Natural killer cell cytotoxicity: how do they pull the trigger?

Natural killer (NK) cells target and kill aberrant cells, such as virally infected and tumorigenic cells. Killing is mediated by cytotoxic molecules which are stored within secretory lysosomes, a specialized exocytic organelle found in NK cells. Target cell recognition induces the formation of a lytic immunological synapse between the NK cell and its target. The polarized exocytosis of secretory lysosomes is then activated and these organelles release their cytotoxic contents at the lytic synapse, specifically killing the target cell. The essential role that secretory lysosome exocytosis plays in the cytotoxic function of NK cells is highlighted by immune disorders that are caused by the mutation of critical components of the exocytic machinery. This review will discuss recent studies on the molecular basis for NK cell secretory lysosome exocytosis and the immunological consequences of defects in the exocytic machinery.     

Partner aggression and problem drinking across the lifespan: how much do they decline?

Cross-sectional analyses from nationally-representative samples demonstrate significant age-related trends in partner aggression and problem drinking. Both behaviors are most prevalent in the early to mid-twenties and increasingly less common thereafter. Aggregate associations based on percentage of individuals displaying the behavior in each age range are dramatically stronger than those found when correlating individuals' ages and behavior. Multilevel modeling demonstrates that group-level effects do not mask associations found at the level of the individual for either problem drinking or partner aggression. An analysis of recent abstracts from psychology journals showed that issues of aggregate and individual data are rarely if ever discussed, and even well-known statistics books in psychology rarely discuss such issues. The interpretation of aggregate data will become increasing important as psychologists themselves, and in collaboration with epidemiologists and sociologists, have access to large data sets that allow for data aggregation. Both aggregate and individual analyses are valid, although they provide answers to different questions. Individual analyses are necessary for predicting individual behavior; aggregate analyses are useful in policy planning for large scale prevention and intervention. Strengths and limitations of cross-sectional community samples and aggregate data are also discussed.     

Elite HIV controllers: myth or reality?

Despite the varying disease progression rates, the majority of HIV-infected individuals eventually progress to AIDS. There is a subset of HIV-positive individuals, who maintain high CD4+ and CD8+ T-cell counts, remain therapy naive and persistently infected with HIV-1 for more than 15 to 20 years. In light of current observations, this subset can be divided into two groups. One shows low detectable plasma viremia (< 5000 HIV-RNA copies/ml), termed long-term nonprogressors. A second group shows plasma HIV-RNA values persistently below 50 copies/ml throughout the course of infection, and termed "elite" or "natural controllers". The features common between both groups are the presence of high CD4+ and CD8+ T-cell counts, strong immune responses, and low but variable cellular proviral DNA load. The group of HIV-positive long-term nonprogressor individuals comprises about 1% of the total HIV population in the world, whereas the "elite" controllers may be much less. Why do some people deteriorate faster, while others remain normal both symptomatically and immunologically for decades? There is a renewed interest in HIV-positive individuals who have survived since the period close to the earlier part of the HIV pandemic in the 1980s and have remained drug-naive. As very little is known about "elite" controllers, the findings discussed here are largely based on previously known and newly emerging aspects of HIV pathogenesis in the context of the long-term nonprogressor group. It is believed that data emerging on long-term nonprogressors will allow us to make scientific inferences to further our research on "elite" controllers. Aspects dealing with cellular, humoral, innate, and adaptive immunity, which are relevant to nonprogressive HIV disease, are beyond the scope of this review.     

Allergic and autoimmune reactions to xenobiotics: how do they arise?

Induction of allergic and autoimmune reactions by drugs and other chemicals constitutes a major public health problem. Elucidation of the underlying mechanisms might help improve diagnostic tools and therapeutic approaches. Here, Peter Griem and colleagues focus on several aspects of neoantigen formation by xenobiotics: metabolism of xenobiotics into reactive, haptenic metabolites; polymorphisms of metabolizing enzymes; induction of costimulatory signals; and sensitization of T cells.     

Divisions of general practice in Australia: how do they measure up in the international context?

