Issue Of Seminars Research Articles

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.

This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future.

Dedication

This special celebratory issue of Seminars in Thrombosis & Hemostasis is dedicated to the memory of all preceding pioneers within the field of hemostasis and thrombosis, as well as the many mentors who have over the many past years helped to develop the emerging talent in the field.

Historical perspectives and memories of progressive supranuclear palsy.

Parkinsonism recalls James Parkinson of London and his description of six patients with "paralysis agitans" in 1817, which neurologist Jean-Marie Charcot renamed Parkinson disease. Its variants, referred to as atypical parkinsonian disorders, are the subject of this issue of Seminars in Neurology through which we continue a journey toward understanding the pathogenesis of these diverse neurodegenerative diseases that are sometimes genetically determined, but are more often sporadic and without familial occurrence.

Edward I. Lee, MD.

I want to thank Dr. Edward Lee for serving as guest editor for this issue of Seminars in Plastic Surgery on “Vascular Anomalies.” I also appreciate the efforts made by the outstanding authors for sharing their knowledge and expertise. Dr. Lee is currently an assistant professor in the Division of Plastic Surgery in the Michael E. DeBakey Department of Surgery at Baylor College of Medicine and Texas Children's Hospital. Dr. Lee specializes in pediatric plastic surgery. He is a graduate of the Baylor College of Medicine in Houston, Texas. Dr. Lee trained in plastic and reconstructive surgery at Baylor, and completed a fellowship in pediatric plastic surgery at Texas Children's Hospital. Dr. Lee has research interests in many aspects of pediatric, craniofacial, and general plastic surgery. He is currently involved in several projects that address surgical outcomes for pediatric patients, including those with vascular lesions. He is a superb clinician and uniquely qualified to edit this issue.

Introduction for the special issue on new paradigms in leukocyte trafficking, lessons for therapeutics

This issue of Seminars in Immunology focuses on recent advances in how immune cells are recruited to sites of tissue and organ injury, viral or bacterial infections, or atherosclerotic lesions. This process of calling leukocytes to affected tissue is the hallmark of inflammation. As beneficial as these mechanisms are for host defense and survival, dysregulation can turn these protective processes against the body and induce chronic inflammatory pathologies such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, or neuropathies. Understanding the molecular processes of immune cell homing will deliver more specific drugable targets for a modern therapeutic armamentarium to defeat inflammatory pathologies. The present issue assembles nine state-of-the-art reviews by outstanding experts in the field describing recent advances.

Platelet-Type von Willebrand Disease: Toward an Improved Understanding of the “Sticky Situation”

We are pleased to highlight in this issue of Seminars in Thrombosis & Hemostasis, the study by Wood et al,1 wherein the authors describe a novel mutation in the platelet GP1BA gene creating a hyperresponsive GPIbα protein—a receptor for von Willebrand factor (VWF)—and causing platelet-type von Willebrand disease (PT-VWD). This is a new naturally occurring mutation in a 23-year-old male patient and is considered the sixth reported mutation thus far in patients described with this disease worldwide. Despite being a rare bleeding disorder, PT-VWD represents a significant challenging clinical problem as it may cause life-threatening bleeding, if not appropriately treated, particularly in situations related to surgeries and childbirth. The clinical diagnosis challenge stems from the close similarity of PT-VWD to the more common bleeding disorder, type 2BVWD.2,3 The discrimination and correct diagnosis can only be made after carefully assessing less commonly performed laboratory tests,3–8 and confirmed only after DNA analysis of the binding regions in the two genes VWF and GP1BA9 has been performed. The report by Woods et al1 highlights some important issues that add to our understanding of this rare but potentially life-threatening bleeding disorder. First, the patient presented with severe bleeding symptoms (rather than mild/moderate bleeding symptoms, and unlike previously reported cases) while also showing other typical laboratory phenotypic data known in this disease such as macrothrombocytopenia, mild spontaneous platelet aggregation, absence from plasma of high-molecular-weight VWF multimers, positive ristocetin-induced platelet aggregation (RIPA) at 0.3 and 0.4 mg/mL, VWF ristocetin cofactor (VWF:RCo) T GP1BA gene mutation that predicted the protein change Try246Leu. This mutation was absent in the unaffected mother and also in 100 healthy control subjects. Second, in that report,1 an attempt was made to quantify the bleeding symptoms in a patient with PT-VWD (bleeding score of 13). The knowledge about variation in bleeding symptoms and the ability to objectively assess these symptoms have proven to be important inmanagement of bleeding disorders and can help predict disease outcome and also aid in treatment.10 The only other such attempt was in a small case series reported recently. This series showed considerable variability in bleeding severity among PT-VWD that is independent of age or gender. The phenotypic variability in type 2B VWD has been reviewed in relation to various mutations and different patients’ cohorts.12 However, a systematic analysis of PT-VWD phenotype and the genotype–phenotype relationship remains to be investigated. Third, for the first time, the level of VWF propeptide (VWFpp) and VWFpp/VWF:Ag ratio was reported in a patient with PT-VWD.1 VWFpp is a 741 amino acid portion that gets cleaved from mature VWF by proteolysis. After cleavage, the VWFpp remains in noncovalent association with the VWF multimers, and both are stored together in the α-granules (megakaryocytes/platelets) or Weibel–Palade bodies (endothelial cells). Upon release and under physiologic pH, the VWF multimers and VWFpp dissociate and are secreted in 1:1 stoichiometric amounts.13 Studies have shown a regulatory role for VWFpp as an intramolecular chaperone for the mature VWF protein and an aid to its storage and multimerization.14,15 The VWFpp circulates in the plasma for a short time, with a half-life of approximately 2 to 3 hours and plasma levels of approximately 1 μg/mL, whereas multimeric VWF circulates with a half-life of approximately 8 to 12 hours and plasma levels of approximately 10 μg/mL.16,17 Recent

