The interaction of the diltiazem with oral and intravenous cyclosporine in rats.

This study investigated the effect of diltiazem on the bioavailability of oral and intravenous cyclosporine (CsA) in rats. While control rats received normal saline, experimental groups received 60 or 90 mg/kg diltiazem orally for 3 days. Each group divided into 2 equal groups that received a single oral dose or i.v. injection of CsA. Pharmacokinetic parameters were analyzed by nonparametric analysis of variance. Pretreatment with 60 or 90 mg/kg diltiazem decreased the area under the blood CsA concentration-time curve (AUC) of oral CsA compared to control group (54.5% and 65.5% for AUC(0-24), 57.6% and 62.2% for AUC(0-infinity), respectively, p<0.05). Mean CsA maximum concentration (Cmax) decreased from 0.4 +/- 0.1 microg/ml to 0.1 +/- 0.0 microg/mL in rats pretreated with 90 mg/kg diltiazem (p<0.05). The absolute bioavailability after oral administration (F(p.o.)) in the 60 or 90 mg/kg diltiazem groups were lower than the control group (9.6% and 8.5% versus 22.6%). Pretreatment with 90 mg/kg but not 60 mg/kg of diltiazem increased the AUC(0-infinity), elimination half-life (t1/2) of intravenous CsA (116.0%, 219.2%, respectively, p<0.05) and decreased the intravenous CsA clearence (CL(i.v.)) (62.9%, p<0.05). Diltiazem decreased the bioavailability of oral CsA, while it increased the bioavailability of intravenous CsA. One must consider this interaction when administering oral or intravenous CsA concomitantly with diltiazem.     

Thrombin activatable fibrinolysis inhibitor and thrombin-antithrombin-III-complex levels in patients with gastric cancer

The relation between cancer and coagulation is the subject of investigation since a relation between tumor and thrombosis has been determined. Antithrombin III is an important thrombin inhibitor, and increased thrombin?Cantithrombin (TAT) complex levels activate coagulation. Activated thrombin activatable fibrinolysis inhibitor (TAFI) inhibits the conversion of plasminogen to plasmin. In addition, it directly inactivates plasmin. Defective fibrinolysis increases the risk of thrombosis. In this study, we evaluated homeostatic parameters, TAFI, and TAT levels in patients with gastric cancer applying to the medical oncology outpatient clinic. Fifty-two patients and 35 healthy controls were included. ELISA was used to measure TAFI and TAT complex levels. These were statistically higher in the patient group (p?<?0.05 and p?=?0.001, respectively). D-dimer levels were higher in stage IV (p?=?0.05). Correlations between lymph nodes and TAFI and TAT levels were examined. Weak but positive correlation between lymph nodes and TAFI was detected (R?=?0.452, p?=?0.027). TAFI and TAT levels were evaluated using relative operating characteristic analysis to differentiate the disease. TAT was more specific than TAFI according to this analysis (TAFI area under curve (AUC), 0.676; TAT AUC, 0.874). Thrombotic events and bleeding disorders need to be borne in mind in gastric cancer. This situation is due to the impairment of the balance between coagulation and fibrinolysis. Further studies are now needed to evaluate the effects of TAFI and TAT on survey and prognosis as well as the potential of these parameters as tumor markers for gastric cancer.     

Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores,Parental Knowledge,and Peer Substance Use

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene–environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; M_age = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene–environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.

     

Kidney transplantation for end‐stage renal disease secondary to familial Mediterranean fever

Although kidney transplantation (KT) is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), data concerning transplant outcome are limited and inconsistent. The aim of this study was to determine the long‐term outcome of KT in patients with amyloidosis secondary to FMF. Kidney transplantation outcome in 24 patients with FMF was compared to that in 72 controls matched for age, gender of recipient, and type of the donor that underwent KT due to end‐stage renal disease (ESRD) not caused by FMF. Mean follow‐up time was 80.3 ± 55.1 months in the FMF group, vs. 86.5 ± 47.6 months in the control group. Death‐censored graft survival at five and 10 yr in the FMF group was 95.8% and 78.4%, respectively, and was comparable to that in the control group. In the FMF group, five‐ and 10‐yr patient survival (87.5 and 65.6%) was shorter than in the control group, but the difference was not statistically significant. The findings show that long‐term outcome of KT in the patients with amyloidosis secondary to FMF was comparable to that in patients with ESRD not caused by FMF. Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post‐transplant period.     

Association of CHRM2 with IQ: Converging Evidence for a Gene Influencing Intelligence

The cholinergic neurotransmitter system is thought to be involved in many aspects of memory, attention, and higher cognition. In the Collaborative Study on the Genetics of Alcoholism (COGA) sample, we have previously reported linkage and association to the cholinergic muscarinic 2 receptor gene (CHRM2) on chromosome 7 with evoked EEG oscillations (Jones et al. 2004), providing evidence that this gene may be involved in human brain dynamics and cognition. In addition, a small number of genetic markers were genotyped in CHRM2 in the Minnesota Twin and Family Study (Comings et al. 2003) and a Dutch family study (Gosso et al. 2006, in press) and both research groups found evidence that this gene may be involved in intelligence. In the COGA sample, we have extensively genotyped SNPs within and flanking the CHRM2 gene. We find evidence of association with multiple SNPs across CHRM2 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R). These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample. Edited by Danielle Posthuma Henri Begleiter—Deceased     

Non-target toxicity of synthetic insecticides on the biological performance and population growth of Bracon hebetor Say

Ecotoxicology - Bracon hebetor Say (Hymenoptera: Braconidae) is an important biological control agent of various species of order Lepidoptera and extensively used in biological control program...     

Effect of the farnesyl transferase inhibitor L-744,832 on the colon cancer cell line DLD-1 and its combined use with radiation and 5-FU

BACKGROUND: Ras oncogenes are found in 25% of human tumors and they significantly affect prognosis. One of the major fields studied to improve anticancer drugs is blockade of the oncogenic ras protein function. One of the mechanisms to block the function of these proteins is to block farnesylation using a farnesyl transferase inhibitor (FTI) and thus to prevent the ras from anchoring to the cell membrane. METHODS: In this study, we investigated the effects of FTI L-744,832 either alone or in combination with 5-fluorouracil (5-FU; 1 microM/l) and radiotherapy (2, 6, and 10 Gy) on the colon cancer cell line DLD-1 with mutations in K-, N- and H-ras, c-myb, c-myc, p53, fos, sis and DNA repair genes. Drugs were added 3 h after cultivation. Radiotherapy was performed on the 3rd day of the study. On the 3rd day, medium and drugs were changed. Evaluations were performed on the 6th day. RESULTS: Administration of L-744,832, neither alone nor its combination with 5-FU and radiation, affected the number of DLD-1 cells and apoptosis rates. Regarding its effects on the cell cycle, L-744,832 was shown to lead to G(0)/G(1) and G(2)/M accumulation in a dose-dependent manner when administered alone. However, in combination with 5-FU, only a G(0)/G(1) accumulation was observed. CONCLUSION: Our study showed that FTI L-744,832 does not effect the cell number and apoptosis rate of DLD-1 cells and it cannot overcome 5-FU and radiation resistance, although it is able to modify some phases of the cell cycle.