ChikvInt: a Chikungunya virus-host protein-protein interaction database.

Chikungunya is a fast-mutating virus causing Chikungunya virus disease (ChikvD) with a significant load of disability-adjusted life years (DALY) around the world. The outbreak of this virus is significantly higher in the tropical countries. Several experiments have identified crucial viral-host protein-protein interactions (PPIs) between Chikungunya Virus (Chikv) and the human host. However, no standard database that catalogs this PPI information exists. Here we develop a Chikv-Human PPI database, ChikvInt, to facilitate understanding ChikvD disease pathogenesis and the progress of vaccine studies. ChikvInt consists of 109 interactions and is available at www.chikvint.com.

Location and type of mutation in the LIS1 gene do not predict phenotypic severity.

BACKGROUND: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. METHODS: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. RESULTS: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. CONCLUSION: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.

Anti-hyperglycemic effects of ginseng: comparison between root and berry.

Previous studies demonstrated that both ginseng root and ginseng berry possess anti-diabetic activity. However, a direct comparison between the root and the berry under the same experimental conditions has not been conducted. In the present study, we compared anti-hyperglycemic effect between Panax ginseng root and Panax ginseng berry in ob/ob mice, which exhibit profound obesity and hyperglycemia that phenotypically resemble human type-2 diabetes. We observed that ob/ob mice had high baseline glucose levels (195 mg/dl). Ginseng root extract (150 mg/kg body wt.) and ginseng berry extract (150 mg/kg body wt.) significantly decreased fasting blood glucose to 143 +/- 9.3 mg/dl and 150 +/- 9.5 mg/dl on day 5, respectively (both P < 0.01 compared with the vehicle). On day 12, although fasting blood glucose level did not continue to decrease in the root group (155 +/- 12.7 mg/dl), the berry group became normoglycemic (129 +/- 7.3 mg/dl; P < 0.01). We further evaluated glucose tolerance using the intraperitoneal glucose tolerance test. On day 0, basal hyperglycemia was exacerbated by intraperitoneal glucose load, and failed to return to baseline after 120 min. After 12 days of treatment with ginseng root extract (150 mg/kg body wt.), the area under the curve (AUC) showed some decrease (9.6%). However, after 12 days of treatment with ginseng berry extract (150 mg/kg body wt.), overall glucose exposure improved significantly, and the AUC decreased 31.0% (P < 0.01). In addition, we observed that body weight did not change significantly after ginseng root extract (150 mg/kg body wt.) treatment, but the same concentration of ginseng berry extract significantly decreased body weight (P < 0.01). These data suggest that, compared to ginseng root, ginseng berry exhibits more potent anti-hyperglycemic activity, and only ginseng berry shows marked anti-obesity effects in ob/ob mice.

Ginseng berry reduces blood glucose and body weight in db/db mice.

In this study, we observed anti-diabetic and anti-obesity effects of Panax ginseng berry in adult C57BL/Ks db/db mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract at 150 mg/kg body wt. for 12 consecutive days. On Day 5, the extract-treated db/db mice had significantly lower fasting blood glucose levels as compared to vehicle-treated mice (180.5+/-10.2 mg/dl vs. 226.0+/-15.3 mg/dl, P < 0.01). On day 12, the extract-treated db/db mice were normoglycemic (134.3+/-7.3 mg/dl) as compared to vehicle-treated mice (254.8+/-24.1 mg/dl; P < 0.01). Fasting blood glucose levels of lean mice did not decrease significantly after treatment with extract. After 12 days of treatment with the extract, glucose tolerance increased significantly, and overall blood glucose exposure calculated as area under the curve (AUC) decreased 53.4% (P < 0.01) in db/db mice. Furthermore, db/db mice treated with extract (150 mg/kg body wt.) showed weight loss from 51.0+/-1.9 g on Day 0, to 46.6+/-1.7 g on Day 5, and to 45.2+/-1.4 g on Day 12 (P < 0.05 and P < 0.01 compared to Day 0, respectively). The body weight of lean littermates also decreased at the same dose of extract. These data suggest that Panax ginseng berry extract may have therapeutic value in treating diabetic and obese patients.

Cardiac toxicity of resibufogenin: electrophysiological evidence.

