Digenean metacercariae of fishes from the lagoon flats of Palmyra Atoll, Eastern Indo-Pacific.

Although many studies on the taxonomy of digenean trematodes of marine fishes have been completed in the Eastern Indo-Pacific (EIP) marine ecoregion, only a few have considered metacercarial stages. Here, the results are presented of a taxonomic survey of the digenean metacercariae of fishes from Palmyra Atoll, a remote and relatively pristine US National Wildlife Refuge located 1680 km SSW of Hawaii. Up to 425 individual fish were collected, comprising 42 fish species, from the sand flats bordering the lagoon of the atoll. Quantitative parasitological examinations of each fish were performed. Morphological descriptions of the encountered digenean metacercariae are provided, together with their prevalence, mean intensities, host and tissue-use. Up to 33,964 individuals were recovered representing 19 digenean metacercaria species from eight families. The species composition of digeneans in lagoon fishes at Palmyra Atoll is a subset of what has previously been reported for the EIP. Further, the large diversity and abundance of metacercariae reported in this study highlight the utility of including this group in future ecological research in the EIP marine ecoregion.

Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for κ-opioid receptors.

2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242) is a novel κ-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a ∼ 20-fold reduced affinity for human µ-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for δ-opioid receptors (K(i) > 4 µM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist-induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3-phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 ± 0.4 to 41.9 ± 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline-induced plasma prolactin with an ID(50) of 2.3 ± 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders.

New superheavy element isotopes: ²4²Pu(48Ca,5n) ²85114.

The new, neutron-deficient, superheavy element isotope ²85114 was produced in 48Ca irradiations of ²4²Pu targets at a center-of-target beam energy of 256 MeV (E*=50 MeV). The α decay of ²85114was followed by the sequential α decay of four daughter nuclides, 281Cn, 277Ds, 273Hs, and 269Sg. 265Rf was observed to decay by spontaneous fission. The measured α-decay Q values were compared with those from a macroscopic-microscopic nuclear mass model to give insight into superheavy element shell effects. The²4²Pu (48Ca,5n²)²85114 cross section was 0.6(-0.5)+0.9 pb.

Antidepressant-like effects of the novel kappa opioid antagonist MCL-144B in the forced-swim test.

Previous studies have demonstrated that kappa opioid receptor (KOR) antagonists reduce stress- and depression-like behaviors. We hypothesized that administration of a novel opioid mixed agonist/antagonist capable of antagonist activity at the KOR would attenuate forced-swim stress (FSS)-induced immobility, an animal model of depression-like behavior. C57Bl/6J mice were exposed to antinociceptive and repeated FSS testing after pretreatment with a graded dose of a novel bivalent morphinan compound, bis(N-cyclobutylmethylmorphinan-3-yl) sebacoylate dihydrochloride (MCL-144B). MCL-144B demonstrated dose- and time-dependent antinociception and KOR-mediated antagonism. In support of the hypothesis, pretreatment with MCL-144B dose-dependently attenuated stress-induced antinociception and immobility in the forced-swim test.

Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn.

Stress contributes to the reinstatement of cocaine-seeking behavior in abstinent subjects. Kappa-opioid receptor antagonists attenuate the behavioral effects of stress, potentially providing therapeutic value in treating cocaine abuse. Presently, the peptide arodyn produced long-lasting kappa-opioid receptor antagonism, suppressing kappa-opioid receptor agonist-induced antinociception at least 3 days after intracerebroventricular administration of 0.3 nmol. C57Bl/6J mice demonstrated cocaine-conditioned place preference, extinction over 3 weeks, and a subsequent reinstatement of place preference. Arodyn pretreatment suppressed stress-induced, but not cocaine-exposed, reinstatement of cocaine place preference. These results verify that arodyn and other kappa-opioid receptor antagonists may be useful therapeutics for cocaine abuse.

Radon survey in the high natural radiation region of Niska Banja, Serbia.

