Echinococcus multilocularis: responses to infection in cotton rats (Sigmodon hispidus)

Various aspects of the responses of cotton rats to intraperitoneal infections with Echinococcus multilocularis were examined to determine if they could be related to the progress of the infection. At 14 weeks post-infection, infected animals had enlarged spleens; there was a slight decrease in packed cell volume, but no reticulocytosis. The number of all four types of leukocytes in the peripheral blood (lymphocytes, monocytes, neutrophils and eosinophils) increased during the course of the infection. In the peritoneal fluid, the numbers of neutrophils increased, monocytes and basophils decreased, and lymphocytes and eosinophils remained unchanged. Antibodies to E. multilocularis were detected in the serum of infected cotton rats as early as 2 weeks post-infection. The mean levels of transaminases (SGOT and SGPT) in the serum of infected animals were higher than in controls, and 5'-nucleotidase levels were elevated in heavily infected animals. There were no differences in responses between male and female animals. Comparison with results previously obtained suggest that both the outcome of the infection, and responses to it, may be under host control.     

Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6.

5-Hydroxytryptamine 2A (5-HT2A) receptors are essential for the actions of serotonin (5-hydroxytryptamine (5-HT)) on physiological processes as diverse as vascular smooth muscle contraction, platelet aggregation, perception, and emotion. In this study, we investigated the molecular mechanism(s) by which 5-HT activates 5-HT2A receptors using a combination of approaches including site-directed mutagenesis, molecular modeling, and pharmacological analysis using the sensitive, cell-based functional assay R-SAT. Alanine-scanning mutagenesis of residues close to the intracellular end of H6 of the 5-HT2A receptor implicated glutamate Glu-318(6.30) in receptor activation, as also predicted by a newly constructed molecular model of the 5-HT2A receptor, which was based on the x-ray structure of bovine rhodopsin. Close examination of the molecular model suggested that Glu-318(6.30) could form a strong ionic interaction with Arg-173(3.50) of the highly conserved "(D/E)RY motif" located at the interface between the third transmembrane segment and the second intracellular loop (i2). A direct prediction of this hypothesis, that disrupting this ionic interaction by an E318(6.30)R mutation would lead to a highly constitutively active receptor with enhanced affinity for agonist, was confirmed using R-SAT. Taken together, these results predict that the disruption of a strong ionic interaction between transmembrane helices 3 and 6 of 5-HT2A receptors is essential for agonist-induced receptor activation and, as recently predicted by ourselves (B. L. Roth and D. A. Shapiro (2001) Expert Opin. Ther. Targets 5, 685-695) and others, that this may represent a general mechanism of activation for many, but not all, G-protein-coupled receptors.     

Future trends in worldwide river nitrogen transport and related nitrous oxide emissions: a scenario analysis

We analyze possible future trends in dissolved inorganic nitrogen (DIN) export by world rivers and associated emissions of nitrous oxide (N2O). Our scenarios either assume that current trends continue or that nitrogen (N) inputs to aquatic systems are reduced as a result of changes in agriculture practices and fuel combustion technologies. The results indicate that moderate changes in the human diet in North America and Europe, reducing worldwide fertilizer use by only 16%, relative to Business-as-Usual (BAU) levels, may reduce DIN export rates to the North Atlantic and European Seas by about one third and associated N2O emissions by 36 to 77%. We furthermore calculate that relatively large reductions in NOy deposition rates in Europe (of about 80%) may reduce DIN export by rivers by a moderate 8% or less, relative to BAU levels. The potential effect of reduced NOy deposition on riverine DIN export is moderate, because most N in European rivers stems from agriculture, and not from fuel combustion. Nevertheless, the calculated 9% reduction (relative to BAU) in DIN inputs to the North Sea as a potential side effect of air pollution control may help achieve the international policy targets for reduced N inputs to the North Sea.     

Intratumoral Administration of Holmium-166 Acetylacetonate Microspheres: Antitumor Efficacy and Feasibility of Multimodality Imaging in Renal Cancer

Purpose

The increasing incidence of small renal tumors in an aging population with comorbidities has stimulated the development of minimally invasive treatments. This study aimed to assess the efficacy and demonstrate feasibility of multimodality imaging of intratumoral administration of holmium-166 microspheres (¹⁶⁶HoAcAcMS). This new technique locally ablates renal tumors through high-energy beta particles, while the gamma rays allow for nuclear imaging and the paramagnetism of holmium allows for MRI.

Methods

¹⁶⁶HoAcAcMS were administered intratumorally in orthotopic renal tumors (Balb/C mice). Post administration CT, SPECT and MRI was performed. At several time points (2 h, 1, 2, 3, 7 and 14 days) after MS administration, tumors were measured and histologically analyzed. Holmium accumulation in organs was measured using inductively coupled plasma mass spectrometry.

