Treatment of tobacco dependence: integrating recent progress into practice

Tobacco use is one of the leading preventable causes of death in developed countries. Adoption of approaches that have demonstrated efficacy to improve the treatment of tobacco dependence are critical to reduce the health consequences of tobacco use. We summarize the latest epidemiologic data on tobacco use, the mechanisms that underlie tobacco dependence, and advances in pharmacotherapy and nonpharmacologic interventions available for the treatment of tobacco dependence. Specifically, we discuss the use of nicotine replacement therapy, bupropion and varenicline in primary care settings.Smoking is currently responsible for the death of 1 in 10 adults worldwide, or about 5 million deaths each year. Half of the 650 million people who smoke today will eventually be killed by tobacco,¹ and this morbidity and mortality can be mostly avoided if people stop smoking.² The prevalence of smoking varies greatly around the world. Over 4.5 million people are current smokers in Canada, representing 18% of the population aged 15 years and older.³ Smoking prevalence is still high in countries such as China and India (approximately 50% and 30% respectively among males) and is on the rise in developing countries.⁴ Consequently, tobacco use is one of the few causes of death that is increasing globally.⁴In Canada and other Western countries, considerable progress has been made in decreasing tobacco use. Interestingly, there has also been a decrease in the quantity of tobacco smoked, as indicated by the number of cigarettes smoked per day (now 15.4 cigarettes on average per day among daily smokers in Canada, compared with 18.4 in 1990) and by the increasing proportion of smokers who do not smoke daily.³ Tobacco use also differs between males and females, although the gap is narrowing. In Canada, males continue to smoke more than females overall, but there is currently no significant sex-related difference in smoking prevalence among adolescents. The prevalence of tobacco use among females is increasing. This trend is alarming, since the health consequences are now affecting women at high rates: in Canada, the prevalence of lung cancer among women is now higher than that of breast cancer.     

Occupational therapy for patients with problems in personal activities of daily living after stroke: systematic review of randomised trials

Objective To determine whether occupational therapy focused specifically on personal activities of daily living improves recovery for patients after stroke.Design Systematic review and meta-analysis.Data sources The Cochrane stroke group trials register, the Cochrane central register of controlled trials, Medline, Embase, CINAHL, PsycLIT, AMED, Wilson Social Sciences Abstracts, Science Citation Index, Social Science Citation, Arts and Humanities Citation Index, Dissertations Abstracts register, Occupational Therapy Research Index, scanning reference lists, personal communication with authors, and hand searching.Review methods Trials were included if they evaluated the effect of occupational therapy focused on practice of personal activities of daily living or where performance in such activities was the target of the occupational therapy intervention in a stroke population. Original data were sought from trialists. Two reviewers independently reviewed each trial for methodological quality. Disagreements were resolved by consensus.Results Nine randomised controlled trials including 1258 participants met the inclusion criteria. Occupational therapy delivered to patients after stroke and targeted towards personal activities of daily living increased performance scores (standardised mean difference 0.18, 95% confidence interval 0.04 to 0.32, P=0.01) and reduced the risk of poor outcome (death, deterioration or dependency in personal activities of daily living) (odds ratio 0.67, 95% confidence interval 0.51 to 0.87, P=0.003). For every 100 people who received occupational therapy focused on personal activities of daily living, 11 (95% confidence interval 7 to 30) would be spared a poor outcome.Conclusions Occupational therapy focused on improving personal activities of daily living after stroke can improve performance and reduce the risk of deterioration in these abilities. Focused occupational therapy should be available to everyone who has had a stroke.     

Feedback control in active sensing: rat exploratory whisking is modulated by environmental contact

Rats sweep their facial whiskers back and forth to generate tactile sensory information through contact with environmental structure. The neural processes operating on the signals arising from these whisker contacts are widely studied as a model of sensing in general, even though detailed knowledge of the natural circumstances under which such signals are generated is lacking. We used digital video tracking and wireless recording of mystacial electromyogram signals to assess the effects of whisker-object contact on whisking in freely moving animals exploring simple environments. Our results show that contact leads to reduced protraction (forward whisker motion) on the side of the animal ipsilateral to an obstruction and increased protraction on the contralateral side. Reduced ipsilateral protraction occurs rapidly and in the same whisk cycle as the initial contact. We conclude that whisker movements are actively controlled so as to increase the likelihood of environmental contacts while constraining such interactions to involve a gentle touch. That whisking pattern generation is under strong feedback control has important implications for understanding the nature of the signals reaching upstream neural processes.     

The K15 protein of Kaposi's sarcoma-associated herpesvirus recruits the endocytic regulator intersectin 2 through a selective SH3 domain interaction

Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8, is closely associated with several cancers including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The rightmost end of the KSHV genome encodes a protein, K15, with multiple membrane-spanning segments and an intracellular carboxy-terminal tail that contains several conserved motifs with the potential to recruit interaction domains (i.e., SH2, SH3, TRAF) of host cell proteins. K15 has been implicated in downregulating B cell receptor (BCR) signaling through its conserved motifs and may thereby play a role in maintaining viral latency and/or preventing apoptosis of the infected B cells. However, K15's mode of action is largely unknown. We have used mass spectrometry, domain and peptide arrays, and surface plasmon resonance to identify binding partners for a conserved proline-rich sequence (PPLP) in the K15 cytoplasmic tail. We show that the PPLP motif selectively binds the SH3-C domain of an endocytic adaptor protein, Intersectin 2 (ITSN2). This interaction can be observed both in vitro and in cells, where K15 and ITSN2 colocalize to discrete compartments within the B cell. The ability of K15 to associate with ITSN2 suggests a new role for the K15 viral protein in intracellular protein trafficking.     

