Proportion Of Baseline Research Articles

Predictors of postoperative infectious complications after partial nephrectomy: Analysis at a referral institution

ObjectiveInfectious complications after partial nephrectomy (PN) remain a significant concern. We aimed to analyze predictive factors of postoperative infectious complications (PICs) occurring after PN. MethodsData on patients undergoing PN for renal masses between January 2018 and May 2023 were retrieved from prospectively maintained institutional database and retrospectively analyzed. Patients were stratified into two groups based on the occurrence of PICs during admission for PN. A PIC was defined by clinical and/or imaging findings of an infectious process plus microbial isolation upon culture examination. Multivariable logistic regression analysis after adjusting for potential confounders evaluated predictors of PIC. ResultsSix-hundred and twenty-eight patients underwent PN; rough incidence of PICs was 11.6%, with median time to PIC onset of 1 (interquartile range 0–3) day. Compared to patients without PIC events, the PIC group showed a significantly higher proportion of open surgeries (53.6% vs. 20.4%, p<0.001), hemoglobin drop vs. baseline (−2.6 g/dL vs. −1.7 g/dL, p=0.001), bleeding events (23.2% vs. 10.1%, p<0.01), postoperative transfusion (5% vs. 18.8%, p<0.001), and urinary leakage (4.1% vs. 0.2%, p=0.01). At multivariable logistic regression, the odds of experiencing a PIC were statistically significantly lower after minimally-invasive surgery (odds ratio 0.32, 95% confidence interval 0.17–0.59), and higher for patients who received transfusion (odds ratio 2.64, 95% confidence interval 1.38–5.05). ConclusionsWe underlined factors that impact the occurrence of PICs and, consequently, duration of hospitalization following PN. By addressing these predictors, clinicians can promote enhanced patient recovery.

Cerebral perfusion and metabolism with mild hypercapnia vs. normocapnia in a porcine post cardiac arrest model with and without targeted temperature management

AimTo determine whether targeting mild hypercapnia (PaCO2 7 kPa) would yield improved cerebral blood flow and metabolism compared to normocapnia (PaCO2 5 kPa) with and without targeted temperature management to 33 °C (TTM33) in a porcine post-cardiac arrest model. Methods39 pigs were resuscitated after 10 minutes of cardiac arrest using cardiopulmonary bypass and randomised to TTM33 or no-TTM, and hypercapnia or normocapnia. TTM33 was managed with intravasal cooling. Animals were stabilized for 30 minutes followed by a two-hour intervention period. Hemodynamic parameters were measured continuously, and neuromonitoring included intracranial pressure (ICP), pressure reactivity index, cerebral blood flow, brain-tissue pCO2 and microdialysis. Measurements are reported as proportion of baseline, and areas under the curve during the 120 min intervention period were compared. ResultsHypercapnia increased cerebral flow in both TTM33 and no-TTM groups, but also increased ICP (199% vs. 183% of baseline, p = 0.018) and reduced cerebral perfusion pressure (70% vs. 84% of baseline, p < 0.001) in no-TTM animals. Cerebral lactate (196% vs. 297% of baseline, p < 0.001), pyruvate (118% vs. 152% of baseline, p < 0.001), glycerol and lactate/pyruvate ratios were lower with hypercapnia in the TTM33 group, but only pyruvate (133% vs. 150% of baseline, p = 0.002) was lower with hypercapnia among no-TTM animals. ConclusionIn this porcine post-arrest model, hypercapnia led to increased cerebral flow both with and without hypothermia, but also increased ICP and reduced cerebral perfusion pressure in no-TTM animals. The effects of hypercapnia were different with and without TTM.(Institutional protocol number: FOTS, id 14931)

Intravitreal Therapy for Uveitic Macular Edema—Ranibizumab versus Methotrexate versus the Dexamethasone Implant: The MERIT Trial Results

