Highly Diastereo- and Enantioselective CuH-Catalyzed Synthesis of 2,3-Disubstituted Indolines

A diastereo- and enantioselective CuH-catalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles, olefins, and substituted aromatic groups, renders this technique highly valuable for the synthesis of a variety of cis-2,3-disubstituted indolines in high yield and enantioeselectivity.National Institutes of Health (U.S.) (Award GM46059)Danish Council for Independent Research (Postdoctoral Fellowship

The normalisation of drug supply: The social<i>supply</i>of drugs as the “other side” of the history of normalisation

Aims: Describes how the relative normalisation of recreational drug use in the UK has been productive of, and fused with, the relatively normalised and non-commercial social supply of recreational drugs. Methods: Semi-structured interviews with 60 social suppliers of recreational drugs in two studies (involving a student population n = 30 and general population sample n = 30). Respondents were recruited via purposive snowball sampling and local advertising. Findings: Both samples provided strong evidence of the normalised supply of recreational drugs in micro-sites of friendship and close social networks. Many social suppliers described “drift” into social supply and normalised use was suggested to be productive of supply relationships that both suppliers and consumers regard as something less than “real” dealing in order to reinforce their preconceptions of themselves as relatively non-deviant. Some evidence for a broader acceptance of social supply is also presented. Conclusions: The fairly recent context of relative normalisation of recreational drug use has coalesced with the social supply of recreational drugs in micro-sites of use and exchange whereby a range of “social” supply acts (sometimes even involving large amounts of drugs/money) have become accepted as something closer to gift-giving or friendship exchange dynamics within social networks rather than dealing proper. To some degree, there is increasing sensitivity to this within the criminal justice system

Factors associated with pastoral community knowledge and occurrence of mycobacterial infections in human-animal interface areas of Nakasongola and Mubende districts, Uganda

<p>Abstract</p> <p>Background</p> <p>Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens whose role in human and animal disease is increasingly being recognized. Major concerns are their role as opportunistic pathogens in HIV/AIDS infections. The role of open natural water sources as source and livestock/wildlife as reservoirs of infections to man are well documented. This presents a health challenge to the pastoral systems in Africa that rely mostly on open natural water sources to meet livestock and human needs. Recent study in the pastoral areas of Uganda showed infections with same genotypes of NTM in pastoralists and their livestock. The aim of this study was to determine the environmental, animal husbandry and socio-demographic factors associated with occurrence and the pastoral community knowledge of mycobacterial infections at the human-environment-livestock/wildlife interface (HELI) areas in pastoral ecosystems of Uganda.</p> <p>Methods</p> <p>Two hundred and fifty three (253) individuals were subjected to a questionnaire survey across the study districts of Nakasongola and Mubende. Data were analyzed using descriptive statistics and multivariable logistic regression analysis.</p> <p>Results</p> <p>Humans sharing of the water sources with wild animals from the forest compared to savannah ecosystem (OR = 3.3), the tribe of herding pastoral community (OR = 7.9), number of rooms present in household (3-5 vs. 1-2 rooms) (OR = 3.3) were the socio-demographic factors that influenced the level of knowledge on mycobacterial infections among the pastoral communities. Tribe (OR = 6.4), use of spring vs. stream water for domestic use (OR = 4.5), presence of sediments in household water receptacle (OR = 2.32), non separation of water containers for drinking and domestic use (OR = 2.46), sharing of drinking water sources with wild animals (OR = 2.1), duration of involvement of >5 yrs in cattle keeping (OR = 3.7) and distance of household to animal night shelters (>20 meters) (OR = 3.8) were significant socio-demographic factors associated with the risk of occurrence of mycobacterioses among the pastoral communities in Uganda.</p> <p>Conclusion</p> <p>The socio-demographic, environmental and household related factors influence the risk of occurrence as well as pastoralists' knowledge of mycobacterial infections in the pastoral households at the human-environment-livestock/wildlife pastoral interface areas of Uganda.</p

The Big Drink Debate: perceptions of the impact of price on alcohol consumption from a large scale cross-sectional convenience survey in north west England

