bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparative analysis of tourism policy networks.
Authors: McLeod M. , Chambers D. , Airey D.
Published: February 2018

This chapter examines the formal network relationships that influence the tourism policy making process. It commences with a brief review of the literature on social network analysis, which provides the foundation for exploration of policy networks. In order to illustrate the complexities of the tourism policy making process and the importance of networks within this context, an empirical analysis is presented of the actors involved in the tourism policy making process in two Caribbean countries (Jamaica and Trinidad and Tobago).
SIRF: Quantitative in situ analysis of protein interactions at DNA replication forks
Authors: Roy Sunetra , Luzwick Jessica W. , Schlacher Katharina
Published: February 2018

DNA replication reactions are central to diverse cellular processes including development, cancer etiology, drug treatment, and resistance. Many proteins and pathways exist to ensure DNA replication fidelity and protection of stalled or damaged replication forks. Consistently, mutations in proteins involved in DNA replication are implicated in diverse diseases that include defects during embryonic development and immunity, accelerated aging, increased inflammation, blood disease, and cancer. Thus, tools for efficient quantitative analysis of protein interactions at active and stalled replication forks are key for advanced and accurate biological understanding. Here we describe a sensitive single-cell–level assay system for the quantitative analysis of protein interactions with nascent DNA. Specifically, we achieve robust in situ analysis of protein interactions at DNA replication forks (SIRF) using proximity ligation coupled with 5′-ethylene-2′-deoxyuridine click chemistry suitable for multiparameter analysis in heterogeneous cell populations. We provide validation data for sensitivity, accuracy, proximity, and quantitation. Using SIRF, we obtained new insight on the regulation of pathway choice by 53BP1 at transiently stalled replication forks.
IL-7–dependent maintenance of ILC3s is required for normal entry of lymphocytes into lymph nodes
Authors: Yang Jie , Cornelissen Ferry , Papazian Natalie , Reijmers Rogier M. , Llorian Miriam , Cupedo Tom , Coles Mark , Seddon Benedict
Published: February 2018

IL-7 is essential for the development and homeostasis of T and B lymphocytes and is critical for neonatal lymph node organogenesis because Il7−/− mice lack normal lymph nodes. Whether IL-7 is a continued requirement for normal lymph node structure and function is unknown. To address this, we ablated IL-7 function in normal adult hosts. Either inducible Il7 gene deletion or IL-7R blockade in adults resulted in a rapid loss of lymph node cellularity and a corresponding defect in lymphocyte entry into lymph nodes. Although stromal and dendritic cell components of lymph nodes were present in normal numbers and representation, innate lymphoid cell (ILC) subpopulations were substantially decreased after IL-7 ablation. Testing lymphocyte homing in bone marrow chimeras reconstituted with Rorc−/− bone marrow confirmed that ILC3s in lymph nodes are required for normal lymphocyte homing. Collectively, our data suggest that maintenance of intact lymph nodes relies on IL-7–dependent maintenance of ILC3 cells.
System-Wide Analysis Unravels the Differential Regulation and In Vivo Essentiality of Virulence-Associated Proteins B and C Toxin-Antitoxin Systems of Mycobacterium tuberculosis
Authors: Agarwal Sakshi , Tiwari Prabhakar , Deep Amar , Kidwai Saqib , Gupta Shamba , Thakur Krishan Gopal , Singh Ramandeep
Published: February 2018

Toxin-antitoxin (TA) systems are bicistronic genetic modules that are ubiquitously present in bacterial genomes. The Mycobacterium tuberculosis genome encodes 90 putative TA systems, and these are considered to be associated with maintenance of bacterial genomic stability or bacterial survival under unfavorable environmental conditions. The majority of these in M. tuberculosis have been annotated as belonging to the virulence-associated protein B and C (VapBC) family. However, their precise role in bacterial physiology has not been elucidated. Here, we functionally characterized VapC toxins from M. tuberculosis and show that overexpression of some homologs inhibits growth of Mycobacterium bovis bacillus Calmette-Guérin in a bacteriostatic manner. Expression profiling of messenger RNA revealed that these VapC toxins were differentially induced upon exposure of M. tuberculosis to stress conditions. We also unraveled that transcriptional cross-activation exists between TA systems in M. tuberculosis. This study provides the first evidence for the essentiality of VapBC3 and VapBC4 systems in M. tuberculosis virulence.
The critical role of Bach2 in regulating type 2 chronic airway inflammation
Authors: Yamashita Masakatsu , Kuwahara Makoto
Published: February 2018