Background

Since the late 1980s, there has been evidence of an international trend towards more organised primary care. This has taken a number of forms including the emergence of primary care organisations. Underpinning such developments is an inherent belief in evidence that suggests that well-developed primary care is associated with improved health outcomes and greater cost-effectiveness within health systems. In Australia, primary care organisations have emerged as divisions of general practice. These are professionally-led, regionally-based, and largely government-funded voluntary associations of general practitioners that seek to co-ordinate local primary care services, and improve the quality of care and health outcomes for local communities.

Discussion

In this paper, we examine and debate the development of divisions in the international context, using six roles of primary care organisations outlined in published research. The six roles that are used as the basis for the critique are the ability of primary care organisations to: improve health outcomes; manage demand and control costs; engage primary care physicians; enable greater integration of health services; develop more accessible services in community and primary care settings; and enable greater scrutiny and assurance of quality of primary care services.

Summary

We conclude that there has been an evolutionary approach to divisions' development and they now appear embedded as geographically-based planning and development organisations within the Australian primary health care system. The Australian Government has to date been cautious in its approach to intervention in divisions' direction and performance. However, options for the next phase include: making greater use of contracts between government and divisions; introducing and extending proposed national quality targets for divisions, linked with financial or other incentives for performance; government sub-contracting with state-based organisations to act as purchasers of care; pursuing a fund-holding approach within divisions; and developing divisions as a form of health maintenance organisation. The challenge for the Australian Government, should it wish to see divisions' role expand, is to find mechanisms to enable this without compromising the relatively strong GP engagement that increasingly distinguishes divisions of general practice within the international experience of primary care organisations.

     

Haloarchaeal viruses: how diverse are they?

Hypersaline lakes are highly productive microbial environments that provide many advantages for microbial ecologists, including stable communities of relatively low diversity (mainly haloarchaea). An important component of these communities is comprised of their non-cellular parasites, i.e., their viruses. Few viruses of halobacteria (haloviruses) have been isolated and studied even though a wide selection of host species have been formally described (and easily cultured) for ten years. Hypersaline waters have been shown to contain very high concentrations of virus-like particles (at least 10(7) particles/ml), particularly fusiform particles, but laboratory isolations of new haloviruses have been very slow and the detailed study of selected examples even slower. Here we provide an outline of the reported haloviruses, including fusiform and unpublished isolates from this laboratory, and we discuss their diversity and the future directions for this research.     

Memory NK cells: why do they reside in the liver?

Immune memory is the hallmark of adaptive immunity. However, recent studies have shown that natural killer (NK) cells, key components of the innate immune system, also mediate memory responses in mice and humans. Strikingly, memory NK cells were liver-resident in some models, raising the question as to whether the liver is a special organ for the acquisition of NK cell memory. Here, we review the characteristics of NK cell memory by summarizing recent progress and discuss how the liver may generate both the initiation and the recall phase of memory. We propose that the liver may have unique precursors for memory NK cells, which are developmentally distinct from NK cells derived from bone marrow.     

Social support interventions: do they work?

Presence of support has repeatedly been linked to good long-term health outcomes based on demonstrations of better immune function, lower blood pressures, and reduced mortality (among others). Despite a massive literature on the benefits of support, there is surprisingly little hard evidence about how, and how well, social support interventions work. Using a computerized search strategy, 100 studies that evaluated the efficacy of such interventions were located. The presenting problems ranged from cancer, loneliness, weight loss, and substance abuse to lack in parenting skills, surgery, and birth preparation. For the purpose of review and evaluation, studies were subdivided into (1) group vs. individual interventions, (2) professionally led vs. peer-provided treatment, and (3) interventions where an increase of network size or perceived support was the primary target vs. those where building social skills (to facilitate support creation) was the focus. On the whole, this review provided some support for the overall usefulness of social support interventions. However, because of the large variety of existing different treatment protocols and areas of application, there is still not enough evidence to conclude which interventions work best for what problems. Specific methodological and conceptual difficulties that plague this area of research and directions for future research are discussed.