Regulation of firing of dopaminergic neurons and control of goal-directed behaviors

There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.     

Decreased proliferation of hippocampal progenitor cells in APPswe/PS1dE9 transgenic mice

A recent hypothesis suggests that there is impaired hippocampal neurogenesis in Alzheimer's disease. Here we examined the proliferation, the first stage in neurogenesis, of hippocampal progenitor cells in amyloid precursor protein with Swedish mutation and presenilin-1 with deletion of exon 9 (APPswe/PS1dE9) transgenic mice. Compared with age-matched wild-type mice, transgenic mice at 5 months of age with low amyloid beta-peptide (Abeta) levels and subtle Abeta deposits showed normal proliferation of hippocampal progenitor cells; however, transgenic mice at 9 months of age with high Abeta levels and numerous Abeta deposits showed decreased proliferation of these cells. The number of proliferating cells in male transgenic mice was indistinguishable from that in female transgenic mice. These results indicate that neurogenesis is decreased with degrees of Abeta pathology, and that there is no gender difference in their proliferation in APPswe/PS1dE9 transgenic mice.     

Efficient entrapment of poorly water-soluble pharmaceuticals in hybrid nanoparticles

Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.     

Association with 5'-untranslated region and response to interferon in chronic hepatitis C

BACKGROUND/AIMS: The 5'-untranslated region (5'UTR) of hepatitis C virus (HCV) is a useful region for determinations of genotype and viral load. 5'UTR can be used for simultaneous analysis of HCV genotype and viral load, therefore several assays have been described. A method which used direct sequencing of the 5'UTR can also be used to identify mutations in this region. The objective of the present study was to evaluate possible associations of 5'UTR mutations with responsiveness to interferon (IFN) therapy in chronic hepatitis C patients. METHODOLOGY: Seventy patients with chronic hepatitis C were included in this study. The relations between responsiveness to IFN therapy and HCV genotype, viral load, and 5'UTR mutations before IFN treatment were evaluated. RESULTS: We detected HCV genotype 1a (n = 5), 1b (n = 32), 2a (n = 15), 2b (n = 12), and 3a (n = 6). Forty-eight patients were non-sustained responders (NR). Seven of 37 (18.9%) patients with the 1a or 1b genotype were sustained responders (SR), and 14 of 27 (51.9%) patients with genotype 2a or 2b were SR. Responses of patients with genotype 1 were poorer than those of patients with genotype 2. HCV viral loads of all SR patients infected with genotype la or 1b were less than 100 KIU/mL, but more than 50% of SR patients infected with genotype 2a or 2b had viral loads over 100 KIU/mL. Thus, viral load in patients with genotype 1 is strongly associated with IFN sensitivity. 5'UTR were well conserved, and there were no differences in the distribution of genotypes between SR and NR. CONCLUSIONS: The 5'UTR is a suitable region for determining HCV genotype and viral load, which are predictors of responsiveness to IFN therapy, but specific mutations of the 5'UTR do not appear to be associated with responsiveness to IFN.     

Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy

Hypoadiponectinemia is associated with insulin resistance. However, there is very limited information about the relationship between plasma adiponectin and cardiac autonomic nervous function. We tested the hypothesis that hypoadiponectinemia is associated with cardiac sympathetic overactivity in patients with type 2 diabetes mellitus. Thirty-three male type 2 diabetic patients not on insulin treatment were classified into a hypoadiponectinemia group (plasma adiponectin concentration, <4.0 microg/mL; age, 58.6 +/- 8.6 years [mean +/- SD]; n = 14) and an age-matched normoadiponectinemia group (serum adiponectin concentration, >/=4.0 microg/mL; age, 58.2 +/- 8.1 years; n = 19). In each patient, baroreflex sensitivity, heart rate variability, plasma norepinephrine concentration, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphic findings were assessed. Compared with the normoadiponectinemia group, the hypoadiponectinemia group had a higher body mass index (P < .01), higher plasma concentrations of glucose and insulin (P < .05 and P < .01, respectively), higher homeostasis model assessment of insulin resistance (HOMA-IR) values (P < .005), higher plasma triglyceride levels (P < .05), and lower plasma high-density lipoprotein cholesterol levels (P < .05). In the hypoadiponectinemia group, the autonomic function measurements included a lower baroreflex sensitivity (P< .05) and a lower delayed myocardial uptake of (123)I-MIBG (P < .01) with a higher washout rate (P < .05). Multiple regression analysis revealed that the plasma adiponectin level was independently associated with HOMA-IR (F = 9.916) and the percent washout rate of (123)I-MIBG (F = 5.985). Our results suggest that in middle-aged men with type 2 diabetes mellitus, hypoadiponectinemia is associated with cardiac sympathetic overactivity as determined by (123)I-MIBG scintigraphy.     

