Multicenter Evaluation of Fixed-Wire PTCA Catheters with Modified Distal Tips: Initial and 2-Month Follow-Up Results

Lesions in the distal portion of coronary arteries are technological challenges with currently available percutaneous transluminal coronary angioplasty (PTCA) equipment. A study was performed at multiple centers to determine if new "fixed-wire" devices with a modified distal tip (a 2-cm flexible tip and 1-cm standard tip) would be useful in these situations. Three hundred twenty-three patients were included in the study, 75% male, mean age 63 ± 11 years. Four hundred ninety-three lesions were attempted; the overall success rate was 85%. Forty-six (14.2%) clinical complications occurred including: 5 deaths (1.1%); 2 nonfatal myocardial infarctions (0.6%); and 6 emergency coronary artery bypass grafting procedures (2.6%). A device malfunction was noted in 32 patients (9.9%), and included: 8 balloon ruptures or perforations (2.0%); 6 bent or damaged tips (1.9%); and 4 shaft/manifold leaks (1.2%). Two-month follow-up assessment for restenosis was done in 352 of 371 (95%) patients and at that time 89% were asymptomatic, had a negative functional test, or patent PTCA site by angiography. The new fixed-wire PTCA catheters with 1- and 2-cm flexible tips hold promise for dilating lesions in distal locations with an acceptable rate of complications. Additional investigation is needed to determine their role in the treatment of coronary artery disease with PTCA.     

Long-Term Protection against HIV-1 Infection Conferred by tat or rev Antisense RNA Was Affected by the Design of the Retroviral Vector

We have constructed a series of retroviral vectors in which the expression of antisense RNA targeted at the full length coding sequence of HIV-1 tat or rev was driven by three different promoters and in the context of double-copy or single-copy vectors. Jurkat cells transduced by these vectors were shown to express the expected tat or rev antisense RNA without alteration in cell proliferation or surface CD4 expression. After challenge with HIV, four patterns of protection were identified, with the degree of protection being determined primarily by the design of the expression system. In those patterns showing long-term complete protection, we could detect no HIV p24 in the culture supernatants or in the cells, and no HIV RNA or HIV proviral DNA (by PCR), during a 23-week follow-up. Experiments designed to rescue any live virus still formed in the culture after 20 weeks’ challenge demonstrated that, with some constructs, infectious virus could no longer be isolated, while with other constructs, only a low level of infectious virus was still being formed and providing a continuing virus challenge, although all other markers of infection remained undetectable. Our results demonstrated that antisense RNA expression driven by tRNA promoter in the context of a double-copy vector conferred better long-term protection against HIV infection compared to that driven by HIV LTR or MLV LTR promoters, and that the optimized vectors may be useful in developing a gene therapy against HIV-1 infection and AIDS.     

THE [LACTATE]/[PYRUVATE] RATIO AND ALCOHOL METABOLISM: EXPERIMENTS WITH NALOXONE IN FASTING NORMAL MALE VOLUNTEERS

Naloxone administration to fasting normal male volunteers reversesthe acute ethanol-induced increase in the blood [lactate]/[pyruvate]ratio, but fails to lower blood-ethanol concentration. The resultsare discussed in relation to factors affecting ethanol eliminationand the mechanism of antagonism of acute alcohol intoxicationby naloxone.     

Cardiac stimulus intensity and heartbeat detection: Effects of tilt-induced changes in stroke volume

The effects of variations in stroke volume on the intensity of cardiac stimuli was examined in a series of three experiments that empolyed classical psychophsical methods to assess heartbeat detection. Stroke volume was manipulated by passive body tilt and recorded using impedance cardiography while subjects performed heartbeat detection tasks. The postural manipulation generated little or no change in contractility or momentum but did produce substantial changes in stroke volume. However, this potential source of variation in cardiac stimulus magnitude did not influence either the precision of heartbeat detection or the temporal location of heartbeat sensations. It is concluded that the intensity dimension of the heartbeat stimulus is not determined by stroke volume.     

Sensitivity to mechanical stimuli and the role of general sensory and perceptual processes in heartbeat detection

Sensitivity to heartbeat sensations is commonly assessed using tasks that require individuals to judge the simultaneity of heartbeats and tones. In two experiments, we investigated the suitability of this paradigm for examining cardioception. In the first experiment, participants judged the simultaneity of near–threshold vibrations and suprathreshold tones. Precision in judging vibration–tone simultaneity was directly related to the detectability of the mechanical stimuli, thereby supporting use of the simultaneity paradigm to assess heartbeat detection. In the second experiment, we examined the influences of sensitivity to mechanical stimuli and the ability to make intermodality simultaneity judgments on the precision of heartbeat detection. We measured participants' vibrotactile thresholds, precision in judging light–tone simultaneity, and precision in judging heartbeat–tone simultaneity. The ability to judge the simultaneity of lights and tones accounted for 24.3% of the variance in precision of heartbeat detection, and mechanical sensitivity accounted for a further 8.5%.     

