Usefulness of CTC and DTC-BM Detection for Adjuvant Therapy Effects and Prognosis Prediction in Early Breast Carcinoma: Results of 8-11 Years of Follow-up Evaluation.

BACKGROUND: Circulating tumor cells (CTCs) reportedly have been detected in the peripheral blood of more than 50% of breast carcinoma cases with distant metastases. Moreover, the survival period is shorter for patients who had more than five CTCs after a single chemotherapy treatment. However, a few data show the relationships between CTCs and expressions of disseminated tumor cells in the bone marrow (DTCs-BM), including treatment effects and prognoses in early breast carcinomas. METHODS: In this study, CTCs and DTC-BMs were measured by the CellSearch System for 20 patients with stages 1-3 carcinomas, who were followed for 8-11 years. RESULTS: CTCs in 2 (10%) of 20 breast carcinomas, more than 1 CTC was detected before adjuvant therapy, and both cases showed a decrease to 0 after chemotherapy. DTC-BMs in 19 (95%) of the 20 primary cases, more than 1 cell was found in the BM. After adjuvant therapy, 16 cases showed a decrease to 0-10 cells, 2 cases to 11-20 cells, and 2 cases to more than 21 cells. Six patients experienced recurrence. One of the two CTC-positive cases (>21 cells) had bone and liver metastasis within 11 months. Among the DTC-BM cases, only 1 (16.7%) of the 6 primary patients with 11-20 cells had recurrence, whereas 4 (80%) of the 5 patients with more than 21 cells had recurrence 3-6 years later. CONCLUSIONS: Detection of DTC-BMs is useful for observing adjuvant therapy effects and for predicting relatively late-phase metastasis. The cluster status of CTCs suggests early relapsing.

Strength and Viscosity Effects on Perturbed Shock Front Stability in Metals.

Computational modeling and experimental measurements on metal samples subject to a laser-driven, ablative Richtmyer-Meshkov instability showed differences between viscosity and strength effects. In particular, numerical and analytical solutions, coupled with measurements of fed-through perturbations, generated by perturbed shock fronts onto initially flat surfaces, show promise as a validation method for models of deviatoric response in the postshocked material. Analysis shows that measurements of shock perturbation amplitudes at low sample thickness-to-wavelength ratios are not enough to differentiate between strength and viscosity effects, but that surface displacement data of the fed-through perturbations appears to resolve the ambiguity. Additionally, analytical and numerical results show shock front perturbation evolution dependence on initial perturbation amplitude and wavelength is significantly different in viscous and materials with strength, suggesting simple experimental geometry changes should provide data supporting one model or the other.

Gene therapy improves dental manifestations in hypophosphatasia model mice.

BACKGROUND AND OBJECTIVE: Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non-specific alkaline phosphatase (TNSALP) activity. The disease is caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL) encoding TNSALP. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia. Although there are no known fundamental treatments or effective dental approaches to prevent early exfoliation of primary teeth in affected patients, several possible treatments have recently been described, including gene therapy. Gene therapy has also been applied to TNSALP knockout mice (Alpl-/- ), which phenocopy the infantile form of hypophosphatasia, and improved their systemic condition. In the present study, we investigated whether gene therapy improved the dental condition of Alpl-/- mice. MATERIAL AND METHODS: Following sublethal irradiation (4 Gy) at the age of 2 d, Alpl-/- mice underwent gene therapy using bone marrow cells transduced with a lentiviral vector expressing a bone-targeted form of TNSALP injected into the jugular vein (n = 3). Wild-type (Alpl+/+ ), heterozygous mice (Alpl+/- ) and Alpl-/- mice were analyzed at 9 d of age (n = 3 of each), while Alpl+/+ mice and treated or untreated Alpl-/- mice were analyzed at 1 mo of age (n = 3 of each), and Alpl+/- mice and Alpl-/- mice with gene therapy were analyzed at 3 mo of age (n = 3 of each). A single mandibular hemi-section obtained at 1 mo of age was analyzed using a small animal computed tomography machine to assess alveolar bone formation. Other mandibular hemi-sections obtained at 9 d, 1 mo and 3 mo of age were subjected to hematoxylin and eosin staining and immunohistochemical analysis of osteopontin, a marker of cementum. RESULTS: Immunohistochemical analysis of osteopontin, a marker of acellular cementum, revealed that Alpl-/- mice displayed impaired formation of cementum and alveolar bone, similar to the human dental phenotype. Cementum formation was clearly present in Alpl-/- mice that underwent gene therapy, but did not recover to the same level as that in wild-type (Alpl+/+ ) mice. Micro-computed tomography examination showed that gene therapy improved alveolar bone mineral density in Alpl-/- mice to a similar level to that in Alpl+/+ mice. CONCLUSIONS: Our results suggest that gene therapy can improve the general condition of Alpl-/- mice, and induce significant alveolar bone formation and moderate improvement of cementum formation, which may contribute to inhibition of early spontaneous tooth exfoliation.

