photocoagulation, surgical extraction of CNV, foveal translocation and photodynamic therapy on myopic CNV in the short-term [1]. Soubrane et al. reviewed the new advances on surgery, laser photocoagulation and PDT, considering some of the potential effects of triamcinolone, pegaptanib and ranibizumab in CNV secondary to age related macular degeneration (AMD) [2]. Novack et al. reported on the pharmacological therapy of CNV in AMD [3]. The aim of this review is to summarize the recent advances in myopic CNV pathophysiology and the new therapeutic targets and drugs that are changing the clinical management of myopic CNV.

Genetics of Congenital Heart Disease

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease.

Sudden Unexpected Death in Infancy (SUDI) — The Role of the Pathologist

The involvement of a pathologist with forensic and pediatric training in all stages of the assessment of sudden and unexpected infant death (SUDI) is crucial as pathologists are among a limited group of medical practitioners who have been trained in evaluating the interaction of injuries, disease processes, and post-mortem changes. However problems exist, with variations in the quality of pediatric autopsy practice and in diagnostic categories that are applied. While the development of standard definitions and protocols has improved this situation, use of the term SUDI as an umbrella term has also assisted in evaluating trends and reducing the impact of diagnostic shift. The following paper reviews the contributions that may be made by pathologists in cases of SUDI, from an initial evaluation of a death scene, through the autopsy process, discussions with families, research and participation in multidisciplinary death review committees.

Endovascular Repair of Thoracic Aortic Aneurysms

A thoracic aortic aneurysm is a potentially life-threatening condition that involves a structural weakness of the aortic wall, which can lead to aneurysm, rupture, or dissection. Optimal treatment strategies for lesions of the thoracic aorta are still controversial. Open surgery is complex and is associated with significant morbidity and mortality. Endovascular stenting has emerged as an alternative to open repair in patients requiring surgery for thoracic aortic pathology. Endovascular treatment of vascular disease involving the descending thoracic aorta can be performed safely. It is an alternative option to open repair, less invasive, and carries a relatively low risk. Due to the low morbidity and mortality of endovascular repair, this option has become attractive to many surgeons lately. Stent grafting has become the first-line approach to traumatic thoracic aortic transections in some trauma centers. However, the challenges of accurate placement within an angulated arch, size of the delivery system, and uncertainty regarding long-term durability have been cited as reasons for caution. Major challenges are the technical aspects of the procedure and the learning curve to handle the delivery system and the variability in the anatomy of the aorta. The goal of this article is to review endovascular repair of the thoracic aorta in the current literature outlining some recent patents.

Sleep in Pediatric Pulmonary Diseases

Sleep problems are common in pediatric patients with chronic respiratory disorders. Nocturnal awakenings are frequent in children with asthma. Chronobiologic rhythms impact the pathophysiology of nocturnal asthma. Poor sleep quality can lead to impaired school performance, neurocognitive defects and attention problems in children. As lung function worsens sleep disruption becomes more prominent in patients with cystic fibrosis. Bronchopulmonary dyplasia has been associated with hypoxia during sleep. These infants have been reported to have reduced total sleep time, sleep fragmentation and reduced REM sleep. Nocturnal respiratory variations are exaggerated at night in children with sickle cell disease and the nocturnal hypoxia has been associated with painful crisis. Adenotonsillar hypertrophy with attendant obstructive sleep apnea worsen these episodes in sickle cell disease. In children with kyphoscoliosis hypoventilation at night worsens during REM sleep. Nocturnal hypoventilation generally precedes respiratory failure. Sleep-disordered breathing with excessive daytime sleepiness has been well described in pediatric neuromuscular disorders. Abnormal sleep patterns including sleep-disordered breathing occur in infants with apnea of prematurity and sudden infant death syndrome. Further research in this diverse group of sleep disorders in children exploring the pathophysiology and treatment is essential.

Increased Paternal Age and Child Health and Development

The large number of adverse health outcomes associated with advanced paternal age is not widely recognized by the pediatric community. An exploration of the clinical and public health implications of this issue is required so as to develop appropriate policies. Included in this review are the clinically relevant conditions and diseases currently known to be associated with increasing paternal age, including diminutions in child IQ and social function [1], increased rates of low birth weight, certain childhood cancers, autistic spectrum disorders, schizophrenia, achondroplasia, Apert syndrome, Crouzon syndrome, and Multiple Endocrine Neoplasia (MEN). Other conditions for which there may be increased rates, but for which the data are still inconclusive, also are discussed. As men delay childbearing in the developed world, there is a need for pediatricians to be aware of the potential consequences. This paper provides pediatricians with a reference for conditions in children that are related to advanced paternal age, assisting them in maintaining a high index of suspicion, and for use in responding to questions from parents about this issue.

