Pharmacologic Agents for Tobacco Dependence Treatment: 2011 Update

Tobacco use remains the most important worldwide cause of preventable death due mainly to cancer, cardiovascular disease, and chronic lung disease. If the current tobacco pandemic continues for another 20 years, the annual global tobacco-attributable mortality will exceed 8 million. In the US and many European countries, public health and tobacco control efforts combined with effective tobacco dependence treatment using combined behavioral treatment and pharmacotherapy have contributed significantly to steadily declining rates of tobacco use. Subsequent declines in cardiovascular disease and lung cancer death rates are directly attributable to these lower rates of tobacco use. Despite smoking bans, health warnings and effective pharmacotherapy, one in five Americans continue to smoke. Continued research in tobacco dependence treatment has resulted in newer and more effective pharmacotherapy. In this review, we provide a current update of pharmacologic agents for tobacco dependence treatment and a discussion of recent controversy regarding adverse effects of some these medications.     

Inhibition of dendritic cell maturation by malaria is dose dependent and does not require Plasmodium falciparum erythrocyte membrane protein 1

Red blood cells infected with Plasmodium falciparum (iRBCs) have been shown to modulate maturation of human monocyte-derived dendritic cells (DCs), interfering with their ability to activate T cells. Interaction between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and CD36 expressed by DCs is the proposed mechanism, but we show here that DC modulation does not require CD36 binding, PfEMP1, or contact between DCs and infected RBCs and depends on the iRBC dose. iRBCs expressing a PfEMP1 variant that binds chondroitin sulfate A (CSA) but not CD36 were phagocytosed, inhibited lipopolysaccharide (LPS)-induced phenotypic maturation and cytokine secretion, and abrogated the ability of DCs to stimulate allogeneic T-cell proliferation. CD36- and CSA-binding iRBCs showed comparable inhibition. P. falciparum lines rendered deficient in PfEMP1 expression by targeted gene knockout or knockdown also inhibited LPS-induced phenotypic maturation, and separation of DCs and iRBCs in transwells showed that inhibition was not contact dependent. Inhibition was observed at an iRBC:DC ratio of 100:1 but not at a ratio of 10:1. High doses of iRBCs were associated with apoptosis of DCs, which was not activation induced. Lower doses of iRBCs stimulated DC maturation sufficient to activate autologous T-cell proliferation. In conclusion, modulation of DC maturation by P. falciparum is dose dependent and does not require interaction between PfEMP1 and CD36. Inhibition and apoptosis of DCs by high-dose iRBCs may or may not be physiological. However, our observation that low-dose iRBCs initiate functional DC maturation warrants reevaluation and further investigation of DC interactions with blood-stage P. falciparum.     

Comparative genetic analysis of genomic DNA sequences of two human isolates of Tanapox virus

Members of the genus Yatapoxvirus, which include Tanapox virus (TPV) and Yaba monkey tumor virus, infect primates including humans. Two strains of TPV isolated 50 years apart from patients infected from the equatorial region of Africa have been sequenced. The original isolate from a human case in the Tana River Valley, Kenya, in 1957 (TPV-Kenya) and an isolate from an infected traveler in the Republic of Congo in 2004 (TPV-RoC). Although isolated 50 years apart the genomes were highly conserved. The genomes differed at only 35 of 144,565 nucleotide positions (99.98% identical). We predict that TPV-RoC encodes 155 ORFs, however a single transversion (at nucleotide 10241) in TPV-Kenya resulted in the coding capacity for two predicted ORFs (11.1L and 11.2L) in comparison to a single ORF (11L) in TPV-RoC. The genomes of TPV are A+T rich (73%) and 96% of the sequence encodes predicted ORFs. Comparative genomic analysis identified several features shared with other chordopoxviruses. A conserved sequence within the terminal inverted repeat region that is also present in the other members of the Yatapoxviruses as well as members of the Capripoxviruses, Swinepox virus and an unclassified Deerpox virus suggests the existence of a conserved near-terminal sequence secondary structure. Two previously unidentified gene families were annotated that are represented by ORF TPV28L, which matched homologues in certain other chordopoxviruses, and TPV42.5L, which is highly conserved among currently reported chordopoxvirus sequences.     