To evaluate the effectiveness of 3 different intravitreal treatments for persistent or recurrent uveitic macular edema (ME): dexamethasone implant, methotrexate, and ranibizumab. Single-masked, randomized controlled clinical trial. Patients with minimally active or inactive uveitis and persistent or recurrent uveitic ME in one or both eyes. Patients at 33 centers were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME received the same treatment in both eyes. The primary outcome, measured at 12 weeks, was reduction in central subfield thickness (CST) expressed as a proportion of baseline (CST per CST at baseline) assessed with spectral-domain OCT by readers masked to treatment assignment. Secondary outcomes included improvement and resolution of ME, change in best-corrected visual acuity (BCVA), and elevations in intraocular pressure (IOP). One hundred ninety-four participants (225 eligible eyes) were randomized to dexamethasone (n= 65 participants and 77 eyes), methotrexate (n= 65 participants and 79 eyes), or ranibizumab (n= 64 participants and 69 eyes). All received at least 1 injection of the assigned treatment. At the 12-week primary outcome point, each group showed significant reductions in CST relative to baseline: 35%, 11%, and 22% for dexamethasone, methotrexate, and ranibizumab, respectively. Reduction of ME was significantly greater in the dexamethasone group than for either methotrexate (P < 0.01) or ranibizumab (P= 0.018). Only the dexamethasone group showed a statistically significant improvement in BCVA during follow-up (4.86 letters; P < 0.001). Elevations of IOP by 10 mmHg, to 24 mmHg or more, or both were more common in the dexamethasone group; IOP spikes to 30 mmHg or more were uncommon overall and were not significantly different among groups. Reductions in BCVA of 15 letters or more were more common in the methotrexate group and typically were attributable to persistent ME. At 12 weeks, in eyes with minimally active or inactive uveitis, dexamethasone was significantly better at treating persistent or recurrent ME than methotrexate or ranibizumab. Risk of IOP elevation was greater with dexamethasone, but elevations to levels of 30 mmHg or more were infrequent. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Five-year follow-up study of a population-based prospective cohort of men with low-risk prostate cancer: the treatment options in prostate cancer study (TOPCS): study protocol

IntroductionActive surveillance (AS) is recommended for men with low-risk prostate cancer (LRPC) to reduce overtreatment and to maintain patients’ quality of life (QOL). However, whether African American (AA) men can...

Periocular Triamcinolone vs. Intravitreal Triamcinolone vs. Intravitreal Dexamethasone Implant for the Treatment of Uveitic Macular Edema: The PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT) Trial

To evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI). Multicenter, randomized clinical trial. Patients with uveitic ME. Patients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes. The primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks. All treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65-0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56-0.86) had larger reductions in CST than PTA (P < 0.0001). Intravitreal dexamethasone implant was noninferior to ITA at 8 weeks (PropBL IDI/PropBL ITA, HR, 0.88; 99.87% CI, 0.71-1.08). Both ITA and IDI treatments also were superior to PTA treatment in improving and resolving uveitic ME. All treatment groups demonstrated BCVA improvement throughout follow-up. Both ITA and IDI groups had improvements in BCVA that was 5 letters greater than in the PTA group at 8 weeks (P < 0.004). The risk of having IOP ≥24 mmHg was higher in the intravitreal treatment groups compared with the periocular group (HR, 1.83; 95% CI, 0.91-3.65 and HR, 2.52; 95% CI, 1.29-4.91 for ITA and IDI, respectively); however, there was no significant difference between the 2 intravitreal treatment groups. Intravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments.

Tailored Versus Generic Knowledge Brokering to Integrate Mood Management Into Smoking Cessation Interventions in Primary Care Settings: Protocol for a Cluster Randomized Controlled Trial.

BackgroundBoth tobacco smoking and depression are major public health problems associated with high morbidity and mortality. In addition, individuals with depression are almost twice as likely to smoke and less likely to achieve smoking cessation. In the Smoking Treatment for Ontario Patients program, an established smoking cessation program in Ontario, Canada, 38% of smokers in primary care settings have current or past depression with 6-month quit rates that are significantly lower than those without depression (33% versus 40%, P<.001). Integrating self-help mood management (eg, relaxation exercises and mood monitoring) with smoking cessation treatment increases long-term quit rates by 12%-20%. However, integration in real-world settings has not been reported. It is unclear which knowledge translation strategy would be more effective for motivating clinicians to provide resources on mood management to eligible patients.ObjectiveThe objectives of this study are to investigate the following comparisons among depressed smokers enrolled in a smoking cessation program: 1) the effectiveness of generalized, exclusively email-based prompts versus a personalized knowledge broker in implementing mood management interventions; 2) the effectiveness of the two knowledge translation strategies on smoking quit rates; and 3) the incremental costs of the two knowledge translation strategies on the implementation of mood management interventions.MethodsThe study design is a cluster randomized controlled trial of Family Health Teams participating in the Smoking Treatment for Ontario Patients program. Family Health Teams will be randomly allocated 1:1 to receive either generalized messages (related to depression and smoking) exclusively via email (group A) or be assigned a knowledge broker who provides personalized support through phone- and email-based check-ins (group B). The primary outcome, measured at the site level, is the proportion of eligible baseline visits that result in the provision of the mood management intervention to eligible patients.ResultsRecruitment for the primary outcome of this study will be completed in 2018/2019. Results will be reported in 2019/2020.ConclusionsThis study will address the knowledge gap in the implementation strategies (ie, email-based prompts versus a knowledge broker) of mood management interventions for smokers with depression in primary care settings.Trial RegistrationClinicalTrials.gov NCT03130998; https://clinicaltrials.gov/ct2/show/NCT03130998 (Archived on WebCite at www.webcitation.org/6ylyS6RTe)