Resibufogenin (RBG) is a single compound isolated from Chansu, a traditional Chinese medicine obtained from the skin venom gland of the toad. Formulations of Chansu have been widely applied in China, Japan, and other Asian countries for a long time and are currently used as alternative medicines. However, there have been several reports about the toxicity of Chansu and its medical formulations in the United States recently. As digitalis, RBG possesses both pharmacologic and toxicologic effects. According to our study results, RBG, one of major ingredient of Chansu, induced delayed afterdepolarization and triggered arrhythmias both in cardiac fiber in vitro and in beating heart in vivo at the high concentrations. The electrophysiologic toxic effects of RBG, the possible mechanism of toxicity, and treatment possibilities are discussed in the present review

Biphasic effect of cardiac glycosides on action potential duration in isolated Purkinje fibers.

Despite the historical use of cardiac glycosides, the data describing the electrophysiological characteristics of this class of drug are not fully clear. The present study reported the biphasic effect of cardiac glycosides, digoxin (1.25 microM) and acetylstrophanthidin (0.15 microM), on action potential duration in isolated Purkinje fibers by the conventional glass microelectrode technique. At the cycle lengths of 990, 690 and 490 msec., action potential duration lengthened within 10 min. and shortened after 10 min. of digoxin and acetylstrophanthidin administration. The biphasic effect was observed at a concentration of 4.0 mM [K(+)]o. However, at a higher [K(+)]o concentration of 5.4 mM, only the shortening effect on action potential duration was recorded. These results suggest that the biphasic effect of cardiac glycosides on action potential duration is related to the concentration of extracellular potassium and is not related to the stimulating cycle lengths.

Gastric effects of cholecystokinin and its interaction with leptin on brainstem neuronal activity in neonatal rats.

Cholecystokinin (CCK) is a major gastrointestinal neuropeptide that is secreted in response to food ingestion. It is involved in the feedback regulation of gastric emptying and also modulates food intake. Leptin, a hormone that regulates food intake and energy balance, is secreted from adipose tissue, gastric mucosa, fundic glands, and other tissues. In a previous report we showed that gastric effects of leptin activated the nucleus tractus solitarius (NTS) neurons responding to gastric vagal stimulation. In this study, using the same in vitro neonatal rat preparation, we investigated the gastric effects of CCK and its interaction with leptin on NTS neurons receiving gastric vagal inputs. We observed that peripheral gastric effects of CCK (300 nM) produced a mean activation response of 271 +/- 3.9% compared with control level (100%) in 33 (60%) neurons tested (P <.01), and this response was abolished by a CCK-A receptor antagonist. A concentration-dependent effect of CCK (10 nM-1.0 microM) on NTS neuronal discharge frequencies was shown. We also observed that leptin (10 nM) applied to the stomach produced a mean activation response of 183 +/- 5.3% in 13 (50%) NTS units that responded to CCK (P <.01). Furthermore, we evaluated the combined effect of CCK and leptin in two groups of NTS neurons. Those NTS units that showed activation responses to both CCK (300 nM) and leptin (10 nM) had a subadditive effect that produced a mean activation response of 338 +/- 12.9% compared with the control level in all 10 (100%) neurons tested (P <.01). Eight (36%) of another 22 units that were not affected by either CCK (300 nM) or leptin (10 nM) alone had an activation response (151 +/- 5.2%; P <.05) when the same concentrations of CCK and leptin were applied together. Subsequently, by comparing the effects of CCK and leptin on a whole-stomach preparation to a partial-stomach preparation, we examined the area of the stomach in which gastric receptors contributed most to NTS unitary activity. We showed that the distal stomach containing the pylorus determined CCK gastric activity, whereas both the proximal and distal stomach are important for leptin's effect. Our data suggest that leptin modulates the potency of CCK signals that modify food intake in the neonatal rat.

Clinical and economic effects of pulmonary artery catheterization in nonemergent coronary artery bypass graft surgery.

OBJECTIVE: To examine the association between use of pulmonary artery catheterization with hospital outcomes and costs in nonemergent coronary artery bypass graft (CABG) surgery. DESIGN: Retrospective cohort study. SETTING: Fifty-six community-based hospitals in 26 states. PARTICIPANTS: A total of 13,907 patients undergoing nonemergent CABG surgery between January 1, 1997, and December 31, 1997. MEASUREMENTS AND MAIN RESULTS: Discharge abstracts for each patient were examined. Stratified and multivariate analyses were used to assess the impact of pulmonary artery catheters (PACs) on in-hospital mortality, length of stay in the intensive care unit, total length of stay, and hospital costs. Outcomes were adjusted for patient demographic factors, hospital characteristics, and hospital volume of PAC use in the year of analysis. Fifty-eight percent of the patients received a PAC. After adjustment, the relative risk of in-hospital mortality was 2.10 for the PAC group compared with the patients who did not receive a PAC (95% confidence interval [CI], 1.40 to 3.14; p < 0.001). The mortality risk was significantly higher in hospitals with the lowest third of PAC use (odds ratio, 3.35; 95% CI, 1.74 to 6.47; p < 0.001) and not significantly increased in the highest two thirds of users (odds ratio, 1.62; 95% CI, 0.99 to 2.66; p = 0.09). Days spent in critical care were similar; however, total length of hospital stay was 0.26 days longer in the PAC group (p < 0.001). Hospital costs were $1,402 higher in the PAC group. CONCLUSION: In the setting of nonemergent CABG surgery, pulmonary artery catheterization was associated with an increased risk of in-hospital mortality, greater length of stay, and higher total costs, particularly in hospitals with low volume of PAC use.

