Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats

BackgroundVagus nerve stimulation (VNS) has been introduced as a therapeutic option for treatment-resistant depression. The neural and chemical mechanisms responsible for the effects of VNS are largely unclear.MethodsBilateral removal of the olfactory bulbs (OBX) is a validated animal model in depression research. We studied the effects of vagus nerve stimulation (VNS) on disturbed one-way active avoidance learning and neurogenesis in the hippocampal dentate gyrus of rats.ResultsAfter a stimulation period of 3 weeks, OBX rats acquired the learning task as controls. In addition, the OBX-related decrease of neuronal differentiated BrdU positive cells in the dentate gyrus was prevented by VNS.ConclusionsThis suggests that chronic VNS and changes in hippocampal neurogenesis induced by VNS may also account for the amelioration of behavioral deficits in OBX rats. To the best of our knowledge, this is the first report on the restorative effects of VNS on behavioral function in an animal model of depression that can be compared with the effects of antidepressants.     

Defining algorithms for efficient therapeutic drug monitoring of mycophenolate mofetil in heart transplant recipients

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0h with postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12h profiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12h was performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between "predicted AUC" and "measured AUC." C1h provided the highest coefficient of determination (r2 = 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12h when compared with C0h (r2 = 0.14). The best estimation of MPA-AUC0-12h was achieved with four sampling points with the algorithm AUC = 1.25*C1h + 5.29*C4h + 2.90*C8h + 3.61*C10h (r2 = 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h + 1.19*C1h + 3.60*C2h (r2 = 0.84) and AUC = 1.65*C0.5h + 4.74*C2h (r2 = 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0h for therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12h based on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.     

针刺足三里对对乙酰氨基酚诱发大鼠肝损伤的影响

目的：观察针刺足三里对对乙酰氨基酚（ APAP）多次给药诱发大鼠肝损伤血清转氨酶和肝脏病理学变化的影响,探讨针刺对药源性肝脏损伤的保护作用。方法75只SD大鼠随机分为正常对照组（ NC组）、APAP模型1组（ APAP1组）、针刺＋APAP 模型1组（ ZC＋APAP1组）、 APAP模型2组（ APAP2组）、针刺＋APAP模型2组（ ZC＋APAP2组）。 APAP1组和APAP2组大鼠每天分别按体重灌胃给予APAP 300、600 mg／kg;APAP1组和APAP2组大鼠每天分别按体重灌胃给予 APAP 300、600 mg／kg后即刻针刺其后肢足三里穴20 min;NC组灌胃给予相同体积剂量的生理盐水。各组大鼠连续给药或针刺14 d后,检测血清转氨酶活性和检查肝脏病理学变化情况。结果与NC组相比,ZC＋APAP1组、APAP2组和ZC＋APAP2组大鼠血清AST和ALT活性均显著升高（P＜0．05或P＜0．01）;与APAP1组、APAP2组相比, ZC＋APAP1组、ZC＋APAP2组大鼠血清AST、ALT活性均显著性升高（P＜0．05或P＜0．01）。 APAP1组和ZC＋APAP1组间肝脏病理学改变,差异无统计学意义（P＞0．05）,而APAP2组与ZC＋APAP2组肝脏病理学改变显著（P＜0．05）。结论针刺足三里促进APAP诱导大鼠血清AST和ALT活性的升高;但肝脏病理组织学检查结果显示,针刺足三里对APAP多次给药诱发大鼠肝损伤具有一定的保护作用。     

Ultraviolet-light induced p53 mutational spectrum in yeast is indistinguishable from p53 mutations in human skin cancer

Ultraviolet (UV) light has been associated with the development of human non-melanoma skin cancers (NMSC). Such cancers often exhibit mutations in the p53 tumour suppressor gene. In order to determine the UV-induced p53 mutation spectrum, a yeast expression vector that harbours a human wild-type p53 cDNA was UV-irradiated in vitro and transfected into a yeast strain that contained the ADE2 gene regulated by a p53-responsive promoter. Forty-five mutant clones contained 51 mutations. Seven mutations were tandem base pair substitutions, four of which being CC-->TT, hallmark mutations of UV mutagenesis. Eighty percent (41/51) of the mutations were single or non-tandem base pair substitutions, the majority of which (27/41) were C-->T transitions. Ninety-five percent of such mutations occurred at dipyrimidine sites. Through a rigorous statistical test, the UV-induced p53 mutation spectrum appears to differ significantly (P < 0.008) from the one induced by the antineoplastic drug chloroethyl-cyclohexyl-nitrosourea, and to be indistinguishable from the one observed in NMSC (P = 0.4). These results demonstrate that the assay allows the determination of carcinogen-specific p53 mutation fingerprints and represents a new tool for molecular epidemiology.      

The Effect of Body Mass Index on the Outcome of Critically Ill Surgical Patients

Background: The incidence of obesity is rising, and an increasing number of obese patients are admitted to surgical intensive care units (SICUs). However, it is not clear whether obesity is an independent risk factor for increased morbidity and mortality in SICU patients. We examined the effect of obesity on morbidity and mortality in patients admitted to the SICU in this study. Method: We reviewed prospectively acquired SICU data in normal and obese patients with an SICU length of stay >24 hours. Comparability of the groups was assessed using a χ² test or Fisher exact test, as appropriate, for categorical variables and analysis of variance (ANOVA) or the Kruskal‐Wallis test, as appropriate, for continuous variables. Results: Of the 1792 consecutive patients evaluated, 711 had a normal body mass index (BMI), and 993 were either preobese or obese. There was no statistically significant difference across the 5 BMI groups with respect to any of the 3 comorbidity indices (Acute Physiology and Chronic Health Evaluation III [APACHE III], Simplified Acute Physiology Score, or Multiple Organ Dysfunction Score). There was no statistically significant difference in the intensive care unit (ICU) length of stay and hospital length of stay or time‐to‐ICU mortality (log‐rank test P = .054) among the 5 BMI groups. A Cox regression analysis and backward elimination algorithm selected APACHE III to be the most important explanatory variable for survival time. Conclusion: Obesity does not affect the mortality of patients admitted to the SICU. We conclude that obesity cannot be used as an independent predictive mortality outcome variable in patients admitted to the SICU.     

Aims and status of the German DFG ‐ Transregio Research Group Xenotransplantation

Allotransplantation is the therapy of choice for endstage diseases. Due to the organ shortage, three times respectively twice as many patients are currently waiting for kidneys or hearts as are actually transplanted annually in Germany. Consequently, the mortality rate on the heart transplant list is around 16%; if patients have to wait more than 24 months for a kidney, the graft survival after 10 years will be less than half when compared to those who are able to receive an organ within 6 months. Therefore, porcine xenotransplantation of kidneys and hearts will be a very much needed alternative clinical technique – including (porcine) xenogenic islet cell transplantation for diabetic patients with hypoglycaemic attacks – a large number of persons, if one considers that the number of people suffering from diabetes worldwide increased by nearly 50% over the last decade. Of course, much more work is needed before clinical xenotransplantation will become a safe and long lasting alternative. The α(1,3)‐galactosyltransferase KO, PERV C free pigs – held in specific pathogen free units – must express several human transgenes, like a complement regulator molecule (in order to suppress non Gal‐AB's) and HLA‐E (protection from NK‐cell cytotoxicity). Some kind of accommodation will be necessary (e.g. via Hemoxygenase‐1 or PDL‐1 – a negative costimulatory receptor which also increases the CD4⁺ CD25^high Fox p3⁺ subset). An overexpression of thrombomodulin (TM) would finally be necessary in order to overcome the disparity between porcine (TM) and human (Thrombin) proteins and possibly avoid microvascular thrombotic disease. And to top all these desires of a clinical transplant specialist, all the genetic engineering should be achieved in close connection within one chromosome, preferably an artificial one, in order to make all these changes hereditary. The just mentioned strategies are the main topics of the DFG‐Transregio Research Group. The following abstracts will highlight the respective progress and will also inevitably evaluate arising problems. International leaders in our field will give their results and opinion – an interchange which is necessary within the small but very active xenotransplantation research field. It is my sincere belief that a clinical scenario of xenotransplantation will be possible in the near future.     

Evaluation of the anticonvulsant and muscle relaxant effects of the methanol root bark extracts of Annona senegalensis

ObjectiveTo investigate the potentials of the root bark of Annona (A.) senegalensis in the control of seizure and related hypnotic and motor incoordination effects in mice using experimental models.MethodsThe methanol extract (ME) of the root bark of A. senegalensis was studied in mice using pentylenetetrazole (PTZ) induced convulsions, phenobarbitone induced sleeping time and motor coordination test on rota-rod performance. Acute toxicity and lethality (LD₅₀) test as well as phytochemical analysis were also carried out.ResultsThe extract (200, 400, 800 mg/kg) exhibited a non-dose dependent significant (P <0.05) delay in the onset of both tonic and clonic phases of seizure induced by PTZ (60 mg/kg, s.c.) as well as offered a 100% protection (200 mg/kg) in mice from PTZ induced seizures. The extract significantly (P <0.05) decreased the latency and increased the duration of phenobarbitone induced sleeping time. At 200 mg/kg, the extract exhibited a significant (P <0.05) motor incoordination. The acute toxicity test revealed an oral LD₅₀ of 1 296 mg/kg, while the phytochemical studies showed the presence of alkaloids, resins, glycosides, carbohydrate, reducing sugar, flavonoids, terpenoids, saponins and tannins.ConclusionThe extract of A. senegalensis possessed anticonvulsant activity with pronounced hypnotic and muscle relaxant effects.     

Intriguing issues of EGFR targeting in head and neck cancer

We have read the recent comprehensive review by Cruz et al.[1] regarding the targeting of receptor tyrosine kinases andtheir therapeutic perspectives in head and neck squamous cellcarcinomas (HNSCC). The major focus of this report was epidermalgrowth factor receptor (EGFR) biology and targeting. However,we feel     

Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents.

BACKGROUND: Studies are inconsistent as to whether patients with bipolar disorder are more frequently affected by autoimmune thyroiditis. AIM: To study the prevalence of autoimmune thyroiditis in offspring of bipolar patients. METHOD: In 1998 140 children (age 12-21 years) of bipolar parents were evaluated psychiatrically using the K-SADS-PL and blood was drawn to determine thyroperoxidase antibodies (TPO-Abs) and serum TSH. Blood samples of high school students (aged 12-19 years, n=77) and young adults (aged 20-35 years, n=52) were used as comparisons. At follow-up the offspring were psychiatrically evaluated and tested for TPO-Abs and TSH twice (14 months and 55 months after enrollment). RESULTS: TPO-Abs were predominantly found in female bipolar offspring, who had a significantly higher prevalence of positive TPO-Ab titers (9 out of 57 female offspring subjects) as compared to the female high school and young adult comparisons (4 out of 103 female control subjects). In TPO-Ab positive offspring (n=11) a raised prevalence of 55% of thyroid failure (i.e. a raised serum TSH or l-thyroxine treatment) was evident. TPO-Ab positive offspring did not show a raised prevalence of mood disorders (or any psychopathology) as compared to the TPO-Ab negative offspring. CONCLUSION: Our study suggests that bipolar offspring are more vulnerable to develop thyroid autoimmunity independently from the vulnerability to develop psychiatric disorders.