Although Bach2 (broad complex-tramtrack-bric a brac and Cap’n’collar homology 2) plays an important role in regulating Th2 cell differentiation and type 2 immune responses, the underlying molecular mechanisms remain unclear. Our current studies demonstrate that Bach2 associates with Batf (basic leucine zipper transcription factor ATF-like) family transcription factors and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2–Batf complex antagonizes the recruitment of the interferon regulatory factor 4 (Irf4)-containing Batf complex to activator protein 1 (AP-1) motifs in the Th2 cytokine gene locus and suppresses Th2 cytokine production and/or Th2 cell differentiation. The deletion of Batf ameliorated the spontaneous development of type 2 airway inflammation that is found in mice with Bach2 deficiency specifically in T cells. Interestingly, Bach2 regulates Batf and Batf3 expression via two distinct pathways. First, the Bach2–Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf–Irf4 complex. Second, Bach2 suppresses interleukin 4 (IL-4)-induced augmentation of Batf and Batf3 expression through the regulation of IL-4 production. These findings suggest that IL-4 and Batf family transcription factors form a positive feedback amplification loop to induce Th2 cell differentiation and that Bach2–Batf interactions block the formation of this amplification loop. Furthermore, we found that reductions in Bach2 confer an innate immunological function on CD4 T cells to induce antigen-independent cytokine production. Some Bach2-deficient lung CD4 T cells showed characteristic features similar to pathogenic Th2 cells, including IL-33 receptor expression and IL-33-dependent Th2 cytokine production. These results suggest a critical role for Bach2 in regulating Th2 cell differentiation and the subsequent onset of chronic type 2 inflammation.
Automatic population of eMeasurements from EHR systems for inpatient falls
Authors: Cho Insook , Boo Eun-Hee , Lee Soo-Youn , Dykes Patricia C
Published: February 2018

Objective

Representing nursing data sets in a standard way will help to facilitate sharing relevant information across settings. We aimed to populate nursing process and outcome metrics with electronic health record (EHR) data and then compare the results with event reporting systems.

Methods

We used the “eMeasure” development process of the National Quality Forum adopted by the American Nurses Association. We used operational definitions of quality measures from the American Nurses Association and the US Institute for Healthcare Improvement and employed concept mapping of local data elements to 2 controlled vocabularies to define a standard data dictionary: (1) Logical Observation Identifiers Names and Codes and (2) International Classification for Nursing Practice. We assessed feasibility using the nursing data set of 7829 and 8199 patients from 2 general hospitals with different EHR systems. Using inpatient falls as a use case, we compared the populated measures with results from the event reporting systems.

Results

We identified 17 care components and 118 unique concepts and matched them with data elements in the EHRs. Including suboptimal mapping, 98% of the assessment concepts mapped to Logical Observation Identifiers Names and Codes and 52.9% of intervention concepts mapped to International Classification for Nursing Practice. While not all process indicators were available from event reporting systems, we successfully populated 9 fall prevention process indicators and the fall rate outcome indicator from the 2 EHRs. We were unable to populate the falls with an injury rate indicator.

Conclusions

EHR data can populate fall prevention process measure metrics and at least one inpatient fall prevention outcome metric.
The impact of cognitive and behavioural change on quality of life of caregivers and patients with ALS and other neurological conditions
Authors: Burke Tom , Galvin Miriam , Maguire Sinead , Pender Niall , Hardiman Orla
Published: February 2018

Cognitive and behavioural changes are relatively common in patients with ALS, but often receive less emphasis than the loss of physical strength and function. There is extensive literature on the impact of cognitive and behavioural changes on Quality of Life (QoL) in caregivers and the patients themselves in a variety of other neurological conditions, the implications of which are directly applicable in many respects to ALS. Based on this information, a number of intervention strategies may be employed, including psycho-educational and psychotherapeutic interventions, group-based support services, cognitive stimulation/training, and multidisciplinary interventions, among others. Specific strategies can be used to manage cognitive and behavioural dysfunction in patients, and may serve to improve the QoL of patients and caregivers, while lessening caregiver burden.
Hastened death: Physician-assisted suicide and euthanasia in ALS
Authors: Russell James A. , Simmons Zachary
Published: February 2018

Amyotrophic lateral sclerosis (ALS), more than any other disease, promotes patient interest in hastened death. From an ethical perspective, end-of-life decision making should pivot on patient-centric considerations. However, medical decisions made by patients and their physicians are embedded in societal mores and the law. Opinions regarding the morality of physician participation in hastened-death and its incorporation into public policy remain sharply divided. This chapter attempts to provide a contemporary and measured review of the differing perspectives and the current status of physician participation in hastened-death. The focus will be on issues particularly relevant to ALS patients and those of us who care for them. Our primary goal is to provide for ALS clinicians a foundation upon which their individual consciences may determine whether their lawful participation in hastened-death can ever be considered an ethically permissible action or a socially acceptable policy.
Haematology
Authors: Provan Drew
Published: February 2018