Effects of data limitations on heartbeat detection in the method of constant stimuli

In the method of constant stimuli applied to measuring heartbeat detection, subjects judge the simultaneity of heartbeats and exteroceptive comparison stimuli presented at various intervals after the R-wave (0, 100, 200, 300, 400, and 500 ms). Using versions of this procedure, investigators have found that between 20% (Yates, Jones, Marie, & Hogben, 1985) and 54% (Brener, Liu, & Ring, 1993) of subjects can detect heartbeat sensations. Whereas Yates et al. used a single comparison stimulus on each trial and Brener et al. used 10, the present study examined whether this disparity in heartbeat detection performance could be attributed to the number of comparison stimuli presented on each trial. In each of 360 trials, 30 subjects judged the simultaneity of heartbeat sensations and tones following 1, 5, or 10 comparison stimulus presentations. Significantly fewer subjects met the criterion for heartbeat detection with I tone presentation (13%) than with either 5 (43%) or 10 (47%) tone presentations. It is concluded that a single stimulus presentation imposes data limitations that result in underestimation of the accuracy of heartbeat detection. The presentation of at least 5 stimuli in each trial alleviates this limitation.     

Design of Animal Carcinogenicity Studies for Goodness-of-Fit of Multistage Models

Design of Animal Carrinogenkity Studies for Goodness-of-Fitof Multistage Models. PORTIER, C. J., AND HOEL, D. G. (1984).Fundam. Appl. Toxicol. 4, 949–959. The effect of bioassaydesign changes on the variability of risk estimates in the experimentaldose region is investigated. Three-dose designs with a controlgroup and other "usual" designs utilizing 200 animals are studiedin detail. Constraints on the minimum power of the linear trendtest in proportions are used to eliminate designs with unacceptablepower. An acceptable design region is compared to designs aimedat improving the low dose extrapolation. A group of designsacceptable for a range of objectives is proposed.     

Modification by Nickel of Instrumental Thermoregulatory Behavior in Rats1

Modification by Nickel of Instrumental Thermoregulatory Behaviorin Rats. WATANABE, C, WEISS, B., COX, C, AND ZIRIAX, J. (1990).Fundam. Appl. Toxicol. 14, 578–588. The effects of NiCl₂on the colonic temperature and thermoregulatory behavior (TRB)of rats were examined. TRB was evaluated in an instrumental(operant) setting in which rats were required to press a leverto obtain convectional heat (SEEK) or to avoid heat (ESCAPE).Orthogonal polynomial regression was used to describe the responsepatterns in both the SEEK and ESCAPE situations. Two milligramsper kilogram of Ni (ip) caused rapid, transient hypothermiaat an ambient temperature of 21°C. When given access toheat reinforcement, rats responded for heat at a lower rateimmediately after 2 or 5 mg/kg of Ni (up to 5–15 min)than after saline. Subsequently, response rates rose 30 minor more after Ni injection. A converse pattern was found withthe heat escape situation. These observations, confirmed bytwo contrasting procedures, indicate that the changes were thermoregulatoryin nature and cannot be explained by nonspecific sup-pressiveor excitatory effects of Ni. They further suggest that Ni-inducedhypothermia results from an altered body temperature set point.The subsequent reversal in behavior probably arises from a directaction of Ni on autonomic effector mechanisms. The origin andbiological significance of these findings require further investigation.Physical requirements and response topography are discussedas critical variables in the interpretation of experiments requiringsimilar responses under different ambient temperatures.     

Modification of Lead Distribution by Diethyldithiocarbamate

Modification of Lead Distribution by Diethyldithiocarbamate.WEISS, B., CORY-SLECHTA, D. A., AND COX, C. (1990). Fundam.Appl. Toxicol. 15, 791–799. Many reports indicate thatdithiocarbamates such as diethyldithiocarbamate (DDC), administeredin conjunction with exposure to various metals, can elevatethe brain levels of such metals at the same time that they promoteexcretion from other sites. To more clearly define the effectsof DDC on lead (Pb) distribution after prolonged exposure torelatively low levels, male Long-Evans rats were provided withdrinking water containing 0, 50, or 500 ppm Pb acetate. Duringthe 12-week experimental period, DDC was administered by ipinjection twice weekly in a dose of 100 mg/kg. Every 3–4weeks, urine and blood samples were taken 24 hr before and aftera scheduled DDC injection. DDC administration exerted no discernibleeffect on bone Pb levels and showed only an interaction withPb dose, but not independent effects on kidney levels. Bothliver and brain Pb levels attained much higher levels in theDDC-treated rats than in animals exposed to Pb alone. The sequentialmeasures of Pb in blood and urine and of -aminolevulinic acidrevealed complex patterns of change over time. One possibleexplanation, at least for the elevated levels of Pb in brain,is the lipophilic character of the Pb-DDC complex, which facilitatesentry into the central nervous system; it may also explain theelevated levels in liver. This property, common to many chelators,suggests their use in model systems to study the neurotoxicproperties of metals.