<p>Abstract</p> <p>Background</p> <p>A large-scale survey was conducted in 2008 in north west England, a region with high levels of alcohol-related harm, during a regional 'Big Drink Debate' campaign. The aim of this paper is to explore perceptions of how alcohol consumption would change if alcohol prices were to increase or decrease.</p> <p>Methods</p> <p>A convenience survey of residents (≥ 18 years) of north west England measured demographics, income, alcohol consumption in previous week, and opinions on drinking behaviour under two pricing conditions: low prices and discounts and increased alcohol prices (either 'decrease', 'no change' or 'increase'). Multinomial logistic regression used three outcomes: 'completely elastic' (consider that lower prices increase drinking and higher prices decrease drinking); 'lower price elastic' (lower prices increase drinking, higher prices have no effect); and 'price inelastic' (no change for either).</p> <p>Results</p> <p>Of 22,780 drinkers surveyed, 80.3% considered lower alcohol prices and discounts would increase alcohol consumption, while 22.1% thought raising prices would decrease consumption, making lower price elasticity only (i.e. lower prices increase drinking, higher prices have no effect) the most common outcome (62%). Compared to a high income/high drinking category, the lightest drinkers with a low income (adjusted odds ratio AOR = 1.78, 95% confidence intervals CI 1.38-2.30) or medium income (AOR = 1.88, CI 1.47-2.41) were most likely to be lower price elastic. Females were more likely than males to be lower price elastic (65% vs 57%) while the reverse was true for complete elasticity (20% vs 26%, P < 0.001).</p> <p>Conclusions</p> <p>Lower pricing increases alcohol consumption, and the alcohol industry's continued focus on discounting sales encourages higher drinking levels. International evidence suggests increasing the price of alcohol reduces consumption, and one in five of the surveyed population agreed; more work is required to increase this agreement to achieve public support for policy change. Such policy should also recognise that alcohol is an addictive drug, and the population may be prepared to pay more to drink the amount they now feel they need.</p

Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation

Background and Purpose: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA). Experimental Approach: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholineinduced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619. Key Results: Acetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilastincubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast. Conclusions and Implications: Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channelsThis study was supported by Ministerio de Ciencia e Innovación (SAF 2009-10374), Ministerio de Economía y Competitividad (SAF 2012-38530), and Fundación Mapfre. F.E. Xavier is recipient of research fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil

Venous gas embolism as a predictive tool for improving CNS decompression safety

A key process in the pathophysiological steps leading to decompression sickness (DCS) is the formation of inert gas bubbles. The adverse effects of decompression are still not fully understood, but it seems reasonable to suggest that the formation of venous gas emboli (VGE) and their effects on the endothelium may be the central mechanism leading to central nervous system (CNS) damage. Hence, VGE might also have impact on the long-term health effects of diving. In the present review, we highlight the findings from our laboratory related to the hypothesis that VGE formation is the main mechanism behind serious decompression injuries. In recent studies, we have determined the impact of VGE on endothelial function in both laboratory animals and in humans. We observed that the damage to the endothelium due to VGE was dose dependent, and that the amount of VGE can be affected both by aerobic exercise and exogenous nitric oxide (NO) intervention prior to a dive. We observed that NO reduced VGE during decompression, and pharmacological blocking of NO production increased VGE formation following a dive. The importance of micro-nuclei for the formation of VGE and how it can be possible to manipulate the formation of VGE are discussed together with the effects of VGE on the organism. In the last part of the review we introduce our thoughts for the future, and how the enigma of DCS should be approached

Airway smooth muscle as a target of asthma therapy: history and new directions

Ultimately, asthma is a disease characterized by constriction of airway smooth muscle (ASM). The earliest approach to the treatment of asthma comprised the use of xanthines and anti-cholinergics with the later introduction of anti-histamines and anti-leukotrienes. Agents directed at ion channels on the smooth muscle membrane (Ca(2+ )channel blockers, K(+ )channel openers) have been tried and found to be ineffective. Functional antagonists, which modulate intracellular signalling pathways within the smooth muscle (β-agonists and phosphodiesterase inhibitors), have been used for decades with success, but are not universally effective and patients continue to suffer with exacerbations of asthma using these drugs. During the past several decades, research energies have been directed into developing therapies to treat airway inflammation, but there have been no substantial advances in asthma therapies targeting the ASM. In this manuscript, excitation-contraction coupling in ASM is addressed, highlighting the current treatment of asthma while proposing several new directions that may prove helpful in the management of this disease