N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside induces sedative and hypnotic effects via GAD enzyme activation in mice.

BACKGROUND AND PURPOSE: N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an analog of N(6)-(4-hydroxybenzyl) adenine riboside (NHBA), which was originally isolated from Gastrodia elata Blume. Our laboratory has previously demonstrated that B2 can produce strong sedative and hypnotic effects, but the mechanism remains to be determined. There is evidence that gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the brain, plays a major role in sleep regulation, and participates in the sedative and hypnotic effects of B2. Therefore, we studied the interactions between B2 and several GABAergic neurochemical parameters based on the sedative and hypnotic effects of B2. EXPERIMENTAL APPROACH: The GABA and glutamic acid (Glu) in the mouse brain were derivatized with o-phthalaldehyde (OPA) and measured by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The GAD and GABA-T enzyme activities were determined by measuring GABA and NADH production, respectively. The sleep structure analyses were performed by EEG studies in mice. KEY RESULTS: B2 increased the GABA levels and GAD enzyme activity in the mouse hypothalamus and cortex. The EEG results confirmed that B2 significantly shortened the sleep latency and increased the amount of NREM sleep. The GAD enzyme inhibitor semicarbazide (SCZ) blocked the sedative and hypnotic effects of B2. CONCLUSIONS AND IMPLICATIONS: These findings suggest that the GAD enzyme plays a significant role in the sedative and hypnotic effects of B2. Therefore B2 may be a promising candidate for further clinical studies and the appropriate use of GAD agonist may be a promising approach for sleep disorders.

The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics.

Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.

Benefits of care coordination for children with complex disease: a pilot medical home project in a resident teaching clinic.

OBJECTIVE: To study the integration of comprehensive care coordination for children with complex disease in our resident education clinic at University of California Los Angeles by analyzing alterations in medical resource use. STUDY DESIGN: The Pediatric Medical Home Project at University of California Los Angeles was designed to include 4 basic elements: 1) 60-minute intake appointment; 2) follow-up appointments twice the length of a standard visit; 3) access to a "family liaison"; and 4) a family notebook ("All about Me" binder). From the initial cohort of 43 patients, encounter data on 30 were analyzed to determine use of outpatient, urgent, emergency department (ED), and inpatient services. Encounters for each patient were compared for a period of 1 year before and 1 year after enrollment. RESULTS: The average number of ED visits per patient decreased from 1.1 +/- 1.7 before enrollment to 0.5 +/- 0.9 after medical home enrollment (P = .02). However, no significant change was found in use of any of the other health care resources studied. CONCLUSIONS: Incorporating a program of care coordination according to the principles of the medical home into an outpatient pediatric residency teaching clinic may not only serve as a training vehicle for pediatric residents, but also create favorable alterations in medical resource use.

Measuring the effects of massage on exercise performance and cardiopulmonary response in children with and without heart disease: a pilot study.

BACKGROUND: Congenital heart disease, a common and serious birth defect, affects 8 per 1000 live-born infants. Decreased exercise capacity and development of obesity is common in this population. These children may benefit from therapies, such as massage therapy, that could enhance cardiovascular and skeletal muscle function when they exercise. PURPOSE: A pilot study conducted at the pediatric cardiology clinic of the Mattel Children's Hospital of the University of California-Los Angeles examined the safety and feasibility of measuring the effects of pre-exercise massage on exercise performance and cardiopulmonary response in children with and without heart disease. PARTICIPANTS AND METHODS: SIXTEEN CHILDREN (MEAN AGE: 9.2 ± 2.2 years) participated in the study. Ten participants had various forms of heart disease, and six children were healthy. A female certified massage therapist with specialized training in pediatric massage provided a 30-minute massage to the participants. Using a standard protocol, each participant underwent two exercise tests: one test with and one without pre-exercise massage. Heart rate, blood pressure, and oxygen uptake (VO(2)) were measured in the participants. RESULTS: All recruited participants completed the study. No adverse events occurred during any of the exercise tests or massage sessions. Measurements during exercise with or without a preceding massage were compared, and the pre-exercise massage condition yielded a significantly higher heart rate and higher minute ventilation. Measurements during exercise in children with heart disease and in healthy participants showed no significant differences in peak heart rate, blood pressure, peak VO(2), peak work rate, minute ventilation, or respiratory quotient. CONCLUSIONS: In this study, peak heart rate, peak VO(2), and peak minute ventilation were higher when children received a massage before exercise testing. Larger studies will be needed to investigate the strength of this finding. Future studies should include measurements of anxiety and psychological factors in addition to cardiopulmonary measures.

Expression of cyclooxygenase-2 in human and an animal model of rheumatoid arthritis.

An inducible form of cyclooxygenase-2 (COX-2) has been shown to be upregulated in vitro by various pro-inflammatory agents, such as lipopolysaccharide, IL-1 and TNF, COX-2 appears to be responsible for the increase in prostaglandin synthesis at the site of inflammation. To examine the involvement of COX-2 in inflammation, we analysed the expression of this gene in human rheumatoid arthritis (RA) and in rat adjuvant-induced arthritis. Immunocytochemical studies of synovial membrane biopsies from human RA, osteoarthritic (OA) and normal joints using a COX-2 specific antibody showed positive staining in RA, but not in normal synovial membranes. Specifically, expression of COX-2 was detected in synovial lining cells, lymphoid aggregates and endothelial cells of blood vessels. Although some positive staining was observed in the OA joints, the number of stained cells was dramatically lower and the staining of the cells was less intense than in the rheumatoid tissue. By reverse transcription and polymerase chain reaction analysis, COX-2 mRNA was detected in the rat adjuvant arthritic limb, whereas no COX-2 mRNA was detectable in the normal limb. These observations indicate that COX-2 expression is upregulated in inflammatory joint disease and that COX-2 is a potential therapeutic target for specific inhibition.

Microvascular changes in rat glomeruli as a consequence of small differences in selenium exposure.

This paper evaluates the effect of small differences in selenium exposure, within the safe range, on the glomerular vascular tufts of rats fed high-sucrose diets. In the first experiment male Wistar rats were housed in galvanized cages and were provided sucrose-based diets to induce a mild chronic insult to the microcirculation. One group of rats received the diet prepared to contain 0.10 mg Se/kg and another group 0.21 mg Se/kg. To assure that the galvanized metal cages were not influencing the results of the experiment this protocol was repeated in a second experiment wherein rats were housed in stainless steel cages. The levels of Se used supported normal activity of the long-term indicator of Se sufficiency, erythrocyte glutathione peroxidase. In both experiments rats fed diets containing 0.21 mg Se/kg had larger Bowman's capsules (P < 0.01) and vascular tufts (P < 0.01). Vascular tufts from these rats also contained a higher proportion of open capillary lumen (P < 0.01), contained less cytoplasmic and extracellular material (P < 0.001), and had larger nuclei (P < 0.001) than those fed 0.10 mg Se/kg. A third study was designed to determine if the selenium-dependent differences in nuclear size were indicative of this being a site of incorporation. Year-old rats subjected to the same protocol as those in the second experiment were given 75Se, by injection into the femoral vein, to label the sites of incorporation. Glomeruli were purified and subjected to subcellular fractionation. Ninety percent of the radioactivity was associated with the crude nuclear fraction. Purification of the crude nuclear fraction demonstrated that the radioactivity was associated with the nuclei.