Haematology is the study of disorders of the blood, both malignant and non-malignant. The diagnosis of blood disease relies on morphology of blood and marrow, along with specialized assays which include coagulation, red cell enzymes, flow cytometry, cytogenetics, and other molecular assays. This chapter covers most of the diseases commonly encountered clinically and provides details relating to these specialized assays used in the modern haematology laboratory.
Infectious and tropical diseases
Authors: Provan Drew
Published: February 2018

This is a brief outline of the current clinical and laboratory investigations of patients suffering from infectious diseases, including those from the tropics. It includes clinical and epidemiological assessment of the patient with fever. The appropriate investigations are discussed and cover the wide range of organisms now found in clinical practice via parasitology, mycology, bacteriology, and virology. Understanding of the laboratory techniques available is important in order to guide their rational use and understand their limitations. The techniques range from traditional methods such as microscopy and culture to newer molecular techniques such as MALDI-TOF and nucleic acid detection polymerase chain reaction. The section on clinical investigation in action outlines the approach to the patient with pyrexia of unknown origin. The increasingly important and complex clinical and laboratory assessment of antimicrobial resistance is also outlined, including how the laboratory fits in with this agenda.
Neurology
Authors: Provan Drew
Published: February 2018

This chapter on neurological investigations provides a concise discussion of the major techniques available for the investigation of patients presenting with neurological problems. Topics include: (1) when to organize, and how to perform, a lumbar puncture, and the interpretation of the cerebrospinal fluid results; (2) a concise introduction to neuroimaging, including functional magnetic resonance imaging (fMRI) and diffusion tractography (DTI); (3) when to request an electroencephalogram (EEG), common EEG abnormalities, and specialist EEG techniques; (5) evoked potential studies; (6) clinical applications of transcranial magnetic stimulation (TMS); (7) a concise account of neuroimmunological testing; (8) an introduction to neurogenetics; and (9) how to perform the edrophonium (Tensilon®) test. It is written for students, general physicians, and neurologists in training.
Renal medicine
Authors: Provan Drew
Published: February 2018

This chapter reviews the investigations required for the diagnosis and classification of acute and chronic kidney diseases. Detailed guidance is provided on the choice of methods to measure or estimate the glomerular filtration rate and to quantify albuminuria/proteinuria. It offers a rational approach to the choice of blood and urine tests in the investigation of patients presenting with haematuria, proteinuria, renal tubular dysfunction, and disorders of acid–base balance. It reviews the pertinent radiological investigations used alongside specialist urine and immunology tests to aid diagnosis. There is a detailed review of the rational investigation of patients with recurrent kidney stone disease. Guidance is provided on laboratory investigation of suspected renal bone disease and on the role of renal biopsy in the investigation of kidney disease.
Radiology
Authors: Provan Drew
Published: February 2018

This chapter gives an overview of the role of radiological investigations in the management and work-up of common clinical conditions across a spectrum of specialties. It also provides an insight into basic interpretation skills and pitfalls when approaching common radiological tests. In addition to providing an evidence-based approach to the utilization of radiological resources, differential diagnoses are provided throughout. Where appropriate, indications and contraindications for radiological techniques are given to provide an essential bedside resource for the practising clinician. More advanced sections tackle the physics underlying each modality, as well as specialized interventional radiology and its role in minimally invasive clinical practice.
Nuclear medicine
Authors: Provan Drew
Published: February 2018

Nuclear medicine is a rapidly evolving branch of medical imaging, which uses radionuclides or radiopharmaceuticals for diagnostic and therapeutic purposes. Nuclear medicine techniques employ a carrier molecule, selected to target the organ/tissue of interest, tagged with a gamma-emitting radioisotope. Nuclear medicine procedures can detect early physiological responses to disease processes, generally before structural changes have taken place. Characterization of abnormalities often relies upon pattern recognition within a particular clinical setting. In this chapter, various procedures and tracers (single photon emission computed tomography (SPECT) and positron emission tomography (PET)) used in nuclear medicine are described in a systematic way, including their common indications, interpretation criteria, advantages, and pitfalls with classical examples.
Oligoarticular disease
Authors: Keat Andrew
Published: February 2018

Oligoarthritis is a pattern of arthritis which most commonly resolves into a member of the spondyloarthritis family or sarcoidosis. Uncommonly it progresses to forms of arthritis more commonly associated with polyarthritis or monoarthritis and rarely it is associated with malignant or paraneoplastic syndromes. Three key aspects of diagnosis are consideration of possible diagnoses in the patient’s age and ethnic groups; careful consideration of the personal and family history; and a search for and correct identification of characteristic associated features. This frequently involves collaborative working with other specialists including dermatologists, ophthalmologists, genitourinary physicians, respiratory physicians, and others. Precise diagnosis usually then involves subsequent investigation for diagnostic features including evidence of recent infection, HLA B27, autoantibodies, tissue-specific features of sarcoidosis, inflammatory bowel disease, and, occasionally, malignant disease. Management is dependent on clear diagnosis and precise delineation of underlying conditions such as infection.
The purpose of this chapter is to provide a guide to the diagnostic approach and an algorithm for routine clinical practice. Detailed descriptions of the conditions included and investigations appropriate for the establishment or exclusion of individual diagnoses are discussed elsewhere in this volume.
Spinal pain
Authors: Gaffney Karl , Hamilton Louise
Published: February 2018

