The interferon in TLR signaling: more than just antiviral

The Toll-like receptor (TLR) system is responsible for the recognition of infectious agents leading to initiation of the primary innate, and later adaptive, immune response. Genetic technologies have enabled the discovery of new factors involved in these systems, their genetic manipulation and the global analyses of their effects on gene expression. Furthermore, this increased understanding has resulted in the need to reassess our preconceptions about the functions of well-known molecules. For example, type I interferons (IFNs), which were discovered as antiviral proteins, are now known to be produced in response to TLR activation by many pathogens, including bacteria. Should we be surprised? Has the inflammatory response unexpectedly highjacked the body's antiviral system? Or are we too easily blinkered by preconceptions from how a compound was discovered?     

Energy translocation across cell membranes and membrane models

Fatty acid transport is an important process in cellular energy distribution and storage in both normal and pathological states, especially obesity-linked type 2 diabetes mellitus. Fatty acid transport has been studied by the complementary approaches of cell biology and biophysics. According to the latter approach, specific proteins that enhance the uptake and storage of fatty acids are posited as fatty acid translocases, which facilitate fatty acid movement from the outer to inner leaflets of the plasma membrane. According to biophysical studies conducted in vitro, fatty acid translocation occurs by a rapid diffusive process that does not require a protein. Herein, we critically review these two mechanisms and their importance in the regulation of fatty acid uptake in vivo.     

Controlling the statistics of action: obstacle avoidance

Task optimization in the presence of signal-dependent noise (TOPS) has been proposed as a general framework for planning goal-directed movements. Within this framework, the motor command is assumed to be corrupted by signal-dependent noise, which leads to a distribution of possible movements. A task can then be equated with optimizing some function of the statistics of this distribution. We found the optimal trajectory for obstacle avoidance by minimizing the mean-squared error at the end of the movement while keeping the probability of collision with the obstacle below a fixed limit. The optimal paths accurately predicted the empirical trajectories. This demonstrates that controlling the statistics of movements in the presence of signal-dependent noise may be a fundamental and unifying principle of goal-directed movements.     

The non-immunosuppressive immunophilin ligand GPI-1046 potently stimulates regenerating axon growth from adult mouse dorsal root ganglia cultured in Matrigel

We used explant cultures of adult mouse dorsal root ganglia with spinal nerve attached growing in Matrigel to assess the effects of the non-immunosuppressive immunophilin ligand GPI-1046 [Snyder et al. (1998) TIPS 19, 21-26] on the growth rate of regenerating sensory axons and found a potent stimulation of axon growth. In these explant cultures, naked, unfasciculated axons emerge from the cut end of the spinal nerve and continue to grow in the Matrigel for up to eight days [Tonge et al. (1996) Neuroscience 73, 541-551]. Some axons are entirely smooth whilst others show prominent varicosities. Some of the former express the phosphorylated neurofilament epitope recognised by monoclonal antibody RT97, a marker for large calibre, myelinated axons, whilst the latter express calcitonin gene-related peptide, predominantly a marker for unmyelinated, and small diameter myelinated sensory axons. Many of the axons in these cultures also express the low-affinity neurotrophin receptor p75. GPI-1046 has been shown to have striking stimulatory effects on embryonic primary sensory axons growing in vitro and it was therefore of interest to see whether it could also enhance regenerating sensory axon growth from the adult ganglia in our cultures. GPI-1046 potently stimulated axon growth in our cultures in a dose-dependent manner. The stimulatory effect was not dependent on the class of sensory axon. These observations show that GPI-1046 is a potent stimulator of regenerating axons from adult, primary sensory neurones. The cellular site of action of GPI-1046 is unknown. To distinguish between a direct effect of the drug on neurones and an indirect effect we compared the effects of GPI-1046 on explant and dissociated cultures. In confirmation of previous results, we found that GPI-1046 potently stimulated axon outgrowth from explants of embryonic chick dorsal root ganglia. However, the drug was without effect on dissociated embryonic dorsal root ganglion neurones, suggesting that non-neuronal cells are important for axon growth stimulation.     

Effect of combined supplementation with vitamin E and alpha-lipoic acid on myocardial performance during in vivo ischaemia-reperfusion

Reactive oxygen species (ROS) contribute significantly to myocardial ischaemia-reperfusion (I-R) injury. Recently the combination of the antioxidants vitamin E (VE) and alpha-lipoic acid (alpha-LA) has been reported to improve cardiac performance and reduce myocardial lipid peroxidation during in vitro I-R. The purpose of these experiments was to investigate the effects of VE and alpha-LA supplementation on cardiac performance, incidence of dysrhythmias and biochemical alterations during an in vivo myocardial I-R insult. Female Sprague-Dawley rats (4-months old) were assigned to one of the two dietary treatments: (1) control diet (CON) or (2) VE and alpha-LA supplementation (ANTIOXID). The CON diet was prepared to meet AIN-93M standards, which contains 75 IU VE kg-1 diet. The ANTIOXID diet contained 10 000 IU VE kg(-1) diet and 1.65 g alpha-LA kg(-1) diet. After the 14-week feeding period, significant differences (P<0.05) existed in mean myocardial VE levels between dietary groups. Animals in each experimental group were subjected to an in vivo I-R protocol which included 25 min of left anterior coronary artery occlusion followed by 10 min of reperfusion. No group differences (P>0.05) existed in cardiac performance (e.g. peak arterial pressure or ventricular work) or the incidence of ventricular dysrhythmias during the I-R protocol. Following I-R, two markers of lipid peroxidation were lower (P<0.05) in the ANTIOXID animals compared with CON. These data indicate that dietary supplementation of the antioxidants, VE and alpha-LA do not influence cardiac performance or the incidence of dysrhythmias but do decrease lipid peroxidation during in vivo I-R in young adult rats.     

January 1997 - 7 Year Old Girl with Seizures

A seven year old girl presented with six month history of seizures. An MRI scan showed a cortical lesion in the left temporal lobe which was resected. Neuropathology examination demonstrated meningioangiomatosis, an unusual hamartomatous condition sometimes associated with neurofibromatosis 2. Approximately 50 cases of meningioangiomatosis have been reported in the literature. These are reviewed and compared to the current case.     

A multi-modal treatment program for childhood trauma recovery:Women Recovering from Abuse Program (WRAP).

This article describes the Women Recovering from Abuse Program (WRAP), an outpatient day-hospital program for women suffering from the sequelae of childhood abuse. WRAP was conceived in 1998 by clinicians who advocated for its development based on a growing need to provide women who had experienced childhood trauma an alternative to an inpatient program. WRAP draws from a Stage 1 treatment approach to address chronic interpersonal trauma and dissociation by incorporating psychopharmacology, individual and group psychotherapy. The program is structured into two phases: a preparatory Building Resources Group (BRG) and an intensive multimodal segment comprised of seven types of group therapy. Each group is described in terms of the treatment rationale and its structure and process. Two research studies to date support the effectiveness of WRAP.