Trapping of excess energy in a nano-layered microenvironment to promote chemical reactions.

Nano-layered hybrid compounds composed of a polyfluoroalkyl azobenzene surfactant (abbreviated as C3F-Azo-C6H) and layered inorganic nanosheets undergo three-dimensional morphological changes such as reversible shrinkage and expansion of interlayer spaces, and nanosheet sliding by photo-irradiation. Previously, we have investigated the photoreactivity of C3F-Azo-C6H/clay nano-layered hybrids in various microenvironments and found a remarkable enhancement in the photoreactivity for the cis-trans photo-isomerization reaction (Φcis-trans = 1.9). In this paper, nanosecond and microsecond dynamics of trans-C3F-Azo-C6H and its assembly in various microenvironments have been studied by laser flash photolysis to get deeper insight into the extraordinary reactivity of the molecular assembly in the nano-layered microenvironment. In solution, the molecular trans-C3F-Azo-C6H exhibited only a depletion of the trans-form of azobenzene upon the laser pulse excitation. On the other hand, in the case of the C3F-Azo-C6H/clay hybrid film, the depletion of the trans-form was drastically recovered in three steps on nano- and microsecond timescales. This indicates that the once reacted C3F-Azo-C6H molecule (cis-C3F-Azo-C6H) was reverted back to the trans-form after the laser pulse. It is considered that the excess energy provided by the photo-excitation, which is immediately dissipated to the surrounding media through the intermolecular vibrational modes in solution, is trapped in the nano-layered microenvironment to thermally revert the cis-form back to the trans-form. Conversely, in the case of cis-trans isomerization of the C3F-Azo-C6H/clay hybrid film upon photo-irradiation, the reactivity would be much enhanced by the additional contribution of the thermal excess energy efficiently trapped in the nano-layered microenvironment. As compared with the hydrocarbon analogue (C3H-Azo-C6H), the subsequent recovery was very much enhanced in the C3F-Azo-C6H/clay film. The polyfluoroalkyl part of the surfactant layer plays a key role in the retarded dissipation of the excess energy by photo-excitation, which might be coupled with the three-dimensional morphological motion with efficient isomerization reactions.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study.

BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.

Mapping and recombination analysis of two moth colour mutations, Black moth and Wild wing spot, in the silkworm Bombyx mori.

