Characterization of the complete mitochondrial genomes of two Critically Endangered wedgefishes: Rhynchobatus djiddensis and Rhynchobatus australiae.

We present the complete mitochondrial genomes of the Critically Endangered whitespotted wedgefish, Rhynchobatus djiddensis (Forsskål, 1775), and bottlenose wedgefish, Rhynchobatus australiae (Whitley, 1939), with the R. djiddensis mitogenome documented for the first time. The genomes for R. djiddensis and R. australiae are 16,799 and 16,805 bp in length, respectively. Both comprise 13 protein-coding regions, 22 tRNA genes, two rRNA genes, and a non-coding control region. All protein-coding regions consistently start with the ATG start codon; however, the alternative start codon GTG is observed at the start of the COX1 gene. NADH2, COX2, and NADH4 have incomplete stop codons: T or TA, and tRNALeu and tRNASer , have atypical codons: UAA, UGA, GCU, and UAG. The phylogenetic analysis places R. djiddensis and R. australiae within the Rhynchobatus genus, separate from other families in the order Rhinopristiformes. We also highlight the most variable gene regions to expedite future primer design, of which NADH2 was the most variable (4.5%) when taking gene length into account. These molecular resources could promote the taxonomic resolution of the whitespotted wedgefish species complex and aid in the genetic characterization of populations of these and related species.

Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention.

BACKGROUND: One of the most unusual causes of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease, is ticlopidine hydrochloride, an antiplatelet agent used to prevent strokes in high-risk populations or following coronary artery stent placement. Recently, Hoffman-LaRoche Pharmaceuticals, following reports of 20 deaths from ticlopidine-associated TTP, updated the information about the hematologic adverse effects of the drug. OBJECTIVES: To review our recent findings on ticlopidine-associated hematologic toxic effects, which served as the impetus for the revised warnings, and to discuss the implications of these findings. METHODS: Data were obtained from the Food and Drug Administration's MedWatch program, published phase 3 clinical trials and case reports, hematologists, and plasmapheresis centers. RESULTS: No cases of TTP have been reported in phase 3 ticlopidine trials. In contrast, postmarketing surveillance has identified serious adverse drug reactions to ticlopidine, resulting in 259 deaths, with TTP accounting for 40 of these deaths. Detailed information was available on 98 cases of ticlopidine-associated TTP. Compared with 42 patients in the coronary artery stent setting, 56 patients with ticlopidine-associated TTP in the stroke prevention setting were more likely to be women (62.5% vs 28.6%; P = .01). Before the onset of TTP in patients receiving stroke prevention therapy and patients with stent placement, ticlopidine had been used for less than 2 weeks in 5.4% and 2.4%, between 2 and 3 weeks in 17.9% and 21.4%, between 3 and 4 weeks in 30.4% and 38.1%, and between 4 and 12 weeks in 46.4% and 38.1%, respectively. Death occurred in almost 60% of all patients not receiving plasmapheresis compared with 21.9% of patients receiving plasmapheresis for stroke prevention and 14.3% of patients receiving plasmapheresis in the stent setting. CONCLUSIONS: Use of ticlopidine requires frequent physician visits and laboratory tests for at least 3 months in the stroke prevention setting, while, with short-term use in the coronary artery stent setting, adverse events are less likely to occur. These factors, as well as competition from clopidogrel bisulfate, a new antiplatelet agent, potentially limit the feasibility of ticlopidine as a stroke prevention agent, while having less impact on its use following coronary artery stent placement.

The effects of a cumulative alcohol dosing procedure on laboratory aggression in women and men.

OBJECTIVE: This study directly compared the effects of cumulative alcohol dosing procedure on aggression in both women and men. METHOD: Thirteen women and 13 men consumed three beverages 1 hour apart. There were two experimental conditions: (1) a placebo day, when subjects consumed three 240 ml beverages, each containing only 1 ml of alcohol; and (2) an alcohol day, when subjects consumed three 240 ml beverages, each containing 0.35 g/kg of 95% alcohol. Alcohol doses for women were reduced by 8%. Prior to beverage consumption, and periodically after consumption, subjects participated in 25-minute laboratory testing sessions designed to measure aggression. In this paradigm, subjects could earn points by responding on a button, or aggress toward a fictitious opponent who ostensibly subtracted earnings from them. RESULTS: Both women and men showed an increase in aggressive responding after drinking alcohol but not placebo. As a group the greatest increases were observed after consuming the second alcohol drink (BAC = 0.08%). Aggressive responding, however, remained elevated for several hours after alcohol consumption. A post hoc analysis of the data indicated that subjects with high aggression levels under placebo conditions showed the greatest increases in aggression under alcohol conditions. CONCLUSIONS: These results indicate that at least under these conditions, alcohol does increase aggression in both women and men. The aggression-increasing effects of alcohol appear to be long-lasting and specific to individuals with the higher aggressive tendencies while sober.