Spinal pain is a very common complaint, and one which rheumatologists must be confident in managing. While most cases are non-specific and self-limiting it is important not to miss the small proportion of patients with pain caused by inflammation, infection, or infiltration. A thorough history is of key importance in this respect, and the approach to the patient with back pain is discussed including physical examination and the value of targeting investigations. The management of common and important causes of back pain is outlined.
Obstetrics and pregnancy
Authors: Østensen Monika , Dolhain Radboud , Ruiz-Irastorza Guillermo
Published: February 2018

Rheumatic diseases occur mostly in women, often during their childbearing years. Most women with rheumatic disease wish to have children, even when functional disability is present. Better therapy and better prognosis for many of the rheumatic diseases has resulted in more patients considering pregnancy. The interaction of pregnancy and rheumatic diseases is varied, ranging from spontaneous improvement to aggravation, sometimes severe, of disease symptoms. Likewise, rheumatic diseases differ with regard to the occurrence of complications during pregnancy, and pregnancy outcome. This chapter describes fertility, the course of maternal disease during pregnancy, and fetal outcome.
Genetics of rheumatoid arthritis
Authors: Eyre Steve , Worthington Jane , Viatte Sebastien
Published: February 2018

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping, and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. Widespread utilization of this approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 100 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease, and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.
Genetics of spondyloarthropathies
Authors: Brown Matthew
Published: February 2018

Spondyloarthropathies are a diverse group of conditions, of which ankylosing spondylitis is the prototypic disease, with shared clinical features, genetic risk factors, and histopathological characteristics. These conditions are highly familial and heritable. Several genes have been associated with spondyloarthropathies, with genes in the IL-23 signalling pathway being shared by the major types of spondyloarthritis. These discoveries have already led to the development and successful clinical introduction of novel treatments for psoriasis and psoriatic arthritis, and major advances in our understanding of the pathogenesis of the conditions. Many more genes remain to be identified which are involved in these common conditions; identifying these genes is likely to be highly informative as to their causes.
Pain neurophysiology
Authors: Schaible Hans-Georg , Straub Rainer H.
Published: February 2018

Physiological pain is evoked by intense (noxious) stimuli acting on healthy tissue functioning as a warning signal to avoid damage of the tissue. In contrast, pathophysiological pain is present in the course of disease, and it is often elicited by low-intensity stimulation or occurs even as resting pain. Causes of pathophysiological pain are either inflammation or injury causing pathophysiological nociceptive pain or damage to nerve cells evoking neuropathic pain. The major peripheral neuronal mechanism of pathophysiological nociceptive pain is the sensitization of peripheral nociceptors for mechanical, thermal and chemical stimuli; the major peripheral mechanism of neuropathic pain is the generation of ectopic discharges in injured nerve fibres. These phenomena are created by changes of ion channels in the neurons, e.g. by the influence of inflammatory mediators or growth factors. Both peripheral sensitization and ectopic discharges can evoke the development of hyperexcitability of central nociceptive pathways, called central sensitization, which amplifies the nociceptive processing. Central sensitization is caused by changes of the synaptic processing, in which glial cell activation also plays an important role. Endogenous inhibitory neuronal systems may reduce pain but some types of pain are characterized by the loss of inhibitory neural function. In addition to their role in pain generation, nociceptive afferents and the spinal cord can further enhance the inflammatory process by the release of neuropeptides into the innervated tissue and by activation of sympathetic efferent fibres. However, in inflamed tissue the innervation is remodelled by repellent factors, in particular with a loss of sympathetic nerve fibres.
Pathogenesis of juvenile idiopathic arthritis
Authors: Bending David , Nistala Kiran , Wedderburn Lucy R. , Rosser Elizabeth C.
Published: February 2018

Although the term juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases, they all share a common pathological hallmark: inflammation of the synovium. Highly activated T cells, monocytes, and neutrophils are attracted to the joint and secrete mediators that not only perpetuate inflammation, but also may attenuate immune regulation. In the oligoarticular and polyarticular forms of JIA, which are thought to be autoimmune conditions, dysregulated adaptive immunity is a likely factor in disease pathogenesis; the nature of the interactions between T-effector cells (Teffs) and T-regulatory cells (Tregs) is probably a key factor in controlling disease progression. Factors that affect the frequency and function of Tregs and/or the sensitivity of Teffs to mechanisms of immune suppression will therefore impact the disease course. In the systemic form of JIA, however, dysregulation of innate immune pathways appears more central to disease pathogenesis, resulting in augmented levels of interleukins IL-1β‎‎, IL-6, and IL-18. In the end, a final common pathological pathway in JIA is the activation of monocytes and neutrophils which are the principal mediators of joint inflammation and damage. This is supported by the fact that the therapies that have targeted innate cytokine pathways have shown greater success in the treatment of JIA.
Autoimmune serology
Authors: Hamann Philip , McHugh Neil
Published: February 2018