Many lepidopteran insects exhibit body colour variations, where the high phenotypic diversity observed in the wings and bodies of adults provides opportunities for studying adaptive morphological evolution. In the silkworm Bombyx mori, two genes responsible for moth colour mutation, Bm and Ws, have been mapped to 0.0 and 14.7 cM of the B. mori genetic linkage group 17; however, these genes have not been identified at the molecular level. We performed positional cloning of both genes to elucidate the molecular mechanisms that underlie the moth wing- and body-colour patterns in B. mori. We successfully narrowed down Bm and Ws to ~2-Mb-long and 100-kb-long regions on the same scaffold Bm_scaf33. Gene prediction analysis of this region identified 77 candidate genes in the Bm region, whereas there were no candidate genes in the Ws region. Fluorescence in-situ hybridisation analysis in Bm mutant detected chromosome inversion, which explains why there are no recombination in the corresponding region. The comparative genomic analysis demonstrated that the candidate regions of both genes shared synteny with a region associated with wing- and body-colour variations in other lepidopteran species including Biston betularia and Heliconius butterflies. These results suggest that the genes responsible for wing and body colour in B. mori may be associated with similar genes in other Lepidoptera.

Increase in paratyphoid fever cases in Japanese travellers returning from Cambodia in 2013.

In 2013, an unusual increase of paratyphoid fever cases in travellers returning from Cambodia was reported in Japan. From December 2012 to September 2013, 18 cases of Salmonella Paratyphi A infection were identified. Microbiological analyses revealed that most isolates had the same clonal identity, although the epidemiological link between these cases remains unclear. It was inferred that the outbreak was caused by a common and persistent source in Cambodia that was likely to have continued during 2014. The information of surveillance and laboratory data from cases arising in travellers from countries with limited surveillance systems should be timely shared with the country of origin.

Identification and functional analysis of a Masculinizer orthologue in Trilocha varians (Lepidoptera: Bombycidae).

We recently showed that the Masculinizer gene (Masc) plays a primary role in sex determination in the lepidopteran model insect Bombyx mori. However, it remains unknown whether this Masc protein-dependent sex determination system is conserved amongst lepidopteran insects or within the family Bombycidae. Here we cloned and characterized a Masc homologue (TvMasc) in Trilocha varians (Lepidoptera: Bombycidae), a species closely related to B. mori. To elucidate the role of TvMasc in the sex determination cascade of T. varians, TvMasc expression was knocked down in early embryos by the injection of small interfering RNAs (siRNAs) that targeted TvMasc mRNAs. Both female- and male-type splice variants of Tvdsx, a doublesex (dsx) homologue in T. varians were observed in control siRNA-injected embryos. By contrast, only female-type splice variants were observed in TvMasc siRNA-injected embryos. These results indicate that the TvMasc protein directly or indirectly regulates the splicing patterns of Tvdsx. Furthermore, we found that male-type splice variants of B. mori dsx (Bmdsx) were produced in TvMasc-overexpressing BmN4 cells. The mRNA level of B. mori Imp, a gene whose product induces male-specific Bmdsx splicing also increased. These results suggest that Masc genes play similar roles in the sex-determination cascade in Bombycidae.

Positional cloning of the sex-linked giant egg (Ge) locus in the silkworm, Bombyx mori.

The giant egg (Ge) locus is a Z-linked mutation that leads to the production of large eggs. Cytological observations suggest that an unusual translocation of a large fragment of the W chromosome bearing a putative egg size-determining gene, Esd, gave rise to giant egg mutants. However, there is currently no molecular evidence confirming either a W-Z translocation or the presence of Esd on the W chromosome. To elucidate the origin of giant egg mutants, we performed positional cloning. We observed that the Bombyx mori. orthologue of the human Phytanoyl-CoA dioxygenase domain containing 1 gene (PHYHD1) is disrupted in giant egg mutants. PHYHD1 is highly conserved in eukaryotes and is predicted to be a Fe(II) and 2-oxoglutarate-dependent oxygenase. Exon skipping in one of the two available Ge mutants is probably caused by the insertion of a non-long terminal repeat transposon into intron 4 in the vicinity of the 5' splice site. Segmental duplication in Ge(2) , an independent allele, was caused by unequal recombination between short interspersed elements inserted into introns 3 and 5. Our results indicate that (1) Bombyx PHYHD1 is responsible for the Ge mutants and that (2) the Ge locus is unrelated to the W-linked putative Esd. To our knowledge, this is the first report describing the phenotypic defects caused by mutations in PHYHD1 orthologues.

Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector.

As both the immune system and the blood-brain barrier (BBB) are likely to be developmentally immature in the perinatal period, neonatal gene transfer may be useful for the treatment of lysosomal storage disease (LSD) with neurological involvements such as metachromatic leukodystrophy (MLD). In this experiment, we examined the feasibility of single-strand adeno-associated viral serotype-9 (ssAAV9)-mediated systemic neonatal gene therapy of MLD mice. ssAAV9 vector expressing human arylsulfatase A (ASA) and green fluorescent protein (GFP) (ssAAV9/ASA) was injected into the jugular vein of newborn MLD mice. High levels of ASA expression were observed in the muscle and heart for at least 15 months. ASA was continuously secreted into plasma without development of antibodies against ASA. Global gene transfer into the brain and spinal cord (SC), across the BBB, and long-term ASA expression in the central nervous system were detected in treated mice. Significant inhibition of the accumulation of sulfatide (Sulf) in the brain and cervical SC was confirmed by Alcian blue staining and biochemical analysis of the Sulf content. In a behavior test, treated mice showed a greater ability to traverse narrow balance beams than untreated mice. These data clearly demonstrate that MLD mice model can be effectively treated through neonatal systemic injection of ssAAV9/ASA.

Spontaneous exciton dissociation in carbon nanotubes.

Simultaneous photoluminescence and photocurrent measurements on individual single-walled carbon nanotubes reveal spontaneous dissociation of excitons into free electron-hole pairs. The correlation of luminescence intensity and photocurrent shows that a significant fraction of excitons are dissociating before recombination. Furthermore, the combination of optical and electrical signals also allows for extraction of the absorption cross section and the oscillator strength. Our observations explain the reasons why photoconductivity measurements in single-walled carbon nanotubes are straightforward despite the large exciton binding energies.

Bright laser-driven neutron source based on the relativistic transparency of solids.

Neutrons are unique particles to probe samples in many fields of research ranging from biology to material sciences to engineering and security applications. Access to bright, pulsed sources is currently limited to large accelerator facilities and there has been a growing need for compact sources over the recent years. Short pulse laser driven neutron sources could be a compact and relatively cheap way to produce neutrons with energies in excess of 10 MeV. For more than a decade experiments have tried to obtain neutron numbers sufficient for applications. Our recent experiments demonstrated an ion acceleration mechanism based on the concept of relativistic transparency. Using this new mechanism, we produced an intense beam of high energy (up to 170 MeV) deuterons directed into a Be converter to produce a forward peaked neutron flux with a record yield, on the order of 10(10) n/sr. We present results comparing the two acceleration mechanisms and the first short pulse laser generated neutron radiograph.

Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions.

Gene therapy is expected to open a new strategy for the treatment of refractory vascular diseases, so the development of appropriate gene vectors for vascular lesions is needed. To realize this requirement with a non-viral approach, cyclo(RGDfK) peptide (cRGD) was introduced to block copolymer, poly(ethylene glycol)-block-polycation carrying ethylenediamine units (PEG-PAsp(DET)). cRGD recognizes α(v)ß(3) and α(v)ß(5) integrins, which are abundantly expressed in vascular lesions. cRGD-conjugated PEG-PAsp(DET) (cRGD-PEG-PAsp(DET)) formed polyplex micelles through complexation with plasmid DNA (pDNA) and the cRGD-PEG-PAsp(DET) micelles achieved significantly more efficient gene expression and cellular uptake as compared with PEG-PAsp(DET) micelles in endothelial cells and vascular smooth muscle cells. Intracellular tracking of pDNA showed that cRGD-PEG-PAsp(DET) micelles were internalized via caveolae-mediated endocytosis, which is associated with a pathway avoiding lysosomal degradation and that, PEG-PAsp(DET) micelles were transported to acidic endosomes and lysosomes via clathrin-mediated endocytosis. Further, in vivo evaluation in rat carotid artery with a neointimal lesion revealed that cRGD-PEG-PAsp(DET) micelles realized sustained gene expression, whereas PEG-PAsp(DET) micelles facilitated rapid, but transient gene expression. These findings suggest that introduction of cRGD to polyplex micelles might create novel and useful functions for gene transfer and contribute to the establishment of efficient gene therapy for vascular diseases.

