Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function

Dendritic cells (DCs) can be activated directly by triggering of receptors for pathogens or, indirectly, by exposure to inflammatory signals. It remains unclear, however, whether the two pathways result in qualitatively similar DCs or lead to equivalent adaptive immune responses. Here we report that indirect activation by inflammatory mediators generated DCs that supported CD4(+) T cell clonal expansion but failed to direct T helper cell differentiation. In contrast, exposure to pathogen components resulted in fully activated DCs that promoted T helper responses. These results indicate that inflammation cannot substitute for contact with pathogen components in DC activation and suggest that the function of pattern recognition by DCs is to couple the quality of the adaptive immune response to the nature of the pathogen.     

Verification of the exponential model of body temperature decrease after death in pigs

The authors have conducted a systematic study in pigs to verify the models of post-mortem body temperature decrease currently employed in forensic medicine. Twenty-four hour automatic temperature recordings were performed in four body sites starting 1.25 h after pig killing in an industrial slaughterhouse under typical environmental conditions (19.5-22.5 degrees C). The animals had been randomly selected under a regular manufacturing process. The temperature decrease time plots drawn starting 75 min after death for the eyeball, the orbit soft tissues, the rectum and muscle tissue were found to fit the single-exponential thermodynamic model originally proposed by H. Rainy in 1868. In view of the actual intersubject variability, the addition of a second exponential term to the model was demonstrated to be statistically insignificant. Therefore, the two-exponential model for death time estimation frequently recommended in the forensic medicine literature, even if theoretically substantiated for individual test cases, provides no advantage as regards the reliability of estimation in an actual case. The improvement of the precision of time of death estimation by the reconstruction of an individual curve on the basis of two dead body temperature measurements taken 1 h apart or taken continuously for a longer time (about 4 h), has also been proved incorrect. It was demonstrated that the reported increase of precision of time of death estimation due to use of a multiexponential model, with individual exponential terms to account for the cooling rate of the specific body sites separately, is artifactual. The results of this study support the use of the eyeball and/or the orbit soft tissues as temperature measuring sites at times shortly after death. A single-exponential model applied to the eyeball cooling has been shown to provide a very precise estimation of the time of death up to approximately 13 h after death. For the period thereafter, a better estimation of the time of death is obtained from temperature data collected from the muscles or the rectum.     

Systemic Administration of Immunostimulatory DNA Sequences Mediates Reversible Inhibition of Th2 Responses in a Mouse Model of Asthma

This study investigated whether immunostimulatory DNA sequences (ISS) induce a transient or sustained inhibition of Th2 responses to inhaled antigen. We sensitized mice with subcutaneous injections to develop a Th2 response to ovalbumin (ova) and then administered a dose of ISS prior to ova inhalation challenge. Mice were then rechallenged with ova by inhalation a second time at varying time points after the first ova inhalation (1 to 8 weeks later) to determine whether the ISS dose administered prior to the first ova inhalation protected against a subsequent second ova inhalation challenge. A single dose of ISS inhibited the Th2 response to the first inhalation of ova antigen, as well as 4 weeks later to the second inhalation of ova. However, ISS did not inhibit a Th2 response to the second inhalation of ova 8 weeks later. The reversible inhibition of Th2 responses at 8 weeks suggests the need for repeated ISS administration at monthly intervals.     

Modulation of synaptic transmission in the rabbit coeliac ganglia by gastric and duodenal mechanoreceptors

The involvement of duodenal and gastric mechanoreceptors in the modulation of synaptic transmission was investigated in a rabbit sympathetic prevertebral ganglion. The present study was performed in vitro on the coeliac plexus connected to the stomach and the duodenum. The electrical activity of ganglionic neurons was recorded using intracellular recording techniques. The patterns of synaptic activation of these ganglionic neurons in response to the activation of mechanoreceptors by gastric or duodenal distension were investigated. Although gastric or duodenal distension was unable to elicit any fast synaptic activity in ganglionic neurons, it produced either an inhibition or a facilitation of the fast nicotinic excitatory postsynaptic potentials elicited by stimulation of the thoracic splanchnic nerves. In addition, this distension triggered long-lasting (3-11 min) modifications in the electrical properties of the ganglionic neurons, i.e. slow depolarizations (6-18 mV) or slow hyperpolarizations (3-6 mV), which were sometimes associated with a decrease in the input membrane resistance. After cooling of the nerves connecting the coeliac ganglia to the stomach, the activation of gastric or duodenal mechanoreceptors was no longer able to modify the fast synaptic activation or the electrical properties of the ganglionic neurons. The results demonstrate that gastric and duodenal mechanoreceptors project onto neurons of the coeliac ganglia and change their excitability as well as the central inputs they receive. The long duration of these modifications suggests that gastric and duodenal mechanoreceptors can modulate the activity of the neurons of the coeliac ganglia.     