Autoimmune serology has become central in the characterization of many rheumatic conditions and in many cases the presence of an autoantibody (e.g. anti-citrullinated peptide, rheumatoid factor, ANCA, ANA, ENA, anti-phospholipid antibody), may form part of the diagnostic criteria. Increasingly, as pathogenic mechanisms are derived, the role of these autoantibodies is becoming better understood. This chapter covers the key techniques (immunoflourescence, immunodiffusion, ELISA, immunoblotting, immunoprecipitation) used in autoantibody detection as well as the clinico-pathological significance of a positive result.
Complement
Authors: Pickering Matthew C. , Bakshi Jyoti
Published: February 2018

In this chapter we summarize clinically important aspects of complement biology. This information is used to present a comprehensive overview of complement deficiency states and provide a logical basis for understanding complement assays in clinical practice. Hypocomplementaemic urticarial vasculitis syndrome, a condition associated with anti-C1q antibodies and complement consumption, is discussed. We summarize the use of eculizumab, a monoclonal antibody that targets and inhibits complement C5, in the treatment of haemolysis in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome.
Limb anatomy and medical imaging
Authors: Benjamin Mike , McGonagle Dennis , Miguel Maribel I. , Bong David A. , Möller Ingrid
Published: February 2018

This chapter provides a generalized framework for helping the clinician to understand basic principles of functional anatomy in the limbs in relation to medical imaging, particularly ultrasonography (US). Certain basic design principles that are evident in the limbs are explained: for example, that larger muscles lie proximally, and that tendons are more numerous and longer distally. While the upper limb is ultimately geared to moving the hand with ease and precision in three-dimensional space, the lower limb is both an organ of propulsion and a column supporting body weight. It is important to note that when the foot is on the ground this has an important influence on muscle function. Fundamental principles of muscle design and action are explained, including the distinction between prime movers, antagonists, synergists, and fixators; the fact that movements and not muscles are represented in the cerebral cortex; the all-or-nothing principle of fibre contraction; the modifying influence of gravity on muscle action; and issues relating to fibre architecture. The less appreciated functions of tendons are included and the difference between an enthesis and an enthesis organ is explained. The similar appearance of nerves and tendons in dissections and even in MRI and US images is explained and the importance of fascia is highlighted—particularly its role as an ’ectoskeleton’. Brief mention is made of adipose tissue and blood vessels, and planes of movement between adjacent structures are described in order to inform the ultrasonographer who deals with structures in real time.
Computed tomography
Authors: Hide Geoff , Humphries Jennifer
Published: February 2018

Computed tomography (CT), along with its cross-sectional partner MRI, continues to evolve apace. Although MRI retains the larger role in the musculoskeletal system due to its unparalleled soft tissue contrast and, not least, its lack of ionizing radiation, CT offers significant advantages in many areas. Imaging acute trauma is more rapid with CT, allowing ‘whole body’ assessment of patients following polytrauma, and CT is more useful than MRI in demonstrating the configuration of fractures, aiding surgical planning. CT can clearly identify cortical bone and areas of calcification, making the diagnosis of tarsal coalitions straightforward and facilitating the diagnosis and characterization of bone tumours such as osteoid osteoma and chondroid lesions. CT arthrography supplements standard imaging with intra-articular contrast to allow the detection of subtle joint abnormalities, and CT can demonstrate needles precisely within bone and soft tissue to enable the performance of complex image-guided procedures. Developments in CT have been especially rapid in the past decade and although this has particularly impacted on cardiac imaging, other areas of medicine, including rheumatology, have benefited. High multislice scanners can obtain data for a volume of tissue allowing reconstruction of slices with exceptional detail in any plane, and can rapidly image large areas of the body such as the spine. CT is responsible for a large proportion of the population’s medical radiation exposure. Although techniques allowing reduction in dose continue to advance, radiologists and referrers retain responsibility to ensure that requests for CT examinations are necessary and justifiable.
Nuclear Medicine Imaging and Therapy in Rheumatology
Authors: Al-Nahhas Adil , Zerizer Imene
Published: February 2018

