Pathogenesis of Sjögren's syndrome: what we know and what we should learn

Sj?gren's syndrome (SS) or autoimmune epithelitis is a prototype autoimmune disorder with unique features: a broad clinical spectrum that extends from local exocrinopathy to systemic disease and lymphoma development, and an easy access to the inflamed tissues (minor salivary glands; MSG), which enables the investigators to study the autoimmune processes. The autoimmune lesion consists of lymphocytic infiltrates that develop around the ducts and vary in severity and composition. T cells (mainly CD4(+)) are the dominant lymphocytes in mild MSG lesions, whereas B cells in severe ones. Th1 cytokines predominate in SS infiltrates, albeit Th2 and Th17 responses have been also reported. Notably, increased infiltration by IL-18(+) cells has been associated with parotid gland enlargement and C4-hypocomplementemia, which are adverse prognostic factors for lymphoma development. Even though SS pathogenesis has not been fully revealed, several aspects have been delineated. Among them, the key role of MSG epithelia in the initiation and perpetuation of local autoimmune responses is well-established and involves the capacity of epithelial cells to mediate the recruitment, homing, activation, proliferation and differentiation of immunocytes. In addition, genetic features, including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling, environmental (such as viruses) and hormonal factors are thought to participate in disease pathogenesis. Herein, the known aspects of SS pathogenesis, as well as unmet issues are discussed.     

Adherence intervention research: what have we learned and what do we do next?

Although there is general agreement from studies demonstrating that adherence to inhaled corticosteroid therapy is often inadequate to establish consistent control, relatively little concurrence exists in reports of interventions to correct the problem. Half of the studies reviewed found that the experimental intervention did not change adherence, and behavior change reported by patients was often not accompanied by changes in treatment success. Studies used a variety of methods that differed in quality with findings that were often contradictory. Key limitations in many studies included reliance on inadequate adherence measures, inclusion of convenience samples of well-motivated patients, and assessments of intervention outcomes artificially boosted by attrition of least adherent participants. Research is encouraged into innovative interventions that are brief, easily implemented, and can be tailored to individual patients and diverse clinical settings. Of particular importance is inclusion of hard-to-reach patients, including urban and rural poor and the use of valid measures of adherence at intervals sufficient to establish enduring benefit.     

Working with dreams in therapy: what do we know and what should we do?

Although a potentially helpful therapeutic tool, dream interpretation or dream work is only used occasionally in most forms of psychotherapy. Despite an interest from clinicians and clients alike in using dreams within therapy, many therapists feel unprepared to attend to their clients' dreams. The main goals of this article are to make clinicians aware that integrating dreams into their clinical practice is both accessible and potentially valuable and to allow them to make an informed decision as to what role they want dream work to play in therapy. The paper begins with a brief overview of some of the more common approaches to dream work. The literature on the usefulness and effectiveness of the clinical use of dreams is then reviewed. Finally, based on the integration of the clinical and empirical literature, several guidelines for conducting dream work are presented.     

Do we see what we think we see? The complexities of morphological assessment

Reliable pathological interpretation is vital to so many aspects of tissue‐based research as well as being central to patient care. Understanding the complex processes involved in decision‐making is the starting point to improve both diagnostic reproducibility and the definition of diagnostic groups that underpin our experiments. Unfortunately, there is a paucity of research in this field and it is encouraging to see The Journal of Pathology publishing work in this area. This review attempts to highlight the opportunities that exist in this field and the technologies that are now available to support this type of research. Key amongst these are the use of decision analysis tools such as inference networks, and virtual microscopy that allows us to simulate diagnostic decision‐making. These tools have roles, not only in studying the subtleties of diagnostic decision‐making, but also in delivering new methods of training and proficiency testing. Research which helps us to better understand what we see, why we see it, and standardizing interpretative reasoning in pathological classification is essential for improving the wide range of activities that pathologists support, including clinical diagnosis, teaching, training, and experimental research. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Mouse models of global airway allergy: what have we learned and what should we do next?

Recent epidemiological and clinical data indicate that allergic rhinitis and asthma coexist and should be considered as one airway allergy syndrome. In spite of the importance of this new concept of global airway allergy, it has not fundamentally changed our daily diagnostic and therapeutic strategies so far because of the lack of essential clues to understand the correlation between allergic inflammation in upper and lower airways. Because of the resemblance of experimentally induced allergic airway inflammation in mice to inflamed airways of allergic patients, mouse models can enhance our insight into mechanisms underlying the global airway allergy syndrome. We here review data generated in mice that are relevant for understanding the development of airway allergy and provide new options for research on the so-called 'united airway disease'.     

Cold urticaria – What we know and what we do not know

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterized by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU.     

.VO2max: what do we know, and what do we still need to know?

