Cell damage and autoimmunity: a critical appraisal

In April 2007, an international Colloquium bridging scientific and clinical disciplines was held to discuss the role of cellular and tissue damage in the initiation, development and persistence of autoimmune disease. Five potential etiologic and pathophysiologic processes fundamental to autoimmune disease (i.e. inflammation, infection, apoptosis, environmental exposure and genetics) were the focus of the presentations and integrative discussions at the Colloquium. The information presented on these topics is condensed in this review. Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Further application of well-designed, long-term epidemiologic and population-based studies is urgently needed to relate antecedent exposures with later occurring stigmata of autoimmunity with a goal of discerning potentially susceptible individuals or subpopulations. Suspect infections requiring closer interrogation include EB virus (SLE and other diseases), HCV (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis) and Helicobacter pylori (autoimmune gastritis) among others. And even if a micro-organism was to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Plausible mechanisms include potentiation and diversion of innate immunity; exposure or spillage of intracellular autoantigens; or provision of autoantigenic mimics. Integrity of apoptosis as a critical safeguard against autoimmunity was discussed in the contexts of over-reactivity causing autoantigens to gain enhanced exposure to the immune system, or under-reactivity producing insufficient elimination of autoreactive clones of lymphocytes. Although environmental agents are widely believed to serve as necessary "triggers" of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified and their mechanism of action defined. Finally an essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. They may be predictive of future or impending disease.     

Telomerase and mammalian ageing: a critical appraisal

The telomeres that occur at the end of chromosomes are maintained by the activity of telomerase and are thought to be important protective factors in maintaining the integrity of chromosomes. It now appears that in vitro replicative senescence, which has been observed in cultured somatic cells, is due to a loss of telomere length in those cells, caused by inactivity of telomerase. This has led to the proposition that telomerase activity is an important determinant in organismal ageing. However, many cells in the body do not proliferate regularly and therefore will not lose telomere length. Cells that do proliferate frequently have now been shown to have active telomerase. Other cells, such as fibroblasts, that do not have telomerase activity but proliferate only occasionally may not reach the Hayflick limit during the lifetime of an animal. There is also no correlation between telomere length and the maximal lifespan exhibited by different species. Studies of telomerase knock-out mice have reported some aspects of accelerated ageing after three generations, but the relevance of these observations to normal ageing remains unconvincing. The role of telomerase in producing immortal tumour cells and the possibility that activation of telomerase is an important event in malignant transformation is similarly controversial and open to alternative interpretations. The significance of these and other observations, and how they define the role of telomerase in ageing, is discussed.     

Current anti-doping policy: a critical appraisal

Background  

Current anti-doping in competitive sports is advocated for reasons of fair-play and concern for the athlete's health. With the inception of the World Anti Doping Agency (WADA), anti-doping effort has been considerably intensified. Resources invested in anti-doping are rising steeply and increasingly involve public funding. Most of the effort concerns elite athletes with much less impact on amateur sports and the general public.     

Toll like receptors and autoimmunity: a critical appraisal

There is a constant interplay between the innate and adaptive immune systems, which leads to a protective immune response against pathogens and contributes effectively to self-non-self discrimination. Toll-like receptors (TLRs) are key components of the innate immune system, which activate multiple inflammatory pathways and coordinate systemic defense against pathogens. In addition to recognizing unique molecular patterns associated with different classes of pathogens, TLRs may also recognize a number of self proteins and endogenous nucleic acids. Data originating predominantly from animal models of autoimmune disease and circumstantial data from human patients suggest that inappropriate activation of TLR pathways by endogenous or exogenous ligands may lead to the initiation and/or perpetuation of autoimmune responses and tissue injury.     

Pharmacological treatments for SSc-ILD: Systematic review and critical appraisal of the evidence

Many therapies have been investigated for systemic sclerosis-associated interstitial lung disease (SSc-ILD), including immunosuppressive therapies, antifibrotic agents, immunomodulators and monoclonal antibodies. There is a high unmet medical need to better understand the current evidence for treatment efficacy and safety. This systematic review aims to present the existing literature on different drug treatments investigated for SSc-ILD and to critically assess the level of evidence for these drugs.A systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A structured literature search was performed for clinical trials and observational studies on the treatment of SSc-ILD with pharmaceutical interventions from 1 January 1990 to 15 December 2020. The quality of each reference was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria.A total of 77 references were reviewed and 13 different treatments were identified. We found high-quality evidence for the use of cyclophosphamide, nintedanib, mycophenolate and tocilizumab. Therefore, we would posit that the clinical community has four valid options for treatment of SSc-ILD. Further research is mandatory to provide more evidence for the optimal treatment strategy in SSc-ILD, including the optimal time to initiate treatment, selection of patients for treatment and upfront combination therapy.     