The Role of Contingencies and Stimuli in a Human Laboratory Model of Treatment of Problem Behavior.

Behavioral momentum theory posits a paradoxical implication for behavioral interventions in clinical situations using Differential Reinforcement of Alternative Behavior (DRA): When alternative reinforcers are presented within the same context as the problem behavior, the added reinforcers may decrease the frequency of the behavior but also increase its persistence when the intervention ends. Providing alternative reinforcers in a setting that is distinctively different from that in which the target behavior occurs may avoid or reduce this increase in persistence. The present experiment compared behavioral persistence following standard DRA versus DRA in a different context that was available after refraining from target behavior (Differential Reinforcement of Other Behavior, DRO). We arranged a human laboratory model of treatment intervention using computer games and token reinforcement. Participants were five individuals with intellectual disabilities. Experimental phases included (a) an initial multiple-schedule baseline with token reinforcement for target behaviors A and B, (b) an intervention phase with alternative reinforcement using a conventional DRA procedure for A and a DRO-DRA procedure for B, and (c) an extinction phase with no interventions and no tokens. Response rates as proportion of baseline in the initial extinction phase were greater for A than for B for three of five participants. Four participants whose response rates remained relatively high during the extinction phase then received a second extinction-plus-distraction test with leisure items available. Response rates were greater for A than for B in three of four participants. The results indicate that DRO-DRA contingencies may contribute to reduced post-intervention persistence of problem behavior.

Data presentation options to manage variability in physical activity research.

This paper presents seven tactics for managing the variability evident in some physical activity data. High levels of variability in daily step-count data from pedometers or accelerometers can make typical visual inspection difficult. Therefore, the purpose of the current paper is to discuss several strategies that might facilitate the visual interpretation of highly variable data. The seven strategies discussed in this paper are phase mean and median lines, daily average per week, weekly cumulative, proportion of baseline, 7-day moving average, change point detection, and confidence intervals. We apply each strategy to a data set and discuss the advantages and disadvantages.

Fracture liaison services: do they reduce fracture rates?

The fracture liaison service (FLS) care is considered the most appropriate organizational approach for secondary fracture prevention. We performed a literature search to evaluate to what extent the introduction of a FLS reduced subsequent fracture rates. We identified five studies that compared subsequent fracture rates. These studies varied in study design, proportion of women, baseline and subsequent fracture type [vertebral fracture (VF), non-VF (NVF) or hip fractures], duration of follow-up, response rates of attending the FLS, as well as variables included in adjusted analyses (age, sex, baseline fracture, time dependency). In two studies comparing hospitals with and without a FLS, the adjusted hazard ratio (HR) for subsequent fractures was significantly lower in the FLS hospitals (HR: 0.84 during the first year, 0.44 during the second year for subsequent NVFs after baseline NVF, and 0.67 during the third year for subsequent VFs + NVFs after baseline VFs + NVFs). When comparing fracture rates before (pre-FLS) and after (post-FLS) introduction of a FLS, the adjusted HR for subsequent NVFs after baseline NVF was significantly lower in the post-FLS group after 2 years in one study (HR = 0.65) and nonsignificant in another study for subsequent hip fractures after baseline hip fracture. One study comparing pre-FLS and post-FLS with a follow-up of less than a year did not demonstrate a significant difference in subsequent fracture risk. In conclusion, only five FLS studies with heterogeneous study designs are available, three of them reported a lower subsequent fracture rate related to FLS care. Larger and long-term studies will be needed to further quantify the effect of FLS care on subsequent fracture risk.