Molecular Targets and Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a very significant health problem in the United States. Current therapeutic options are surgery or endovascular stenting. Medical treatment is not very effective and there is no medical therapy that can effect the regression of AAA. Surgical or endovascular intervention for many older patients will be unnecessary if medications could prevent or reduce the progression rate of small AAA by 50%. Basic research has helped to determine the molecular basis of pathogenesis in AAA. Mediators of aortic damage include angiotensin II, leukotriene- LT4, prostaglandin- PGE2, interleukins, tumor necrosis factor, tissue plasminogen activator, c-Jun N-terminal Kinase, NF-κB, Rho kinases, osteoprotegerin and chymases. They work in concert to activate matrix metalloproteinase, serine proteases and cysteine proteases. The result is degradation of aortic wall proteins, extracellular matrix and apoptosis of vascular smooth muscle cells. An enhanced understanding of the pathogenetic pathways has led to significant research and development of new molecules, which can inhibit these pathways and delay the expansion of AAA. We discuss newly patented agents that may have a beneficial role in preventing the progression of AAA.

The Extracellular Matrix of Blood Vessels

Blood vessels are highly organized and complex structure, which are far more than simple tubes conducting the blood to almost any tissue of the body. They are able to autonomously regulate the blood flow, thus providing the tissues an optimal support of oxygen and nutrients and an efficient removal of waste products. In higher organisms, the blood vessel forms a closed circuit system, which additionally has the ability to seal itself in case of leakage as a result of injury. The blood vessel system does not only transport soluble substances, but also serves as “highway” system for leukocytes to patrol the body during the immunological surveillance and to reach the inflammation site quickly. In a complex interplay with the vascular wall, leukocytes are able to penetrate the blood vessel without any obvious leakage. Pathologically, tumor cells subvert the blood vessel system to disseminate from the primary tumor and colonize distant organs during metastasis. The extracellular matrix (ECM) of a blood vessel contributes substantially to the diverse functions of the blood vessel. First, the ECM constitutes the scaffold which keeps the histological structure of the vessel wall in shape but also bears the enormous and permanent mechanical forces levied on the vessel by the pulsatile blood flow in the arteries and by vasoconstriction, which regulates blood flow and pressure. The complex network of elastic fibers and tensile forces-bearing networks are well adapted to accomplish these mechanical tasks. Second, the ECM provides informational cues to the vascular cells, thus regulating their proliferation and differentiation. Third, ECM molecules can store, mask, present or sequester growth factors, thereby modulating their effects remarkably. Furthermore, several ECM molecules serve additional functions within the blood vessel. Their expression is altered in a spatial and temporal pattern during blood vessel formation and remodeling. In contrast to vasculogenesis during embryonic development, blood vessel shows a remarkably and life-long plasticity, which allows the formation and regeneration of new blood vessel even in adulthood. Both physiologically during wound healing and pathologically during tumor growth, the sprouting of new blood vessels during angiogenesis is an important process, in which the ECM takes a key role.

Obstructive Sleep Apnea Syndrome: From Phenotype to Genetic Basis

Obstructive sleep apnea syndrome (OSAS) is a complex chronic clinical syndrome, characterized by snoring, periodic apnea, hypoxemia during sleep, and daytime hypersomnolence. It affects 4-5% of the general population. Racial studies and chromosomal mapping, familial studies and twin studies have provided evidence for the possible link between the OSAS and genetic factors and also most of the risk factors involved in the pathogenesis of OSAS are largely genetically determined. A percentage of 35-40% of its variance can be attributed to genetic factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAS phenotype. Although the role of specific genes that influence the development of OSAS has not yet been identified, current researches, especially in animal model, suggest that several genetic systems may be important. In this chapter, we will first define the OSAS phenotype, the pathogenesis and the risk factors involved in the OSAS that may be inherited, then, we will review the current progress in the genetics of OSAS and suggest a few future perspectives in the development of therapeutic agents for this complex disease entity.

Developments in Non-Surgical Therapies for Abdominal Aortic Aneurysm

The introduction of ultrasound screening combined with the increasingly elderly population means that the number of small abdominal aortic aneurysms (AAAs) detected is expected to increase over the next decade. At present open or endovascular surgery are the only treatment options for AAA. In this mini-review we discuss the rationale and ongoing attempts to develop non-surgical therapies for AAA.

The Association of Connective Tissue Disorders with Cervical Artery Dissections

A predisposing weakness of the vessel wall has been assumed in patients with spontaneous cervical artery dissections (sCAD). Skin biopsies from many patients with sCAD show mild connective tissue alterations. However, their assessment depends on an invasive and highly specialized technique. Clinical signs of connective tissue disease are absent in the majority of CAD patients. In this review we document that only very few CAD patients are affected by known inherited connective tissue disorders like Ehlers-Danlos syndrome, Marfan syndrome or Osteogenesis Imperfecta. In a second part of this review we discuss the possible role of unrecognized or unknown forms of connective tissue disorders in the etiology of CAD.