Effect of wall shear rate on biofilm deposition and grazing in drinking water flow chambers

The effect of four-wall shear rates (34.9, 74.8, 142.5, and 194.5 s(-1)) on bacterial deposition on glass slides in drinking water flow chambers was studied. Biofilm image acquisition was performed over a 50-day period. Bacterial accumulation and surface coverage curves were obtained. Microscopic observations allowed us to obtain information about the dynamics and spatial distribution of the biofilm. During the first stage of biofilm formation (210-518 h), bacterial accumulation was a function of the wall shear rate: the higher the wall shear rate, the faster the bacterial deposition (1.1 and 1.9 x 10(4) bacterial cells . cm(-2) for wall shear rates of 34.9 and 142.5 s(-1), respectively). A new similarity relationship characteristic of a non-dimensional time and function of the wall shear rate was proposed to describe initial bacterial deposition. After 50 days of exposure to drinking water, surface coverage was more or less identical under the entire wall shear rates (7.44 +/- 0.9%), suggesting that biofilm bacterial density cannot be controlled using hydrodynamics. However, the spatial distribution of the biofilm was clearly different. Under low wall shear rate, aggregates were composed of bacterial cells able to "vibrate" independently on the surface, whereas, under a high wall shear rate, aggregates were more cohesive. Therefore, susceptibility to the hydraulic discontinuities occurring in drinking water system may not be similar. In all the flow chambers, significant decreases in bacterial biomass (up to 77%) were associated with the presence of amoebae. This grazing preferentially targeted small, isolated cells.     

Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of beta-galactopyranosyl-(1<-->1)-alpha-mannopyranoside

C-Glycosides in which the pseudoglycosidic substituent is a methylene group have been advertised as hydrolytically stable mimetics of their parent O-glycosides. While this substitution assures greater stability, the lower polarity and increased conformational flexibility in the intersaccharide linker brought about by this change may compromise biological mimicry. In this regard, C-glycosides, in which the pseudoanomeric methylene is replaced with a difluoromethylene group, are interesting because the CF2 group is more of an isopolar replacement for oxygen than CH2. In addition, the CF2 residue is expected to instill conformational bias into the intersaccharide torsions. Herein is described the synthesis and conformational behavior of the difluoromethylene linked C-glycoside of beta-D-galactopyranosyl-(1<-->1)-alpha-D-mannopyranoside. The synthesis centers on the formation of the galactose residue via an oxocarbenium ion-enol ether cyclization. Conformational analysis, using a combination of molecular mechanics, dynamics, and NMR spectroscopy, suggests that the difluoro-C-glycoside populates the non-exo-Gal/exo-Man conformer to a major extent (ca 50%), with a minor contribution ( approximately 15%) from the exo-Gal/exo-Man conformer that corresponds to the ground sate of the parent O-glycoside.     

Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells

Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10(-11)-10(-7) M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ET(A) and ET(B) receptors, cell size, as well as increased expression of myosin heavy chain, alpha-smooth muscle actin, and calponin. ET-1-induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK1/2 by the MAPK/ERK kinase 1/2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M and greater than that induced by cardiotrophin-1. ET-1 induced release of IL-6 but not IL-11, leukemia inhibitory factor, oncostatin M, or cardiotrophin-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.     

A protein interaction map of the mitotic spindle

The mitotic spindle consists of a complex network of proteins that segregates chromosomes in eukaryotes. To strengthen our understanding of the molecular composition, organization, and regulation of the mitotic spindle, we performed a system-wide two-hybrid screen on 94 proteins implicated in spindle function in Saccharomyces cerevisiae. We report 604 predominantly novel interactions that were detected in multiple screens, involving 303 distinct prey proteins. We uncovered a pattern of extensive interactions between spindle proteins reflecting the intricate organization of the spindle. Furthermore, we observed novel connections between kinetochore complexes and chromatin-modifying proteins and used phosphorylation site mutants of NDC80/TID3 to gain insights into possible phospho-regulation mechanisms. We also present analyses of She1p, a novel spindle protein that interacts with the Dam1 kinetochore/spindle complex. The wealth of protein interactions presented here highlights the extent to which mitotic spindle protein functions and regulation are integrated with each other and with other cellular activities.     

Physiological disturbance and recovery dynamics of bonefish (Albula vulpes), a tropical marine fish, in response to variable exercise and exposure to air

Current understanding of the stress response in fishes has largely come from studies of freshwater-adapted salmonids, with proportionately few comparative studies having examined marine fishes. The current study sought to quantify the magnitude of physiological disturbances, recovery dynamics, and post-exercise behaviour in bonefish (Albula vulpes; a tropical marine fish) exposed to several different exercise and air exposure regimens. Results showed that metabolic disturbances (lactate production, hyperglycemia) increased following exercise and exposure to air, and that the magnitude of metabolic disturbance was proportional to the duration of the stressful event. Fish required between 2-4 h to return to resting values. Exercise and exposure to air also resulted in significant increases in plasma Ca2+, Cl- and Na+, but the magnitude of these ionic changes did not vary with exercise or exposure to air duration and required over 4-h to return to baseline levels. Mortality following exercise was observed only for fish that had been exposed to air for 3 min and not in fish that had been exposed to air for 1 min. Together, results from this study provide a physiological basis for management strategies that can improve the post-release survival of bonefish that have been caught during a catch-and-release angling event.