Inferential methods for comparing two single cases

In neuropsychological single-case studies, it is not uncommon for researchers to compare the scores of two single cases. Classical (and Bayesian) statistical methods are developed for such problems, which, unlike existing methods, refer the scores of the two single cases to a control sample. These methods allow researchers to compare two cases' scores, with or without allowing for the effects of covariates. The methods provide a hypothesis test (one- or two-tailed), point and interval estimates of the effect size of the difference, and point and interval estimates of the percentage of pairs of controls that will exhibit larger differences than the cases. Monte Carlo simulations demonstrate that the statistical theory underlying the methods is sound and that the methods are robust in the face of departures from normality. The methods have been implemented in computer programs, and these are described and made available (to download, go to http://www.abdn.ac.uk/~psy086/dept/Compare_Two_Cases.htm).     

G6PDdb, an integrated database of glucose-6-phosphate dehydrogenase (G6PD) mutations

G6PDdb (http://www.rubic.rdg.ac.uk/g6pd/ or http://www.bioinf.org.uk/g6pd/) is a newly created web-accessible locus-specific mutation database for the human Glucose-6-phosphate dehydrogenase (G6PD) gene. The relational database integrates up-to-date mutational and structural data from various databanks (GenBank, Protein Data Bank, etc.) with biochemically characterized variants and their associated phenotypes obtained from published literature and the Favism website. An automated analysis of the mutations likely to have a significant impact on the structure of the protein has been performed using a recently developed procedure. The database may be queried online and the full results of the analysis of the structural impact of mutations are available. The web page provides a form for submitting additional mutation data and is linked to resources such as the Favism website, OMIM, HGMD, HGVBASE, and the PDB. This database provides insights into the molecular aspects and clinical significance of G6PD deficiency for researchers and clinicians and the web page functions as a knowledge base relevant to the understanding of G6PD deficiency and its management.     

DNA sequence chromatogram browsing using JAVA and CORBA

DNA sequence chromatograms (traces) are the primary data source for all large-scale genomic and expressed sequence tags (ESTs) sequencing projects. Access to the sequencing trace assists many later analyses, for example contig assembly and polymorphism detection, but obtaining and using traces is problematic. Traces are not collected and published centrally, they are much larger than the base calls derived from them, and viewing them requires the interactivity of a local graphical client with local data. To provide efficient global access to DNA traces, we developed a client/server system based on flexible Java components integrated into other applications including an applet for use in a WWW browser and a stand-alone trace viewer. Client/server interaction is facilitated by CORBA middleware which provides a well-defined interface, a naming service, and location independence. [The software is packaged as a Jar file available from the following URL: http://www.ebi.ac.uk/jparsons. Links to working examples of the trace viewers can be found at http://corba.ebi.ac.uk/EST. All the Washington University mouse EST traces are available for browsing at the same URL.]     

Improvements in diagnostic tools for early detection of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease characterized by a wide clinical spectrum. The early diagnosis of PsA is currently a challenging topic.

Areas covered: The literature was extensively reviewed for studies addressing the topic area “diagnosis of psoriatic arthritis”. This review will summarize improvements in diagnostic tools, especially referral to the rheumatologist, the role of patient history and clinical examination, laboratory tests, and imaging techniques in getting an early and correct diagnosis of PsA.

Expert commentary: Due to the heterogeneity of its expression, PsA may be easily either overdiagnosed or underdiagnosed. A diagnosis of PsA should be taken into account every time a patient with psoriasis or a family history of psoriasis shows peripheral arthritis, especially if oligoarticular or involving the distal interphalangeal joints, enthesitis or dactylitis. Magnetic resonance imaging and ultrasonography are useful for diagnosing PsA early, particularly when isolated enthesitis or inflammatory spinal pain occur.     