Ullrich Congenital Dystrophy and Bethlem Myopathy: Current Knowledge on the Clinical Spectrum, Pathogenesis, and Future Therapeutic Avenues of Collagen VI Related Muscular Dystrophies

Ullrich congenital muscular dystrophy (UCMD) is a genetically and clinically heterogeneous muscle disorder causing severe muscle weakness with proximal joint contractures and distal hyperlaxity linked to collagen VI deficiency. It was initially described within the wider group of muscular congenital dystrophies. Collagen VI is an extracellular matrix protein forming a microfibrillar network. The protein is composed of three different α-chains encoded by separate genes named COL6A1, COL6A2, and COL6A3 in humans. Mutations of collagen VI gene are also responsible for Bethlem myopathy (BM), a relatively mild dominantly inherited disorder characterised by proximal weakness and distal joint contractures that was previously believed to be a completely separate entity. The pathogenesis of both diseases is still poorly understood. However, some recent data, obtained from experiments mouse models and from human myoblast cultures provide valuable insights into the pathogenesis of UCMD. A potential mitochondrial involvement may become the focus of specific therapeutic approaches. In this review we emphasise the typical clinical and biochemical findings that will help the paediatrician to identify collagenopathies within the complex diagnostic group of congenital muscular dystrophies, and outline the current understanding of UCMD pathogenesis, management, and potential therapeutic avenues.

Actions of Selected Cardiovascular Hormones on Arterial Stiffness and Wave Reflections

The large conduit arteries of the thorax and abdomen are elastic while those in the arms and legs are muscular. Alterations in wall properties of elastic arteries occur over time and are usually permanent in nature; acute changes can, however, occur is response to a change in transmural pressure. Chronic alterations in properties of muscular arteries are minimal but changes (e.g vasoconstriction, vasodilation or tone) do occur in response to smooth muscle cell (SMC) stimulation. In general an increase in arterial stiffness (and wave reflection) increases systolic blood pressure (BP) and is detrimental while a decrease is beneficial. The augmentation in systolic BP increases left ventricular (LV) mass, wasted energy, tension-time index (TTI) and myocardial oxygen demand while the fall in diastolic BP decreases coronary artery perfusion causing a mismatch in ventricular/vascular coupling and an imbalance in the myocardial oxygen supply/demand ratio. Cardiovascular hormones such as renin, angiotensin, aldosterone, parathormone, sympathomimetic amines and endothelin induce vasoconstriction and increase arterial stiffness while insulin, thyroxine, testosterone, atrial natriuretic peptide (ANP), estrogen and nitric oxide (NO) have the opposite effect. The undesirable effects can be reversed with selected blocking agents. Vasodilator drugs have little direct active effect on large elastic arteries and unaugmented BP but can markedly reduce wave reflection amplitude and duration and augmentation index by decreasing stiffness of the muscular arteries and reducing transmission velocity of the reflected wave from the periphery to the heart. This decrease in amplitude and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic BP, arterial wall stress, wasted LV energy and TTI.

Studies on Nonsense Mediated Decay Reveal Novel Therapeutic Options for Genetic Diseases

Scientific breakthroughs have often led to commercially viable patents mainly in the field of engineering. Commercialization in the field of medicine has been restricted mostly to machinery and engineering on the one hand and therapeutic drugs for common chronic ailments such as cough, cold, headache, etc, on the other. Sequencing of the human genome has attracted the attention of pharmaceutical companies and now biotechnology has become a goldmine for commercialization of products and processes. Recent advances in our understanding of basic biological processes have resulted in the opening of new avenues for treatment of human genetic diseases, especially single gene disorders. A significant proportion of human genetic disorders have been shown to be caused due to degradation of transcripts for specific genes through a process called nonsense mediated decay (NMD). The modulation of NMD provides a viable therapeutic option for treatment of several genetic disorders and therefore has been a good prospect for patenting and commercialization. In this review the molecular basis for NMD and attempts to treat genetic diseases which result from NMD are discussed.

Periostin as a Heterofunctional Regulator of Cardiac Development and Disease

Periostin (Postn) is a heterofunctional secreted extracellular matrix (ECM) protein comprised of four fasciclin domains that promotes cellular adhesion and movement, as well as collagen fibrillogenesis. Postn is expressed in unique growth centers during embryonic development where it facilitates epithelial-mesenchymal transition (EMT) of select cell populations undergoing reorganization. In the heart, Postn is expressed in the developing valves, cardiac fibroblasts and in regions of the outflow track. In the adult, Postn expression is specifically induced in areas of tissue injury or areas with ongoing cellular re-organization. In the adult heart Postn is induced in the ventricles following myocardial infarction, pressure overload stimulation, or generalized cardiomyopathy. Here we will review the functional consequences associated with Postn induction in both the developing and adult heart. The majority of data collected to date suggest a common function for Postn in both development and disease as a potent inducible regulator of cellular reorganization and extracellular matrix homeostasis, although some alternate and controversial functions have also been ascribed to Postn, the validity of which will be discussed here.