A homolog of the human Hermansky-Pudluck syndrome-5 (HPS5) gene is responsible for the oa larval translucent mutants in the silkworm, Bombyx mori.

Normally, many granules containing uric acid accumulate in the larval integument of the silkworm, Bombyx mori. These uric acid granules cause the wild-type larval integument to be white or opaque, and the absence of these granules results in a translucent integument. Although about 30 B. mori loci governing larval translucency have been mapped, most have not been molecularly identified yet. Here, based on a structural analysis of a deletion of chromosome 14 that included the oa (aojyuku translucent) locus, we concluded that the BmHPS5 encoding a Bombyx homolog of the HPS5 subunit of biogenesis of lysosome-related organelles complex-2 is the candidate for the oa locus. Nucleotide sequence analyses of cDNAs and genomic DNAs in three mutant strains, each of which were homozygous for the respective allele of the oa locus (oa, oa ( 2 ), and oa ( v )), revealed that each mutant strain has a frame shift or a premature stop codon (caused by deletion or nonsense mutation, respectively) in the BmHPS5 gene. Our findings indicate that some genes that cause the translucent phenotype in Bombyx, some HPS-associated genes in humans, and some genes that cause mutant eye color phenotypes in Drosophila are homologous and participate in an evolutionarily conserved mechanism that leads to biogenesis of lysosome-related organelles.

Monoenergetic ion beam generation by driving ion solitary waves with circularly polarized laser light.

Experimental data from the Trident Laser facility is presented showing quasimonoenergetic carbon ions from nm-scaled foil targets with an energy spread of as low as ±15% at 35 MeV. These results and high-resolution kinetic simulations show laser acceleration of quasimonoenergetic ion beams by the generation of ion solitons with circularly polarized laser pulses (500 fs, λ=1054 nm). The conversion efficiency into monoenergetic ions is increased by an order of magnitude compared with previous experimental results, representing an important step towards applications such as ion fast ignition.

Interspecies linkage analysis of mo, a Bombyx mori locus associated with mosaicism and gynandromorphism.

The mo (hereditary mosaic) mutation is one of the most famous and interesting mutations of the silkworm, Bombyx mori. Females homozygous for mo generate mosaic and gynandromorphic offspring due to non-elimination of polar bodies and subsequent double fertilization events, irrespective of the genotype of the mated males. Although mo was first reported in 1927, the locus has not been mapped to linkage groups, as the mutation is unstable and appears to be sensitive to genetic background. In this study, linkage analysis of mo was performed using PCR-based markers on single nucleotide polymorphism linkage maps. Bombyx mandarina was used as the mating partner for the B. mori mo strain, as it is easier to identify polymorphic markers between B. mori and B. mandarina than within B. mori strains. Surprisingly, we identified two homozygous linkage groups (LGs) in all of the 12 B(1) (first backcross generation) moths that had deposited mosaic eggs. It was revealed that +( mo ) is located on the M chromosome of B. mandarina, which corresponds to two linkage groups of B. mori, LG 14 and 27. Based on further linkage analysis using B. mori as a mating partner, mo was mapped to LG 14. Additionally, we found that mo activity could be modified by a gene(s) on LG 17.

Involvement of brown adipose tissue in subcutaneous fat necrosis of the newborn.

