The trypanocide diminazene aceturate is accumulated predominantly through the TbAT1 purine transporter: additional insights on diamidine resistance in african trypanosomes

Resistance to diminazene aceturate (Berenil) is a severe problem in the control of African trypanosomiasis in domestic animals. It has been speculated that resistance may be the result of reduced diminazene uptake by the parasite. We describe here the mechanisms by which [(3)H]diminazene is transported by Trypanosoma brucei brucei bloodstream forms. Diminazene was rapidly accumulated through a single transporter, with a K(m) of 0.45 +/- 0.11 micro M, which was dose dependently inhibited by pentamidine and adenosine. The K(i) values for these inhibitors were consistent with this transporter being the P2/TbAT1 adenosine transporter. Yeast expressing TbAT1 acquired the ability to take up [(3)H]diminazene and [(3)H]pentamidine. TbAT1-null mutants had lost almost all capacity for [(3)H]diminazene transport. However, this cell line still displayed a small but detectable rate of [(3)H]diminazene accumulation, in a nonsaturable manner. We conclude that TbAT1 mediates [(3)H]diminazene transport almost exclusively and that this explains the observed diminazene resistance phenotypes of TbAT1-null mutants and field isolates.     

Risk of ventricular proarrhythmia with selective opening of the myocardial sarcolemmal versus mitochondrial ATP-gated potassium channel

Myocardial ATP-gated potassium channels (K-ATPs) are critical in the intracellular signaling cascade resulting in ischemic preconditioning (IP). Mitochondrial K-ATP channels seem to be responsible for IP, whereas the functions of K-ATP channels in the sarcolemmal membrane are less well understood. The proarrhythmic potential of specific versus nonspecific opening of K-ATP channels has not been investigated. In this study, Langendorff-perfused rabbit hearts were exposed to either pinacidil (1.25 microM), a nonselective K-ATP channel agonist, or selective mitochondrial or sarcolemmal K-ATP channel agonists or antagonists. The hearts were then subjected to 12 min of hypoxic perfusion and 40 min of reoxygenation. Hearts were monitored for the induction of ventricular fibrillation (VF). No heart subjected to hypoxia-reoxygenation without drug treatment developed VF (0 of 5). Pinacidil pretreatment induced VF (12 of 14; p = 0.004 versus control). Pinacidil's effect was blocked by HMR-1098 (1-[5-[2-(5-chloro-o-anisamide)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea) (1 microM), a selective sarcolemmal K-ATP channel antagonist (1 of 7; p = 0.007 versus pinacidil; N.S. versus control). Hearts pretreated with 5-hydroxydecanoate (5-HD) (100 microM), a putatively selective mitochondrial K-ATP channel blocker developed VF in one of eight trials (N.S. versus control). 5-HD did not alter the effects of pinacidil (6 of 8; p < 0.05 versus control; N.S. versus pinacidil alone). Selective mitochondrial K-ATP channel activation with [(3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride] (BMS-191095) (6 microM) resulted in zero of five hearts developing VF (N.S. versus control). Our data suggest that selective opening of the sarcolemmal K-ATP channel during hypoxia-reoxygenation induced VF, whereas opening of the mitochondrial channel was not associated with VF. The findings suggest that caution should be exercised when developing compounds aimed at inducing IP, and nonspecific opening of the K-ATP channel should be avoided.     

The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride

Positron emission tomography and [11C]raclopride were used to assess the dopaminergic response to cigarette smoking in ten smokers. Nicotine-deprived smokers were scanned twice on separate days. In one condition, participants smoked their usual brand of cigarettes while in the scanner and in the other condition they remained nicotine abstinent. On each day, subjects monitored the hedonic properties of their experience as well as their levels of craving. Initial analyses revealed no significant differences between the conditions in [11C]raclopride binding potential (BP) in the caudate, putamen, or ventral striatum. Because previous research suggested that drug-induced dopamine transmission is related to levels of craving and/or hedonic drug effects, the relationship between these variables and [11C]raclopride BP was examined. Craving levels were reduced by smoking but were not systematically related to BP change. However, the hedonic response to smoking was correlated with BP reduction in the caudate (P < 0.001) and posterior putamen (P < 0.05) but not in the ventral striatum. Post hoc analyses revealed that only five of the ten smokers reported mood-elevating effects in response to the smoking procedure. In these subjects, smoking was associated with decreased [11C]raclopride BP in the caudate. On the other hand, among subjects that reported a diminished mood response to smoking there was an increase in BP in the caudate and putamen. These results suggest that pleasurable drug experiences are associated with increased dopamine transmission in the dorsal striatum while unpleasant experiences may be related to decreased dopamine release in this region.     

Patient care advisers: helping cardiac surgery patients to exercise choice

Cardiac surgical centres have received funds to appoint at least one patient care adviser as part of the Government's Patient Choice Initiative. Mostly from a nursing background, their role is to ensure patients who have been waiting more than six months have the choice of receiving surgery sooner at another centre. This paper describes this national initiative.     

Requesting and interpreting trauma radiographs: a role extension for accident & emergency nurses

Government supported expansion of the nursing role within Accident & Emergency (A&E) departments in the United Kingdom (UK) has begun to break down the traditional barriers to professional practice. Today, many nurses working within A&E departments are both requesting and interpreting radiographic examinations as part of their normal working practice. However, role expansion does not occur without increased responsibility. Unsatisfactory requests for radiography and inaccurate radiographic interpretation may result in inappropriate patient treatment, misuse of resources, patient recall and litigation. Nurses undertaking these role extensions need to ensure that their levels of knowledge and skill to perform the role are appropriate and adequately supported. This article summarises the results of a national questionnaire survey of A&E nurse managers that aimed to identify current working practices, including education, training and limitations to practice, with respect to the requesting and interpretation of trauma radiographs by A&E nurses.     

Photoperiodic programming of body weight through the neuroendocrine hypothalamus

The photoperiodic mammal undergoes quite remarkable changes in physiology as part of its natural adaptations to seasonal fluctuations in the environment. Changes in energy balance and body weight are among these adaptations. In some seasonal mammals, such as the Siberian hamster (Phodopus sungorus), these changes in body weight have been explored in detail, and there is evidence for tightly controlled systems of energy balance that are coordinated by photoperiod acting via the temporal pattern of melatonin secretion from the pineal gland. The pathways and systems involved appear to be quite distinct from the hypothalamic pathways identified to regulate energy balance in studies of both mice and rats thus far. Instead it appears that in the Siberian hamster a tightly regulated system under the control of photoperiod is able to reset the tone of the systems involved in energy balance regulation. Understanding how photoperiod and melatonin act within the hypothalamus to regulate energy balance offers potentially fundamental and important new insights into the control of energy balance. This review describes the current state of our knowledge.