Myxoma virus M063R is a host range gene essential for virus replication in rabbit cells

The myxoma virus M063R gene product exhibits some sequence similarity to the poxvirus host range gene, C7L, of vaccinia virus. To address the potential host range function of the M063R gene product in rabbits, a deletion mutant of myxoma virus (vMyx63KO) was generated and characterized. vMyx63KO replicated to normal titre levels and produced foci that were indistinguishable from those produced by MV in vitro in a monkey kidney cell line (BGMK) that are permissive for wild type MV. However, vMyx63KO failed to replicate in all rabbit cell lines tested, including both primary and established cells lines, as well as cells derived from a variety of tissues. M063R expression was not required for myxoma virus binding, entry or early gene expression, whereas DNA replication was aborted and late genes were not expressed in vMyx63KO infected rabbit cells. Thus, the replication block for vMyx63KO in rabbit cells preceded the stage of late gene expression and DNA replication. Finally, an in vivo pathogenesis study indicated that vMyx63KO failed to cause any signs of classic myxomatosis in infected rabbits, but functioned as a non-replicating vaccine and provided protection for subsequent challenge by wild type myxoma virus. Altogether, these observations demonstrate that M063R plays a critical role in determining the host specificity of myxoma virus in rabbit cells.     

Evaluating the utility of national‐scale data to estimate the local risk of foot‐and‐mouth disease in endemic regions

Knowledge of the distribution of foot‐and‐mouth disease (FMD) is required if control programmes are to be successful. However, data on the seroprevalence and incidence of affected villages in developing countries with endemic disease are scarce. This is partly due to resource constraints as well as the logistical challenges of conducting intensive surveys and diagnostic testing in remote locations. In this study, we evaluated the performance of low resolution national‐scale data against high resolution local survey data to predict the FMD serological status of 168 villages in the Mandalay and Sagaing Regions of central Myanmar using both logistic regression and random forest modelling approaches. Blood samples for ELISA testing were collected from approximately 30 cattle per village in both the 6 to 18 month age range and in the over 18 month age range to distinguish between recent and historical exposure, respectively. The results of the animal level tests were aggregated to the village level to provide the outcome of interest (village positive or not positive for FMD), and three explanatory data sets were constructed: using only nationally available data, using only data collected by survey and using the combined survey and nationally available data. The true seroprevalence of FMD at the village level was 61% when only young animals were included, but increased to 87% when all animals were included. The best performing model was a logistic regression model using the combined national and survey data to predict recent infection in villages. However, this still incorrectly classified 40% of villages, which suggests that using national‐level data were not reliable enough for extrapolating seroprevalence in regions where conducting detailed surveys is impractical. Other methods for collected data on FMD such as the use of local reporting should be explored.     

Substance P-induced intestinal secretion of water and electrolytes.

This study was initiated to determine if raised (carcinoid) plasma concentrations of substance P induced jejunal secretion of water and electrolytes. Five dogs had isolated and cannulated 25 cm jejunal segments perfused at 2 ml/min with a neutral, isotonic perfusate. Saline, 1.0 ml, was infused intravenously during basal and recovery periods, while substance P was administered intravenously at 75 ng/kg/min (55 pmol/kg/min) during the four 15 minute experimental periods. Infusion increased plasma SP concentrations from basal (5.8 +/- 1.3 pg/ml) to a mean plateau level of 121.2 +/- 25.2 pg/ml (mean +/- SEM). During SP infusion, intestinal secretion of water, Na+, and Cl- were documented (H2O basal +102 +/- 60 to SP -275 +/- 60; microliter/min; Na+ basal +19.8 +/- 7.2 to SP -23.2 +/- 7.5 microEq/min; Cl- basal 21.7 +/- 7.5 to SP -16.5 +/- 5.6 microEq/min). Under basal conditions, there was minimal secretion of potassium (-0.264 +/- 0.282 microEq/min); during SP infusion, K+ flux was altered to significant secretion (-1.784 +/- 0.271 microEq/min). Serum concentrations of Na and Cl were unchanged during SP infusion, but serum potassium concentrations fell from 4.64 +/- 0.12 to 3.85 +/- 0.40 mEq/l. The data demonstrate that substance P at levels noted in the carcinoid syndrome induces significant jejunal secretion of water and electrolytes in the dog.     

Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy

Although the safety profiles of coronary stents eluting sirolimus or paclitaxel do not seem to differ from those of bare metal stents in the short-to-medium term, concern has arisen about the potential for late stent thromboses related to delayed endothelialisation of the stent struts. We report four cases of angiographically-confirmed stent thrombosis that occurred late after elective implantation of polymer-based paxlitaxel-eluting (343 and 442 days) or sirolimus-eluting (335 and 375 days) stents, and resulted in myocardial infarction. All cases arose soon after antiplatelet therapy was interrupted. If confirmed in systematic long-term follow-up studies, our findings have potentially serious clinical implications.     

Specific detection of Mycobacterium paratuberculosis DNA associated with granulomatous tissue in Crohn's disease.

The role of mycobacteria, specifically Mycobacterium paratuberculosis, in Crohn's disease has aroused considerable controversy for many years. Using the ultra sensitive polymerase chain reaction some studies have reported detection of M paratuberculosis DNA in as many as 65% of Crohn's disease patients but also in patients without disease. Other studies have been negative for both groups. We therefore designed a double blind control trial to investigate the presence of mycobacterial DNA in age, sex, and tissue matched paraffin wax embedded tissues from 31 Crohn's disease tissues, 20 diseased gut control tissues, and 10 ulcerative colitis tissues. The specimens were coded and analysed blind with three separate polymerase chain reactions (PCR) based on DNA sequences specific for M paratuberculosis (IS900), M avium (RFLP type A/1) (IS901), and the Mycobacterium genus (65 kDa gene, TB600). The number of granulomata and presence of acid fast bacilli in each Crohn's disease tissue was also investigated. The sensitivity of the system was determined using similarly prepared gut tissue from an animal infected with M paratuberculosis. Four of 31 Crohn's disease tissues and none of the 30 control and ulcerative colitis derived tissues amplified M paratuberculosis DNA. Crohn's disease tissues containing granulomata were significantly more likely to amplify M paratuberculosis specific DNA on PCR than the non-Crohn's disease tissues (p = 0.02). All the positive Crohn's disease tissues contained granulomata, and none contained acid fast bacilli. Equivalent numbers of Crohn's and non-Crohn's disease tissues amplified the region of the 65 kD gene on PCR for non-specific mycobacterial DNA (11/31 and 9/30 respectively). No sections produced an amplified product with the IS901 PCR. These results suggest that few Crohn's disease gut biopsy sections contain M paratuberculosis DNA in association with granulomata. The absence of such DNA in any control and ulcerative colitic tissue strengthens the case for it having a specific association, which may be pathogenic, with Crohn's disease in this minority of patients.     

Priapism following continuous thoracic epidural anaesthesia: emergency or a benign condition?

Priapism is a rare complication of epidural anaesthesia, and the pathophysiology is poorly understood. In general, 95% of all priapism episodes is ischemic because of decreased penile blood flow, and therefore requires immediate treatment. A case is reported of a 45‐year‐old male patient in which a clear relation is demonstrated between continuous thoracic epidural analgesia and priapism after transabdominal nephrectomy. The level of epidural anaesthesia supports the theory that the erection is a consequence of increased penile blood flow, thus a relatively harmless condition. However, confirmation by serial cavernous blood gas analysis or colour duplex ultrasonography is mandatory. Until this hypothesis is confirmed, termination of epidural infusion is advised as a primary treatment.