Corticofugal modulation of the information processing in the auditory thalamus of the cat

Summary Single unit activity of 355 cells was recorded in the auditory thalamus of anesthetized cats before, during, and after the inactivation by cooling of the ipsilateral primary auditory cortex (AI). Most of the units (n = 288) showed similar functional characteristics of firing before and after the cryogenic blockade of AI. The spontaneous firing rate remained unchanged by cooling in 20% of the units and decreased in the majority of them (60%). In some regions, i.e. dorsal division of the medial geniculate body (MGB), lateral part of the posterior group of the thalamus, and auditory sector of the reticular nucleus of the thalamus, the maximum firing rate evoked by white noise bursts was generally affected by cooling in the same direction and to the same extent as the spontaneous activity. Units in the ventral division of MGB showed a characteristic increase of signal-to-noise ratio during cortical cooling. The corticofugal modulation led to the appearance or disappearance of the best frequency of tuning in 51 units and changed it by more than 0.5 octave in 34 units. The bandwidths of different response patterns to pure tones stimulation were used to define a set of functional properties. During cryogenic blockade of AI, two cortically modulated sub-populations of units were usually distinguished that exhibited changes for a given functional property. The complexity and diversity of the effects of cortical inactivation suggest that the corticothalamic projection may be the support for selective operations such as an adaptive filtering of the incoming acoustic signal at the thalamic level adjusted as a function of cortical activity.     

Glucocorticoids Decrease Hippocampal and Prefrontal Activation during Declarative Memory Retrieval in Young Men

Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design. It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both hippocampal and prefrontal brain regions that are crucially involved in memory processing. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Central and peripheral control of postprandial pyloric motility by endogenous opiates and cholecystokinin in dogs

The role of endogenous opiates and cholecystokinin (CCK) in the control of postprandial pyloric myoelectric activity was investigated in conscious dogs with chronically implanted intraparietal electrodes at the gastroduodenal junction. Meals consisted of either 20 g/kg of canned food (standard meal) or the same food supplemented with 0.5 mL/kg of arachis oil (fat meal). During the 6 hours after standard and fat meals, the number of pyloric spike bursts, 2-4 seconds in duration, was 61.8 +/- 15.8 and 49.9 +/- 12.7/15 minutes, respectively. Administered 15 minutes before a fat meal, naloxone (50 micrograms/kg IV) decreased the number of spike bursts by 31.4%, whereas methyl-levallorphan, a peripheral opiate antagonist, increased postprandial spike activity by 22.2% when administered IV (0.5 mg/kg) and decreased it when administered intracerobroventricularly at a dose of 10 micrograms/kg. These two antagonists administered in the same conditions before a standard meal had no effect on the postprandial spike activity. A 1-hour infusion of cholecystokinin octapeptide (CCK-8), 500 ng.kg-1.h-1 IV and 50 ng.kg-1.h-1 intracerebroventricularly, performed 1 hour after a standard meal induced a 19.6% and 15.8% decrease in the number of pyloric spike bursts, respectively. Both naloxone IV (50 micrograms/kg) and methyl-levallorphan intracerebroventricularly (10 micrograms/kg) administered before the infusion of CCK-8 reinforced this pyloric inhibition, which was antagonized by methyl-levallorphan IV (0.5 mg/kg). The CCK antagonist asperlicin, 200 micrograms/kg IV and 20 micrograms/kg intracerebroventricularly, administered before a fat meal increased pyloric spike bursts by 22.0% and 31.5%, respectively. These results indicate that after a fat meal, endogenous opiates exert a peripheral inhibitory and central stimulatory control of pyloric motility; they suggest the involvement of both peripheral and central release of CCK.     

Antitumor activity of magainin analogues against human lung cancer cell lines.

Magainin 1 and magainin 2, originally isolated from African clawed frog Xenopus laevis skin, inhibit the growth of bacteria and fungi. Synthetic magainin A (MAG A) and magainin G (MAG G) are more potent against bacteria and protozoa. In order to determine the antitumor activity of these analogues, we have tested these two analogues against six small cell lung cancer (SCLC) cell lines NCI-H82, NCI-H526, NCI-H678, NCI-H735, NCI-H841, and NCI-H889, which were known to differ by more than 10-fold in their sensitivity to different chemotherapeutic agents, and four normal human fibroblast cell lines. Semiautomated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays of the six SCLC cell lines revealed average concentrations producing 50% inhibition (IC50) values of 2.6 microM (range, 0.49-9.30 microM) for cisplatin, 2.5 microM (range, 0.39-6.00 microM) for etoposide, and 138.8 nM (range, 55.0-450.0 nM) for doxorubicin. The average IC50 of MAG A was 8.64 microM (range, 6.23-11.7 microM) and that of MAG G was 8.82 microM (range, 4.44-12.5 microM) against the SCLC cell lines. Despite a 10-fold difference in sensitivity to standard chemotherapeutic agents, the IC50 of MAG A and MAG G differs by less than 3-fold. The average IC50 against four normal human fibroblast cell lines was 21.1 microM (range, 12.7-25.6 microM) for MAG A and 29.2 microM (range, 21.3-34.8 microM) for MAG G. Combined exposure to the IC50 concentration of MAG A or MAG G plus IC50 of etoposide or cisplatin decreased the percentage of surviving SCLC cells to 29.0% (range, 26.1-31.7%). MAG A or MAG G had an additive effect when used with standard chemotherapeutic agents. These data suggest that MAG A and MAG G have in vitro antitumor activity against SCLC cell lines.     