Prophylactic immunoglobulin therapy in secondary immune deficiency – an expert opinion

Introduction: In primary immunodeficiency (PID), immunoglobulin replacement therapy (IgRT) for infection prevention is well-established and supported by a wealth of clinical data. On the contrary, very little evidence-based data is available on the challenges surrounding the use of IgRT in secondary immune deficiencies (SID), and most published guidelines are mere extrapolations from the experience in PID.

Areas covered: In this article, four European experts provide their consolidated opinion on open questions surrounding the prophylactic use of IgRT in SID, based on their clinical experience. The main topics are IgRT initiation, route of administration, dose optimization, and therapy discontinuation. The authors hope this discussion will be of assistance to practicing physicians in their daily decision-making.

Expert commentary: Although growing experience indicates that IgRT could play an important role in the management of SID, very little robust evidence is available to guide clinical practice. The authors stress the urgent need for new studies in the field and discuss points they find of importance to design them adequately.     

REPORT on the Fourth International Workshop on Chromosome 9: held at Williamsburg, Virginia, USA, April 23–25, 1995

The Fourth International Workshop on Chromosome 9 was a highly successful endeavor in terms of the growth of the map, both genetic and physical, the amount of data entered into GDB, and the continued comradeship in the sharing of data and resources that was exemplified. SIGMA remained a stable and valuable part of the chromosome 9 mapping effort. A new subsection outlining the morbid anatomy of chromosome 9 was included. Finally, specific goals were set for the community to aim for over the upcoming months. These included extending the information about the ease of use of genetic markers, and coordinating across numerous groups the meiotic breakpoint mapping of many microsatellite markers. Workshop files are available by anonymous ftp from ftp.gene.ucl.ac.uk (128.40.82.1) in the subdirectory /pub/c9workshop/1995, or by using a World Wide Web browser (such as Mosaic or Netscape) via the Chromosome 9 Home Page (at the URL http://www.gene.ucl.ac.uk/chr9home.html ).     

Inflammatory biomarkers for asthma endotyping and consequent personalized therapy

Introduction: We argue that asthma be considered a syndrome caused by multiple inflammatory pathogenic processes. Bronchial hyperresponsiveness, reversible airflow limitation, and chronic airway inflammation characterize asthma pathophysiology. Personalized Medicine, i.e. a tailored management approach, is appropriate for asthma management and is based on the identification of discrete phenotypes and endotypes. Biomarkers can help define phenotypes and endotypes. Several biomarkers have been described in asthma, but most of them are not commonly available or still need external validation.

Areas covered: This review presents useful pragmatic biomarkers available in daily clinical practice for assessing airway inflammation in asthmatic patients.

Expert commentary: Eosinophil counts and serum allergen-specific IgE assessments are the most reliable biomarkers. Lung function, mainly concerning FEF_25-75, and nasal cytology may be envisaged as ancillary biomarkers in asthma management. In conclusion, biomarkers have a clinical relevance in asthma in identifying asthma endotypes to direct personalized therapy.     

Focussing on the foot in psoriatic arthritis: pathology and management options

Introduction: Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory arthritis characterised by a range of musculoskeletal conditions including enthesitis, dactylitis and synovitis as well as skin and nail manifestations. The foot is a complex mixture of tissues, all of which can be involved in this disease and is frequently the presenting feature.

Areas covered: In this under-researched area, articles were reviewed from the authors’ publications as well as from other known authors. This review will discuss how PsA affects the foot and ankle with a particular focus on synovitis, tenosynovitis, enthesitis, dactylitis, bone erosion and psoriatic skin and nail disease. The use of imaging is discussed. Conventional radiography is consistently used, however magnetic resonance imaging and ultrasound should be used routinely to diagnose, assess and monitor the disease appropriately. The complex nature of PsA in the foot and ankle should be considered when managing the condition and treatment should be individualized to relieve pain, maintain mobility and improve quality of life.

Expert commentary: The foot and ankle remains a neglected area in PsA. Problems with the foot and ankle should be prioritised as they can significantly impact on patients’ quality of life. Focussing treatment on the foot and ankle can significantly improve outcome.     

