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Since muramyl dipeptide (MDP) was recognized as a potent monocyte/macrophage activating agent, many MDP analogues were synthesized and tested for their ability to augment the host immune defence system against neoplasms. This study was performed to determine whether the newly synthesized desmuramyl N-acyl dipeptides LK 409 and LK 410 were also capable of affecting the immune system. For this purpose, the peritoneal macrophages were incubated in vitro with these two agents and TNF-alpha production was measured. In addition, the effect of LK 409 and LK 410 on TNF-alpha and IL-1 RNA levels in in vivo stimulated macrophages was determined by quantitative polymerase chain reaction (RT-PCR). None of the LK 409 and LK 410 concentrations tested were able to render macrophages in vitro to excrete a detectable amount of TNF-alpha in the supernatant fluid. However, the TNF-alpha and IL-1 RNA levels in macrophages of in vivo treated mice (C57Bl/6) were increased in comparison to mock-treated mice. The results indicate that LK 409 and LK 410 are capable of inducing an increase in TNF-alpha and IL-1 RNA levels, yet in vitro TNF-alpha production remains under detectable levels (40 U/ml).

The effects of acetylcholine on isolated uterine artery rings of non-pregnant and pregnant guinea-pigs were investigated. Acetylcholine induced a concentration- and endothelium-dependent relaxation of both types of vessels, with similar pD2 (non-pregnant: pD2 = 7.66; pregnant: pD2 = 7.59) and maximal response values. The pKA values (non-pregnant vs. pregnant) of acetylcholine were 6.17 vs. 6.09. The occupancy response relationship was non-linear since the half-maximal response to acetylcholine (non-pregnant vs. pregnant) was obtained with 2.86 vs. 2.91% receptor occupancy. In quiescent preparations, the muscarinic receptor antagonists, atropine, pirenzepine, N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octane-diamine tetrahydrochloride (methoctramine) and para-fluoro-hexahydro-sila-difenidol (pFHHSiD), produced parallel rightward shifts of the curves for acetylcholine and the slopes of the Schild plots were not significantly different from unity. The plots constrained to a slope of unity gave the following -log KB values (non-pregnant vs. pregnant): atropine (9.68 vs. 9.75), pirenzepine (6.75 vs. 6.53), methoctramine (6.13 vs. 6.23) and pFHHSiD (7.88 vs. 7.96). It is concluded that, in guinea-pig uterine arteries, acetylcholine induces endothelium-dependent relaxation and acts as a full agonist, regardless of pregnancy status. We suggest that the relaxation induced by acetylcholine, in either non-pregnant or pregnant guinea-pig uterine artery, is mediated via the M3 subtype of muscarinic receptors.

In this study, we tried to define in vitro interactions of two antitumor agents that have different sites and different mechanisms of action. Vinblastine (VLB) in combination with human recombinant interferon-alpha A/D (rHuIFN-alpha A/D) and in combination with murine recombinant interferon-gamma (rMuIFN-gamma) was studied. The effect of the combination was determined with cell growth kinetics assay on B-16 melanoma and the interaction defined by means of Spector's formula. Both the combination of rHuIFN-alpha A/D with VLB and the combination of rMuIFN-gamma with VLB synergistically inhibited cell growth in vitro. There was a positive biochemical modulation between the two drugs, but it is still unknown whether it occurred at the level of uptake into the cell, metabolism within the cell or egress from the cell.

Efficiency of organisation of management of the injured and diseased in combat operations in 1991/2 and results of hospital treatment are studied. The questionnaire was established for collection of data about stationary treatment of the wounded and diseased in 7 military and 15 civilian medical institutions. Data about 9.243 injured of whom only 5.57% were civilians are especially analysed. In most cases injuries were inflicted by mine-explosive devices (48.77% in combat and 6.27% in non-combat operations), then those inflicted by bullets (38.58% in combat and 8.02% in non-combat operations). Self-inflicted injuries occurred in 5.79% in combat and 10.32% in non-combat operations. Injuries inflicted in non-combat operations were found in a high percentage (46.60). They mostly occurred in the open air (41.26%). Injuries of extremities are predominant (64.70%), then injuries of the head and neck (17.90%), thorax (9.90%), abdomen and pelvis (7.50%). Young men (20-24 years old) were commonly injured but the older ones (over 40 years) have been also frequently injured (18.30%). Evacuation of the wounded and diseased was performed mainly by ambulances (about 60%) or helicopters (16%), especially to the medical institutions far in the country (to M.M.A. up to 60%). The first aid was given within the first ten minutes after injury in 55.00% and within 30 minutes in 65.58% of cases. Mutual aid was most frequently applied (33.12%) and then first aid given by general practitioners (32.12%). Surgical treatment was provided one hour after injury to every fourth wounded (24.08%) and after six hours to more than one third of the wounded (31.88%).(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrosarcoma-SA-I-tumor-bearing mice were treated s.c. in the vicinity of tumors (peri-tumorally) or intravenously, with recombinant human TNF-alpha lacking 1 to 3 amino acids from N-terminal part (TNF-alpha Nv3). Tumor growth delay, observed after both routes of TNF-alpha Nv3 application, was statistically significant, though a better anti-tumor effect was achieved after peri-tumoral application. TNF-alpha Nv3 serum levels were determined in these animals and compared with TNF-alpha Nv3 serum levels in healthy animals, which were treated with TNF-alpha Nv3 either s.c. or i.v. The peak serum levels of TNF-alpha Nv3 applied peri-tumorally/s.c. were significantly higher in tumor-bearing than in healthy mice, whereas smaller differences in peak serum levels were found after i.v. application, which might correlate with anti-tumor activity. Whatever the route of application, TNF-alpha Nv3 elimination from the serum of tumor-bearing mice was slower than that in healthy animals. Also, comparison of TNF-alpha Nv3 pharmacokinetic parameters for tumor-free and sarcoma- or melanoma-bearing mice has demonstrated that the pharmacokinetics of TNF-alpha Nv3 are modified in tumor-bearing animals.