Information processing in long delay memory-guided saccades: further insights from TMS

The performance of memory-guided saccades with two different delays (3 s and 30 s of memorisation) was studied in eight subjects. Single pulse transcranial magnetic stimulation (TMS) was applied simultaneously over the left and right dorsolateral prefrontal cortex (DLPFC) 1 s after target presentation. In both delays, stimulation significantly increased the percentage of error in amplitude of memory-guided saccades. Furthermore, the interfering effect of TMS was significantly higher in the short delay compared to that of the long delay paradigm. The results are discussed in the context of a mixed model of spatial working memory control including two components: First, serial information processing with a predominant role of the DLPFC during the early period of memorisation and, second, parallel information processing, which is independent from the DLPFC, operating during longer delays.     

The cationic polymerization of 3-chloro-2-methyl-1-propene

The polymerization of 3-chloro-2-methyl-1-propene was investigated at temperatures between 0 and ?80°C, using AlCl₃ and AlBr₃ as initiators. The molecular weights of the resulting oily products depend on the polymerization temperature and varied in the range of the number-average molecular weight M?_n = 400–620. The course of polymerization was studied and the characteristic groupings in the oligomeris were identified by means of ¹H NMR and ¹³C NMR spectroscopy. Based on the results the mechanism of partial reactions was discussed to explain the new type of propagation in the cationic polymerization.     

A novel logistic model based on clinicopathological features predicts microsatellite instability in colorectal carcinomas.

High-frequency microsatellite instability has been reported to be associated with good prognosis in colorectal adenocarcinoma. However, methods to assess microsatellite instability (MIN) are based on genetic assays and are not ideally suited to most histopathology laboratories. The aim of the present study was to develop a model for prediction of MIN status in colorectal cancer based on phenotypic characteristics. Clinicopathological features of a cohort of 204 patients with primary colon cancer were retrospectively reviewed following predetermined criteria. Genetic assessment of MIN status was performed on DNA extracted from sections of formalin-fixed, paraffin-embedded specimens by testing a panel of 11 microsatellite markers. Logistic regression analysis generated a mathematical tool capable of identifying colorectal tumors displaying MIN status with a sensitivity of 77.8% and a specificity of 96.8%. Features associated with instability included the proximal location of the lesions, occurrence of solid and/or mucinous differentiation, absence of cribriform structures, presence of peritumoral Crohn-like reaction, expansive growth pattern, high Ki67 proliferative index, and p53-negative phenotype. This approach predicts microsatellite instability in colorectal carcinoma with an overall assigned accuracy of 95.1% and a negative predictive value of 97.8%. Implementation of this tool to routine histopathological studies could improve the management of patients with colorectal cancer, especially those presenting with stage II and III of the disease. It will also assist in identifying a subset of patients likely to benefit from adjuvant chemotherapy.     

Inhibitors of cytochrome P450 4A suppress angiogenic responses

Cytochrome P450 enzymes of the 4A family (CYP4A) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) in blood vessels of several vascular beds. The present study examined the effects of inhibiting the formation of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenol) formamidine (HET0016) on the mitogenic response of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) in vitro, and on growth factor-induced angiogenesis in the cornea of rats in vivo. HET0016 (10 micromol/L and 20 microg, respectively) abolished the mitogenic response to VEGF in HUVECs and the angiogenic response to VEGF, basic fibroblast growth factor, and epidermal growth factor in vivo by 80 to 90% (P < 0.001). Dibromododecenyl methylsulfonimide (DDMS), a structurally and mechanistically different inhibitor of 20-HETE synthesis, also abolished angiogenic responses when tested with VEGF. Additionally, administration of the stable 20-HETE agonist, 20-hydroxyeicosa-6(Z) 15(Z)-dienoic acid (WIT003) induced mitogenesis in HUVECs and angiogenesis in the rat cornea in vivo. We studied the ability of HET0016 to alter the angiogenic response in the rat cornea to human glioblastoma cancer cells (U251). When administered locally into the cornea, HET0016 (20 microg) reduced the angiogenic response to U251 cancer cells by 70%. These results suggest that a product of CYP4A product, possibly 20-HETE, plays a critical role in the regulation of angiogenesis and may provide a useful target for reduction of pathological angiogenesis.