Immunomodulatory properties of cyclic hexapeptide oxytocin antagonists.

The thymic repertoire of neuroendocrine 'self' antigens has been previously described on the basis of the intrathymic expression of neurohypophysial (NHP)- and tachykinin-related peptide signals and receptors. According to that model, the cryptocrine signalling between thymic epithelial/nurse cells and thymocytes through NHP-related signals and receptors constitutes one accessory pathway in the process of T-cell differentiation and/or activation. A pharmacological manipulation of that novel type of cell-to-cell signalling was tested by the investigation of the immunomodulatory properties of novel cyclic hexapeptide oxytocin (OT) antagonists (MSD Research Laboratories). These compounds were found to significantly inhibit the productions of cytokines (mainly IL-1 beta and IL-6) elicited by anti-CD3 treatment of human whole blood cell cultures. Cytokine productions were more significantly reduced by OT antagonists in whole blood cell cultures derived from female volunteers than in those obtained from male donors, suggesting an influence of the gonadal steroid environment on the expression of NHP peptide receptors by immune cells. These observations support the concept of novel immunomodulating approaches through immune-specific neuropeptide antagonists, as well as the pharmacological value of such strategies in selective immunotherapy.     

Impairments in spatial generalization of visual skills after V4 and TEO lesions in macaques (Macaca mulatta)

The authors tested the spatial generalization of shape and color discriminations in 2 monkeys, in which 3 visual field quadrants were affected, respectively, by lesions in area V4, TEO, or both areas combined. The fourth quadrant served as a normal control. The monkeys were trained to discriminate stimuli presented in a standard location in each quadrant, followed by tests of discrimination performance in new locations in the same quadrant. In the quadrant affected by the V4 + TEO lesion, the authors found temporary but striking deficits in spatial generalization of shape and color discriminations over small distances, suggesting a contribution of areas V4 and TEO to short-range spatial generalization of visual skills.     

Optimization of multiple spin-echo sequences for 3D polymer gel dosimetry

The overall performance of polymer gel dosimeters for three-dimensional radiation dosimetry is determined by the temporal and spatial stability of the gels, dose sensitivity and image quality with respect to both systematic and stochastic deviations. The dose resolution (D(p)delta) is determined by the dose sensitivity and the signal-to-noise ratio (SNR) in the dose images. The dose sensitivity can be altered by changing the chemical composition of the polymer gel. The SNR is determined by the scanner and the imaging sequence. In the dose verification of conformal radiotherapy treatments the chosen number of slices may reach a number of 10-20. For these experiments, to obtain a sufficient SNR within a reasonable measurement time using a certain MR scanner, the imaging sequence should be optimized. A few other studies have emphasized the importance of optimizing the imaging sequence with respect to dose resolution (D(p)delta) or SNR but do not give quantitative values for the optimal sequence parameters for scanning a polymer gel dosimeter in three dimensions. In this paper, it is proved that a multiple spin-echo sequence is preferable to a single spin-echo sequence. It is also shown that when using a multiple spin-echo sequence it is not the inter-echo time that should be optimized but the number of echoes. An algebraical expression is derived for the dose resolution in terms of sequence parameters. A mathematical formalism and look-up tables are provided that can be used to optimize both a single and a slice-selective multiple spin-echo sequence to acquire a set of dose images at various locations. The use of the optimization protocol is illustrated by some examples. The optimization protocol enables the user to derive the optimal sequence parameters to acquire a set of dose maps obtained by quantitative T2 imaging for each polymer gel dosimeter within the shortest time possible.     

Detection and characterisation of an overmodified type III collagen by analysis of non-cutaneous connective tissues in a patient with Ehlers-Danlos syndrome IV.

The clinical and biochemical observations in a patient with a mild form of Ehlers-Danlos syndrome (EDS) type IV are described. The patient's skin fibroblasts produced markedly diminished amounts of type III collagen. SDS-polyacrylamide gel electrophoresis of collagens produced by cells obtained from other, non-cutaneous tissues showed two forms of collagen alpha 1(III) chains, a normal and a slow migrating, mutant form. Further analysis confirmed that the type III collagen molecules containing mutant alpha chains which were overmodified had a lower thermal stability and were poorly secreted into the extracellular medium. The protein defect was mapped by in situ cyanogen bromide digestion and was located in alpha 1(III) CB9, the C-terminal peptide of the collagen triple helix. This study shows that non-cutaneous connective tissues can be a useful source for the study of type III collagen defects in patients with EDS type IV.     