Screening Aortic Drug Treatments Through Arterial Compliance Measurements

Abdominal aortic aneurysm (AAA) is a common and deadly problem. The aortic diameter increases in association with a complex remodeling process that includes changes in the structure and content of key proteins, elastin and collagen. As these changes occur, the tissue mechanical properties also change. The natural history of AAA is progressive enlargement to a point of mechanical tissue failure typically followed by death. Currently, the marker used to predict the risk of impending rupture is the largest transverse diameter. After reaching a diameter threshold of 5.5 cm the AAA needs to be surgically repaired. This criterion does not consider any patient-specific information or heterogeneity of the AAA that may, in some cases, lead to rupture before the AAA reaches the standard intervention threshold. Conversely, in many patients, continued observation beyond this threshold is safe. While no medical treatment is yet approved, doxycycline (Doxy) has been shown to greatly reduce AAA growth in animal models and has been shown to slow growth in 1 small clinical trial. While larger prospective randomized trials are needed, one unknown is what effect Doxy has on the structural integrity of the aortic wall. That is, does slowed AAA growth, by Doxy treatment, prevent rupture, or does the wall continue to weaken and the AAA instead ruptures at a smaller diameter? Using an established animal model of AAA, we begun to determine the changes in tissue mechanics compliance of the aorta as the AAA develops. Our current research is focused on verifying that these changes mimic the observed changes seen in the human population as reported by other researchers, so that we can confidently study how potential drug therapies may affect wall strength and compliance in the human population. The long-term objectives are to understand better factors related to progression of AAA and help verify that drug therapy with Doxy will decrease the chance of rupture by preventing wall weakening and maintaining function of the aorta.

Molecular Genetics of Abdominal Aortic Aneurysm: Therapeutic Implications

An abdominal aortic aneurysm (AAA) is usually asymptomatic until the catastrophic event of rupture. Ruptured aneurysms cause ∼5000 deaths each year in the UK. A recent randomized control led trial showed the efficacy of screening for AAA. If a screening programme is implemented, there will be an increase in the detection of small AAAs. AAAs are normally not surgically repaired until their diameter exceeds 5.5cm. A policy of ‘watchful waiting’ is however not risk free as 10% of asymptomatic AAA that rupture are less than 5 cm in diameter. An effective pharmacological treatment to limit aneurysm growth and the risk of rupture would justify screening programmes. The use of agents such as MMP inhibitors, HMG CoA inhibitors and anti-infective agents has yielded disappointing results in clinical trials so far. Adoption of a targeted or personalized treatment strategy may conceivably refine the ongoing efforts to develop efficacious and safe novel treatments for AAA. The cause of AAAs is multifactorial, but 15-20% of patients inherit this condition. There is an approximately 7-fold increase in the prevalence of aortic aneurysms in the male siblings of affected individuals. A monogenic disorder resulting in AAA has not been found, but it is plausible that an inherited predisposition to “sporadic” AAAs may also exist. Over the past decade, there have been an increased interest in identifying specific genes that could be responsible in AAA expansion and progression. This manuscript provides an integrated overview of (1) linkage studies, (2) association studies and (3) micro array analysis aimed at identifying the genes responsible for the development and continued expansion of AAA, and the implications for discovery of novel drug targets and personalized therapy.

Notch Signaling in Cardiovascular Disease and Calcification

Recent increase in human lifespan has shifted the spectrum of aging-related disorders to an unprecedented upsurge in cardiovascular diseases, especially calcific aortic valve stenosis, which has an 80% risk of progression to heart failure and death. A current therapeutic option for calcified valves is surgical replacement, which provides only temporary relief. Recent progress in cardiovascular research has suggested that arterial and valve calcification are the result of an active process of osteogenic differentiation, induced by a pro-atherogenic inflammatory response. At molecular level, the calcification process is regulated by a network of signaling pathways, including Notch, Wnt and TGFbeta/BMP pathways, which control the master regulator of osteogenesis Cbfa1/Runx2. Genetic and in vitro studies have implicated Notch signaling in the regulation of macrophage activation and cardiovascular calcification. Individuals with inactivating Notch1 mutations have a high rate of cardiovascular disorders, including valve stenosis and calcification. This article reviews recent progress in the mechanism of cardiovascular calcification and discusses potential molecular mechanisms involved, focusing on Notch receptors. We propose a calcification model where extreme increases in vascular wall cell density due to inflammation-induced cell proliferation can trigger an osteogenic differentiation program mediated by Notch receptors.