The role of imaging in juvenile idiopathic arthritis

Introduction: The prognosis of juvenile idiopathic arthritis (JIA) has changed dramatically due to the availability of novel drugs. Prompt diagnosis and treatment are essential to prevent permanent joint damage. As a result, methods to improve JIA diagnosis and prognosis are of high priority to tailor treatment strategies and maximize their efficacy. Musculoskeletal ultrasound and magnetic resonance imaging are more sensitive than clinical examination and radiography in the detection of joint involvement and might play a substantial role to optimize the management of JIA.

Areas covered: This review compiles an inventory of potential uses of imaging studies in the modern practice of pediatric rheumatology, together with a critical analysis of the major challenges that are still to be addressed. Imaging appearance of normal growth-related changes of the musculoskeletal system will be discussed.

Expert commentary: Knowledge of the evolving patterns of skeletal maturity is paramount to define pathological findings and avoid misinterpretations. Establishing a novel radiological algorithm for a rational use of imaging in JIA is of high priority to allow a speedier integration of imaging into the clinical workflow and decision-making process.     

Biomarkers in sarcoidosis

Introduction: Numerous biomarkers have been evaluated for the diagnosis, assessment of disease activity, prognosis, and response to treatment in sarcoidosis. In this report, we discuss the clinical and research utility of several biomarkers used to evaluate sarcoidosis.

Areas covered: The sarcoidosis biomarkers discussed include serologic tests, imaging studies, identification of inflammatory cells and genetic analyses. Literature was obtained from medical databases including PubMed and Web of Science.

Expert commentary: Most of the biomarkers examined in sarcoidosis are not adequately specific or sensitive to be used in isolation to make clinical decisions. However, several sarcoidosis biomarkers have an important role in the clinical management of sarcoidosis when they are coupled with clinical data including the results of other biomarkers.     

Targeted therapies: what they teach us about the pathogenesis of psoriasis and psoriatic arthritis

Introduction: Biologic therapy has revolutionized treatment pathways in psoriatic joint and skin disease. It has also provided a useful tool with which pathological pathways of this condition may be explored.

Areas covered: This review presents data on the clinical and biological effects of targeted therapy in psoriatic arthritis and psoriasis. Therapeutic agents covered include inhibitors of TNFα, inhibitors of the IL-23/IL-17 axis and inhibitors of intracellular small molecules involved in the transduction of the inflammatory signal. Trial data on clinical and imaging efficacy is reviewed in parallel with studies on biological effects at tissue level. Pathological insights gained from the use of these treatments are explored.

Expert commentary: A close relationship exists between specific pathological types and clinical manifestations of psoriatic disease, including responses to treatment. Studying these relationships is likely to improve understanding of disease and enable rational selection of specific treatments for patients with specific pathotypes.     

A software tool to straighten curved chromosome images

A software tool for straightening curved chromosomes has been developed and integrated into the freely available image analysis application Image SXM (available via the Internet at http://reg.ssci.liv.ac.uk). This new tool straightens curvilinear objects in one simple step after minimal input from the user. The ends of a curvilinear chromosome are identified by the user using the mouse and a window is opened displaying the object as it would appear if it was straightened out. This image processing produces linear images of chromosomes with no loss of resolution or spatial calibration, making subsequent analysis significantly more straightforward.     