The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses

Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi). Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response. Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.     

A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: Further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201

This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named "Sardinian haplotype" because of its frequency (12-15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of "Sardinian haplotype" was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p less than 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.     

Interferon synthesis in x-irradiated animals v. Origin of mouse serum interferon induced by polyinosinic-polycytidylic Acid and encephalomyocarditis virus

The radioresistant cell systems producing serum interferon after intravenous administration of polyinosinic-polycytidylic acid [poly(I·C)] or encephalomyocarditis virus in mice were studied in rat-to-mouse radiation chimeras. Interferon induced by poly(I·C) became of donor type within 3 months after grafting of irradiated C3H/He mice with Wistar rat bone marrow cells; this indicated that it was made in cells derived from the hemopoietic system. In contrast, encephalomyocarditis virus-induced interferon remained of recipient type in xenogeneic chimeras up to 3 months after grafting, which indicated that the bulk of this interferon originated from a cell population not derived from the hemopoietic system. To ascertain that the respective radiosensitivities of the systems producing rat interferon in chimeras corresponded to that of normal mice, some rat-to-mouse chimeras were subjected to a second X irradiation 1 month after the first irradiation and restoration. Circulating interferon production was studied 4 days later. As expected, the re-irradiation strongly depressed rat serum interferon production induced by Newcastle disease virus but had no effect on rat interferon synthesis induced by poly (I·C). These results point to a macrophage origin for the bulk of poly(I·C)-induced circulating interferon.     

Small-scale field trial of a sensing device for detecting peridomestic populations of Triatoma infestans (Hemiptera: Reduviidae) in northwestern Argentina

Two prototypes of sensing devices for detecting peridomestic populations of Triatoma infestans Klug were tested in paired trials with bamboo canes in Amamá and nearby rural villages under triatomine surveillance. In infested peridomestic structures housing domestic animals, 1-2 pairs of numbered devices were placed per test site, left for 3-9 nights, and inspected for evidence of infestation. Prototype A was a black plastic cylinder 19 cm high and 10 cm diameter, with a screw cap on the top, 2 openings in the bottom, and a removable central structure made of resistant plastic coated with leather. Prototype B had square leather pieces rolled into cylinders instead of the central structure. Prototype A was significantly more sensitive than the bamboo cane with pleated paper inside in 13 test sites in which 20 pairs were tried. In a smaller series involving 7 pairs, prototype B also detected infestations more frequently than the cane. Triatomine feces were the signs most frequently recorded by both prototypes, whereas the bamboo canes recorded no feces. Ten T. infestans and 1 Triatoma guasayana Wygodzinsky & Avalos were collected from the prototypes placed on the ground or walls, not beneath the thatched roofs of the animal shelters, whereas only 3 T. infestans were collected from the canes. This study describes an effective sensing device for detecting T. infestans populations in outdoor animal shelters and provides quantitative field data on its performance.     

Cimetidine and placebo-cimetidine in the treatment of patients with chronic gastric ulcer (a multiclinical randomized double-blind comparative study)

The efficacy of a 4-week cimetidine treatment was examined by a double-blind randomized study in 37 outpatients with endoscopically verified chronic gastric ulcer. The patients received a daily dose of 3 times 1 tablet and, at night before going to bed 2 more tablet, thus a total amount of 1 g cimetidine, or cimetidine-placebo, but in case of complaints they could take in addition a mixed alkaline powder. Patients not recovering in response to a 4-week treatment, were then administered daily 5 tablets of cimetidine up to their complete recovery. Endoscopic, laboratory and clinical examinations were carried out every other week. As a result of a 4-week treatment, 56% of the cimetidine group recovered. The difference was not significant (P less than 0.2). The size of the ulcer and the intensity of the complaints were reduced significantly in both groups. The decrease in the size of the ulcer was significantly greater in the first two weeks of cimetidine treatment than in the cimetidine-placebo group (P less than 0.05). This favourable dynamics of ulcer healing was not felt in the second two weeks of treatment, and after four weeks there was no difference in the size of the residual ulcer to between the two groups. Cimetidine seemed to be a suitable drug for treating chronic gastric ulcer, since its healing rate proved to be better than that of placebo, the gain in weight also was favourable and there were no side-effects.