Incentive effects of paying demand response in wholesale electricity markets

Recently issued U.S. Federal Energy Regulatory Commission regulations require comparable treatment of demand reduction and generation in the wholesale electric market so that they are compensated at the same market clearing price. The new regulations measure demand reduction as a reduction from a “customer baseline,” a historically based estimate of the expected consumption. In this paper, we study the incentive effects on the efficiency of the demand response regulation using a static equilibrium model and a dynamic extension of the model. Our analysis provides three main results. Firstly, our analysis shows that the demand reduction payment will induce consumers to (1) inflate the customer baseline by increasing consumption above the already excessive level during normal peak periods and (2) exaggerate demand reduction by decreasing consumption beyond the efficient level during a demand response event. This result persists when applied to alternative baseline designs in a dynamic model. Secondly, we study alternative policy remedies to restore the efficiency of demand response regulation and introduce a new approach to define the customer baseline as a fixed proportion of an aggregate baseline. In particular, the aggregate baseline approach can significantly weaken or eliminate the incentive to inflate the baseline. Finally, we illustrate that if the baseline inflation problem is solved and demand and supply functions are linear, the current policy can produce a net social welfare gain. However, the welfare improvement requires that demand reduction be paid only when the wholesale price is at least twice the fixed retail rate. This argues that the policy should include a sufficiently high threshold price below which demand response is not dispatched.

Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice

Several studies have investigated the reinforcing effects of food in genetically engineered mice lacking dopamine D(2) receptors (DA D(2)Rs); however, behavioral economic analyses quantifying reinforcement have not been conducted. The role of DA D(2)Rs in food reinforcement was examined by comparing responding under various fixed-ratio (FR) schedules of reinforcement, and effects of extinction, satiation, and the DA D(2)R antagonist eticlopride, in mice with and without genetic deletions of the receptor. Response rates of DA D(2)R knockout (KO) mice were generally lower than those of littermate wild-type (WT) and heterozygous (HET) mice. The demand curve (consumption vs. FR value) for KO mice decreased more steeply than that of HET or WT mice, suggesting that reinforcing effectiveness is decreased with DA D(2)R deletion. Prefeeding decreased, whereas extinction increased overall response rates as a proportion of baseline, with no significant genotype differences. Both (+)- and (-)-eticlopride dose-dependently decreased responding in all genotypes with (-)-eticlopride more potent than (+)-eticlopride in all but KO mice. The enantiomers were equipotent in KO mice, and similar in potency to (+)-eticlopride in WT and HET mice. That prefeeding and extinction did not vary across genotypes indicates a lack of involvement of DA D(2)Rs in these processes. Differences between (-)-eticlopride effects and extinction indicate that DA D(2)R blockade does not mimic extinction. The maintenance of responding in KO mice indicates that the DA D(2)R is not necessary for reinforcement. However, the economic analysis indicates that the DA D(2)R contributes substantially to the effectiveness of food reinforcement.

Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure*

High cutoff hemofilters are characterized by an increased effective pore size designed to facilitate the elimination of inflammatory mediators in sepsis. Clinical data on this new renal replacement modality are lacking. Prospective, randomized clinical trial. University hospital, intensive care units. : Thirty patients with sepsis-induced acute renal failure. Patients were allocated to high cutoff (n = 20) or conventional (n = 10) hemofiltration in a 2:1 ratio. Median renal replacement dose was 31 mL/kg/hr. For high cutoff hemofiltration, a high-flux hemofilter with an in vivo cutoff point of approximately 60 kilodaltons was used. Conventional hemofiltration was performed with a standard high-flux hemofilter (PF11S). The impacts of high cutoff hemofiltration on the need for norepinephrine and on plasma levels and clearance rates for interleukin (IL)-6 and IL-1 receptor antagonist (IL-1ra) were analyzed. Absolute values, but also adjusted values (expressed as proportion of baseline), were analyzed. The observation period was restricted to 48 hrs. Apart from higher antithrombin III levels at entry into the study, main clinical and laboratory parameters were comparable between both groups. The median norepinephrine dose at entry into the study was 0.30 microg/kg/min in the high cutoff group and 0.21 microg/kg/min in the conventional hemofiltration group (p = .448). Only the high cutoff group showed a significant decline (p = .0002) in "adjusted" norepinephrine dose over time. Clearance rates for IL-6 and IL-1ra were significantly higher in the high cutoff hemofiltration group (p < .0001), which translated into a significant decline of the corresponding plasma levels (p = .0465 for IL-6; p = .0293 for IL-1ra). In this pilot study, high cutoff hemofiltration has been shown to exert a beneficial effect on the need for norepinephrine in septic patients with acute renal failure. In addition, we demonstrate that high cutoff hemofiltration is superior to conventional hemofiltration in the elimination of IL-6 and IL-1ra from the circulating blood of septic patients.