BACKGROUND: Subcutaneous fat necrosis (SCFN) of the newborn is a rare condition that manifests within days after birth. The interscapular region, axillae and shoulders are the most commonly affected sites, corresponding to anatomic sites of brown adipose tissue (BAT) in newborns. OBJECTIVE: We postulated a specific involvement of BAT in SCFN and searched for brown adipocytes at affected sites. METHODS: Biopsy specimens were immunostained with antibodies against uncoupling protein 1 (UCP-1) and examined by electron microscopy. We also examined BAT by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography and computed tomography (PET-CT) scanning. RESULTS: A few cells in biopsy specimens from two patients bound antibodies against UCP-1, and brown adipocytes were detected at several stages of degeneration. PET-CT scans revealed lower uptake of (18)F-FDG at major sites of SCFN. CONCLUSION: SCFN and BAT can be found at the same sites, suggesting a pathophysiological connection.

Syntrophic acetate oxidation in two-phase (acid-methane) anaerobic digesters.

The microbial processes involved in two-phase anaerobic digestion were investigated by operating a laboratory-scale acid-phase (AP) reactor and analyzing two full-scale, two-phase anaerobic digesters operated under mesophilic (35 °C) conditions. The digesters received a blend of primary sludge and waste activated sludge (WAS). Methane levels of 20% in the laboratory-scale reactor indicated the presence of methanogenic activity in the AP. A phylogenetic analysis of an archaeal 16S rRNA gene clone library of one of the full-scale AP digesters showed that 82% and 5% of the clones were affiliated with the orders Methanobacteriales and Methanosarcinales, respectively. These results indicate that substantial levels of aceticlastic methanogens (order Methanosarcinales) were not maintained at the low solids retention times and acidic conditions (pH 5.2-5.5) of the AP, and that methanogenesis was carried out by hydrogen-utilizing methanogens of the order Methanobacteriales. Approximately 43, 31, and 9% of the archaeal clones from the methanogenic phase (MP) digester were affiliated with the orders Methanosarcinales, Methanomicrobiales, and Methanobacteriales, respectively. A phylogenetic analysis of a bacterial 16S rRNA gene clone library suggested the presence of acetate-oxidizing bacteria (close relatives of Thermacetogenium phaeum, 'Syntrophaceticus schinkii,' and Clostridium ultunense). The high abundance of hydrogen consuming methanogens and the presence of known acetate-oxidizing bacteria suggest that acetate utilization by acetate oxidizing bacteria in syntrophic interaction with hydrogen-utilizing methanogens was an important pathway in the second-stage of the two-phase digestion, which was operated at high ammonium-N concentrations (1.0 and 1.4 g/L). A modified version of the IWA Anaerobic Digestion Model No. 1 (ADM1) with extensions for syntrophic acetate oxidation and weak-acid inhibition adequately described the dynamic profiles of volatile acid production/degradation and methane generation observed in the laboratory-scale AP reactor. The model was validated with historical data from the full-scale digesters.

Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs.

Mast cells perform a significant role in the host defense against parasitic and some bacterial infections. Here we show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via histamine release. A large number of mast cells were found in a circumscribed ventral region of the hypothalamus, including the pars tuberalis and median eminence. When these intracranial mast cells were passively sensitized with immunoglobulin E via either the intracerebroventricular or intravenous route, there was a marked increase in the adrenal cortisol secretion elicited by a subsequent antigenic challenge (whether this was delivered via the central or peripheral route). Comp.48/80, a mast cell secretagogue, also increased cortisol secretion when administered intracerebroventricularly. Pretreatment (intracerebroventricularly) with anti-corticotropin--releasing factor antibodies or a histamine H(1) blocker, but not an H(2) blocker, attenuated the evoked increases in cortisol. These data show that in the dog, degranulation of brain mast cells evokes hypothalamic-pituitary-adrenal responses via centrally released histamine and corticotrophin-releasing factor. On the basis of these data, we suggest that intracranial mast cells may act as an allergen sensor, and that the activated adrenocortical response may represent a life-saving host defense reaction to a type I allergy.