Predictors of vascular disease in myelodysplastic syndromes.

The escalating link between somatic mutations commonly seen in myelodysplastic syndromes (MDS) and atherosclerotic vascular disease has increased the interest in management and associations of these conditions. We present a retrospective study examining clinical and molecular variables associated with vascular disease in patients with MDS. This study included a comprehensive evaluation of 236 patients with MDS. Our study has multiple findings. Mutations in ASXL1 correlated with increased risk of vascular disease for the entire cohort (P = .013). Though this has been replicated in other studies, there are no guidelines at this time for preventing vascular events in these patients. Our study also showed that lower ferritin levels may be linked to increased vascular events (P = .043), therefore the optimal use of supportive red blood cell transfusions in patients with MDS and the overall impact of inflammatory markers such as erythrocyte sedimentation rate and c-reactive protein should be re-addressed. Furthermore, our study showed that patients with Trisomy 8 in the low-risk MDS cohort (based on IPSS-R scores) were protected from vascular events (P = .036). Our findings of lower ferritin being linked with increased risk of vascular events as well as patients with Trisomy 8 being protected from vascular events may impact patient care. There do not appear to be any prior studies with these findings. In addition, given the connection between MDS and atherosclerotic vascular disease, we believe guideline-based management of cardiac risk factors among MDS patients may improve overall outcomes. Further studies with larger patient cohorts are needed to further investigate these findings.

Triple Therapy versus Dual or Monotherapy with Long-Acting Bronchodilators for Chronic Obstructive Pulmonary Disease. A Systematic Review and Meta-analysis.

Rationale: There is uncertainty on the use of using triple therapy (inhaled corticosteroids/long-acting ß-agonist/long-acting muscarinic antagonist) inhaler therapy for patients with chronic obstructive pulmonary disease (COPD), who complain of dyspnea and/or exercise intolerance.Objectives: We conducted a systematic review and meta-analyses to estimate the safety and efficacy of using triple therapy compared with long-acting ß-agonist/long-acting muscarinic antagonist dual therapy or monotherapy with a single long-acting bronchodilator in patients with stable COPD who complained of dyspnea and/or exercise intolerance.Methods: A search of MEDLINE, Embase, and the Cochrane Library databases was conducted for randomized controlled trials pertaining to the clinical question. A systematic approach was used to screen, abstract, and critically appraise the studies. The grading of recommendations assessment, development, and evaluation method was applied to rate the certainty/quality of the evidence.Results: Eleven studies were eligible for inclusion (n = 14,145 patients). Pairwise random-effects meta-analysis revealed an increase in risk of pneumonia (relative risk, 1.47; 95% confidence interval [95% CI], 1.20-1.80; P < 0.001) and decreased risk of acute exacerbations of COPD (AECOPDs) (relative risk, 0.75; 95% CI, 0.68-0.82; P < 0.001) with triple therapy compared with treatment with dual and monotherapy long-acting bronchodilator therapy. No significant difference in dyspnea scores (standardized mean difference, 0.09; 95% CI, -0.02 to 0.19; P = 0.09) or risk of hospitalization (rate ratio, 0.78; 95% CI, 0.58-1.06; P = 0.11) was noted. When subgroup analysis based on inhaler class was performed, no significant difference was noted between the groups in any of the critical outcomes studied. For patients with a history of one or more AECOPDs in the past year, triple therapy resulted in 230 fewer AECOPDs and 16 more cases of pneumonia per 1,000 patients.Conclusions: In patients with COPD who complain of dyspnea and/or exercise intolerance, triple therapy is not superior to maintenance long-acting bronchodilator therapy, except in patients with a history of one or more exacerbations in the past year, in whom the benefits of reduction in AECOPD outweigh the increased risk of pneumonia.

Oral Methylphenidate Treatment of an Adolescent ADHD Rat Model Does Not Alter Cocaine-Conditioned Place Preference during Adulthood: A Negative Report.

The stimulant, methylphenidate (MPH), is commonly used to treat attention deficit hyperactivity disorder (ADHD) and has been increasingly prescribed for school age children and adolescents. Concerns regarding its long-term effects on later substance use disorders (SUDs) have been raised. Previous animal studies have produced contradictory results regarding whether early exposure to MPH increases or protects against SUD in adulthood. The goal of our study was to determine if clinically relevant doses of MPH during adolescence alter cocaine responsiveness in adulthood in a rat model of ADHD, the spontaneous hypertensive rat (SHR). We pretreated SHRs with saline or MPH (2.5 mg/kg once or twice day) via oral gavage during their dark cycle from postnatal day 35 (p35) to p44. Adult rats (p80) were assessed in an eight-session cocaine-conditioned place preference test (CPP). Four doses of cocaine were administered via intraperitoneal injection (i.p.) during the conditioning sessions: 1, 5, 10 and 20 mg/kg. Once per day MPH treatment had a small sensitizing effect on baseline general locomotor activity in a novel environment at p80 as well as a limited suppressive effect on reward-specific locomotor activity as measured by the decreased preference to enter the cocaine-paired chamber. This treatment did not have any effect on the amount of time that rats chose to spend in the cocaine-paired chamber. Twice per day MPH treatment had no effect on locomotion or drug-preference. Our results suggest that MPH treatment of ADHD rats during adolescence does not alter preference for cocaine in adulthood.