UNSIGNALED DELAY OF REINFORCEMENT, RELATIVE TIME, AND RESISTANCE CHANGE

Two experiments with pigeons examined the effects of unsignaled, nonresetting delays of reinforcement on responding maintained by different reinforcement rates. In Experiment 1, 3-s unsignaled delays were introduced into each component of a multiple variable-interval (VI) 15-s VI 90-s VI 540-s schedule. When considered as a proportion of the preceding immediate reinforcement baseline, responding was decreased similarly for the three multiple-schedule components in both the first six and last six sessions of exposure to the delay. In addition, the relation between response rates and reinforcement rates was altered such that both parameters of the single-response version of the matching law (i.e., k and Re) were decreased. Experiment 2 examined the effects of unsignaled delays ranging from 0.5 s to 8.0 s on responding maintained by a multiple VI 20-s VI 120-s schedule of reinforcement. Response rates in both components increased with brief unsignaled delays and decreased with longer delays. As in Experiment 1, response rates as a proportion of baseline were affected similarly for the two components in both the first six and last six sessions of exposure to the delay. Unlike delays imposed between two stimulus events, the effects of delays between responses and reinforcers do not appear to be attenuated when the average time between reinforcers is longer. In addition, the disruptions produced by unsignaled delays appear to be inconsistent with the general finding that responding maintained by higher rates of reinforcement is less resistant to change.

Toward Cost‐Benefit Analysis of Acute Behavioral Effects of Toluene in Humans

There is increasing interest in being able to express the consequences of exposure to potentially toxic compounds in monetary terms in order to evaluate potential cost-benefit relationships of controlling exposure. Behavioral effects of acute toluene exposure could be subjected to cost-benefit analysis if the effects of toluene were quantitatively compared to those of ethanol ingestion, which has been monetized for applied contexts. Behavioral effects of toluene and ethanol were quantified by meta-analysis of studies from the peer-reviewed literature describing their effects on choice reaction time (reaction time in a test requiring a subject to choose among two or more alternatives before responding). The internal doses of these compounds were estimated by a general physiological and toxicokinetic (GPAT) simulation from exposure parameters provided in the reports. The reported effects were converted to a common metric (proportion of baseline) and related to the estimated internal doses of toluene and ethanol, from which dose-effect equations were fitted. The estimated effect of toluene was compared to the estimated effect of ethanol on the same dependent variable by deriving a dose-equivalence equation (DEE) to express the dose of toluene as an equivalent dose of ethanol on the basis of equal effect magnitude. A nomogram was constructed by GPAT simulation to relate the environmental exposure concentration of toluene to the equivalent effect magnitude of a range of ethanol internal doses. Behavioral effects and their evaluation are determined by internal doses, which in turn are determined by a variety of variables. In addition to concentration and duration of exposure, which determine internal dose by pharmacokinetic processes, the activity level of exposed persons is a major factor. This analysis provides a continuous function of the consequences of toluene exposure expressed as ethanol-equivalent doses within confidence limits. The resulting function has the potential to estimate the monetary values of behavioral deficits caused by a range of exposures to toluene from existing monetized information on ethanol.

A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans.

The literature on behavioral effects of exposure to toluene is difficult to assess due, in part, to a wide variety of exposure conditions employed and outcomes measured. This study investigated whether previous experiments would be more consistent with each other if toluene exposure parameters were expressed not as concentration and duration, but as estimated amount of toluene in tissues. A physiologically based pharmacokinetic (PBPK) model was used to estimate concentration of toluene in arterial blood (CaTOL) from published studies in rats and humans exposed acutely to toluene vapor. Data for rats were selected from studies of avoidance behavior using both rate of responding and measures of successful responding. Data for humans were from studies of choice reaction time (CRT). Behavioral measures were converted to proportion of baseline to place them on a common scale across experiments. A meta-analysis was done to fit dose-effect curves using CaTOL and the rescaled effects. Results demonstrated that effects were an orderly function of CaTOL and were not influenced by concentration or duration of exposure, except as exposure influenced CaTOL. In rats, response rates first increased, reached a peak, and then declined as CaTOL increased. Successful avoidance in rats and CRT in humans always declined as CaTOL increased. In rats, response rates were increased by 10% at CaTOL approximately 13 ml/L. In humans, reaction times increased by 10% at CaTOL approximately 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.

