IL-18-induced CD83+CCR7+ NK helper cells

In addition to their cytotoxic activities, natural killer (NK) cells can have immunoregulatory functions. We describe a distinct "helper" differentiation pathway of human CD56+CD3- NK cells into CD56+/CD83+/CCR7+/CD25+ cells that display high migratory responsiveness to lymph node (LN)-associated chemokines, high ability to produce interferon-gamma upon exposure to dendritic cell (DC)- or T helper (Th) cell-related signals, and pronounced abilities to promote interleukin (IL)-12p70 production in DCs and the development of Th1 responses. This helper pathway of NK cell differentiation, which is not associated with any enhancement of cytolytic activity, is induced by IL-18, but not other NK cell-activating factors. It is blocked by prostaglandin (PG)E2, a factor that induces a similar CD83+/CCR7+/CD25+ LN-homing phenotype in maturing DCs. The current data demonstrate independent regulation of the "helper" versus "effector" pathways of NK cell differentiation and novel mechanisms of immunoregulation by IL-18 and PGE2.     

Activation of plasminogen as a feature in its assay.

Seven laboratories collaborating in a study of two intermediate purity plasminogen preparations (64/23, 63/6) observed that the amount of activator (urokinase or streptokinase) and the time of activation of plasminogen influenced the amount of plasmin generated. Using casein and a synthetic polypeptide (S-2251) as substrates, the authors subsequently showed that complete activation of plasminogen was difficult to achieve without acitivity losses due to plasmin autodigestion. Comparison of the polypeptide subunits (on SDS electrophoresis) of the various plasminogen activation mixtures with their plasmin activity allowed the conclusion that at maximum generation of plasmin from plasminogen, some plasminogen remains in the form of an inactive plasminogen intermediate (PLG-i).     

Modelling the disposable soma theory of ageing

We describe a mathematical model, developed using the Mathematica programming system of the disposable soma theory of ageing. The model makes explicit predictions about the optimal strategies for investment in somatic maintenance versus investments in growth and reproduction and confirms the central prediction of the disposable soma theory that the optimum investment in somatic maintenance is less than what would be required for indefinite longevity. We also describe how the optimal investment in maintenance is affected by varying the parameters that specify the schedules of reproduction and mortality.     

How local community knowledge about malaria affects insecticide-treated net use in northern Ghana

Large-scale trials of insecticide-treated nets (ITNs) throughout Sub-Saharan Africa demonstrated that they reduce child mortality in malaria endemic communities. These encouraging results have generated interest in ITNs as a viable malaria control strategy in many malaria endemic countries. However, regular use of ITNs under routine or non-project conditions has been beset with several problems. This paper explores how local community knowledge about malaria acts as a barrier to the use of ITNs in three settings. We employed structured formal observation and a range of interviewing techniques which included informal interviews, focus group discussions, semi-structured in-depth interviews, and structured survey interviewing. People recognize the term 'malaria' but have limited biomedical knowledge of the disease, including its aetiology, the role of the vector, and host response. Convulsions and anaemia are rarely linked to malaria. The people acknowledged a role for ITNs in nuisance reduction, but not for malaria prevention.     

Terminal Schwann cell structure is altered in diaphragm of mdx mice

The diaphragm muscle of the mdx mouse is a model system of Duchenne muscular dystrophy, since it completely lacks dystrophin and shows severe fiber necrosis and loss of specific muscle force by 4-6 weeks of age. Changes in neuromuscular junction structure also become apparent around 4 weeks including postsynaptic acetylcholine receptor declustering, loss of postsynaptic junctional folds, abnormally complex presynaptic nerve terminals, and muscle fiber denervation. Normally, terminal Schwann cells (TSCs) cap both nerve terminals and acetylcholine receptors at the neuromuscular junction, and play a crucial role in regeneration of motor axons following muscle denervation by guiding axons to grow from innervated junctions to nearby denervated junctions. However, their role in restoring innervation in dystrophic muscle is unknown. We now show that TSCs fail to cap fully the neuromuscular junction in dystrophic muscle; TSCs extend processes, but the organization of these extensions is abnormal. TSC processes of dystrophic muscle do not form bridges from denervated fibers to nearby innervated endplates, but appear to be directed away from these endplates. Adequate signaling for TSC reactivity is present, since significant muscle fiber denervation and acetylcholine receptor declustering are present. Thus, significant structural denervation is present in the diaphragm of mdx mice and the ability of TSCs to form bridges between adjacent endplates to guide reinnervation of muscle fibers is impaired, possibly attenuating the ability of dystrophic muscle to recover from denervation and ultimately leading to muscle weakness.     

An evidence-based staging system for cutaneous melanoma

A completely revised staging system for cutaneous melanoma was implemented in 2003. The changes were validated with a prognostic factors analysis involving 17,600 melanoma patients from prospective databases. This major collaborative study of predicting melanoma outcome was conducted specifically for this project, and the results were used to finalize the criteria for this evidence-based staging system. In fact, this was the largest prognostic factors analysis of prospectively followed melanoma patients ever conducted. Important results that shaped the staging criteria involved both the tumor-node-metastasis (TNM) criteria and stage grouping for all four stages of melanoma. Major changes in the staging include: (1) melanoma thickness and ulceration are the dominant predictors of survival in patients with localized melanoma (Stages I and II); deeper level of invasion (ie, IV and V) was independently associated with reduced survival only in patients with thin or T1 melanomas. (2) The number of metastatic lymph nodes and the tumor burden were the most dominant predictors of survival in patients with Stage III melanoma; patients with metastatic nodes detected by palpation had a shorter survival compared with patients whose nodal metastases were first detected by sentinel node excision of clinically occult or "microscopic" metastases. (3) The site of distant metastases (nonvisceral versus lung versus all other visceral metastatic sites) and the presence of elevated serum lactate dehydrogenase (LDH) were the dominant predictors of outcome in patients with Stage IV or distant metastases. (4) An upstaging was implemented for all patients with Stage I, II, and III disease when a primary melanoma is ulcerated by histopathological criteria. (5) Satellite metastases around a primary melanoma and in-transit metastases were merged into a single staging entity that is grouped into Stage III disease. (6) A new convention was implemented for defining clinical and pathological staging so as to take into account the new staging information gained from lymphatic mapping and sentinel node biopsy.     

How should COMET influence heart failure practice?

Much clinical experience has led us to assume that the administration of a β-blocker, regardless of dose or frequency, would produce similar mortality benefits in patients with heart failure. The results from the recently published Carvedilol or Metoprolol European Trial (COMET), which found greater benefit of carvedilol than immediate-release metoprolol on mortality, clearly demonstrated this is not true. In heart failure, the COMET results strongly support the use of β-blockers that have proven effective in largescale clinical trials. The primary disagreement regarding COMET concerns the explanation of the efficacy difference between the two β-blockers tested. Pharmacodynamic considerations and hemodynamic data from the COMET trial itself suggest there were unequal degrees of e 67-001-blockade between patients receiving carvedilol and immediaterelease metoprolol. Failure to achieve a similar degree of i,e 67-001-receptor blockade in the two groups prevents conclusions regarding the potential incremental benefits of selective versus nonselective adrenergic blockade. Further studies are needed to determine whether there are additional clinical benefits from the inhibition of adrenergic receptors beyond the proven benefits of i,e 67-001-blockade.