The application of nuclear medicine techniques in the diagnosis and management of rheumatological conditions relies on its ability to detect physiological and pathological changes in vivo, usually at an earlier stage compared to structural changes visualized on conventional imaging. These techniques are based on the in-vivo administration of a gamma-emitting radionuclide whose distribution can be monitored externally using a gamma camera. To guide a radionuclide to the area of interest, it is usually bound to a chemical label to form a ’radiopharmaceutical’. There are hundreds of radiopharmaceuticals in clinical use with different ’homing’ mechanisms, such as 99 mTc HDP for bone scan and 99 mTc MAA for lung scan. Comparing pre- and posttherapy scans can aid in monitoring response to treatment.
More recently, positron emission tomography combined with simultaneous computed tomography (PET/CT) has been introduced into clinical practice. This technique provides superb spatial resolution and anatomical localization compared to gamma-camera imaging. The most widely used PET radiopharmaceutical, flurodeoxyglucose (18F-FDG), is a fluorinated glucose analogue, which can detect hypermetabolism and has therefore been used in imaging and monitoring response to treatment of a variety of cancers as well as inflammatory conditions such as vasculitis, myopathy, and arthritides. Other PET radiopharmaceuticals targeting inflammation and activated macrophages are becoming available and could open new frontiers in PET imaging in rheumatology.
Nuclear medicine procedures can also be used therapeutically. Beta-emitting radiopharmaceuticals, such as yttrium-90, invoke localized tissue damage at the site of injection and can be used in the treatment of synovitis.
Multidisciplinary treatment
Authors: Ryan Sarah , Adams Jo , O’Brien Anne , Williams Anita
Published: February 2018

Multidisciplinary treatment is required to optimize the physical, psychological, and social function of people living with a long-term musculoskeletal condition. Multidisciplinary treatment is usually provided by a team which includes doctors, nurses, and allied health professionals. Each member of the team provides their own unique contribution with the shared goal of suppressing the activity and impact of the condition while educating and supporting people to manage their own symptoms effectively. This chapter focuses on treatment from the perspective of four disciplines: nursing, physiotherapy, occupational therapy, and podiatry.
Biologics in paediatric rheumatic diseases
Authors: Lovell Daniel J. , Ruperto Nicolino , Brunner Hermine I. , Martini Alberto
Published: February 2018

The introduction of biological therapies into the treatment of children with rheumatic diseases has dramatically changed our expectation about treatment goals in children with a wide variety of forms of chronic arthritis. The outcomes of these children have been dramatically improved. The application of biological therapies to other paediatric rheumatic diseases has been much more limited and a change in treatment of these other rheumatic diseases has been less impacted by the introduction of biological therapies. The overall safety profile of biological therapies in children reveal issues that are similar to those in adults both in the frequency and types of toxicities. The paediatric-specific safety issues are childhood vaccinations and varicella. Biologic therapies have been included in recently developed validated treatment guidelines for juvenile idiopathic arthritis (JIA). Biologic therapies for children with rheumatic diseases have advanced greatly in the last decade and many exciting studies are ongoing and in development.
Vaccination in immunocompromised children
Authors: Heijstek Marloes , Abinun Mario , Wulffraat Nico
Published: February 2018

Can immunocompromised children be safely and effectively vaccinated? This chapter discusses the recommendations from the European League Against Rheumatism (EULAR) for the immunization of immunocompromised patients. Patients with rheumatic or autoinflammatory diseases treated with high-dose glucocorticoids, high-dose disease-modifying antirheumatic drugs (DMARDs), or biologicals are considered immunocompromised. Safe and effective vaccination is crucial in these patients, given their increased risk of infection.
Safe vaccination implies that vaccination has no effect on disease activity and has only mild adverse effects. Effective vaccination denotes that patients are protected against infections after immunization. Particularly in severely immunosuppressed patients, concerns arise on the safety of (live-attenuated) vaccines and on the detrimental effect of immunosuppressive treatment on the immunogenicity of vaccines.
Overall, vaccinations do not increase disease activity and do not cause severe adverse events. It is recommended to withhold live-attenuated vaccines in patients on high-dose immunosuppressive drugs and biologicals, but booster vaccinations can be considered when essential.
Generally, immunogenicity of vaccines is good with some exceptions: responses are reduced in patients on high-dose glucocorticoids and rituximab; methotrexate reduces responses to (pneumococcal) polysaccharide vaccines; and tumour necrosis factor alpha (TNFα‎) may lower vaccine-induced antibody concentrations and may cause accelerated waning of immunity. Offering vaccination before immunosuppressive drugs and/or measuring antibodies after immunization is recommended.
Lyme borreliosis
Authors: Krause Andreas , Fingerle Volker
Published: February 2018