An ontology of human developmental anatomy

Human developmental anatomy has been organized as structured lists of the major constituent tissues present during each of Carnegie stages 1-20 (E1-E50, approximately 8500 anatomically defined tissue items). For each of these stages, the tissues have been organized as a hierarchy in which an individual tissue is catalogued as part of a larger tissue. Such a formal representation of knowledge is known as an ontology and this anatomical ontology can be used in databases to store, organize and search for data associated with the tissues present at each developmental stage. The anatomical data for compiling these hierarchies comes from the literature, from observations on embryos in the Patten Collection (Ann Arbor, MI, USA) and from comparisons with mouse tissues at similar stages of development. The ontology is available in three versions. The first gives hierarchies of the named tissues present at each Carnegie stage (http://www.ana.ed.ac.uk/anatomy/database/humat/) and is intended to help analyse both normal and abnormal human embryos; it carries hyperlinked notes on some ambiguities in the literature that have been clarified through analysing sectioned material. The second contains many additional subsidiary tissue domains and is intended for handling tissue-associated data (e.g. gene-expression) in a database. This version is available at the humat site and at http://genex.hgu.mrc.ac.uk/Resources/intro.html/), and has been designed to be interoperable with the ontology for mouse developmental anatomy, also available at the genex site. The third gives the second version in GO ontology syntax (with standard IDs for each tissue) and can be downloaded from both the genex and the Open Biological Ontology sites (http://obo.sourceforge.net/).     

Immunogenicity of biologic therapies: causes and consequences

Introduction: Antibodies or fusion proteins termed biologics allow the targeted therapy of diseases. Many of these agents have proven superior efficacy and safety to conventional therapies, and subsequently revolutionized the management of numerous chronic diseases. Repetitive administration of these protein-based therapeutics to immunocompetent patients elicit immune responses in the form of Anti Drug Antibodies (ADAs), which in turn impact their pharmacological properties and may trigger adverse events.

Areas covered: Structural characteristics determining the immunogenicity of biologics are reviewed along with strategies to minimize it. Next, the different types of treatment-emerging ADAs, their potential clinical implications, and assays to detect them are addressed. Emphasis is put on the review of data on the immunogenicity of different types of biologics across numerous indications. Finally, practical considerations are discussed on how to manage patients with issues around the immunogenicity of their biologic treatment.

Expert commentary: Immunogenicity is a clinically relevant criterion when selecting a biologic. Besides intrinsic properties of the agent (namely its structure), its respective mode of action, dosing regimen, comedication, and the indication treated must be considered. ADA detection assays need to be standardized to improve comparability of available data and to allow clinical decision-making.     

Treatment of adult-onset still’s disease: up to date

Introduction: Adult onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60-70% of patients may develop a chronic polyphasic form of the disease or a chronic polyarthritis. Due to rarity of disease, treatment of AOSD is not based on controlled study, but on case based experiences.

Areas covered: Recently, the application of anti-cytokine therapy based on pathophysiology has resulted in significant progress in the treatment of AOSD. Here, we review current knowledge of the pathogenesis, disease progression, currently available biomarkers of disease activity, standard therapeutic agents, utility of biologic agents, future perspectives for treatment and treatment of macrophage activation syndrome.

Expert commentary: Accumulated clinical data suggest that chronic disease can be classified into two subsets: dominant systemic disease, and the arthritis subgroup. IL-1 inhibitors may be more efficient for systemic manifestations and IL-6 inhibitor for both joint involvement and systemic manifestations. TNF inhibitors must be reserved for patients with purely chronic articular manifestations. For ideal management of patients, it is very important to measure disease activity accurately during follow up, but no single biomarker has been classified as ideal.

New therapeutic agents and composite biomarkers are needed to improve the outcome of patients with AOSD by identifying disease activity properly.     

Recombinant human C1 esterase inhibitor (Conestat alfa) for prophylaxis to prevent attacks in adult and adolescent patients with hereditary angioedema

Introduction: Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a debilitating and potentially lethal disease. Management includes on-demand treatment of angioedema and their prophylaxis. Plasma derived C1-INH is an established treatment for both on demand and prophylaxis of HAE. Conestat alfa is a recombinant form of human C1-INH (rhC1-INH) produced in transgenic rabbits. It has granted drug’s registration as treatment option for acute HAE attacks in adults and adolescents in Europe, America, and other countries. Long-term prophylaxis with rhC1-INH received recent consideration in clinical trials.

Areas covered: This review will critically appraise available information about rhC1-INH (conestat alfa) prophylactic treatment in adult and adolescent patients with congenital C1-INH deficiency. Results from a phase II randomized placebo-controlled trial for prophylaxis of severe HAE evidenced positive treatment outcomes for its application, both twice or once weekly.

