An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy

Inflammation plays an important role in a wide range of human diseases. Chemokines are a group of proteins which control the migration and activation of the immune cells involved in all aspects of the inflammatory response. Chemokines bind to specific receptors of the seven-transmembrane spanning type on target leukocytes and also bind to cell-surface glycosaminoglycans (GAG). Leukocytes express a range of chemokine receptors which can cross-desensitise each other, potentially allowing a single chemokine receptor agonist to desensitise all the chemokine receptors on a cell. If an appropriate single receptor agonist is engineered to be non-chemotactic itself, then a treated cell will lose the potential to migrate in response to chemokines towards any developing site of inflammation. A non-GAG-binding but receptor agonistic form of the chemokine CCL7 can inhibit leukocyte recruitment in response to a diverse range of chemokines in vitro and in vivo. We hypothesise that this modified chemokine mediates its effect by inducing homologous and heterologous receptor desensitisation and further propose that other suitable candidates could include agonistic chemokine receptor-specific antibodies or small molecule chemokine receptor agonists. Hence, an appropriate chemokine receptor agonist could be used to inhibit multiple chemokine receptors, thereby producing a powerful and robust anti-inflammatory effect. This review considers the mechanisms leading to chemokine receptor desensitisation and discusses the potential to develop a new class of anti-inflammatory agents based on targeted stimulation of chemokine receptors.     

Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline

The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to L-methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests. However, while aminoindan (1 microM), the major metabolite of rasagiline does not interfere with the neuroprotective activities of rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, L-methamphetamine (1 microM), inhibits them. In contrast to L-methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of rasagiline is blocked by ERK inhibitor, PD98059 (20 microM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of rasagiline in treatment of Parkinson's disease.     

The simple design of complement factor H: Looks can be deceiving

The complement system is a powerful component of innate immunity which recognizes and facilitates the elimination of pathogens and unwanted host material. Since complement can also lead to host tissue injury and inflammation, strict regulation of its activation is important. One of the key regulators is complement factor H (CFH), a protein with an ever-expanding list of relevant functions. Inherited mutations in CFH can account for membranoproliferative glomerulonephritis (MPGN) type II, atypical hemolytic uremic syndrome, and age-related macular degeneration. The former can be associated with excessive systemic complement activation from dysfunctional CFH, while the latter two are associated with mutations affecting the ability of CFH to bind to anionic surfaces such as on endothelial cells and glomerular and retinal capillary walls. Mice with targeted deletion of CFH can spontaneously develop MPGN and have increased susceptibility to models of GN. In the rodent, CFH on platelets functions as the immune adherence receptor, analogous to CR1 on primate erythrocytes. In mice, platelets lacking CFH are unable to effectively clear immune complexes which results in their accumulation in glomeruli. The same switch also appears to be true in the rodent podocyte where CFH is present in place of CR1 in human podocytes. Thus, CFH has a variety of functions which can affect the diverse roles the complement system plays in health and disease.     

Peptide-beta2-microglobulin-MHC fusion molecules bind antigen-specific T cells and can be used for multivalent MHC-Ig complexes

Recombinant soluble MHC molecules are widely used for visualization, activation and inhibition of antigen-specific immune responses. Using a genetic approach, we have generated two novel peptide-beta2-microglobulin-MHC constructs. We have linked the MHC molecule with the peptide of interest, without limiting the recognition by the cognate TCR. This molecule can also be joined with the IgG heavy chain resulting in a dimeric MHC-Ig fusion protein. These molecules bind antigen-specific T cells with high specificity and sensitivity, therefore, providing a valuable tool for detection as well as enrichment of antigen-specific T cells.     

The amplitude of physiological tremor can be voluntarily modulated

The objective of this study was to determine whether it was possible to voluntarily modulate physiological tremor (PT), i.e., reduce its amplitude. We recorded the postural index finger tremor of 30 healthy participants with a laser in four conditions: (A) eyes closed, without any attempt to modulate PT amplitude, (B) no visual feedback, trying to reduce PT amplitude, (C) visual feedback, trying to reduce PT amplitude. For conditions B and C, subjects were asked to avoid using muscle contraction as a means to stabilize the finger. Finally, (D) subjects were asked to reduce PT amplitude using voluntary muscle contraction to stabilize the finger. We used electromyography to monitor the extensor digitorum communis and flexor digitorum superficialis. Total amplitude of PT did not change significantly between conditions A and B. In condition C, a significant decrease of PT amplitude was observed. A significant increase in tremor amplitude was observed in D compared with other conditions, confirming that co-contraction was not used to modulate the amplitude of PT in other conditions. Subsequently, we formed three subgroups based on their ability to modulate PT: Most Improved (n = 7), Least Improved (n = 16) and Not Improved (n = 7). Although oscillations within the low frequency bands increased only in the Not Improved group, oscillations within the 8–12 and 16–30 Hz bands either remained stable or decreased for all participants, supporting a disassociation between mechanical-reflex and central components of PT. Our results show that it is possible to voluntarily modulate PT. Therefore, a cortical influence is being exerted on tremor.     