Lyme borreliosis (LB) is a multisystem infectious disease caused by the tick-borne spirochete Borrelia burgdorferi. The most frequent clinical manifestations include erythema migrans, meningoplyneuritis, and arthritis. Diagnosis of LB is made on clinical grounds and usually supported by a positive serology. Early diagnosis and treatment almost always leads to a rapid healing of the disease. However, in late manifestations gradual remission of symptoms may take several weeks to months. In rare cases, the pathogen can persist for many years or induce a persisting immunopathological response that may cause acrodermatitis chronica atrophicans, chronic neuroborreliosis of the central nervous system, or antibiotic resistant Lyme arthritis. However, even these chronic manifestations usually slowly regress after thorough antibiotic and symptomatic therapy, although in part with irreversible organ defects.
Pathogenesis of rheumatoid arthritis
Authors: Thomas Ranjeny , Cope Andrew P.
Published: February 2018

In depth molecular and cellular analysis of synovial tissue and fluid from patients with rheumatoid arthritis has provided important insights into understanding disease pathogenesis. Advances in the 1980s and 1990s included modern cloning strategies, sensitive and specific assays for inflammatory mediators, production of high-affinity neutralizing monoclonal antibodies, advances in flow cytometry, and gene targeting and transgenic strategies in rodents. In the 21st century, technological platforms offer unparalleled opportunities for systematic and unbiased interrogation of the disease process at a whole-genome level. Here we describe the key molecular and cellular characteristics of the inflamed synovium and how infiltrating cells get there. With this background, we outline current concepts of the different phases of disease, how the first phase of genetic susceptibility evolves into autoimmunity, triggered by the exposome, prior to the onset of clinically apparent inflammatory disease. We then describe the pathways that actively contribute to this early inflammatory phase and document the key effector cells and molecules of the innate and adaptive immune systems that orchestrate and maintain chronic synovial inflammatory responses. We summarize how this inflammatory milieu translates to cartilage destruction and bone resorption in synovial joints, and conclude by reviewing those factors in inflamed synovium that promote immune homeostasis.
Sjögren’s syndrome—clinical features
Authors: Bowman Simon , Hamburger John , Price Elizabeth , Rauz Saaeha
Published: February 2018

Sjögren’s syndrome is a chronic, immune-mediated, condition of unknown aetiology characterized by focal lymphocytic infiltration of exocrine glands associated with dry mouth and eyes. It occurs in its own right (primary Sjögren’s syndrome, pSS), or as a late feature of other rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus or scleroderma (secondary Sjögren’s syndrome).
There is a strong female bias. pSS typically affects women in their middle years with an estimated prevalence of 0.1–0.6%. 75% of patients have anti-Ro and/or anti-La antibodies, often with raised immunoglobulin levels (hypergammaglobulinaemia). In patients without these antibodies the diagnosis can be confirmed by salivary gland biopsy.
Treatment is generally symptomatic using artificial tears, saliva replacements/stimulants and good dental hygiene. Three-quarters of patients with pSS report significant fatigue with a negative impact on quality of life. This can be the most disabling symptom. Approximately 20% of patients develop systemic features including persistent salivary gland swelling, cutaneous vasculitis, peripheral neuropathy, interstitial lung disease, autoimmune cytopenias or renal tubular acidosis. Hydroxychloroquine and corticosteroids are the most widely used therapies for systemic features.
There is a 44fold increased risk of mucosa-associated lymphoid tissue (MALT) B-cell lymphoma in pSS, typically affecting the salivary glands. On account of abnormalities in the B-cell system in pSS there is current interest in the use of anti-B-cell directed monoclonal antibodies to treat pSS and a number of clinical trials are in progress. This approach is already successfully in use for treating MALT lymphoma in pSS.
Gout
Authors: Dalbeth Nicola
Published: February 2018

Gout is a common and treatable disorder of purine metabolism. Gout typically presents as recurrent self-limiting episodes of severe inflammatory arthritis affecting the foot. In the presence of persistent hyperuricaemia, tophi, chronic synovitis, and joint damage may develop. Diagnosis of gout is confirmed by identification of monosodium urate (MSU) crystals using polarizing light microscopy. Hyperuricaemia is the central biochemical cause of gout. Genetic variants in certain renal tubular urate transporters including SLC2A9 and ABCG2, and dietary factors including intake of high-purine meats and seafood, beer, and fructose, contribute to development of hyperuricaemia and gout. Gout treatment includes: (1) management of the acute attack using non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or low-dose colchicine; (2) prophylaxis against gout attacks when commencing urate-lowering therapy (ULT), with NSAIDs or colchicine; and (3) long-term ULT to achieve a target serum urate of less than 0.36 mmol/litre. Interleukin (IL)-1β‎ is a central mediator of acute gouty inflammation and anti-IL-1β‎ therapies show promise for treatment of acute attacks and prophylaxis. The mainstay of ULT remains allopurinol. However, old ULT agents such as probenecid and benzbromarone and newer agents such as febuxostat and pegloticase are also effective, and should be considered in patients in whom allopurinol is ineffective or poorly tolerated. Management of gout should be considered in the context of medical conditions that frequently coexist with gout, including type 2 diabetes, hypertension, dyslipidaemia, and chronic kidney disease. Patient education is essential to ensure that acute gout attacks are promptly and safely managed, and long-term ULT is maintained.
Paget’s disease of bone
Authors: Ralston Stuart H.
Published: February 2018