The effects of alcohol on the aggressive responding of women.

OBJECTIVE: The purpose of this study was to determine the effects of a range of alcohol doses on the aggressive responding of women. METHOD: The Point Subtraction Aggression Paradigm was used. It has two response options available to the subject: (1) point-maintained responding, emitting 100 responses on one button earned the subject 10 cents; and (2) aggressive responding, emitting 10 responses on an alternative button ostensibly subtracted 10 cents from another person also working to earn money. Aggressive responses were engendered by a random-time schedule of point loss (every 6 sec. to 120 sec.), and instructions attributed these point losses to button presses made by another fictitious subject. Ten female subjects participated, and each experienced placebos and three alcohol doses, 0.25, 0.50, and 1.00 g of 95% alcohol per kg of body weight. RESULTS: The most important finding was that the 1.00 g/kg alcohol dose produced statistically significant increases in aggressive responding relative to placebo. There was, however, a small subset of individuals whose greatest increase in aggressive responding occurred after consuming the 0.25 g/kg alcohol dose. Rates of point-maintained responding were unaffected by the 0.25 and 0.50 g/kg alcohol doses and slightly suppressed by the 1.00 g/kg alcohol dose. CONCLUSIONS: These results are important because the handful of previous studies with women have provided little evidence for increased aggression after alcohol consumption in women. These observed inconsistencies between this study and previous studies may be attributed to procedural differences, which have varied considerably across studies.

Effects of nicotine on cooperative responding among abstinent male smokers.

The effects of nicotine on human cooperative responding in abstinent male smokers were examined. During episodes occurring at random times through a session, concurrently available cooperative and independent responses were maintained by points exchangeable for money. Cooperative responses simultaneously added points to counters marked "Your Earnings" and "Other's Earnings" only if the subject's and another person's responses ostensibly coincided. Independent responses added points only to the counter marked "Your Earnings". After the first daily session abstinent subjects smoked ad libitum, received either 0, 2 or 4mg nicotine gum or abstained from smoking. Increases from this first session in time allocated to the cooperative response option, proportion of cooperative responses and cooperative response rate were significantly greater following ad libitum smoking or acute administration of 4mg nicotine. No effects of nicotine abstinence were observed on independent response rate. These results suggest effects on sociability may maintain nicotine use and increase relapse risk in abstinent smokers.

Effects of ethanol on human free-operant cooperative responding.

The effects of ethanol (0.5, 0.75 and 1.00 g/kg) on human cooperative behavior were examined. Ethanol or placebo was administered 30 min before the second of five trials. During the first of two alternating schedule components, button presses were maintained by a random interval (RI) 60-s schedule of point additions to a counter marked 'Your Earnings'. During the second, Choice, component a concurrent RI 60-s schedule maintained button presses on two manipulanda. Subjects randomly assigned to the social group were instructed that they were paired with another person and could earn points working with or independently of this person. Working together, the cooperative response, simultaneously produced points on counters marked 'Other's Earnings' and 'Your Earnings'. Working independently, the independent response produced points only on the counter marked 'Your Earnings'. The other person was fictitious. The instructions for the non-social group did not mention another subject and the counter marked 'Other's Earnings' was not visible but schedule contingencies were identical to those for the social instruction group. For the social instructions group, 1.00 g/kg ethanol increased the proportion of cooperative responses and time allocated the cooperative option. For the non-social instruction group, time allocated to the topographically identical but non-social equivalent of the cooperative response decreased at the same dose. No significant between-group effects were observed following acute administration of 0.50 and 0.75 g/kg ethanol. These results suggest that the instructions established a functionally distinct social, cooperative, response which was differentially affected by ethanol.

Acute and chronic alcohol tolerance in humans: effects of dose and consecutive days of exposure.

Male social drinkers received doses of either 0.75 or 1.0 g/kg body weight of alcohol over 5 consecutive days. The beverage was divided into three equal drinks, and subjects performed an eye-hand coordination motor task after each drink. The breath alcohol concentration (BAC) was assessed at each performance measurement period. Performance was also assessed when the BAC level on the descending limb of the BAC curve was similar to each of the three BAC measurements on the ascending curve. Each group developed chronic tolerance (comparing the daily postalcohol performance with the daily prealcohol performance) by the 4th day of exposure. The development of a degree of acute tolerance (assessed by comparing the performance on the ascending and descending limbs of the BAC curve) was not observed consistently in the 1.0 g/kg dose group, but was seen in more than half of the subjects in the 0.75 g/kg dose group by the 4th and 5th day of exposure.