Nailfold capillaroscopy in systemic lupus erythematosus: A systematic review and critical appraisal

Nailfold capillaroscopy is an easy, non-invasive technique to assess microvascular involvement in rheumatic diseases. Multiple studies describe capillaroscopic changes in systemic lupus erythematosus (SLE), including a wide range of non-specific findings. On behalf of the European League Against Rheumatism (EULAR) study group on microcirculation in rheumatic diseases, a systematic review was done to obtain all original research studies (in English) in which SLE patients had capillaroscopy. Forty such studies are identified. This article firstly provides a résumé of the results of these studies according to capillaroscopic parameters (density, dimensions, morphology, haemorrhages), semi-quantitative assessment and qualitative assessment of capillaroscopy in SLE patients. Secondly, the correlations between capillaroscopic parameters in SLE patients and clinical and laboratory parameters (including auto-immune parameters) are outlined. The following capillaroscopic parameters are found to be significantly more prevalent in SLE patients compared to healthy controls: tortuous capillaries, abnormal morphology and haemorrhages. Hairpin-shaped capillaries are significantly less prevalent than in healthy persons. The semi-quantitatively determined nailfold capillaroscopic score (NFC score) in SLE patients is also higher than in healthy controls. Several correlations between clinical and laboratory parameters and capillaroscopic parameters are identified in the review. Disease activity is correlated with NFC score in seven studies, with abnormal morphology (i.e. “meandering”) in one study and with haemorrhages in one study. Frequent attacks of Raynaud's phenomenon (RP) and gangrene are significantly correlated with dilated capillaries. In two studies a possible correlation between anti-SSA antibodies and lower density of capillaries is withheld. About other immune parameters conflicting results are found. In one study a significant negative correlation is found between 24-hour proteinuria and abnormal morphology (i.e. “meandering”). For the first time, an overview of the nailfold capillaroscopic changes that have been described in SLE and their correlations with clinical and laboratory findings is given. Further large-scale research on the identification of capillaroscopic changes in SLE and their correlations with standardised clinical and laboratory parameters, is ongoing at the EULAR study group on microcirculation in rheumatic diseases.     

Assessment of physical activity: a critical appraisal

Assessment of physical activity in a free-living environment is important for understanding relations between physical activity and health and determining the effectiveness of interventions. Techniques include behavioral observation, questionnaires in the form of diaries, recall questionnaires and interviews, and physiological markers like heart rate, calorimetry, and motion sensors. The doubly labeled water method has become the gold standard for the validation of field methods of assessing physical activity. Then, questionnaires show a low reliability and validity but can be adequately applied as an activity-ranking instrument. The heart rate requires individual calibration to be an effective method to assess physical activity only at group level. The indicated method for the assessment of habitual physical activity in daily life is a doubly labeled water validated accelerometer. Future developments are simultaneous measurement of body acceleration and heart rate for the assessment of physical fitness. A new generation of accelerometers will provide information on body posture and activity recognition to allow objective assessment of subjects’ habitual activities, options for a healthy change, and effects of the follow-up of any changes.     

Cognitive causes of social phobia: a critical appraisal

This review examined critically studies issuing from the cognitive therapy (CT) model claiming to have unveiled cognitive causal factors of social phobia. Additionally, it examined outcome studies of CT-inspired interventions and other treatments having included measurements of cognitive constructs. Overall, we found no evidence consistently supporting the claim that social phobics are characterized by typical cognitive processes. Moreover, we found neither corroborating evidence for a controlling effect of such cognitive processes on social phobic conduct, nor consistent indications that cognitive therapies or techniques effect cognitive changes differently than other approaches. The evidence suggests rather, that cognitive factors change concurrently with other features of psychopathology as part of an overall improvement during or after effective therapy, regardless of therapeutic approach.     

A systematic review of the content of critical appraisal tools

Background  

Consumers of research (researchers, administrators, educators and clinicians) frequently use standard critical appraisal tools to evaluate the quality of published research reports. However, there is no consensus regarding the most appropriate critical appraisal tool for allied health research. We summarized the content, intent, construction and psychometric properties of published, currently available critical appraisal tools to identify common elements and their relevance to allied health research.     

