Immune targeting of PD-1(hi) expressing cells during and after antiretroviral therapy in SIV-infected rhesus macaques.

High-level T cell expression of PD-1 during SIV infection is correlated with impaired proliferation and function. We evaluated the phenotype and distribution of T cells and Tregs during antiretroviral therapy plus PD-1 modulation (using a B7-DC-Ig fusion protein) and post-ART. Chronically SIV-infected rhesus macaques received: 11 weeks of ART (Group A); 11 weeks of ART plus B7-DC-Ig (Group B); 11 weeks of ART plus B7-DC-Ig, then 12 weeks of B7-DC-Ig alone (Group C). Continuous B7-DC-Ig treatment (Group C) decreased rebound viremia post-ART compared to pre-ART levels, associated with decreased PD-1(hi) expressing T cells and Tregs in PBMCs, and PD-1(hi) Tregs in lymph nodes. It transiently decreased expression of Ki67 and α4ß7 in PBMC CD4(+) and CD8(+) Tregs for up to 8 weeks post-ART and maintained Ag-specific T-cell responses at low levels. Continued immune modulation targeting PD-1(hi) cells during and post-ART helps maintain lower viremia, keeps a favorable T cell/Treg repertoire and modulates antigen-specific responses.

Cerebral angiographic findings in thromboangiitis obliterans.

Transient ischemic attacks (TIAs) or ischemic stroke may complicate thromboangiitis obliterans (TAO). However, there has been debate regarding the mechanism of ischemic stroke in TAO. We report the case of a patient with TAO who developed repeated TIAs. An angiogram showed multiple alternative areas of arterial occlusions in the distal segments of both middle cerebral arteries. Extensive collateral vessels around the occluded segment were also observed, which resembled the "tree root" or "corkscrew" vessels described in the peripheral arteries in TAO. Our patient illustrates that cerebral manifestations of TAO may occur with vascular changes that are identical with those encountered in the limb arteries in TAO.

A laboratory study of hydromorphone and cyclazocine on smoking behavior in residential polydrug users.

The effects of cyclazocine and hydromorphone on spontaneous and laboratory cigarette smoking were compared in a double-blind, placebo-controlled, crossover study. Participants (seven men, one woman) received oral doses of placebo, cyclazocine (0.2, 0.4, and 0.8 mg) and hydromorphone (5 and 15 mg) in a randomized order on experimental days. Spontaneous smoking was recorded during two intervals on the experimental days: a 3-h period 5-8 h after drug administration (Interval 1), and the rest of the day (Interval 2). Measures of smoking topography and subjective and physiologic effects of a single cigarette were obtained on the experimental days. Neither hydromorphone nor cyclazocine significantly changed spontaneous smoking when compared to the placebo condition; however, compared to hydromorphone (5 mg), cyclazocine (0.4 and 0.8 mg) decreased spontaneous smoking during Interval 1. Hydromorphone (5 and 15 mg) and cyclazocine (0.4 and 0.8 mg) diminished smoking-induced increases in heart rate. Compared to the placebo condition, cyclazocine (0.2 and 0.4 mg) reduced exhaled carbon monoxide (CO) boost, a measure of smoke exposure. Further studies of the effects of kappa opioid agonists on smoking behavior may lead to a better understanding of the role of opiates in smoking behavior.

Quantitative comparisons between a nicotine delivery device (Eclipse) and conventional cigarette smoking.

In 1997, R. J. Reynolds introduced Eclipse, a nicotine delivery device (NDD) purported to deliver lower levels of smoke than conventional cigarettes. This NDD uses a carbon fuel element to vaporize the nicotine in the rod; the user then inhales the nicotine vapor. In the present study, the effects of this NDD on smoking topography; substance delivery factors; and physiological, subjective, and biochemical markers of smoking were compared with commercial cigarettes (referred to as Own Brand). All smoking occurred ad lib with the cigarette or NDD hand-held (conventional) or held in a topography mouthpiece. A total of 10 adults (seven males) smoked on five occasions: NDD conventional, NDD topography, Own Brand conventional, Own Brand topography (twice). Sessions were separated by at least 24 hr. Measures were taken before and 2, 5, 10, 15, 30, and 60 min after smoking. The NDD took longer to smoke (366 s vs. 292 s), required more puffs (14.8 vs. 10.8), and caused a larger increase in exhaled carbon monoxide (CO; 7.3 ppm vs. 4.2 ppm) than Own Brand. However, venous plasma nicotine boost was significantly larger 2 min after smoking Own Brand as compared with the NDD (16.4 ng/ml vs. 10.7 ng/ml). Puff volume (90.7 ml vs. 63.0 ml) and puff velocity (81.6 ml/s vs. 58.2 ml/s) were greater after the NDD than Own Brand, whereas inter-puff interval and puff duration were similar. Subjects rated the NDD as less satisfying (5.2 vs. 9.8), less rewarding (9.5 vs. 14.3), and more aversive (5.0 vs. 3.1) than their own brand. The results of this study indicate that this NDD exposes the user to significant quantities of nicotine, CO, and possibly other harmful components of tobacco smoke. The findings further validate the use of a topography device as an effective instrument to quantify smoke exposure.

