High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-A^b and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.     

Possible mechanisms of valproate in migraine prophylaxis

Valproate has been shown to be an effective prophylactic treatment in migraine. Investigation of the mechanism of its antimigraine action is difficult due to the broad range of its biochemical effects and the complex nature of migraine pathophysiology. Valproate increases brain GABA levels and, in doing so, may suppress migraine-related events in the cortex, perivascular parasympathetics or trigeminal nucleus caudalis. There is experimental evidence that it suppresses neurogenic inflammation and directly attenuates nociceptive neurotransmission. In addition, valproate reportedly alters levels of excitatory and inhibitory neurotransmitters and exerts direct effects on neuronal membranes in vitro. Valproate's observed effect may ultimately result from a combination of actions at different loci.     

Improved survival of children with sepsis and purpura: effects of age,gender, and era

Background  

To gain insight into factors that might affect results of future case-control studies, we performed an analysis of children with sepsis and purpura admitted to the paediatric intensive care unit (PICU) of Erasmus MC-Sophia Children's Hospital (Rotterdam, The Netherlands).     

Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency

The G protein G(s)alpha is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G(s)-signaling pathways by developing mice with liver-specific G(s)alpha deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARgamma coactivator-1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide-1 levels and pancreatic alpha cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic G(s)-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.     

Modeling small-molecule release from PLG microspheres: effects of polymer degradation and nonuniform drug distribution.

Modeling release of small molecules from degradable microspheres is important to the design of controlled-release drug delivery systems. Release of small molecules from poly(d,l-lactide-co-glycolide) (PLG) particles is often controlled by diffusion of the drug through the polymer and by polymer degradation. In this study, a model is developed to independently determine the contributions of each of these factors by fitting the release of piroxicam from monodisperse 50-microm microspheres made with PLG of different initial molecular weights. The dependence of the drug diffusivity on polymer molecular weight was determined from in vitro release of piroxicam from monodisperse 10-microm PLG microspheres, and the polymer degradation rate was experimentally measured using gel permeation chromatography. The model also incorporates the effect of nonuniform drug distribution within the microspheres, which is obtained from confocal fluorescence microscopy. The model results agree well with experiments despite using only one fit parameter.     

Case-control study of subjective and objective differences in sleep patterns in older adults with insomnia symptoms

Older adults have high prevalence rates of insomnia symptoms, yet it is unclear if these insomnia symptoms are associated with objective impairments in sleep. We hypothesized that insomnia complaints in older adults would be associated with objective differences in sleep compared with those without insomnia complaints. To test this hypothesis, we conducted a cross‐sectional study in which older adults with insomnia complaints (cases, n = 100) were compared with older adults without insomnia complaints (controls, n = 100) using dual‐night in‐lab nocturnal polysomnography, study questionnaires and 7 days of at‐home actigraphy and sleep diaries. Cases were noted to have reduced objective total sleep time compared with controls (25.8 ± 8.56 min, P = 0.003). This was largely due to increased wakefulness after sleep onset, and not increased sleep latency. When participants with sleep‐related breathing disorder or periodic limb movement disorder were excluded, the polysomnography total sleep time difference became even larger. Cases also had reduced slow‐wave sleep (5.10 ± 1.38 min versus 10.57 ± 2.29 min, effect size −0.29, P = 0.04). When comparing self‐reported sleep latency and sleep efficiency with objective polysomnographic findings, cases demonstrated low, but statistically significant correlations, while no such correlations were observed in controls. Cases tended to underestimate their sleep efficiency by 1.6% (±18.4%), while controls overestimated their sleep efficiency by 12.4% (±14.5%). In conclusion, we noted that older adults with insomnia complaints have significant differences in several objective sleep findings relative to controls, suggesting that insomnia complaints in older adults are associated with objective impairments in sleep.     

Contrast sensitivity of MT receptive field centers and surrounds

Neurons throughout the visual system have receptive fields with both excitatory and suppressive components. The latter are responsible for a phenomenon known as surround suppression, in which responses decrease as a stimulus is extended beyond a certain size. Previous work has shown that surround suppression in the primary visual cortex depends strongly on stimulus contrast. Such complex center-surround interactions are thought to relate to a variety of functions, although little is known about how they affect responses in the extrastriate visual cortex. We have therefore examined the interaction of center and surround in the middle temporal (MT) area of the macaque (Macaca mulatta) extrastriate cortex by recording neuronal responses to stimuli of different sizes and contrasts. Our findings indicate that surround suppression in MT is highly contrast dependent, with the strongest suppression emerging unexpectedly at intermediate stimulus contrasts. These results can be explained by a simple model that takes into account the nonlinear contrast sensitivity of the neurons that provide input to MT. The model also provides a qualitative link to previous reports of a topographic organization of area MT based on clusters of neurons with differing surround suppression strength. We show that this organization can be detected in the gamma-band local field potentials (LFPs) and that the model parameters can predict the contrast sensitivity of these LFP responses. Overall our results show that surround suppression in area MT is far more common than previously suspected, highlighting the potential functional importance of the accumulation of nonlinearities along the dorsal visual pathway.