Paget’s disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal abnormalities of bone remodelling which disrupt normal bone architecture, leading to expansion and reduced mechanical strength of affected bones. This can lead to various complications including deformity, fracture, nerve compression syndromes, and osteoarthritis, although many patients are asymptomatic. Genetic factors play a key role in the pathogenesis of PDB. This seems to be mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which increase susceptibility to environmental triggers. Environmental factors which have been suggested to predispose to PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are helpful in defining disease extent. Serum alkaline phosphatase levels can be used as a measure of disease activity. Inhibitors of bone resorption are the mainstay of medical management for PDB and bisphosphonates are regarded as the treatment of choice. Bisphosphonates are highly effective at reducing bone turnover in PDB and have been found to heal osteolytic lesions, and normalize bone histology. Although bisphosphonates can improving bone pain caused by elevated bone turnover, most patients require additional therapy to deal with symptoms associated with disease complications. It is currently unclear whether bisphosphonate therapy is effective at preventing complications of PDB.
Fibromyalgia and chronic widespread pain syndromes—adult onset
Authors: Kuttikat Anoop , Shenker Nicholas , Shaikh Maliha
Published: February 2018

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, excessive fatigue, unrefreshing sleep, and other associated somatic symptoms. FMS is common in the general population with an estimated prevalence of 2-4% and is about six times more common in females than males. FMS causes significant individual and societal costs.
The precise aetiology of FMS remains unclear. Dysfunctional pain processing within the central nervous system is the primary abnormality. FMS is a clinical diagnosis based on pattern recognition and it can coexist with other conditions. A multidisciplinary approach, incorporating patient education, physical therapies, psychological therapies, and pharmacotherapy, is effective in managing these patients.
Panniculitides
Authors: Sunderkötter Cord , Requena Luis
Published: February 2018

Panniculitis is an inflammation that originates primarily in the subcutaneous fatty tissue (panniculus adiposus). It is associated with rheumatological diseases and with adverse events to rheumatological therapies (e.g. poststeroid panniculitis, erythema nodosum, infective panniculitis). The panniculitides are classified histopathologically into mostly septal panniculitis and mostly lobular panniculitis, according to the major or denser localization of the infiltrate, and also into those with or without vasculitis. Additional criteria involve the composition of the inflammatory infiltrate, the cause, and an underlying or associated disease. The clinical hallmarks of panniculitis are subcutaneous nodules or plaques, often located on the lower limb. A deep excisional biopsy is often required for a more precise diagnosis, given the often sparse and monotonous clinical symptoms. Erythema nodosum is the most common form and a typical example of septal panniculitis. It occurs in response to many different provoking factors, the most common trigger in children being a ’strep throat’, in adults sarcoidosis. Clinically, it presents with a sudden symmetrical appearance of painful, tender, warm, erythematous nodes or plaques, usually on the shins, which resemble bruises. Classical and cutaneous polyarteriitis nodosa present a mostly septal panniculitis associated with vasculitis. Here subcutaneous, partially ulcerating nodules are surrounded by livedo racemosa. The mostly lobular panniculitides not associated with vasculitis include lupus panniculitis (lupus erythematosus profundus, typically with ensuing lipoatrophy and predilection for the upper part of the body), panniculitis in dermatomyositis (often calcifiying), cold panniculitis, pancreatic panniculitis, panniculitis due toα‎‎-antitrypsin deficiency, poststeroid panniculitis (in children after rapid withdrawal of corticosteroids), calciphylaxis (with and without renal failure), and factitious panniculitis (after mechanical, physical, or chemical injuries to the subcutaneous tissue, often self-inflicted). Nodular vasculitis (formerly erythema induratum Bazin) is a lobular panniculitis with vasculitis involving mostly the small blood vessels of the fat lobule. It appears to present a (hyper)reactive response to certain infections (tuberculosis, streptococci, candida) or to cold exposure or chronic venous insufficiency in susceptible females. In conclusion, the panniculitides are a heterogenous group of diseases requiring a systematic work-up and knowledge of certain histological or clinical criteria.
Monitoring of the kidneys, liver, and other vital organs
Authors: Werdan Karl , Patel Brijesh , Girndt Matthias , Ebelt Henning , Schröder Jochen , Nuding Sebastian
Published: February 2018

The prognosis of critically ill cardiac patients in the critical care unit and intensive cardiac care unit depends not only on the underlying cardiac disease, but also on the development of secondary organ complications and failures. Therefore, close monitoring of vital organs is mandatory in all critically ill cardiac patients to detect the development of non-cardiac organ failure as early as possible.