Smoking topography: reliability and validity in dependent smokers.

Data from two studies were analyzed to determine whether smoking through the mouthpiece of a topography unit yields consistent measures over time and to verify that smoking through a mouthpiece results in a similar degree of smoke exposure as conventional smoking. In both studies, subjects smoked their usual brand of cigarette ad libitum. In study A, subjects (n=7) smoked through a mouthpiece on 4 separate experimental days. In study B, subjects (n=10) smoked on 2 separate days: Once conventionally and once through a mouthpiece. In both studies, exhaled carbon monoxide (CO) and physiological effects (heart rate and blood pressure) were measured before and after smoking. In study B, plasma nicotine concentrations also were measured. In study A, puff volume, puff duration, interpuff interval, and maximum puff velocity averaged 30.8 ml,.9 s, 19.9 s, and 44.6 ml/s, respectively. Intraclass correlation coefficients computed for puff volume (0.66), puff duration (0.75), and maximum puff velocity (0.68) indicated that these measures showed good reliability. In study B, smoking through the mouthpiece yielded similar topographical (time to smoke and number of puffs per cigarette) measures as conventional smoking. Also similar were changes in biochemical values: Plasma nicotine (18.5 ng/ml vs. 25.5 ng/ml), exhaled CO (4.6 ppm vs. 5.1 ppm), and heart rate (8.6 beats/min vs. 7.4 beats/min) for conventional and topography mouthpiece smoking conditions, respectively. Topography measures did not differ significantly between the two studies. Overall, the data from these two small-sample studies suggest that smoking topography provides a valid and reliable index of conventional smoking and an indirect measure of smoke exposure.

Clove cigarette smoking: biochemical, physiological, and subjective effects.

Alternative tobacco products such as clove (kreteks) and bidi cigarettes have become increasingly popular among US smokers. The nicotine content of a popular clove cigarette (Djarum Special) filler averaged 7.4 mg; conventional cigarettes contained 13.0 mg. However, smoke yields from standardized machine-smoking analysis indicated it delivered more nicotine, carbon monoxide (CO), and tar than conventional cigarettes. In a clinical study, nicotine delivery, physiologic, and subjective effects of the clove cigarette were compared to their own brand of cigarette in 10 adult smokers (7 males). Average time to smoke the clove cigarette (549 s) and number of puffs (15.1) were significantly greater than own brand (314 s and 9.4 puffs). Increases in venous plasma nicotine and exhaled CO after smoking the clove cigarette (17.4 ng/ml; 6 ppm) were similar to those after own brand (17.6 ng/ml; 4.5 ppm). Maximal changes in heart rate (HR), systolic, and diastolic blood pressures (BP) did not differ significantly between the clove and own brand of cigarette. Compared to their own brand of cigarette, the clove cigarette was rated as better tasting and being distinctly different. Our findings indicate that clove cigarettes deliver significant quantities of nicotine, CO, and presumably other toxic components of tobacco smoke. Taste satisfaction, aromatic odor, and novelty may contribute to their appeal to young smokers.

Nicotine delivery from smoking bidis and an additive-free cigarette.

The present study was conducted to determine whether smoking bidis, an additive-free cigarette, and conventional cigarettes caused similar biochemical, physiological and subjective effects. This was an open-label, within-subject design. In each session, subjects (n = 10) smoked a single cigarette: an unfiltered Natural American Spirit, an unfiltered Irie bidi, an unfiltered Sher bidi, or one of the participant's own brand. The presentation of the cigarettes was randomized. Before and up to 1 h after smoking, biochemical markers [plasma nicotine levels and exhaled carbon monoxide (CO)] and physiological effects of nicotine (heart rate and blood pressure) were measured. After smoking, subjects completed two standardized tests of cigarette liking and cigarette sensations. American Spirit (32.1 ng/ml) and Irie bidi (26.0 ng/ml) cigarettes increased plasma nicotine more than the participant's own brand (18.5 ng/ml). Subjects smoked longer and took more puffs to consume the American Spirit (452.8 s, 14 puffs) and Sher bidi (354.4 s, 14 puffs) than the participant's own brand (297.4 s, 10 puffs). In spite of differences in nicotine delivery, participants rated all cigarettes as similar in nicotine content. Overall, the results indicate that bidis and the additive-free cigarette delivered nicotine, CO and (presumably) other toxic components of tobacco smoke in equal or greater amounts than conventional cigarettes. These results do not support an emerging belief that bidi cigarettes are safer than conventional brands.