The current naming of plant viruses: a critical appraisal

The revised International Code of Virus Classification and Nomenclature [7] followed by the Seventh Report of the International Committee on Taxonomy of Viruses (ICTV) [9] have generated a lot of criticism [2,4–6]. The main causes of criticism are (i) use of monomials instead of non-latinized binomials, as has been practice for some time in the past, e.g., tobacco mosaic tobamovirus, tobacco ringspot nepovirus etc. (ii) in toto italicization of official virus names. Following the expression of different views among virologists on this issue, it is being debated and an opportunity has been provided for reconsideration of the revised ICTV code [1,8,10]. This note attempts to analyse the existing critisms being raised and justifies the continuation of the present ICTV code.     

Hypermobile Ehlers–Danlos syndrome: A review and a critical appraisal of published genetic research to date

The Ehlers–Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers–Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study.     

Human leucocyte antigen typing: techniques and technology, a critical appraisal

Methods for the identification of Human Leukocyte Antigens (HLA) have changed significantly since this group of polymorphic proteins were first characterized by serological reagents in the 1960s and 1970s. The invention and development of the Polymerase Chain Reaction (PCR) has been key in the progress of methods for HLA genotyping. As the complexity of HLA polymorphism has unravelled so it has exposed the weaknesses in techniques such as PCR - Restriction Fragment Length Polymorphism (RFLP) and Reference Strand Mediated Conformation Analysis (RSCA), which are no longer in use today. Methods which have been considered routine laboratory tools in recent years, such as Sequence-Specific Primer - PCR and Sequencing Based Typing (SBT) are now also threatened with extinction, not only because of the depth of HLA variation but also because of the rapid development of Next Generation Sequencing and technologies which will follow this. This review describes the merits and disadvantages of current technologies available to HLA Typing laboratories, future trends and the problems posed by new alleles.     

Cyclothymic disorder: a critical review

Cyclothymic disorder is a subtype of bipolar disorder included in the Diagnostic and Statistical Manual of Mental Disorders since 1980, but largely neglected in research. Additionally, it is rarely diagnosed clinically, in spite of evidence that it may be the most prevalent form of bipolar disorder. Neglect has contributed to confusion about the diagnosis and clinical presentation of cyclothymic disorder. Its status as a mood disorder is also ambiguous due to overlap in terminology and symptoms with temperament and personality disorders. Subthreshold bipolar disorder appears more prevalent among young people than previously thought, and follows a range of trajectories from remission to escalation-raising questions about risk factors and traits associated with the varied course. Cyclothymic disorder may be an important diathesis for major mood disorders. Constructs such as cyclothymic disorder link major mood disorder and peri-clinical fluctuations of mood, thus warranting a prominent role in dimensional models of mood and psychopathology. Current evidence indicates that cyclothymic disorder is a prevalent and highly impairing disorder on the bipolar spectrum, with the potential to make unique contributions to our understanding of the risk factors and outcomes associated with bipolar disorder. The inclusion of cyclothymic disorder in future research studies is essential to accurate diagnosis and effective treatment for the full spectrum of bipolar disorder, as well as understanding the developmental trajectory of bipolar spectrum disorders.     

Predicting the future: a critical appraisal of cancer prognosis studies

Many studies have attempted to define useful prognostic and predictive factors in cancer but few have achieved acceptance in clinical practice because of methodological weaknesses. These include failure to test clearly formulated hypotheses, inadequate sample size, inappropriate multiple significance testing, arbitrary definition of patient groups, inadequately reproducible assays, and failure to verify prognostic factors with data independent of the data which suggested the original hypothesis. This unsatisfactory situation will persist until critical attention is routinely paid to study design and prospective validation of supposed prognostic and predictive factors, without which classical approaches will be suboptimally exploited and the flood of data from new molecular technologies will not be used effectively. We propose that prognostic factors should be evaluated in three phases: I, assay definition; II, retrospective testing; III, prospective testing, ideally as a designed part of clinical trials.     

Replicative senescence: a critical review

Human cells in culture have a limited proliferative capacity. After a period of vigorous proliferation, the rate of cell division declines and a number of changes occur in the cells including increases in size, in secondary lysosomes and residual bodies, nuclear changes and a number of changes in gene expression which provide biomarkers for senescence. Although human cells in culture have been used for over 40 years as models for understanding the cellular basis of aging, the relationship of replicative senescence to aging of the organism is still not clear. In this review, we discuss replicative senescence in the light of current information on signal transduction and mitogenesis, cell stress, apoptosis, telomere changes and finally we discuss replicative senescence as a model of aging in vivo.