Differential effects of triazolam and ethanol on awareness, memory, and psychomotor performance.

Eight normal, healthy, male volunteers each received four triazolam doses (0, 2, 4, and 8 micrograms/kg) and four ethanol doses (0, 0.25, 0.5 and 1.0 g/kg) in a double-blind, double-dummy experiment in which within-subject dose sequence was determined by a balanced Latin square design. Triazolam and ethanol produced dose-related and time-related effects on subject ratings of mood and perceived drug effects and objective measures of memory and psychomotor performance. Dose-response curves for the two drugs were not parallel, and therefore, comparisons of the two drugs were based upon comparisons of the high dose of each drug. Although the two high-dose conditions generally were not different from one another, there were differences in their relative effect sizes, which were important. The high dose of each drug produced comparable degrees of impairment on two different psychomotor tasks. Triazolam, but not ethanol, produced significant impairment on two different memory tasks. The relative effects of each drug on subject ratings of mood and perceived drug effects varied across different subject-rated measures. Only ethanol significantly increased subject ratings of alcohol strength and feeling drunk. In comparison to ethanol, triazolam tended to produce less-pronounced subject ratings of drug effect magnitude, drug liking, and estimated performance impairment. However, less-pronounced subjective effects of triazolam were not universally observed on all subject ratings. Triazolam produced greater effects on several sedative symptoms and produced comparable effects on several mood factor scales.

Human avoidance responding with added point loss: effects of tobacco and abstinence.

Male smokers responded on a free-operant avoidance schedule with a response--point loss interval of 20 seconds and a point loss--point loss interval of 5 seconds. Unavoidable point losses were presented at variable times during the sessions. In Experiment 1 subjects were exposed to three tobacco abstinence conditions and an ad lib smoking condition. The conditions were nicotine gum, placebo gum, and no gum or cigarettes. In Experiment 2 subjects were administered tobacco smoke which delivered varying doses of nicotine. The smoke was administered by the spirometric method. Responding in each experiment was assessed during the session and also for 10 seconds following each of the unavoidable point losses. Results for Experiment 1 showed that the effect of smoke/nicotine abstinence on overall responding and for the interval following point losses differed across subjects. Results for Experiment 2 showed very little effect of acute nicotine dosing on the overall responding and varying effects on the responding during the interval following unavoidable point losses. These results are contrasted with previous research which has investigated tobacco smoke/nicotine abstinence and acute tobacco smoke dosing in experimental situations which were established as social via instructions.

Safety and predictive value of exercise stress testing within three days after percutaneous transluminal coronary angioplasty.

The safety and efficacy of exercise stress testing within three days of successful coronary angioplasty was evaluated in 226 patients with coronary artery disease; 137 patients had single-vessel disease (SVD) and 89 had multi-vessel disease (MVD). Comparisons were made between patients with SVD and MVD and between patients whose vessels restenosed and those whose vessels remained patent. The post-angioplasty exercise test was positive in 48% of SVD and 49% of MVD patients. However, a positive result did not predict future restenosis. There was a significantly [p = 0.004] higher proportion of patients in the MVD group, compared with the SVD group, who exhibited greater than or equal to 2mm ST-depression, but again this was not indicative of restenosis. No complications as a direct result of having an early exercise test occurred. Exercise stress testing proved safe and was effective in demonstrating relief from angina in most patients early after coronary angioplasty. It did not, however, predict restenosis.

Effects of spirometric administration of tobacco smoke containing varying amounts of nicotine on physiological measures and subject ratings.

A previously developed spirometric methodology of tobacco smoke administration was evaluated by determining the effects of varying nicotine delivery on various physiological and subjective measures. Eight male tobacco smoking subjects were administered 60cc volumes of tobacco smoke drawn from University of Kentucky research cigarettes, or air. Subjects were exposed to four bouts of smoke administration conducted over an 8h day. Each smoking bout was separated by 2h and involved 20 smoke administrations at the rate of one every 30sec. Each smoke administration consisted of 60cc of air or 60cc drawn from 0.3, 1.2 or 2.7mg nicotine yield cigarettes, followed by 1 liter of air which forced the smoke or air deep into the lungs. Carbon monoxide (CO), blood pressure, and heart rate were measured before and after each smoking bout, and subject ratings of smoke effects were completed after each smoking bout. In a separate study, blood samples were collected on two occasions before and after administration of the two highest nicotine yield cigarettes to determine changes in nicotine plasma levels. Data indicated that the spirometric method produced: (1) similar CO boosts across nicotine yields, and (2) changes in heart rate, blood pressure, subject ratings and plasma nicotine levels which were directly related to the nicotine yield of cigarettes.

