Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the mammalian brain. In Drosophila, mutation of the PACAP homologue results in behavioral defects, including impaired olfaction-associated learning and changes in ethanol sensitivity. Here, we report the generation of mice lacking the PACAP gene (PACAP ؊/؊ ). PACAP ؊/؊ mice were born in the expected Mendelian ratios but had a high early-mortality rate. The surviving adult PACAP ؊/؊ mice displayed remarkable behavioral changes; they exhibited hyperactive and explosive jumping behaviors in an open field, increased exploratory behavior, and less anxiety in the elevated plus maze, emergence, and novel-object tests. Analysis of PACAP ؊/؊ mice brains revealed that the serotonin metabolite 5-hydroxyindoleacetic acid was slightly decreased in the cortex and striatum compared with wild-type mice. The present study provides evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. P ituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide (VIP)͞ secretin͞glucagon family of peptides and exists in two amidated forms, PACAP38 and PACAP27, that share an identical 27-aa N terminus and are alternatively processed from a 176-aa precursor called preproPACAP (1, 2). The primary structure of PACAP38 has been conserved significantly during evolution from protochordates to mammals, suggesting that the peptide exerts important activities throughout the vertebrate phylum (1, 2). In Drosophila, recent molecular cloning and transgenic rescue experiments in the memory-mutant amnesiac, which has behavioral defects that include impaired olfaction-associated learning and changes in ethanol sensitivity, demonstrated that the amnesiac gene encodes a neuropeptide homologous to vertebrate PACAP (3, 4). In addition, mammalian PACAP activated both the cAMP and Ras͞Raf signal-transduction pathways in Drosophila neurons, suggesting a neuromodulatory role of amnesiac (Drosophila PACAP) in specific neuronal populations (5). In mammals, PACAP occurs in neuronal elements, where it acts as a pleiotropic neuropeptide via three heptahelical G protein-linked receptors-one PACAP-specific (PAC 1 ) receptor and two receptors that it shares with VIP (VPAC 1 and VPAC 2 ). PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and the mobilization of calcium (1, 2, 6). Histochemical studies have shown that PACAP immunoreactivity is observed in several brain regions, including the dopamine (DA) and serotonin (5-HT) systems, with high concentrations found in the nucleus accumbens, hypothalamus, amygdala, substantia nigra, and dorsal raphe (7-9). PAC 1 receptor also is expressed throughout the target areas of both the mesocorticolimbic and nigrostriatal DA systems as well as 5-HT system (10). In addition, VPAC 1 and VPAC 2 recepto...
Although embryonic stem (ES) cell lines derived from mice and primates are used extensively, the development of such lines from other mammals is extremely difficult because of their rapid decline in proliferation potential and pluripotency after several passages. This study describes the establishment of rabbit ES cell lines with indefinite proliferation potential. It was found that the feeder cell density determines the fate of rabbit ES cells, and that maximum proliferation potential was obtained when they were cultured on a feeder cell density of one-sixth of the density at confluency. Higher and lower densities of feeder cells induced ES cell differentiation or division arrest. Under optimized conditions, rabbit ES cells were passaged 50 times, after which they still possessed high telomerase activity. This culture system enabled efficient gene transduction and clonal expansion from single cells. During culture, rabbit ES cells exhibited flattened monolayer cell colonies, as reported for monkey and human ES cells, and expressed pluripotency markers. Embryoid bodies and teratomas formed readily in vitro and in vivo respectively. These ES cell lines can be safely cryopreserved for later use. Thus, rabbit ES cells can be added to the list of stable mammalian ES cells, enabling the rabbit to be used as a small animal model for the study of human cell transplantation therapy.
Fabry disease-a genetic disorder characterized by the accumulation of globotriaosylceramide in cell lysosomes resulting from an X-linked deficiency of α-galactosidase A activity-presents with multiorgan manifestations, including progressive renal disease. Recently, its prevalence has been reported to be higher in hemodialysis (HD) patients than in the general population. We, therefore, examined patients on maintenance dialysis living in the Nagasaki Prefecture, Japan, to clarify the prevalence of Fabry disease. We screened 933 patients on maintenance dialysis, who were residents of Nagasaki Prefecture in Japan, for α-galactosidase A activity using a dried blood spot on filter paper. Patients with low α-galactosidase A activity were clinically assessed; subsequently, genetic analysis of the α-Galactosidase A gene (MIM:30064) was performed in these patients. Of the 933 patients, 55 had low α-galactosidase A activity; of these, one male and two females had α-Galactosidase A mutations. The prevalence of Fabry disease was thus 0.32%, which was similar to that reported previously. However, one mutation was newly identified, while the E66Q mutation observed in two patients was as previously identified. These two patients with the E66Q mutation were excluded because of the possibility of polymorphism; the prevalence of Fabry disease in the HD population was finally calculated to be 0.11%. The prevalence of Fabry disease in patients on maintenance dialysis living in Nagasaki Prefecture was 0.32%. Dried blood spot screening was considered as a simple and effective method for screening patients on maintenance dialysis for Fabry disease.
Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis.
These results suggest that the maximum sweat ion reabsorption rate on the back is higher than that of forearm without sex differences. Furthermore, exercise training in distance runners and sprinters improves the maximum sweat ion reabsorption rate on the back.
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