IRehab: Incorporating iPads and Other Tablets in Aphasia Treatment

I am just going to let this issue of Seminars in Speech and Language speak for itself. It is a clinical cornucopia of iPad (Apple Inc., Cupertino, CA)/tablet ideas for clinicians in practice. To all but the Luddites among us, even the most technologically timid are aware that the practice of treatment in adult neurogenic communication disorders is being deeply (and to my view, positively) affected by technology, most particularly by advances in tablet and iPad technology and its thunderous appearance in the world of rehabilitation for aphasia and related disorders. This issue should comfort beginners among us.

An Overview of Methods for Comparative Effectiveness Research

Comparative effectiveness research (CER) is a broad category of outcomes research encompassing many different methods employed by researchers and clinicians from numerous disciplines. The goal of cancer-focused CER is to generate new knowledge to assist cancer stakeholders in making informed decisions that will improve health care and outcomes of both individuals and populations. There are numerous CER methods that may be used to examine specific questions, including randomized controlled trials, observational studies, systematic literature reviews, and decision sciences modeling. Each has its strengths and weaknesses. To both inform and serve as a reference for readers of this issue of Seminars in Radiation Oncology as well as the broader oncology community, we describe CER and several of the more commonly used approaches and analytical methods.

Voice Treatment for Nonspecific Chronic Cough and Paradoxical Vocal Fold Motion Disorder in Children

Seminars in Speech and Language, Volume 34, No. 1, is devoted to types and treatment of voice disorders in children. School speechlanguage pathologists (SLPs) may sometimes find it difficult to put children with voice problems on their caseloads because they must show how the disorder affects academic performance. The authors in this issue of Seminars make clear that pediatric voice disorders do impact academic performance. Voice disorders are associated with school absenteeism; decreased participation in academic classes, physical education, and extracurricular activities; and negative attention from classmates and school personnel, thus impacting academic performance and social well-being. Some voice disorders, such as vocal nodules, are familiar to SLPs; others, such as paradoxical vocal fold motion disorder (PVFMD) and nonspecific chronic cough (NSCC), are less familiar. In their article in this issue, Gallena and Kerins describe the nature, assessment, and treatment of NSCC and PVFMD.

David y. Khechoyan, MD.

I want to thank Dr. David Khechoyan for serving as guest editor for this issue of Seminars in Plastic Surgery on orthognathic surgery. We also appreciate the efforts made by each outstanding author for sharing with us their knowledge and expertise.

