Biologic therapies: what and when?

Over the past two decades, major advances have been made in the understanding of the immune system and disease pathogenesis. This has coincided with the development of biologic therapies--monoclonal antibodies and fusion proteins. The decision of when to use such treatment in the clinic is not always straightforward. In addition to immune biology, the focus of this review will be on the application of these treatments to immune-mediated diseases and the molecular targets involved in pathogenesis, specifically those that have US Food and Drug Administration/European Medicines Agency approval. Brief comments will be made on biologics that have approval for non-immune disorders.     

Antimicrobial photodynamic therapy – what we know and what we don’t

Considering increasing number of pathogens resistant towards commonly used antibiotics as well as antiseptics, there is a pressing need for antimicrobial approaches that are capable of inactivating pathogens efficiently without the risk of inducing resistances. In this regard, an alternative approach is the antimicrobial photodynamic therapy (aPDT). The antimicrobial effect of aPDT is based on the principle that visible light activates a per se non-toxic molecule, the so-called photosensitizer (PS), resulting in generation of reactive oxygen species that kill bacteria unselectively via an oxidative burst. During the last 10–20 years, there has been extensive in vitro research on novel PS as well as light sources, which is now to be translated into clinics. In this review, we aim to provide an overview about the history of aPDT, its fundamental photochemical and photophysical mechanisms as well as photosensitizers and light sources that are currently applied for aPDT in vitro. Furthermore, the potential of resistances towards aPDT is extensively discussed and implications for proper comparison of in vitro studies regarding aPDT as well as for potential application fields in clinical practice are given. Overall, this review shall provide an outlook on future research directions needed for successful translation of promising in vitro results in aPDT towards clinical practice.     

Viruses and other infections in stillbirth: what is the evidence and what should we be doing?

In Australia, as in other developed countries, approximately 40-50% of stillbirths are of unknown aetiology. Emerging evidence suggests stillbirths are often multifactorial. The absence of a known cause leads to uncertainty regarding the risk of recurrence, which can cause extreme anguish for parents that may manifest as guilt, anger or bewilderment. Further, clinical endeavours to prevent recurrences in future pregnancies are impaired by lack of a defined aetiology. Therefore, efforts to provide an aetiological diagnosis of stillbirth impact upon all aspects of care of the mother, and inform many parts of clinical decision making. Despite the magnitude of the problem, that is 7 stillbirths per 1000 births in Australia, diagnostic efforts to discover viral aetiologies are often minimal. Viruses and other difficult to culture organisms have been postulated as the aetiology of a number of obstetric and paediatric conditions of unknown cause, including stillbirth. Reasons forwarded for testing stillbirth cases for infectious agents are non-medical factors, including addressing all parents' need for diagnostic closure, identifying infectious agents as a sporadic cause of stillbirth to reassure parents and clinicians regarding risk for future pregnancies, and to reduce unnecessary testing. It is clear that viral agents including rubella, human cytomegalovirus (CMV), parvovirus B19, herpes simplex virus (HSV), lymphocytic choriomeningitis virus (LCMV), and varicella zoster virus (VZV) may cause intrauterine deaths. Evidence for many other agents is that minimal or asymptomatic infections also occur, so improved markers of adverse outcomes are needed. The role of other viruses and difficult-to-culture organisms in stillbirth is uncertain, and needs more research. However, testing stillborn babies for some viral agents remains a useful adjunct to histopathological and other examinations at autopsy. Modern molecular techniques such as multiplex PCR, allow searches for multiple agents. Now that such testing is available, it is important to assess the clinical usefulness of such testing.     

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.     

Obesity and asthma, what are the links?

PURPOSE OF REVIEW: Obesity is a major cause of morbidity accounting for approximately 300 000 deaths each year and about 7% of the health care budget with an economic impact greater than US dollar 100 billion annually in the United States. Obesity and its sequelae such as cardiovascular disease, diabetes, arthritis or cancer have been on the rise over the last decades. The parallel time trend with an increasing prevalence of asthma has induced a lively debate about a potential link between both conditions. RECENT FINDINGS: A number of prospective studies have shown that weight gain can antedate the development of asthma. Effect modification by sex may occur as some studies have shown effects of body mass index on asthma only among females. However, sex differences are not consistent. Several hypotheses have been proposed to explain the epidemiological associations including alterations in airway mechanics and immune responses, hormonal influences and genetic factors. SUMMARY: There is evidence that obesity and overweight are associated with the development of asthma. Yet, the mechanisms underlying this relation are unclear. Weight reduction among asthmatic patients can result in improvements of lung function demonstrating the potential clinical impact of the findings.     

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.     

Is what goes in what comes out? Encoding and retrieval event-related potentials together determine memory outcome

Understanding memory function amounts to identifying how events (cognitive and neural) at study eventually influence events at test. Many of the proposed cognitive correlates of memory-related event-related potentials (ERPs) at study resemble proposed cognitive correlates of other memory-related ERPs, recorded at test. We wondered whether a given known ERP feature at study might in fact reflect an effective-encoding process that is, in turn, tapped by another specific ERP feature, recorded at test. To this end, we asked which pairs of known memory-related ERP features explain common variance across a large sample of participants, while they perform a word-recognition task. Two early ERP features, the Late Positive Component (study) and the FN400 (test), covaried significantly. These features also correlated with memory success (d′ and response time). Two later ERP features, the Slow Wave (study) and the Late Parietal Positivity (test), also covaried when lures were incorporated into the analysis. Interestingly, these later features were uncorrelated with memory outcome. This novel approach, exploiting naturally occurring subject variability (in strategy and ERP amplitudes), informs our understanding of the memory functions of ERP features in several ways. Specifically, they strengthen the argument that the earlier ERP features may drive old/new recognition (but perhaps not the later features). Our findings suggest the Late Positive Component at study, in some degree, may cause the FN400 to increase at test, together producing effective recognition memory. The Slow Wave at study appears to relate the Left Parietal Positivity at test, but these may play roles in more complex memory judgments and may be less critical for simple old/new recognition.