Effects of spirometric administration of tobacco smoke containing varying amounts of nicotine on human punished and non-punished operant responding.

Lever pulling of male tobacco smokers was maintained by a variable interval 20sec schedule (VI 20) of point presentation. In experiment 1 the rate of lever pulling was suppressed by a punishment contingency which stipulated that lever pulls would produce point subtractions on a variable ratio 30 schedule (VR 30). In experiment 2 the punishment contingency was omitted. Each subject participated in eight sessions each day (Mon. through Fri.). Each block of two 20-min sessions was separated by a period during which tobacco smoke containing varying amounts of nicotine was administered by the spirometry method, which ensured a constant puff volume and deep inhalation. The tobacco smoke conditions were: (1) 0.3mg nicotine yield cigarettes (baseline condition), (2) 1.2mg nicotine yield cigarettes, (3) 2.7mg nicotine yield cigarettes and (4) a condition in which room-temperature air was administered. Subjects remained at baseline conditions until responding stabilized and were then exposed to higher nicotine yield smoke or air for an entire day. Subjects were then returned to baseline conditions before administration of higher nicotine yield smoke or air. In experiment 1 (punishment contingency) lever pulling decreased as a function of increasing nicotine content in tobacco smoke. This effect upon responding was similar to the effects of CNS stimulants on punished responding in non-human subjects. In experiment 2 (no punishment contingency), no consistent effect of tobacco smoke or non-punished responding was observed.

Human aggressive responding during acute tobacco abstinence: effects of nicotine and placebo gum.

Aggressive and point maintained operant responding of heavy nicotine dependent male tobacco smokers were measured during five 25-min sessions conducted over an 8-h period. Responding under three tobacco abstinence conditions was compared to responding during a baseline condition of ad libitum smoking of the subject's preferred brand of cigarettes. The three tobacco abstinence conditions were: (1) placebo gum, (2) nicotine gum or (3) no gum. Under placebo and nicotine gum conditions, subjects were given two pieces of placebo or 2 mg nicotine gum to chew for 30 min prior to each session. Expired air carbon monoxide (CO) levels were measured at the end of each session to monitor smoking under baseline conditions and compliance with nonsmoking requirements under abstinence conditions. Aggressive responding was increased in no gum and placebo gum conditions, with the highest frequency of aggressive responding occurring under no-gum conditions. Aggressive responding during nicotine gum conditions did not differ from baseline ad libitum tobacco smoking. Point maintained responding was either not affected or decreased under placebo and no-gum conditions. These results provided objective data consistent with clinical reports of increased irritability among dependent tobacco smokers during acute tobacco abstinence.

Benzodiazepine-induced impairment of matching-to-sample performance in humans.

The effects of benzodiazepines on a visual pattern matching-to-sample (MTS) task were examined in nine healthy male volunteers. The MTS task employed randomly generated checkerboard-like stimuli presented on a video display. The sample and two comparison stimuli were simultaneously presented. Nonmatching comparison stimuli were randomly generated to be 3.125, 6.25, 12.5, 25.0, 37.5, or 50.0 percent different from the sample. Subjects responded on left or right button manipulanda to identify the matching comparison stimulus. The nonmatching stimulus condition was maintained constant for a 60-sec component and the percentage difference of the nonmatching stimuli was systematically varied across multiple components. The effects of triazolam (2.25-9.0 micrograms/kg) and lorazepam (7.5-45 micrograms/kg) were examined in a within-subjects, double-blind, placebo-controlled study. Under placebo conditions, response rates and accuracy were a positive function of the nonmatching stimulus discriminability. Triazolam produced dose-related decreases in response rate at nonmatching stimulus conditions greater than or equal to 25%. Only the 9.0 micrograms/kg dose of triazolam decreased accuracy and this occurred across all nonmatching stimulus conditions. Lorazepam effects were qualitatively similar but less robust than those of triazolam.

Effects of nicotine gum and tobacco smoking on human avoidance responding.

Three male smokers were exposed to a free-operant avoidance schedule in which a lever press postponed a point subtraction on a counter for twenty seconds. Subtractions were scheduled to occur every 5 seconds in the absence of lever presses. Prior to each experimental session the subject was administered varying amounts of nicotine via either chewing nicotine gum or smoking low or high nicotine yield cigarettes. Smoking cigarettes resulted in increased avoidance responding relative to baseline nonsmoking rates. Chewing nicotine gum did not produce changes in avoidance responding, however, nicotine blood levels produced by chewing nicotine gum were similar to levels produced by smoking cigarettes. The differential responding determined by route of nicotine administration is discussed and the implications for use of nicotine gum as an adjunct for smoking cessation is addressed.