Expert commentary: Phase II clinical studies suggest that rhC1-INH is a viable option for prophylaxis of HAE. Safety and tolerability data are comparable to other available HAE specific drugs, zeroing the possibility for blood-born viral transmission. Sustainability of modern technologies is granting a practically stable and continuous recombinant production process. With other available options, rhC1-INH facilitates tailoring HAE treatment to patients’ needs.     

IgA directly inhibits antigen-dependent B cell activation following distinctive distribution of the antigen in mice

Context: Serum IgA suppresses immune responses when exposed to antigens recognized by the antibody; however, the underlying mechanism remains unclear.

Objective: We herein clarified the relationships between changes in antigen distribution and antigen-dependent B cell activation in the presence or absence of IgA against the antigen in mice.

Materials and methods: DBA/1J and HR-1 mice were intravenously injected with ovalbumin (OVA) and anti-OVA monoclonal IgA OA-4. The distribution of the antigen and B cell responses were measured.

Results: B cell activation by injected OVA, namely, increases in anti-OVA IgG production and the populations of B220⁺GL7⁺ and B220⁺CD69^high splenocytes, was diminished by the co-injection of OA-4. Co-injected OA-4 increased OVA in the serum as well as in the bile and gut. This was coincident with its decrease in the urine due to the inhibition of OVA monomer secretion through the formation of immune complexes. The apparent similarities in the association between fluorescein isothiocyanate (FITC)-OVA and splenic B cells in the presence and absence of OA-4 in vivo appeared to be attributed to compensation between the two effects of OA-4; an increase in serum OVA in vivo and inhibition of the association between OVA and B cells, as suggested by in vitro experiments.

Discussion: Based on these results, the stimulation of B cells by OVA may be directly reduced, at least partly, by the neutralization of OVA by OA-4.

Conclusion: IgA may be an effective drug for the treatment of immune disorders due to its ability to blunt antigen-specific B cell activation.     

Psoriatic arthritis: lessons from imaging studies and implications for therapy

Introduction: Modern imaging may aid in the diagnosis, prognosis and monitoring of therapeutic response in psoriatic arthritis (PsA). Detection of osteitis and technical advances like whole body magnetic resonance imaging (MRI) exemplify the value of this technology.

Areas covered: Ultrasound (US) provides a clinic-based tool for evaluating both joint pathologies and extra-articular structures (especially enthesitis) including skin and nail disease. Recent studies have demonstrated subclinical disease in psoriasis without arthritis, as well as in PsA, with implications for diagnosis and treatment classification. Modern imaging can also facilitate decisions on tapering of expensive biologics, though real-world clinical studies are still lacking.

Expert commentary: The increase in novel PsA therapies should increase the utilization of modern imaging, providing both increased validation of imaging biomarkers as well as responsive outcome measures.     

Body image,body dissatisfaction and weight status in children from Emilia-Romagna (Italy): comparison between immigrant and native-born

Background: Cross-sectional study among immigrant and native children from Emilia-Romagna (Italy).

Aim: The purpose of the present study was to examine the relative contribution of weight status, ethnicity and sex on body dissatisfaction in a sample of children from Emilia-Romagna (Italy).

Subjects and methods: Primary school children (226 immigrants and 1206 Italians) aged 6–11 years were measured: immigrant children were divided into Asians, Africans, Latin Americans and East Europeans. Height and weight were measured and Body Mass Index (BMI) was calculated. Body image perception was assessed using Body Silhouette Charts. A body dissatisfaction score (BDS) was derived by subtracting the "ideal self" from the "self" score.

Results: Weight status disorders were higher in immigrants than in native-born males; Italian females had higher prevalence of underweight and overweight and lower prevalence of obesity than immigrants peers. BDS rose with the increase of weight status categories.

Conclusions: Awareness of body image size and increasing body dissatisfaction with higher weight status is established in childhood, regardless of ethnicity and gender.