A radon survey has been carried out around the town of Niska Banja (Serbia) in a region partly located over travertine formations, showing an enhanced level of natural radioactivity. Outdoor and indoor radon concentrations were measured seasonally over the whole year, using CR-39 diffusion type radon detectors. Outdoor measurements were performed at 56 points distributed over both travertine and alluvium sediment formations. Indoor radon concentrations were measured in 102 living rooms and bedrooms of 65 family houses. In about 50% of all measurement sites, radon concentration was measured over each season separately, making it possible to estimate seasonal variations, which were then used to correct values measured over different periods, and to estimate annual values. The average annual indoor radon concentration was estimated at over 1500 Bq/m3 and at about 650 Bq/m3 in parts of Niska Banja located over travertine and alluvium sediment formations, respectively, with maximum values exceeding 6000 Bq/m3. The average value of outdoor annual radon concentration was 57 Bq/m3, with a maximum value of 168 Bq/m3. The high values of indoor and outdoor radon concentrations found at Niska Banja make this region a high natural background radiation area. Statistical analysis of our data confirms that the level of indoor radon concentration depends primarily on the underlying soil and building characteristics.

Improved immunotherapy of a recombinant carcinoembryonic antigen vaccinia vaccine when given in combination with interleukin-2.

Interleukin-2 (IL-2) has been an effective immune modulator in several active-specific immunotherapy experimental protocols using either viral or oncolysate-based vaccines. In this report, data indicate that IL-2 administration can appreciably augment the therapeutic effect of a single immunization of a recombinant vaccinia virus-carcinoembryonic antigen (rV-CEA) vaccine using a CEA-expressing syngeneic experimental murine model system. A single rV-CEA immunization of C57BL/6 mice bearing palpable CEA-positive colon adenocarcinoma tumors results in complete tumor regression in approximately 20% of the mice. The addition of a course of low-dose IL-2 results in complete tumor regression in 60-70% of the mice. Moreover, the combination of rV-CEA and IL-2 induces systemic immunity, which protects those tumor-free mice from subsequent rechallenge with the CEA-expressing tumor cells. No such tumor regression or protection was observed in those mice immunized with the wild-type vaccinia vaccine (V-Wyeth) alone or with IL-2 administration alone. Cellular immune assays revealed that the addition of IL-2 to rV-CEA immunization significantly increased the CEA-specific T-cell proliferative responses as well as the cytolytic T-cell responses when compared with rV-CEA immunization alone. The enhanced CEA-specific immune response, coupled with the improved experimental therapeutic outcome following IL-2 administration, suggests that treatment with that cytokine may effectively substitute for multiple rV-CEA immunizations in active-specific immunotherapy clinical protocols directed at CEA-expressing tumors.

Admixture of a recombinant vaccinia virus containing the gene for the costimulatory molecule B7 and a recombinant vaccinia virus containing a tumor-associated antigen gene results in enhanced specific T-cell responses and antitumor immunity.

At least two signals are required for the activation of naive T cells by antigen-bearing target cells: an antigen-specific signal, delivered through the T-cell receptor, and a costimulatory signal delivered through the T-cell surface molecule CD28 by its natural ligand B7-1. The immunological benefit of coexpression of B7 with target antigen has been demonstrated with the use of several retroviral systems to transfect antigen-bearing cells. Although engineering recombinant constructs with genes for two or more antigens can mediate the dual expression of those antigens, disadvantages of this approach include the time for construction of each desirable combination and the inability to control differential expression levels of each gene product. An alternative approach would utilize separate constructs that could be admixed appropriately before administration. In this report we describe the functional consequences of the admixture of recombinant vaccinia murine B7-1 (rV-B7) to recombinant vaccinia expressing the human carcinoembryonic antigen gene (rV-CEA). Coinfection of cells resulted in high levels of cell surface expression of both the CEA and B7 molecules. Immunization of mice with various ratios (1:3, 1:1, 3:1) of rV-CEA and rV-B7 demonstrated that an admixture of rV-CEA and rV-B7 at a 3:1 ratio resulted in the generation of optimal CEA-specific T-cell responses. Next, we examined the efficacy of this admixture on antitumor activity. Typically, injection of murine carcinoma cells expressing CEA leads to the death of the host. One immunization of C57BL/6 mice with rV-CEA:rV-B7 (3:1) resulted in no tumor establishment. In contrast, administration of rV-CEA or rV-B7 alone had little or no antitumor effects. These studies demonstrate the advantages of the use of recombinant vaccinia viruses to deliver B7 molecules in combination with a tumor-associated antigen. The availability of the rV-B7 single construct and the ability to alter the B7 ratio could also have potential utility when coinfecting rV-B7 with recombinant vaccinia viruses containing genes for infectious agents or other tumor-associated antigen genes.

Aesthetic preference and lateral preferences.