Genotoxicity of ziram established through wing, eye and female germ-line mosaic assays and the sex-linked recessive lethal test in Drosophila melanogaster.

The genotoxicity of ziram (zinc-dimethyl dithiocarbamate, CAS No. 137-30-4), a carbamate fungicide, is studied in the wing, eye and female germ-line mosaic assays and the sex-linked recessive lethal test in Drosophila melanogaster. First-, second- and third-instar larvae, carrying suitable recessive genetic markers on their first and third chromosomes, were exposed to ziram. Wings and eyes of adults were screened for the induction of mosaic spots and the eggs laid by adult females for germ-line mosaicism. The Basc method was used to detect sex-linked recessive lethals. Ziram is genotoxic to the somatic and germ cells of Drosophila melanogaster.

Genotoxicity of Rogor studied in the sex-linked recessive lethal test and wing, eye and female germ-line mosaic assays in Drosophila melanogaster.

The genotoxic potential of Rogor (dimethoate), an anticholinesterase organophosphate insecticide, has been studied in the sex-linked recessive lethal test and the wing, eye and female germ-line mosaic assays in Drosophila melanogaster. Larvae of different instars carrying suitable recessive genetic markers on their first and third chromosomes were exposed to the LD50 or half of this dose for the entire larval life. The Basc technique was followed for the detection of the induction of sex-linked recessive lethals. The wings and eyes of the adult flies and the eggs laid by the heterozygous females were checked for the induction of mosaicism. It is concluded that Rogor induces sex-linked recessive lethals in immature male germ cells and is recombinogenic and/or mutagenic in both the somatic and the germ-line cells of Drosophila.

Genotoxicity of zineb detected through the somatic and germ-line mosaic assays and the sex-linked recessive-lethal test in Drosophila melanogaster.

The genotoxicity of zineb, a carbamate fungicide, has been tested through eye, wing and female germ line mosaic assays and the sex-linked recessive-lethal test in Drosophila melanogaster. Larvae of different instars, heterozygous for appropriate recessive genetic markers, were exposed to the fungicide in food for different durations of time. The adult eyes and wings were screened for induction of mosaic spots and the eggs laid by the females were checked for induction of female germ-line mosaicism. It is concluded that zineb is genotoxic to both somatic and germ-line cells of Drosophila.

Mutagenicity of dimecron studied in 3 mosaic assays and the sex-linked recessive lethal test in Drosophila melanogaster.

The genotoxicity of dimecron, a systemic organophosphate pesticide, has been tested in the wing, eye and germ line mosaic assays and the sex-linked recessive lethal test in Drosophila melanogaster. Larvae heterozygous for recessive marker mutations were fed the compound for various periods of time. On emergence, the wings and eyes of the adults were screened for mosaic spots and the eggs laid by the females were checked for induction of female germ line mosaicism. Dimecron is mutagenic to the somatic and germ line cells of Drosophila and induces a high frequency of sex-linked recessive lethals.

Genotoxicity of metacid established through the somatic and germ line mosaic assays and the sex-linked recessive lethal test in Drosophila.

The mutagenic potential of metacid (methyl parathion), an anticholinesterase organophosphate pesticide, has been studied in the Drosophila eye, wing and female germ line assays and the sex-linked recessive lethal tests. Larvae 24 h, 48 h and 72 h old, heterozygous for various recessive genetic markers on the first and third chromosomes, were exposed to the LD50 and half of this dose for different periods of time. The eyes and wings were checked for the presence of mosaic spots and eggs laid by the females for germ line mosaicism. The M-5 technique was used to detect the induction of sex-linked recessive lethals. It is concluded that metacid is mutagenic in somatic and germ line cells of Drosophila and induces sex-linked recessive lethals in immature male germ cells.