Applied potential tomography

Applied potential tomography (APT) is a new noninvasive, nonradioactive method of measuring gastric emptying, which generates profiles of emptying of liquids that are similar to those obtained simultaneously by scintigraphy and dye dilution. This study validates the ability of APT to measure emptying of a solid beefburger test meal from the stomach by comparing the results obtained with those obtained simultaneously by scintigraphy. When acid secretion was inhibited, there was a significant correlation between the two methods for the time taken for half the meal to empty from the stomach and the amount of meal emptied at different time intervals. Furthermore, the profiles of gastric emptying obtained by APT resembled those obtained by scintigraphy in most studies. If acid secretion was not inhibited, there was no correlation between values obtained by the two methods.     

The effect of vascular endothelial growth factor on the healing of ischaemic skin wounds.

The effect of exogenous vascular endothelium growth factor (VEGF) on wound healing in an ischaemic skin flap model was evaluated in this study. Seventy-two Sprague-Dawley rats were used. Normal incisional wound and H-shaped double flaps were used as the wound models. The study was divided into two parts. In Part I, VEGF protein levels were determined from the incisional and H-shaped ischaemic wounds at 12 and 24 h, postoperatively. In Part II, tensile strength and immunohistochemical stains were examined to determine the level of microvessel density (MVD) at 1 and 2 weeks, postoperatively in simple incisional wounds, ischaemic wounds, and ischaemic wounds following 1 ml (1 microg/ml) exogenous VEGF injections into the subcutaneous tissue. The results showed a significantly higher level of VEGF protein in the ischaemic wounds than the incisional wounds. Tensile strength was statistically higher in the incisional wound group and in the ischaemic flap wounds with VEGF treatment compared to the ischaemic flaps with no treatment at 1 week, postoperatively (p>0.05). MVD data indicated that ischaemic wound repair with VEGF treatment had significantly higher MVD than the normal incisional wounds and ischaemic wounds without treatment. We conclude that exogenous application of VEGF can increase early angiogenesis and tensile strength in the ischaemic wound.     

Immunohistochemical study of bone GLA protein in primary bone tumors.

METHODS. The immunoreactivity of bone GLA protein (BGP) in primary bone tumors, including osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma of bone (MFH), and giant cell tumor of bone (GCT), was investigated with anti-BGP rabbit serum and peroxidase-antiperoxidase complex. RESULTS. As to intracellular localization, BGP antigenicity was detected in 33 of 35 cases of osteosarcoma and 12 of 25 cases of chondrosarcoma. However, there were no positive findings in all 15 cases of MFH or 20 cases of GCT. In chondrosarcoma, the frequency of positively stained cases increased according to pathologic grading (i.e., 3 of 14 cases of Grade 1, 7 of 9 cases of Grade 2, and 2 of 2 cases of Grade 3). Although the multinucleated cells in MFH or GCT were not immunostained, BGP antigenicity was observed in the multinucleated cells of osteosarcoma (12 of 15 cases). In the matrix of osteosarcoma, BGP immunoreactivity of the tumorous osteoid was observed in 28 of 32 cases. However, in the matrices of chondrosarcoma, MFH, and GCT, BGP immunoreactivity was not observed. CONCLUSION. These results suggest that the immunohistochemical study of BGP is useful for the differential diagnosis of bone tumors.     

Participation of rat liver cytochrome P450 2E1 in the activation of N-nitrosodimethylamine and N-nitrosodiethylamine to products genotoxic in an acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009).

The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines.     

Evidence of secondary neuronal intestinal dysplasia in a rat model of chronic intestinal obstruction.

The etiology of neuronal intestinal dysplasia remains largely unknown. There is, however, supporting evidence of the existence of Hirschprung's disease or chronic intestinal obstruction associated with neuronal intestinal dysplasia. With the aim of investigating the possible development of neuronal intestinal dysplasia linked to chronic intestinal obstruction, we have examined the enteric nervous system response to long-term obstruction in a rat model. Three different surgical techniques were tested in Wistar male rats. In animals that survived longer than the cutoff chronic intestinal obstruction point (6 weeks), full-thickness biopsies and acetylcholinesterase (AChE), NADH, hematoxylin-eosin, and anti-S100 protein stainings were performed. The results of our model indicate that chronic intestinal obstruction induced different degrees of enteric nervous system dysplasia, including histological features of neuronal intestinal dysplasia. The relationship between chronic intestinal obstruction and anomalies of the enteric nervous system, including neuronal intestinal dysplasia, needs to be further studied.