CD97, but not its closely related EGF-TM7 family member EMR2, is expressed on gastric,pancreatic, and esophageal carcinomas

CD97 expression is related closely to the dedifferentiation and tumor stage in thyroid carcinomas. We systematically examined the role of CD97 and its closest relative, EMR2, in normal and malignant gastric, esophageal, and pancreatic tissue. The normal tissues were EMR2-, whereas CD97 was expressed slightly in the parietal cells of gastric mucosa and in exocrine pancreatic cells. Interestingly, intralobular and interlobular pancreatic ducts were CD97+. All tumors were EMR2-. CD97 was expressed by 44 of 50 gastric, 14 of 18 pancreatic, and 10 of 13 esophageal carcinomas. Of the 44 gastric cancers, 27 showed disseminated or scattered tumor cells at the invasion front with stronger CD97 expression than tumor cells located in solid tumor formations. There was no correlation between CD97 levels in the tumors or soluble CD97 in the serum samples and the clinicopathologic features of the patients. Taken together, significant numbers of gastric, esophageal, and pancreatic carcinomas are CD97+, whereas its homolog, EMR2, does not have any role in such tumors.     

Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.     

Detecting danger--or just another odorant? Olfactory sensitivity for the fox odor component 2,4,5-trimethylthiazoline in four species of mammals

2,4,5-trimethylthiazoline (TMT) is a volatile component of the anal gland secretion of the red fox and elicits behavioral and physiological fear responses in the rat. Using instrumental conditioning paradigms, we determined olfactory detection thresholds for TMT in three rats, a natural prey species of the red fox, and compared their performance to that of three squirrel monkeys, three spider monkeys and four pigtail macaques, all non-prey species of the red fox. We found that the rats were able to discriminate concentrations between 0.04 and 0.10 ppt (parts per trillion) of TMT from the odorless solvent which is by far the lowest olfactory detection threshold for an odorant reported in rats so far. In contrast, the spider monkeys needed 0.14-1.38 ppb (parts per billion), the pigtail macaques 0.41-4.07 ppb, and the squirrel monkeys 4.07-13.80 ppb to detect TMT which does not rank among the lowest olfactory thresholds reported for these three primate species. Thus, these results support the assumption that the behavioral relevance of an odorant may be an important determinant of a species' olfactory sensitivity.     

Betamethasone effects on fetal sheep cerebral blood flow are not dependent on maturation of cerebrovascular system and pituitary–adrenal axis

Synthetic glucocorticoids are administered to pregnant women in premature labour to accelerate fetal lung maturation at a time when fetal cerebrovascular and endocrine systems are maturing. Exposure to glucocorticoids at 0.8–0.9 of gestation increases peripheral and cerebrovascular resistance (CVR) in fetal sheep. We examined whether the increase of CVR and its adverse effect on cerebral blood flow (CBF) depend on the current level of maturation of the pituitary–adrenal axis and the cerebrovascular system. Using fluorescent microspheres, regional CBF was measured in 11 brain regions before and 24 h and 48 h after the start of 3.3 μg kg⁻¹ h⁻¹ betamethasone ( n = 8) or vehicle ( n = 7) infusions to fetal sheep at 0.73 of gestation. Hypercapnic challenges were performed before and 24 h after the onset of betamethasone exposure to examine betamethasone effects on cerebrovascular reactivity. Betamethasone exposure decreased CBF by approximately 40% in all brain regions after 24 h of infusion ( P < 0.05). The decline in CBF was mediated by a CVR increase of 111 ± 16% in the cerebral cortex and 129 ± 29% in subcortical regions ( P < 0.05). Hypercapnic cerebral vasodilatation and associated increase in CBF were blunted ( P < 0.05). Fetal CBF recovered after 48 h of betamethasone administration. There were no differences in glucocorticoid induced CBF and CVR changes compared with our previous findings at 0.87 of gestation. We conclude that the cerebrovascular effects of antenatal glucocorticoids are independent of cerebrovascular maturation and preparturient increase in activity of the fetal pituitary–adrenal axis.     

IP-10 and type 1 diabetes: a question of time and location

Chemokines are key signal molecules that attract cells of the host immune system to the site of a potential threat. Virus infections usually induce a massive chemokine and cytokine burst and therefore recruit a large plethora of leukocytes to the site of infection with the goal to restrict and abrogate viral spread. The down side of this massive excitation of the human defense system is non-specific activation of potentially self-reactive lymphocytes. Coupled with an antigen-specific event, for example molecular mimicry between host components and viral proteins, autoimmunity might be the consequence in susceptible individuals. However, activated immune components with autoaggressive potential must find their target and must remain in one site sufficiently long in order to cause chronic tissue damage. In this review we will focus on the influence of the chemokine IP-10 (CXCL10) on the trafficking of autoaggressive cells during the immunopathogenesis of type 1 diabetes (T1D) and explain why IP-10 can have a dual effect on T1D depending on time and location of expression.     