Results

¹⁶⁶HoAcAcMS were successfully administered to tumor bearing mice. A striking near-complete tumor-control was observed in ¹⁶⁶HoAcAcMS treated mice (0.10±0.01 cm³ vs. 4.15±0.3 cm³ for control tumors). Focal necrosis and inflammation was present from 24 h following treatment. Renal parenchyma outside the radiated region showed no histological alterations. Post administration CT, MRI and SPECT imaging revealed clear deposits of ¹⁶⁶HoAcAcMS in the kidney.

Conclusions

Intratumorally administered ¹⁶⁶HoAcAcMS has great potential as a new local treatment of renal tumors for surgically unfit patients. In addition to strong cancer control, it provides powerful multimodality imaging opportunities.     

Echinococcus multilocularis: susceptibility and responses to infection in inbred mice

Kroeze W. K. and Tanner C. E. 1987. Echinococcus multilocularis: susceptibility and responses to infection in inbred mice. International Journal for Parasitology17: 873–883. Of six strains of mice examined, C57L/J mice were the most susceptible to intraperitoneal infections with Echinococcus multilocularis. Five of the six strains developed splenomegaly during the infection. Changes in leukocyte levels in infected mice were most pronounced in the C57L/J and BALB/cJ strains. Two of the six strains of mice, C57BL/6J and C57BL/6J (bg^J), showed low specific IgG responses to E. multilocularis when measured using an ELISA. Many of the responses observed were directly correlated with the parasite burden in infected animals. It is concluded that susceptibility or resistance to E. multilocularis in mice is probably controlled by non-H-2 gene(s); additionally, hematological and immunological responses to infection, although correlated to parasite burden, varied among strains of mice, suggesting some degree of host genetic control of these responses.     

The taste of sodium chloride: masking and adaptation

Human subjects estimated the saltiness of sodium chloride anda mixture of sodium chloride and sucrose. The adapting effectsof sucrose, sodium chloride and a mixture of both substanceswere investigated. The stimuli were delivered by a flow systemto pre-defined tongue areas. After adaptation to NaCl and tothe mixture the subjective intensity of NaCl-saltiness decreased58% and 69% respectively. Also a strong masking effect of saltinesswas observed: 59.1% reduction. No indications of crossadaptationwere found. The results were interpreted in favour of the independencyof adaptation and masking.     

The sour taste of acids. The hydrogen ion and the undissociated acid as sour agents

In the first of two experiments, the sourness of aqueous solutionsof HCl and of several carboxylic acids was measured by meansof a fitter-paper method. Perceived sourness of the carboxylicacids was positively correlated with the dissociation constantK_al. In contrast to HCl, the H⁺ concentration in carboxylicacids appeared not to be the only factor in eliciting sourness.Decreasing pH by buffering of the carboxylic acids with theirsodium salts did not lower perceived sourness. The rank-orderof the acids, according to the amount of NaOH needed for titration,depends on the pH to which it is titrated. The rank-order ofpH 4.4 reasonably fits the sourness rank-order. In the secondexperiment, adaptation and cross-adaptation of HCl, tartaric-lactic-,and acetic acid were measured. Neither self- nor cross-adaptationwas observed in the case of HCl, whereas with the carboxylicacids self- and mutual cross-adaptation did occur. The presentresults suggest that HCl-sourness and the sourness of carboxylicacids are elicited by different receptor processes.     

The relationship between the side tastes of masking stimuli and masking in binary mixtures

Subjects estimated the sweetness of HOH, NaCl, Q₂SO₄, sucroseand of the binary mixture of the three compounds. Another groupof subjects made independent estimates of the bitterness andsaltiness of HOH, Q₂SO₄, NaCl and of the binary mixtures ofNaCl and Q₂SO₄. Apart from their specific main taste, the stimuliappear to also possess a side taste in the modality equal tothe suppressed component, with the exception of Q₂SO₄ whichshowed no sweet side taste. The side tastes are negatively relatedto masking, thus the higher a specific side taste, the lowerthe amount of suppression of that taste in the binary mixture.Apparently, the subjects add these side tastes of the maskingagents to the specific quality of the suppressed sensationsin the mixture. In this way spurious results of low maskingor even enhancement are produced. The obtained results werecompared to data from a study in the literature on taste masking.     

Integrated Approaches for Genome-wide Interrogation of the Druggable Non-olfactory G Protein-coupled Receptor Superfamily

G-protein-coupled receptors (GPCRs) are frequent and fruitful targets for drug discovery and development, as well as being off-targets for the side effects of a variety of medications. Much of the druggable non-olfactory human GPCR-ome remains under-interrogated, and we present here various approaches that we and others have used to shine light into these previously dark corners of the human genome.