A Dosimetric Analysis of Behavioral Effects of Acute Toluene Exposure in Rats and Humans

The literature on behavioral effects of exposure to toluene is difficult to assess due, in part, to a wide variety of exposure conditions employed and outcomes measured. This study investigated whether previous experiments would be more consistent with each other if toluene exposure parameters were expressed not as concentration and duration, but as estimated amount of toluene in tissues. A physiologically based pharmacokinetk (PBPK) model was used to estimate concentration of toluene in arterial blood (⁠C&macr;aTOL) from published studies in rats and humans exposed acutely to toluene vapor. Data for rats were selected from studies of avoidance behavior using both rate of responding and measures of successful responding. Data for humans were from studies of choice reaction time (CRT). Behavioral measures were converted to proportion of baseline to place them on a common scale across experiments. A meta-analysis was done to fit dose-effect curves using C&macr;aTOL and the rescaled effects. Results demonstrated that effects were an orderly function of C&macr;aTOL and were not influenced by concentration or duration of exposure, except as exposure influenced C&macr;aTOL. In rats, response rates first increased, reached a peak, and then declined as C&macr;aTOL increased. Successful avoidance in rats and CRT in humans always declined as C&macr;aTOL increased. In rats, response rates were increased by 10% at C&macr;aTOL ˜ 13 ml/L. In humans, reaction times increased by 10% at C&macr;aTOL ˜ 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.

Coordinate diurnal variation in the strength of startle elicitation and of startle modification in the rat

In order to determine the effect of time of day on reflex modification, we measured the acoustic startle reflex (ASR) in rats (n = 4) to 120-dB tone bursts given alone to provide the ASR baseline, 100 msec after an inhibiting brief noise prepulse, or 10 to 20 sec after the onset of a facilitating noise background for 4–5 days in a test environment illuminated on a 12:12-h light:dark cycle. ASR amplitudes were greater in the dark, and sinusoids with a 24-h period starting at the light:dark transition accounted for about 80% of the variance in ASR amplitudes within each stimulus condition. The absolute differences in amplitude between baseline and either inhibited or facilitated ASR means were also greater in the dark, but relative measures of reflex modification (expressed as a proportion of the ASR baseline) were constant across time of day save for a slight compressive nonlinearity. The outcome for difference scores indicated that those neural mechanisms responsible for ASR elicitation and those responsible for ASR modification by external stimuli are both controlled in part by time of day, and the outcome for the relative response scores indicated further that the sensitivity of these separate reflex control mechanisms to the circadian process must be about equal.

Striatal grafts in rats with unilateral neostriatal lesions—II. In vivo monitoring of gaba release in globus pallidus and substantia nigra

GABA release was recorded in vivo by push-pull perfusion from the globus pallidus and substantia nigra of control rats, rats with unilateral ibotenic acid lesions of the neostriatum, and rats with embryonic striatal tissue grafts implanted in the lesioned striatum. The lesions reduced baseline levels of GABA release to 5% of control levels in the globus pallidus and to 13% of control levels in the substantia nigra pars reticulata. GABA release was substantially restored in both the globus pallidus and substantia nigra of the grafted rats, to 34 and 60%, respectively. Peripheral injection of the dopaminergic stumulant methamphetamine induced a short (lasting approximately 20 min) 4–5 fold increase in GABA release in the intact globus pallidus and a longer (lasting longer than 80 min) increase in the substantia nigra. The stimulatory effect of methamphetamine on GABA release was completely abolished in both sites by the striatal lesions, suggesting that the effect was mediated via a direct or indirect dopaminergic action on striatal output neurons. The grafts reinstated methamphetamine-induced stimulation of GABA release in striatal output targets to a level (as a proportion of baseline) that was similar to that seen in the control rats. The results support the view that activation of the dopaminergic inputs to the striatum is functionally excitatory on the major striatal output projections to the globus pallidus and substantia nigra pars reticulata. The results also support the hypothesis that striatal grafts have the capacity to become functionally incorporated by reciprocal graft-host connections into the neural circuitry of the host brain.