KCTD Hetero-oligomers confer unique kinetic properties on Hippocampal GABA B Receptor-Induced K + Currents

GABAB receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, GABA. GABAB receptors were shown to associate with homo-oligomers of auxiliary KCTD8, KCTD12, KCTD12b, and KCTD16 subunits (named after their T1 K+-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABAB receptors also associate with hetero-oligomers of KCTD subunits. Coimmunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero-oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer measurements in live cells reveal that KCTD12/KCTD16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties on G-protein-activated Kir3 currents. During prolonged receptor activation (one min) KCTD12/KCTD16 hetero-oligomers produce moderately desensitizing fast deactivating K+ currents, whereas KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and nondesensitizing slowly deactivating currents, respectively. During short activation (2 s) KCTD12/KCTD16 hetero-oligomers produce nondesensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/KCTD16 hetero-oligomers increase the duration of slow IPSCs. In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABAB receptors and modulates physiologically induced K+ current responses in the hippocampus

Factors associated with smoking in pregnancy

The aim of this cross-sectional study was to identify factors related to smoking during pregnancy. The sample included 267 puerperae hospitalized in the maternity unit of a university hospital in Porto Alegre/RS. The data were collected through a self-applied instrument and statistically analyzed. The majority of the puerperae (51.3%) were between 18 and 25 years old, 55.4% were nonsmokers, 25.5% were smokers, 19.1% had recently ceased smoking (in abstinence). The nonsmokers had more consultations than the smokers and the abstinent smokers (p=0.025). The number of women who had more than one child was higher among smokers than among nonsmokers and abstinent smokers (p=0.002). Women were more likely to stop smoking before pregnancy when they had a partner who was a nonsmoker (p=0.007). Several factors influence smoking and smoking cessation and these are important in prenatal interventions aimed at pregnant women and their partners

A Randomized Placebo-Controlled Trial of Varenicline for Smoking Cessation Allowing Flexible Quit Dates

Introduction: Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication. Methods: In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18-75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide-confirmed continuous abstinence during Weeks 9-12, and a key secondary endpoint was continuous abstinence during Weeks 9-24. Results: Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9-12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7-9.4; p < .0001) and through 24 weeks follow-up (Weeks 9-24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6-7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively). Conclusions: Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies. © The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco

Nicotine delivery to users from cigarettes and from different types of e-cigarettes

BACKGROUND: Delivering nicotine in the way smokers seek is likely to be the key factor in e-cigarette (EC) success in replacing cigarettes. We examined to what degree different types of EC mimic nicotine intake from cigarettes. METHODS: Twelve participants (‘dual users’ of EC and cigarettes) used their own brand cigarette and nine different EC brands. Blood samples were taken at baseline and at 2-min intervals for 10 min and again at 30 min. RESULTS: Eleven smokers provided usable data. None of the EC matched cigarettes in nicotine delivery (C (max) = 17.9 ng/ml, T (max) = 4 min and AUC(0–>30) = 315 ng/ml/min). The EC with 48 mg/ml nicotine generated the closest PK profile (C (max) = 13.6 ng/ml, T (max) = 4 min, AUC(0–>30) = 245 ng/ml/min), followed by a third generation EC using 20 mg/ml nicotine (C (max) = 11.9 ng/ml, T (max) = 6 min, AUC(0–>30) = 232 ng/ml/min), followed by the tank system using 20 mg/ml nicotine (C (max) = 9.9 ng/ml, T (max) = 6 min, AUC(0–>30) = 201 ng/ml/min). Cig-a-like PK values were similar, ranging from C (max) 7.5 to 9.7 ng/ml, T (max) 4-6 min, and AUC(0–>30) 144 to 173 ng/ml/min. Moderate differences in e-liquid nicotine concentrations had little effect on nicotine delivery, e.g. the EC with 24 mg/ml cartridge had the same PK profile as ECs with 16 mg/ml cartridges. Using similar strength e-liquid, the tank EC provided significantly more nicotine than cig-a-like ECs. CONCLUSIONS: EC brands we tested do not deliver nicotine as efficiently as cigarettes, but newer EC products deliver nicotine more efficiently than cig-a-like brands. Moderate variations in nicotine content of e-liquid have little effect on nicotine delivery. Smokers who are finding cig-a-like EC unsatisfactory should be advised to try more advanced systems

European code against cancer 4th edition: 12 ways to reduce your cancer risk

This overview describes the principles of the 4th edition of the European Code against Cancer and provides an introduction to the 12 recommendations to reduce cancer risk. Among the 504.6 million inhabitants of the member states of the European Union (EU28), there are annually 2.64 million new cancer cases and 1.28 million deaths from cancer. It is estimated that this cancer burden could be reduced by up to one half if scientific knowledge on causes of cancer could be translated into successful prevention. The Code is a preventive tool aimed to reduce the cancer burden by informing people how to avoid or reduce carcinogenic exposures, adopt behaviours to reduce the cancer risk, or to participate in organised intervention programmes. The Code should also form a base to guide national health policies in cancer prevention. The 12 recommendations are: not smoking or using other tobacco products; avoiding second-hand smoke; being a healthy body weight; encouraging physical activity; having a healthy diet; limiting alcohol consumption, with not drinking alcohol being better for cancer prevention; avoiding too much exposure to ultraviolet radiation; avoiding cancer-causing agents at the workplace; reducing exposure to high levels of radon; encouraging breastfeeding; limiting the use of hormone replacement therapy; participating in organised vaccination programmes against hepatitis B for newborns and human papillomavirus for girls; and participating in organised screening programmes for bowel cancer, breast cancer, and cervical cancer

Late Cretaceous-Cenozoic thermal evolution of the northern part of the Central Western Carpathians (Slovakia): revealed by zircon and apatite fission track thermochronology

Tectono-thermal evolution of the northern part of Central Western Carpathians (Slovakia) was revealed by zircon and apatite fission track thermochronology of Neogene deposits, volcanic rocks, and crystalline basement. New fission track ages combined with previous geochronological data are correlated with main tectonic events and important palaeogeographic changes. (1) The palaeo-Alpine burial to more than 10. km depths, heating (> 320 °C) and low-grade metamorphism of the crystalline basement was caused by crustal thickening due to nappe stacking driven by the collisional processes (~. 90-75. Ma). (2) Extensional collapse and exhumation of basement complexes during the Late Cretaceous to Middle Eocene (~. 75-40. Ma). (3) The extension process resulted in a new sedimentary cycle of the Central Carpathian Palaeogene Basin (~. 40-25. Ma) in the northern part of the Central Western Carpathians. During the ensuing burial under the thick sedimentary cover, the crystalline basement of the northern zone resided at 'hotter' conditions (ca > 120 °C and < 200 °C) which led to full annealing of apatite single-grain ages. In the meanwhile the southern zone of the crystalline basement was gradually exhumed to the depth of 5-3. km and occasionally appeared at the erosion surface. (4) Disintegration of the Central Carpathian Palaeogene Basin (~. 25-20. Ma) was closely connected with a partial exhumation of the Central Western Carpathians and intensive denudation. (5) The Middle to Late Miocene (~. 20-9. Ma) subduction of the Outer Carpathians substratum had crucial consequences for the tectonic evolution of the hinterland that was located in the upper crustal plate. The most external zone of the hinterland basement domain (Lúčanská and Krivánska Fatra Mts.) was exhumed to the 5-3. km depth and the intramontane basins were opened. (6) New fission track data and geomorphological criteria refer to the Pliocene-Quaternary mountain building processes in the external zones of the Central Western Carpathians. © 2014 Elsevier B.V