Subjects expressed preference for original or mirror-reversed versions of paintings. Hand preference predicted a significant proportion of the choice variance, but eye, foot and ear preference did not, nor did family sinistrality.

Partial opioids. Medications for the treatment of pain and drug abuse.

Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug-abuse problems. Cyclazocine is a low-liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the mu opioid receptor and as kappa agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying kappa agonist and partial mu agonist properties, a series of 8-amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the mu, delta, and kappa opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the mu, delta and kappa receptors.

14 beta-Chlorocinnamoylamino derivatives of metopon: long-term mu-opioid receptor antagonists.

The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.

Metopon and two unique derivatives: affinity and selectivity for the multiple opioid receptors.

5 beta-Methyl-7,8-dihydromorphinone (metopon), an isomer [6aS-(6a alpha,9a alpha, 10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline- 7-(9aH)-one (compound 1) derived from a photochemical rearrangement of 5 beta-methylmorphinone, and [6aS-(6a alpha,9a alpha,10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14 beta- (p-nitrocinnamoylamino) isoquinoline-7-(9aH)-one (compound 2) were characterized for opioid receptor affinity, selectivity and analgesic properties. In competition binding assays using bovine striatal membranes, the three compounds inhibited the binding of 0.25 nM [3H][D-Ala2,(Me)-Phe4,Gly(ol)5]enkephalin (DAMGO), a mu-selective peptide, with IC50 values less than 5 nM. All three compounds exhibited lower affinity for delta- and kappa-opioid receptors. In the mouse 55 degrees C warm-water tail-flick assay, both metopon and compound 1 displayed antinociception that lasted for 60 min after i.c.v. injection. Morphine sulfate, metopon and compound 1 produced 50% antinociception with i.c.v. doses of 0.83, 2.0 and 4.0 nmol, respectively. The mu-selective, irreversible opioid receptor antagonist beta-funaltrexamine blocked antinociception induced by metopon and compound 1, while delta- and kappa-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the mu-opioid receptor and produced antinociception through this receptor.

Correlation of 210Po implanted in glass with radon gas exposure: sensitivity analysis of critical parameters using a Monte-Carlo approach.

In recent years, 210Po implanted in glass artefacts has been used as an indicator of the mean radon gas concentration in dwellings in the past. Glass artefacts have been selected in many dwellings and the alpha-recoil implanted 210Po concentration has been measured using various techniques. Some of these retrospective techniques use a model to estimate the retrospective radon gas on the basis of this surface 210Po activity. The accumulation of 210Po on glass surfaces is determined by the deposition regime over the exposure period. The 210Po activity is determined not only by the radon progeny deposition velocities, but by other room parameters such as ventilation rate, aerosol conditions and the surface to volume ratio of the room. Up to now in using room models, a nominal or 'base-case' scenario is used, i.e. a single value is chosen for each input parameter. In this paper a Monte-Carlo analysis is presented in which a probability distribution for each parameter is chosen, based on measurements quoted in the literature. A 210Po surface activity is calculated using a single value drawn from each of the parameter distributions using a pseudo-random number generator. This process is repeated n times (up to 20,000), producing n independent scenarios with corresponding 210Po values. This process permits a sensitivity analysis to be carried out to see the effect of changes in inputs on the model output.

Indoor natural radiation levels in Ireland.

The principal results of a preliminary study made on indoor radiation levels in Ireland are presented. During the period 1983-84 measurements were made in over 250 houses. Most measurements were made using passive devices: TLDs for penetrating radiation and CR-39 alpha track plastic detectors for radon measurements. The median value of the doses from penetrating radiation was 0.78 milligray/year with a maximum value of 1.47 m Gy/year detected. The radon concentrations showed a large degree of variability with a median value of 43 Bq/m3. About 10% of the houses had radon air concentrations in excess of 100 Bq/m3 with a maximum of 700 Bq/m3 being recorded. A tentative analysis of the data with regard to the geological situation is presented.

The reduction of indoor air concentrations of radon daughters without the use of ventilation.

The possibility of using filtration and electric fields both separately and in combination to reduce the indoor air concentrations of radon daughters is described in theoretical terms and with reference to investigations in experimental rooms. For energy conservation considerations these investigations were carried out without reducing the radon concentration by ventilation or other means. The importance of aerosols to the effectiveness of these methods is also described. It is demonstrated that it is possible by use of filtration rates of 3 - 4 times per hour to reduce the potential alpha energy concentration by a factor of 4 - 5. In case of low aerosol concentration the corresponding reduction in lung dose may be much smaller, depending upon the dose-exposure model used, due to the filtration-caused change in the partitioning of the radon daughters between the attached and un-attached states.