Fine tuning of the immune response by the Aryl Hydrocarbon Receptor

This issue of Seminars in Immunopathology focuses on the role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in controlling the immune response. AhR has been studied for many years by toxicologists as the receptor mediating the toxic effects of the environmental pollutant 2,3,7,8tetrachlorodibenzo-p-dioxin. However, AhR ligands are provided by the diet and are also generated in the gastrointestinal as a result of complex interactions between the host and the commensal flora. Moreover, endogenous ligands such the 2-(1′H-indole-3′carbonyl)-thiazole-4-carboxylic acid methyl ester or the tryptophan-derivative kynurenine are produced by the metabolism. Thus, the high degree of conservation of AhR throughout evolution and the existence of natural, nontoxic ligands suggests that AhR plays a physiological role in health and disease. The past decade has witnessed significant advances in our understanding of the importance of AhR as a regulator of innate and adaptive immunity. This issue covers several aspects of the role of AhR in the control of the immune response and its relevance for the pathogenesis of immune related diseases. Lawrence and Vorderstrasse outline how AhR influences host response to viruses, bacteria, and parasites, noting how the effects of AhR signaling differ during the response to each pathogen and, therefore, suggesting the existence of pathogen-specific cues that modulate AhR activity. Quintana discusses indetailthe roleofAhR signaling inthecontrol ofT cell and dendritic cell differentiation, and its relevance for the

Old and New Challenges in Hemophilia Management

Welcome to the latest issue of Seminars in Thrombosis & Hemostasis, dealing with some “old” and some “new” hot topics in the field of hemophilia. Thanks to the advances in replacement treatment and in their comprehensive care over the last few decades, persons with hemophilia presently achieve a highly satisfactory quality of life and a life expectancy approaching that of the general male population.[1] Further improvements are confidently awaited from emerging factor concentrates with extended half-life on clinical trials and favorable developments in gene therapy that are overcoming previously disappointing results.[1] [2] Meanwhile, research and clinical efforts are focused on clarifying recognized issues (determinants of bleeding phenotype, assessment of efficacy and safety of treatment in long-term outcomes), facing emerging challenges (age-related comorbidities), and on the whole, optimizing hemophilia management. In this scenario, the 14 hemophilia-related articles in this theme-based issue represent a “bumper issue” that addresses original perspectives and provides recent updates or data, thus renewing interest about such topics.

Why “Neurointerventions” for IR and Why Now?

Why “Neurointerventions” for IR and Why Now?

Correcting Reproductive Health Disparities in Women: An Opportunity to Improve the Health of Future Generations

Reproductive problems pose a significant public health problem for women across all age groups, ethnic, and socioeconomic backgrounds. Women of color, women with few resources, women with limited education, and women from groups such as immigrants, and gay and lesbian who have traditionally faced discrimination, are disproportionately affected. By whatever definition one uses for race and ethnicity, unequal access to care, differences in the pathophysiology of disease, and a disparate response to treatment are all factors that collectively contribute to health disparities in women. Even physiologic processes such as puberty, ovulation, conception, and menopause vary between different ethnic and socioeconomic groups. Of note, reproductive problems are not solely a result of issues related to access to health care. Evidence from the medical literature supports disparities in infertility treatment outcomes and an increased prevalence of problems such as preterm birth, sexually transmitted infections, unintended pregnancy, uterine fibroids, and estrogen-deficiency states.1 In this issue of Seminars in Reproductive Medicine, we focus on these important disparities in reproductive health of women by considering health disparities across the lifespan of women. The guest editors believe preconception and pregnancy represent an unparalleled window of opportunity for intervention(s) that will impact not just the mother and infant but also future generations.

Introduction to Alicia Brooks Armstrong, MD and James Segars, MD

In the current issue of Seminars in Reproductive Medicine, we have dedicated an issue to health disparities in reproductive medicine. We are delighted that our guest editors, Dr. Alicia Brooks Armstrong and Dr. James Segars, have agreed to co-edit this issue. They have recruited a very talented group of investigators to address these important issues.

Matthew T. Lorincz MD, PhD, and John K. Fink, MD

The Guest Editors of this issue of Seminars in Neurology are Matthew T. Lorincz, MD, PhD, and John K. Fink, MD.

Introduction: the unfolded protein response’s role in disease pathophysiology

Introduction: the unfolded protein response’s role in disease pathophysiology

Individual Variability in Aided Outcomes

Researchers are trained to ask broad questions, probing underlying phenomena while assuming observations within a sample are representative of the population. Clinicians, in contrast, work with individuals. For the clinician who prescribes hearing aids, the model of two diagnostically similar patients demonstrating strikingly different aided outcomes has become part of the routine clinical narrative. When the fitting of hearing aids is accompanied by highly variable outcomes, it is difficult to understand if treatment effects are real or artifact, whether the magnitude of an individual’s response is a probable or a chance observation, and ultimately, how experience gained by the clinician from one patient may be applied to other patients. The investigation of individual differences has deep roots in the fields of psychology and education. Within audiology and hearing science, drivers of individual differences have most often been attributed to status-based factors (e. g., cognitive status, fatigue, and attention) or factors related to the individual’s ability to extract and integrate auditory cues. Although the clinical manifestation of individual variability is fueled by these myriad factors, the clinician rarely has insight into these factors. Rather, he or she sees a patient whose outcomes may deviate from established norms, leaving the clinician with little established guidance in treatment selection. Thus, clinicians turn to published guidelines for evidence-based practice. These guidelines are the synthesis of systematic review and provide recommendations that can be used to direct clinical decision making. In this regard, how should a clinician respond when a patient demonstrates outcomes that differ from the expectations set by evidence-based guidelines? By characterizing individual differences and performance ranges in aided outcomes, clinical expectations can be made that encompass more than the mean report alone. This issue of Seminars in Hearing shares a collection of articles that will prepare readers for analysis and interpretation of individual differences that may occur during the evaluation of different hearing aid treatments or outcome measures. The consequent improved understanding of individual differences should help better customize treatment to the individual and their needs.

Musculoskeletal Ultrasound Update

It has been a pleasure to serve as guest editor for this issue of Seminars in Musculoskeletal Radiology. It updates some of the more important applications and addresses new developments in musculoskeletal ultrasound. Unlike other musculoskeletal ultrasound issues or articles, I chose to deviate from the common joint-based organization and instead to arrange the material based on focused topics. In addition, I decided to shorten the length of each article to allow 14 topics to be discussed in a succinct fashion. I am pleased that some of the best known experts in the field have contributed to this issue.

Seeking Balance, Professional and Otherwise

“There is no such thing as work-life balance. Everything worth fighting for unbalances your life.” —Alain de Botton I find the quote attributed to Alain de Botton to be both intriguing and disturbing. I am certain that anybody who reads this editorial (both of you) struggles with the same issue of balance that I do. At times, I too feel like de Botton in that, to do something worthwhile requires a 100% effort. How, then, to feel that we can give 100% in everything that we do? Are there enough hours in the day? The lack of balance in our lives is typically most evident in seeking the inevitable “work-life” balance. Whether one works in academia or private practice, there is always something to do that threatens our personal/family/home time. I know a few practicing interventionalists who seem to be able to compartmentalize the various aspects of their lives, but those individuals are few and far between. There always seems to be something to do, something to accomplish away from what we should expect to be normal work hours. And in the era of electronic communication, it is far too easy to log on to our work e-mail accounts on the weekends and weeknights to decompress the inevitable onslaught of e-mail exchanges on Monday morning. Without a doubt, finding that balance between work and personal life becomes our own personal struggle. Each individual situation is different: Work environment, family support, and personal motivation all contribute to set the tone of our own personal struggle with this important life balance. And although I understand de Botton's point, I must admit that I struggle mightily against the idea that balance is an inaccessible goal. Perhaps it's just more difficult for a physician to accept the concept of the inevitability of the lack of life balance than it is for a Swiss writer (don't worry—I had to look him up, too). It probably is telling that I've been working on editing this Seminars issue all weekend. I have been in e-mail contact with Dan Brown and Bill Rilling about their contributions—and sadly they both responded on a Sunday in short order. There is one other issue I come up against with regard to balance. Let me preface this concept with the statement that I love, truly love, my job as an academic interventionalist. While discussing careers with trainees, I continually come back to the idea that as an academic, I get to be a clinical doctor one day, a researcher the next, and a teacher the following day. I enjoy that diversity more than anything, but it can also lead to a feeling of inadequacy in one or more aspects of this career. Not infrequently I look around our field, or even around my own laboratory, and realize I have some catching up to do with clinical skills, or writing that next paper, or better delivering my vast stores of knowledge to the next generation (frightening to all of us, I'm sure). Add into that mix the inevitable administrative duties and increasingly onerous communication chains, and trying to achieve that appropriate balance in one's professional life seems nearly impossible. Academic so-called triple threats are few and far between these days, for good reason. Who can really do it all? I suppose that this holy grail of balance will likely always seem to be just out of arm's reach, and that continual striving for this level of balance might be the reward in and of itself. I'm choosing to look at it that way: It's more healthy for me and my family, it's less negative, and I need to finish this editorial so I can get going on my other work.