Displaced retinal ganglion cells project to the accessory optic system in the chameleon ( Chamaeleo calyptratus)

Retinal ganglion cells were successfully labelled in the chameleon by retrograde axonal transport of dextran amines that were applied to the nucleus of the basal optic root (nBOR) in an in vitro preparation. Labelled ganglion cells were restricted to the contralateral eye. Many cells were completely stained including their dendritic trees. With few exceptions, all cells had displaced somata that were located at the inner margin of the inner nuclear layer. The labelled ganglion cells had two to six primary dendrites that branched frequently and formed large unistratified dendritic trees within sublamina 1 of the inner plexiform layer. There was extensive overlap of the dendritic trees of neighbouring cells leading to an estimated coverage factor of 2-4. The dendritic field areas varied in size according to the retinal position of the cells and were highest in the central retina around the fovea with a maximum of 0.14 mm(2) and reached a second maximum at the retinal margin with values of 0.08-0.1 mm(2). The smallest dendritic areas (0.04-0.06 mm(2)) were measured midway between the fovea and retinal margin. The size of the soma area was not correlated to the dendritic field size and increased from 100 to 150 microm(2) near the fovea to 150-300 microm(2) at the retinal margin. There was no evidence for a retinotopic organisation of ganglion cell fibres within the nBOR. All cells were of uniform morphology that was identical to the type of nBOR-projecting displaced ganglion cell (DGC) described previously for the bird retina. Similar to birds, the labelled DGCs were the only source of retinal projection to the nBOR. A small fraction of cells had orthotopic somata located in the ganglion cell layer but were otherwise identical to the labelled DGCs. The similarity of chameleon nBOR-projecting ganglion cells to those described in avian retinas mirrors the close phylogenetic relationship of birds and lizards.     

Distinct sites of action of clostridial neurotoxins revealed by double-poisoning of mouse motor nerve terminals

(1) We investigated the effects of single- and double-poisoning with tetanus toxin (TeTx), botulinum neurotoxin type A (BoTx A) and botulinum neurotoxin type B (BoTx B) on spontaneous and nerve-evoked quantal transmitter release at motor endplates of the triangularis sterni preparation of the mouse. (2) Inhibitory effects of TeTx and BoTx B on spontaneous and nerve-evoked transmitter release were very similar, except that the action of BoTx B required 500-fold lower concentrations and was less dependent on temperature. BoTx A caused stronger inhibition of quantal release than TeTx or BoTx B, but was comparatively much easier counteracted by 4-aminopyridine (4-AP). (3) In contrast to BoTx A, with TeTx or BoTx B the increase of transmitter release following onset of 50 Hz nerve stimulation was delayed for a few seconds and synaptic latencies of quanta showed large variations. This release pattern was also evident in all double-poisoning experiments, regardless of intoxication sequence. (4) Inhibition of evoked release was found to be slightly stronger with TeTx than with BoTx B, so the amount of nerve-evoked quanta released after double-poisoning with any sequence of these toxins always approached that of TeTx. In no case supraadditive actions were observed. (5) A strong reduction of evoked quanta was observed when BoTx A was applied in addition to either of the two other toxins. With reversed poisoning sequences (BoTx A-TeTx or BoTx A-BoTx B) the resulting values remained at the extremely low level of BoTx A. (6) In the presence of 4-AP double-poisoning with any combination between BoTx A and TeTx or BoTx B (regardless of intoxication sequence) revealed supra-additive effects, since the number of quanta released was considerably lower than that obtained with any of the toxins alone (in the presence of 4-AP). (7) Our results indicate that tetanus toxin and botulinum toxin type B have a common site of action which is different and independent from that of botulinum toxin type A.This is part of the thesis of M. G. to be presented to the Fachbereich Humanmedizin, Justus-Liebig-Universität Gießen     

The effect of the interferon-gamma-inducible processing machinery on the generation of a naturally tumor-associated human cytotoxic T lymphocyte epitope within a wild-type and mutant p53 sequence context

The human wild-type (wt) p53.264-272 peptide is a universal tumor antigen and recognized by HLA-A*0201 (A2.1)-restricted CTL. Generation of this epitope by constitutive 20S proteasomes is prevented by a p53 R to H hotspot mutation at the C-terminal flanking residue 273. We report on the impact of the interferon-gamma (IFN-gamma)-inducible proteasomal activator PA28 (11S regulator) and the immunoproteasome on the in vitro and cellular processing of wt and mutant (mut) p53 substrates. We found that production of the antigenic 264-272 peptide from wt p53 by constitutive as well as immunoproteasomes is accelerated and amplified by the PA28 activator. PA28 and (immuno)proteasomes were not capable to reconvert the resistance of epitope release from mut p53. Maximum and accelerated antigen production in vitro and on the cellular level required the IFN-gamma-inducible interaction of immunoproteasomes and PA28. We conclude that efficient processing of p53.264272 from wt p53 is governed by the proteasome/PA28 complex. These studies have important implications for p53-specific cancer immunotherapy and demonstrate that the effects of the immunoproteasome and PA28 are influenced by the individual epitope and its flanking sequence context.     

Decreased virulence of a pneumolysin-deficient strain of Streptococcus pneumoniae in murine meningitis

Pneumolysin, neuraminidases A and B, and hyaluronidase are virulence factors of Streptococcus pneumoniae that appear to be involved in the pathogenesis of meningitis. In a murine model of meningitis after intracerebral infection using mutants of S. pneumoniae D39, only mice infected with a pneumolysin-deficient strain were healthier at 32 and 36 h, had lower bacterial titers in blood at 36 h, and survived longer than the D39 parent strain. Cerebellar and spleen bacterial titers, meningeal inflammation, and neuronal damage scores remained uninfluenced by the lack of any of the virulence factors.