Field experience with volume traps for assessing retrospective radon exposures.

Approximately 200 volume traps were retrieved from dwellings in various radon prone areas in Europe. They were analysed for the purpose of retrospective radon assessment. Emphasis is put on specific problems encountered when using field samples as opposed to laboratory exposed samples. It was seen that in very dusty circumstances, direct penetration of radon decay products from the outside to the centre of the volume traps calls for extra caution. Rinsing the samples is proposed as a solution and was tested in field and laboratory conditions, showing good results. An attempt was made to give an assessment of the achievable accuracy of the method. Where possible, the volume trap retrospective results were compared with contemporary measurements or to retrospective results from surface traps. The overall impression is that although volume traps are sometimes hard to find in the field, the high reliability of the results makes it well worth the effort.

Retrospective assessment of historic radon concentrations in Norwegian dwellings by measuring glass implanted Po-210--an international field intercomparison.

The first Norwegian study of historic radon concentrations in 17 dwellings in the high radon areas in Norway has been conducted as part of an international field intercomparison during 1998. The retrospective radon concentration is estimated via measurements of Po-210, the long-lived decay product of Rn-222 implanted in glass surfaces of objects like pictures, mirrors, cabinet-glass, etc. the method called 'surface trap'. Three different surface trap techniques to assess the implanted Po-210 activity and two different procedures to estimate retro radon from Po-210 data were used. The Po-210 and the retrospectively estimated radon results agree reasonably well over a wide range of concentrations. Historic radon concentrations were also estimated from analysis of a smaller number of 'volume trap' samples (pieces of spongy materials), and the results compared to those from 'surface traps'. The retro radon results correlate with contemporary radon results with a correlation coefficient of 0.877. To evaluate uncertainty in Po-210 measurements due to varying position on the glass a study of spatial homogeneity of three sample glasses was conducted and variations between 12% and 18% were found.

Integrated natural radiation exposure studies in stable Yugoslav rural communities.

The results of field investigations of natural radiation exposures of the general population in two stable rural communities in Yugoslavia are presented. The principal emphasis was on exposures to contemporary indoor radon, but measurements of external penetrating radiation absorbed dose rates in air were carried out in the majority of cases. In addition, in a limited number of dwellings, measurements of thoron gas concentrations were made. By means of making a series of sequential 3-month radon measurements, both seasonal variations and annual average radon levels in the dwellings were determined. Using passive alpha track detectors, individual radon and thoron indoor concentrations as high as 9591 Bq m(-3) and 709 Bq m(-3), respectively, were detected while absorbed dose rates in air in the dwellings as high as 430 nGy h(-1) were recorded. On the basis of these different types of measurements, assessments could be made of the integrated natural radiation exposures being received by the populations. In addition to contemporary radon measurements, retrospective radon exposure assessments in most of the dwellings were made on the basis of measurements of 210Po concentrations in both surface (glass) traps and in volume (porous materials) traps. A description is given of the sampling strategies and protocols used in this field work. It is shown that at least one stable rural community receiving high natural radiation exposures, has been clearly identified and plans for future health investigations of the population there are outlined.

Actinide analysis of a depleted uranium penetrator from a 1999 target site in southern Serbia.

Following the detection of 236U in depleted uranium (DU) ammunition used during the Balkans conflict in the 1990s, concern has been expressed about the possibility that other nuclides from the nuclear fuel cycle and, in particular, transuranium nuclides, might be present in this type of ammunition. In this paper, we report the results of uranium and plutonium analyses carried out on a depleted uranium penetrator recovered from a target site in southern Serbia. Our data show the depleted nature of the uranium and confirm the presence of trace amounts of plutonium in the penetrator. The activity concentration of (239+240)PU, at 45.4+/-0.7 Bq kg(-1), is the highest reported to date for any penetrator recovered from the Balkans. This concentration, however, is comparable to that expected to be present naturally in uranium ores and, from a radiological perspective, would only give rise to a very small increase in dose to exposed persons compared to that from the DU itself.

Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour.

BACKGROUND AND PURPOSE: The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits κ opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACH: The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTS: The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and κ and µ opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28-4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS: These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics.