Effect of cardiac resynchronization therapy on global and regional oxygen consumption and myocardial blood flow in patients with non-ischaemic and ischaemic cardiomyopathy.

AIMS: We studied the effects of cardiac resynchronization therapy (CRT) on global and regional myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) in non-ischaemic (NICM) and ischaemic dilated cardiomyopathy (ICM). METHODS AND RESULTS: Thirty-one NICM and 11 ICM patients, all of them acute responders, were investigated. MVO2 and MBF were obtained by 11C-acetate PET before and after 4 months of CRT. In NICM global MVO2 and MBF did not change during CRT, while the rate pressure product (RPP) normalized MVO2 increased (P=0.03). Before CRT regional MVO2 and MBF were highest in the lateral wall and lowest in the septum. Under therapy, MVO2 and MBF decreased in the lateral wall (P=0.045) and increased in the septum (P=0.045) resulting in a more uniform distribution. In ICM, global MVO2, MBF, and RPP did not change under CRT. Regional MVO2 and MBF showed no significant changes but a similar tendency in the lateral and septal wall to that in NICM. CONCLUSION: CRT induces changes of MVO2 and MBF on a regional level with a more uniform distribution between the myocardial walls and improved ventricular efficiency in NICM. Based on the investigated parameters, CRT appears to be more effective in NICM than in ICM.     

Engineered BDNF producing cells as a potential treatment for neurologic disease

ABSTRACT

Introduction: Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression.

Areas covered: The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF.

Expert opinion: Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic.     

Genetic and nongenetic influences on handedness

A brief review of theories of the causes of handedness shows why the major determinant is probably accidental variation, modified in man by a genetic factor inducing dextral bias. Levy's (1976, 1977) criticisms of Annett (1973) are answered by a detailed consideration of Chamberlain's (1928) report and by the presentation of an alternative analysis of the Hull family data using a criterion more similar to that of Rife (1940). The revised analysis is incompatible with the Levy-Nagylaki (1972) model of the genetics of handedness. New data on family preferences in two further student samples support the Hull findings. Data on manual skill in families are more consistent with an accidental than with a polygenic origin of human variability in handedness.     

The reliability of differences between the hands in motor skill

Measures of manual speed on a peg moving task were repeated after intervals ranging from 7 weeks to 18 months. Significant test-retest correlations were found for each hand and for the difference between hands. In a second experiment, with this task, practice was found to improve the speed of each hand but not to eliminate the difference between them. This measure of manual asymmetry can be regarded as moderately reliable.     

Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner

Akt contributes to tumorigenesis by inhibiting apoptosis. Here we establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis. These effects are compounded by deleting both Akt1 and Akt2. In vivo, Akt1 null mice are resistant to MMTV-v-H-Ras-induced tumors and to skin carcinogenesis. Thus, partial ablation of Akt activity is sufficient to suppress tumorigenesis in vitro and in vivo. The effect of Akt deficiency on cell proliferation and oncogenesis is p53 independent but mTORC1 dependent. Surprisingly, upon mTORC1 hyperactivation, the reduction in Akt activity does not impair cell proliferation and susceptibility to oncogenic transformation; thus, Akt may mediate these processes exclusively via mTORC1.     

Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib

Aberrant activation of the epidermal growth factor receptor is frequently observed in neoplasia, notably in tumors of epithelial origin. Attempts to treat such tumors with epidermal growth factor receptor antagonists resulted in remarkable success in recent studies. Little is known, however, about the efficacy of this therapy in biliary tract cancer. Protein expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 was assessed in seven human biliary tract cancer cell lines by immunoblotting. In addition, histological sections from 19 patients with extrahepatic cholangiocarcinoma were analyzed for epidermal growth factor receptor, ErbB-2 and vascular endothelial growth factor receptor-2 expression by immunohistochemistry. Moreover, we sequenced the cDNA products representing the entire epidermal growth factor receptor coding region of the seven cell lines, and searched for genomic epidermal growth factor receptor amplifications and polysomy by fluorescence in-situ hybridization. Cell growth inhibition by gefitinib erlotinib and NVP-AEE788 was studied in vitro by automated cell counting. In addition, the anti-tumoral effect of erlotinib and NVP-AEE788 was studied in a chimeric mouse model. The anti-tumoral drug mechanism in this model was assessed by MIB-1 antibody staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labelling assay, von Willebrand factor staining, and immunoblotting for p-p42/44 (p-Erk1/2, p-MAPK) and p-AKT. Immunoblotting revealed expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 in all biliary tract cancer cell lines. EGFR was detectable in six of 19 (32%) extrahepatic human cholangiocarcinoma tissue samples, ErbB-2 in 16 of 19 (84%), and vascular endothelial growth factor receptor-2 in nine of 19 (47%). Neither epidermal growth factor receptor mutations nor amplifications or polysomy were found in the seven biliary tract cancer cell lines. Gefitinib, erlotinib and NVP-AEE788 caused a significant growth inhibition in vitro; however, there was a significant difference in efficacy (NVP-AEE788>erlotinib>gefitinib). After 14 days of in-vivo treatment, using the chimeric mouse model, tumors had a significantly reduced volume and mass after NVP-AEE788, but not after erlotinib treatment, as compared with placebo. Reduction of proliferation (signalling via the mitogen-activated protein kinase pathway), induction of apoptosis and inhibition of angiogenesis were the main mechanisms of drug action. No significant reduction of anti-apoptotic AKT phosphorylation, however, occurred, which may be a possible counter mechanism of the tumor. Epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 expression was detectable in biliary tract cancer, and receptor inhibition exerts marked effects on tumor growth in vitro and in vivo, which was strongest for the dual EGFR/ErbB-2 inhibitor NVP-AEE788. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.     

Bread enriched with green coffee extract has chemoprotective and antigenotoxic activities in human cells

Recent studies have shown that bread supplemented with functional ingredients was more chemoprotective than nonsupplemented bread. Here we investigated components of a German wheat bread supplemented with green coffee antioxidants (GC) to assess basic biological activities in human cells in culture. We analyzed chlorogenic acid (ChA) in the bread and determined antioxidative activities. Human colon (HT29) and liver (HepG2) cells were incubated with GC and with aqueous extracts of freeze-dried breads, after which cell survival (4' ,6-diamino-2- phenylindole dihydrochloride assay) and H(2)O(2)-induced DNA damage (comet assay) were determined. GC and supplemented bread contained 7- and 880-fold more ChA than normal bread and were significantly more antioxidative (ferric reducing ability of plasma assay, 2.9- and 265-fold; Trolox equivalent antioxidant capacity assay, 1.3- and 24-fold, respectively). Treatment of cells for 24 to 72 h with the samples resulted in a significant inhibition of cell survival in a dose-dependent manner. HepG2 liver cells were more susceptible than HT29 colon cells. No genotoxicity or cytotoxicity was observed after treatment of cells with GC, ChA, or the bread samples. H(2)O(2)-induced DNA damage was reduced significantly after treatment with GC, ChA, and supplemented bread. In conclusion, the supplementation of bread with GC improves the chemoprotective property of normal bread under these in vitro cell culture conditions. Supplementation also increases ChA content and antioxidative capacity. The treatment of the cells with supplemented bread increases resistance of colon and liver cells against H(2)O(2), a source of oxidative stress.     

Histamine receptors in human detrusor smooth muscle cells: physiological properties and immunohistochemical representation of subtypes

The potent inflammatory mediator histamine is released from activated mast cells in interstitial cystitis (IC). Here, we report on the histamine receptor subtypes involved in the intracellular calcium response of cultured smooth muscle cells (cSMC). Fura-2 was used to monitor the calcium response in cSMC, cultured from human detrusor biopsies. The distribution of histamine receptor subtypes was addressed by immunocytochemistry in situ and in vitro. Histamine stimulated a maximum of 92% of the cells (n=335), being more effective than carbachol (70%, n=920). HTMT (H1R-agonist), dimaprit (H2R) and MTH (H3R) lead to significant lower numbers of reacting cells (60, 48 and 54%). Histamine receptor immunoreactivity (H1R, H2R, H3R, H4R) was found in situ and in vitro. Histamine-induced calcium increase is mediated by distinct histamine receptors. Thus, pre-therapeutic evaluation of histamine receptor expression in IC patients may help to optimize therapy by using a patient-specific cocktail of subtype-specific histamine receptor antagonists.     

Intra-operative introital ultrasound in Burch colposuspension reduces post-operative complications

OBJECTIVE: To determine the effect of intra-operative monitoring of bladder neck elevation on cure rate and post-operative complications in patients undergoing colposuspension. DESIGN: Prospective, observational study. SETTING: Urogynaecology units, university hospitals. POPULATION: Ninety women operated on for genuine stress urinary incontinence. METHODS: The topography of the bladder neck and proximal urethra was assessed with pre-, intra- and post-operative introital ultrasound. These measurements were repeated during follow up for up to 48 months after surgery. Burch colposuspension of the bladder neck was performed under intra-operative introital ultrasound control, with reference to the patients' individual pre-operative ultrasound, to achieve a vertical height correction of 1-10 mm. MAIN OUTCOME MEASURES: Mid-term surgical outcome and post-operative complications. RESULTS: Ninety patients underwent colposuspension and 50 (56%) completed 48 months of follow up; 85 women (94%) were objectively continent at 12-month follow up and 42 of 50 (82%) at 48-month follow up. Surgical elevation of the bladder neck resulted in a median intra-operative elevation of 9 mm (7 mm at 48 months). All post-operative measurements demonstrated a significant decrease in linear dorsocaudal movement of the bladder neck during straining (P < 0.001). Funnelling and hypermobility were still decreased 48 months after incontinence surgery (P < 0.001). Voiding difficulty and urgency were uncommon and associated with evidence of funnelling and hypermobility. CONCLUSION: Intra-operative introital ultrasound standardises Burch colposuspension and thus might help to avoid overelevation and associated post-operative complications such as voiding difficulties and de novo urge incontinence without compromising the success of the operation.     

Interaction of the antiviral drug telaprevir with renal and hepatic drug transporters

Telaprevir is a new, direct-acting antiviral drug that has been approved for the treatment of chronic hepatitis C viral infection. First data on drug-drug interactions with co-medications such as cyclosporine, tacrolimus and atorvastatin have been reported recently. Drug transporting proteins have been shown to play an important role in clinically observed drug-drug interactions. The aim of this study was therefore to systematically investigate the potential of telaprevir to inhibit drug transporting proteins. The effect of telaprevir on substrate uptake mediated by drug transporters located in human kidney and liver was investigated on a functional level in HEK293 cell lines that over-express single transporter. Telaprevir was shown to exhibit significant inhibition of the human renal drug transporters OCT2 and MATE1 with IC(50) values of 6.4μM and 23.0μM, respectively, whereas no inhibitory effect on OAT1 and OAT3 mediated transport by telaprevir was demonstrated. Liver drug transporters were inhibited with an IC(50) of 2.2μM for OATP1B1, 6.8μM for OATP1B3 and 20.7μM for OCT1. Our data show that telaprevir exhibited significant potential to inhibit human drug transporters. In view of the inhibitory potential of telaprevir, clinical co-administration of telaprevir together with drugs that are substrates of renal or hepatic transporters should be carefully monitored.