Electrotherapy was investigated for its ability to increase the responsiveness of murine tumors to bleomycin treatment. Mice bearing fibrosarcoma were treated with 250 micrograms bleomycin and then with 0.6 mA direct current (DC) for 60 min. Antitumor effects of single treatments were moderate with bleomycin, but significant with electrotherapy. Combined treatment with bleomycin followed by electrotherapy was more effective than either treatment alone. Tumor growth delay of the animals after combined treatment was greater than the summation of tumor growth delays after single treatments. The results of our study indicate that bleomycin and electrotherapy treatments interact, with electrotherapy potentiating the effectiveness of bleomycin treatment.

This study was designed to evaluate the effect of intracranial self-stimulation (ICSS) on specific immunological reactivity in the rat. Male Wistar rats were implanted with stimulating electrodes in the lateral hypothalamus (LH) and ventral tegmental area (VTA). After recovery from surgery and screening procedure, animals were allowed to self-stimulate 30 minutes daily during different periods of time before or after immunization with sheep red blood cells (SRBC) and bovine serum albumin (BSA). We report here on the in vivo immunoregulating effects of ICSS on plaque-forming cell (PFC) response, hemagglutinin production to SRBC, and antibody titer and hypersensitivity skin reactions to BSA. The effects produced were dependent on the brain area which was stimulated, time relationship of ICSS and immunization, type of immune reaction, and antigen used for immunization. Therefore, ICSS appears to be a significant tool in the regulation of the immune system function, and thus provides further evidence of the interconnections between the immune system and behavior.

Electrotherapy with direct current (DC) was performed on two murine tumor models, fibrosarcoma SA-1 and melanoma B16. Three Pt/Ir cathodes were inserted directly into the subcutaneous tumors and two anodes subcutaneously in the vicinity of the tumor. Significant tumor growth delay was achieved after electrotherapy and was dependent on DC intensity (0.6, 1.0, 1.4 and 1.8 mA). Melanoma B16 tumors were more sensitive to electrotherapy than SA-1 tumors. In order to enhance the antitumor effect of electrotherapy, combined treatment with interleukin-2 (IL-2) was performed. When both therapies were combined significant tumor growth delay and also higher curability rate was achieved. The results imply that electrotherapy can be an effective antitumor therapy and that the effects can be enhanced with additional IL-2 therapy.

During summer Mediterranean spotted fever (MSF) is prevalent in the subcostal part of Croatia (North Dalmatia) as well as in other areas of the Mediterranean coast. We compared the specificity and sensitivity of complement fixation (CF), latex agglutination (Latex-R. conorii), microimmunofluorescence (micro-IF) and enzyme-linked immuno assay (ELISA) for detection and measuring antibodies against Rickettsia conorii in 78 sera from 46 patients with/or suspected Mediterranean spotted fever. The seroreactivity with SFG antigens containing the Rickettsia conorii-antigen(s) as a common determinant, was positive in all four serological tests suggesting that Rickettsia conorii was the probable causative agent of infection in our patients.

Histology of skin lesions and demonstration in them of Rickettsia conorii by direct immunofluorescence test (DIF) are presented in 13 patients with Mediterranean spotted fever (MSF). The lymphohistiocytic vasculitis which dominated the picture is not specific, however, it could be suggestive for the diagnosis of rickettsiosis. By DIF we demonstrated rickettsial coccobacillary forms in all the patients: in 12 macular lesions and in one "tache noire". The diagnosis was also confirmed by indirect immunofluorescence test in each case. DIF test was shown to be sensitive, specific and reliable in early diagnosis of MSF.