Reactivation of familial hemophagocytic lymphohistiocytosis after non-myeloablative cord blood stem cell transplantation resulted in the early graft failure

A 4-year-old girl with familial hemophagocytic lymphohistiocytosis (FHL) underwent unrelated cord blood stem cell transplantation (uCBSCT) using the fludarabine-based non-myeloablative conditioning regimen. Shortly after the uCBSCT, she experienced the reactivation of the FHL, and subsequent graft failure. Considering that the residual recipient lymphocytes, which survived after non-myeloablative conditioning, had a role in the FHL reactivation and in the graft rejection, myeloablative conditioning combined with horse ATG was used to eradicate the recipient lymphocytes in the second CBSCT. Furthermore, in order to prevent rejection, cord blood, the DNA type of which was completely matched in a host to graft (HVG) direction, was selected. In the second uCBSCT, FHL reactivation was noted at a limited level. Complete chimerism was achieved and the NK-cell activity recovered to the normal range. Our case suggests the necessity of the conditioning regimen to eradicate host lymphocytes in the stem cell transplantation for FHL, and the significance of HLA DNA-typing in uCBSCT for pediatric patients.     

Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats

Exercise is often said to increase the generation of reactive oxygen species that are potentially harmful. On the other hand, regular exercise has various health benefits even late in life. The specific aim of this study was to explore effects of regular exercise on oxidative status of DNA in aged animals. We report that 2 months of regular treadmill running of aged rats (21 month old) significantly reduced 8-oxodG content to the level of young adult animals (11 month old) in both nuclear and mitochondrial DNA of the liver. The mitochondrial DNA showed 10-fold higher content of the oxidative lesion than the nuclear DNA. The levels in old animals were 2- and 1.5-fold higher than that in young adults for the nucleus and mitochondria, respectively. The activity of the repair enzyme OGG1 was upregulated significantly in the nucleus but not in mitochondria by the exercise. To our knowledge, this is the first report demonstrating that regular exercise can reduce significantly oxidative damage to both the nuclear and mitochondrial DNA. We suggest that the apparent beneficial outcomes in reducing the DNA damage by regular exercise can be interpreted in terms of hormetic effect by moderate oxidative stress and potential adaptation to stronger stresses.     

Rebamipide enema therapy as a treatment for patients with active distal ulcerative colitis

BACKGROUND: The clinical efficacy of corticosteroids in the treatment of ulcerative colitis (UC) is well-established. However, prolonged usage of these drugs can result in serious complications. Rebamipide {2-(4-chlorobenzoylamino)-3[2-(1H)-quinolinon-4-yl] propionic acid}, a cytoprotective agent, has been reported to have anti-inflammatory activity and to repair mucosal injury in animal colitis models. The aim of the present study was to assess the clinical efficacy and safety of a novel Rebamipide enema therapy in UC patients. METHODS: Twenty patients with the active distal type of UC in whom corticosteroid treatment had been unsuccessful were treated with rectal administration of Rebamipide twice a day for 3 weeks, during which corticosteroid dosage was kept constant. The efficacy of treatment was assessed from clinical symptoms and endoscopic findings. The anti-inflammatory effect of Rebamipide was also examined by monitoring changes in the intensity of histological inflammation and levels of cytokine activity in the rectal mucosa. RESULTS: At 3 weeks after the initiation of Rebamipide enema therapy, 11 patients (55%) achieved clinical remission. Sixteen (80%) were colonoscopically judged to be responders, with decreased levels of interleukin (IL)-1beta but not of IL-8, and an increased ratio of IL-1 receptor antagonist/IL-1beta in organ cultures of mucosal tissues. The change in the number of infiltrating neutrophils was not significantly correlated with the clinical response to this therapy. No side-effects were noted in any patients. CONCLUSION: Rebamipide enema therapy proved to be safe and useful in corticosteroid-refractory patients with the active distal type of UC.