Maximal oxygen uptake (.VO(2,max)) is a physiological characteristic bounded by the parametric limits of the Fick equation: (left ventricular (LV) end-diastolic volume--LV end-systolic volume) x heart rate x arterio-venous oxygen difference. 'Classical' views of .VO(2,max) emphasize its critical dependence on convective oxygen transport to working skeletal muscle, and recent data are dispositive, proving convincingly that such limits must and do exist. 'Contemporary' investigations into the mechanisms underlying peripheral muscle fatigue due to energetic supply/demand mismatch are clarifying the local mediators of fatigue at the skeletal muscle level, though the afferent signalling pathways that communicate these environmental conditions to the brain and the sites of central integration of cardiovascular and neuromotor control are still being worked out. Elite endurance athletes have a high .VO(2,max) due primarily to a high cardiac output from a large compliant cardiac chamber (including the myocardium and pericardium) which relaxes quickly and fills to a large end-diastolic volume. This large capacity for LV filling and ejection allows preservation of blood pressure during extraordinary rates of muscle blood flow and oxygen transport which support high rates of sustained oxidative metabolism. The magnitude and mechanisms of cardiac phenotype plasticity remain uncertain and probably involve underlying genetic factors, as well as the length, duration, type, intensity and age of initiation of the training stimulus.     

PEComa: what do we know so far?

PEComas (tumours showing perivascular epithelioid cell differentiation) are a family of related mesenchymal neoplasms that include angiomyolipoma, lymphangiomyomatosis, clear cell "sugar" tumour of the lung, and a group of rare, morphologically and immunophenotypically similar lesions arising at a variety of visceral and soft tissue sites. These tumours all share a distinctive cell type, the perivascular epithelioid cell or "PEC' (which has no known normal tissue counterpart). PEComas show a marked female predominance and are composed of nests and sheets of usually epithelioid but occasionally spindled cells with clear to granular eosinophilic cytoplasm and a focal association with blood vessel walls. PEComas appear to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites, with a subset occurring in somatic soft tissue and skin. Nearly all PEComas show immunoreactivity for both melanocytic (HMB-45 and/or melan-A) and smooth muscle (actin and/or desmin) markers. A subset of PEComas behave in a malignant fashion. This review examines the members of the PEComa family, with an emphasis on lesions arising outside of the kidney, lung and liver, and discusses preliminary evidence for pathological features that might predict malignant behaviour.     

Zika virus: what we need to know?

Zika virus is one of the emerging viruses and is of significant threat to human health globally. It is a mosquito borne flavivirus similar to dengue, yellow fever, and West Nile viruses. It was reported about 5 decades ago and then it spreads to different parts of the world. Large outbreaks were reported on Yap Islands in 2007. Now it has gained wide attention globally by health communities. Major vector for virus transmission is Aedes aegypti mosquito. ZIKV infection is mostly asymptomatic but it is also responsible to cause mild influenza like illness to serious manifestations. There is no specific anti‐viral treatment is available for ZIKV infection. The virus disseminates very fast due to which it possesses a serious threat especially in those areas where there is lack of specific immunity against virus. Little knowledge is available on its transmission and pathogenicity. Although virus was discovered years ago but its genomic structure is not clearly understood yet. In this review we focus on the current knowledge of epidemiology of ZIKV, its transmission, its structural biology, different aspects of diagnosis and diagnostic challenges as well as highlighted appropriates antiviral drugs and vaccines regarding treatment.     

T-cell-based immunotherapy of melanoma: what have we learned and how can we improve?

The lack of effective treatment for advanced stage melanoma by conventional therapies, such as radiation and chemotherapy, has highlighted the need to develop alternative therapeutic strategies. Among them, immunotherapy has attracted much attention because of the potential role played by immunological events in the clinical course of melanoma and the availability of well-characterized melanoma antigens to target melanoma lesions with immunological effector mechanisms. In recent years, T-cell-based immunotherapy has been emphasized, in part because of the disappointing results of the antibody-based trials conducted in the early 1980s, and in part because of the postulated major role played by T-cells in tumor growth control. In this review, the characteristics of antibody and T-cell-defined melanoma antigens will first be described, with emphasis on those used in clinical trials. Following a review of the current immunization and immunomonitoring strategies, the results from the T-cell-based immunotherapy clinical trials conducted to date will be reviewed.     

Hormonal substitution during menopause: what are we treating?

OBJECTIVES: It is suggested that during menopausal transition, women with vasomotor symptoms benefit from HRT, (hormone replacement therapy) whereas, the use of HRT for other cognitive-vegetative symptoms is questionable. METHODS: The occurrence of menopausal complaints and depressive symptoms was assessed cross-sectionally in 5896 Dutch Caucasian women (47-54 years) of a large community sample in the city of Eindhoven, The Netherlands. Menopausal complaints were assessed using a 22 items self-rating scale (consisting of a vasomotor, uro-genital and a cognitive-vegetative subscale). Depressive symptoms were assessed using the Edinburgh depression scale (EDS). Differences in mean scores were analysed between groups using ANOVA. The independent relationship of depressive symptoms to the intensity of menopausal complaints was assessed, by multiple linear regression analysis. RESULTS: Women using HRT showed the highest scores on all subscales. Oral contraceptive users had significantly lower scores on the vasomotor subscale compared to HRT users and to non users. Depressive symptoms contributed the most, to the explained variance on scores on the menopausal subscales. CONCLUSIONS: Women during menopause presenting several complaints, other than vasomotor origin might be suffering from underlying depression which makes it questionable to prescribe HRT for the latter symptoms.