Behavioral versus insight-oriented marital therapy: labels can be misleading

Snyder, Wills, and Grady-Fletcher (1991) reported a 4-year follow-up comparing insight-oriented (IOMT) with behavioral marital therapy (BMT). The effects of IOMT were more durable than those of BMT. These comments question the adequacy with which the two treatments were represented. The BMT treatment manual adequately represents behavioral technology as it existed in 1980 but fails to include more recent clinical innovations. The IOMT treatment manual includes many clinical skills that are integral to BMT but not included in the BMT manual. Documentation is provided that therapists in the BMT condition were not using these important techniques. These and other questions regarding the adequacy of training and supervision may have compromised the integrity of BMT. Nevertheless, the findings do suggest that traditional BMT technology alone may be neither necessary nor sufficient for long-term change.     

The alcohol paradox: A psychological model

The paradoxical continuation of excessive drinking by chronic alcoholics despite extremely aversive personal deterioration is addressed by a two-factor theory. The theory regards the increasing stereotypy of alcohol-related behaviors as a function of: (a) primary neuropsychological impairments that result from alcohol abuse and (b) secondary fears of catastrophic failure attendant upon brain dysfunction, which leads to acquired aversions to situations that require adaptive behaviors. A schematic quantitative model of this formulation is presented that may be useful to practicing psychologists in explaining perserverative behavior in a variety of brain syndromes.     

Summarizing and coding case records: can the task be delegated?

After several preliminary joint sessions a doctor and a nurse independently constructed summary cards for 100 alphabetically consecutive case records and coded them according to the classification of the Royal College of General Practitioners. The searches and codings were repeated after an interval of at least one month. The error rates of the doctor and the nurse were similar. The interobserver concordance for the ratings was acceptable for broad diagnostic categories, but was less good when strict criteria were applied. It is concluded that the task may be delegated.     

Glatiramer acetate could be a potential antidepressant through its neuroprotective and anti-inflammatory effects

Antidepressants that act by increasing the activity of central serotonergic or noradrenergic systems are the main biological treatments for major depressive disorder (MDD). Although these agents are generally safe and effective, they are far from ideal due to their slow onset and a substantial proportion of MDD patients do not clinically improve, despite maximal dosing. Thus, the development of new antidepressants based on novel theories may help to develop faster and more effective antidepressant agents. Over the last decade, there has been an impressive accumulation of data about non-monoamine systems that might mediate the pathogenesis of, and therapeutic mechanisms in, MDD. For example, MDD has been associated with a decreased central brain-derived neurotrophic factor (BDNF) state and activating the BDNF-signaling pathway may play an important role in the mechanisms of antidepressant therapeutic action. Glatiramer acetate (GA) is a collection of synthetic polypeptides indicated as therapy for relapsing-remitting multiple sclerosis. Both preclinical and clinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity or increase serum BDNF levels. Furthermore, MDD has been associated with an inflammatory process in the brain. Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of interleukin-10. Finally, recent animal studies have suggested that psychosocial stress reduces neurogenesis, whereas antidepressant treatment increases neurogenesis and blocks the effects of stress. Peripheral administration of GA was found to augment neurogenesis, including cell proliferation, migration, and differentiation in rodent brain. From the above evidence, GA could have antidepressant effects by increasing central BDNF, stimulating neurogenesis or through its anti-inflammatory effect. It is also suggested that immediate GA treatment after stress may prevent the development of stress-related psychiatric disorders such as MDD and post-traumatic stress disorder.     

The skin conductance orienting response to semantic stimuli: significance can be independent of arousal

The characteristics of stimuli that elicit skin conductance responses (SCRs) have been conceptualized in varied ways, with strong emphasis on the significance or arousing quality of stimuli. Our goal was to determine whether "significance" can be shown to have an effect on SCRs independent of "arousal," using words as stimuli. Ratings of words indicated that significance is partially independent of arousal. In Study 1, SCRs from 43 participants during presentation of 20 significant, nonarousing words with a negative valence that were either depression related or potentially self-referent and 20 nonsignificant words matched on valence and arousal showed a main effect of significance. In Study 2 (N=44), significant, nonarousing words were sampled more broadly to examine the effects of self-reference and valence. Significance, rather than just negativity or self-reference, elicited SCRs independently of arousal. SCRs to significant words may reflect cognitive and attentional processes that, in turn, might prove useful for the assessment of the cognitive aspects of anxiety.