Nicotine and methamphetamine disrupt habituation of sensory reinforcer effectiveness in male rats.

The reinforcing effectiveness of a sensory stimulus such as light-onset rapidly habituates (Lloyd, Gancarz, Ashrafioun, Kausch, & Richards, 2012). According to memory-based theories, habituation occurs if a memory exists for perceived stimulation, and dishabituation occurs if a memory does not exist and the stimulation is "unexpected." According to Redgrave and Gurney (2006), unexpected response-contingent sensory stimuli increase phasic firing of dopamine neurons, providing a sensory error signal that reflects the difference between perceived and expected stimuli. Together, memory-based theories of habituation and the sensory error signal hypothesis predict a disruption (slowing) of habituation rate by novel response-contingent sensory stimulation or by artificial increases in dopamine neurotransmission by stimulant drugs. To test these predictions, we examined the effects of stimulant drugs on both the operant level of responding (snout-poking) and operant responding for a sensory reinforcer (light-onset) presented according to a fixed ratio 1 schedule. Robust within-session decreases in responding indicating habituation were observed. The effects of stimulant drugs (saline, n = 10; nicotine, 0.40 mg/kg, n = 10; and methamphetamine, 0.75 mg/kg, n = 9) on habituation in rats were determined. Nicotine was found to decrease habituation rate and did not affect response rate, while methamphetamine decreased habituation rate and increased response rate. In addition, introduction of a novel visual stimulus reinforcer decreased habituation rate and increased responding. These findings show that habituation of reinforcer effectiveness modulates operant responding for sensory reinforcers, and that stimulant drugs may disrupt normally occurring habituation of reinforcer effectiveness by increasing dopamine neurotransmission.

Modeling the utility of binaural cues for underwater sound localization.

The binaural cues used by terrestrial animals for sound localization in azimuth may not always suffice for accurate sound localization underwater. The purpose of this research was to examine the theoretical limits of interaural timing and level differences available underwater using computational and physical models. A paired-hydrophone system was used to record sounds transmitted underwater and recordings were analyzed using neural networks calibrated to reflect the auditory capabilities of terrestrial mammals. Estimates of source direction based on temporal differences were most accurate for frequencies between 0.5 and 1.75 kHz, with greater resolution toward the midline (2°), and lower resolution toward the periphery (9°). Level cues also changed systematically with source azimuth, even at lower frequencies than expected from theoretical calculations, suggesting that binaural mechanical coupling (e.g., through bone conduction) might, in principle, facilitate underwater sound localization. Overall, the relatively limited ability of the model to estimate source position using temporal and level difference cues underwater suggests that animals such as whales may use additional cues to accurately localize conspecifics and predators at long distances.

Habituation of reinforcer effectiveness.

In this paper we propose an integrative model of habituation of reinforcer effectiveness (HRE) that links behavioral- and neural-based explanations of reinforcement. We argue that HRE is a fundamental property of reinforcing stimuli. Most reinforcement models implicitly suggest that the effectiveness of a reinforcer is stable across repeated presentations. In contrast, an HRE approach predicts decreased effectiveness due to repeated presentation. We argue that repeated presentation of reinforcing stimuli decreases their effectiveness and that these decreases are described by the behavioral characteristics of habituation (McSweeney and Murphy, 2009; Rankin etal., 2009). We describe a neural model that postulates a positive association between dopamine neurotransmission and HRE. We present evidence that stimulant drugs, which artificially increase dopamine neurotransmission, disrupt (slow) normally occurring HRE and also provide evidence that stimulant drugs have differential effects on operant responding maintained by reinforcers with rapid vs. slow HRE rates. We hypothesize that abnormal HRE due to genetic and/or environmental factors may underlie some behavioral disorders. For example, recent research indicates that slow-HRE is predictive of obesity. In contrast ADHD may reflect "accelerated-HRE." Consideration of HRE is important for the development of effective reinforcement-based treatments. Finally, we point out that most of the reinforcing stimuli that regulate daily behavior are non-consumable environmental/social reinforcers which have rapid-HRE. The almost exclusive use of consumable reinforcers with slow-HRE in pre-clinical studies with animals may have caused the importance of HRE to be overlooked. Further study of reinforcing stimuli with rapid-HRE is needed in order to understand how habituation and reinforcement interact and regulate behavior.

Sensory reinforcement as a predictor of cocaine and water self-administration in rats.

RATIONALE: The ability of locomotor activity in a novel environment (Loco) and visual stimulus reinforcement (VSR) to predict acquisition of responding for cocaine and water reinforcers in the absence of explicit audiovisual signals was evaluated. METHODS: In Experiment 1 (Exp 1), rats (n = 60) were tested for VSR, followed by Loco, and finally acquisition of responding for cocaine (0.3 mg/kg/inf). In Experiment 2 (Exp 2), rats (n = 32) were tested for VSR, followed by Loco, and finally acquisition of responding for water (0.01 mL/reinforcer). RESULTS: There were three main findings. First, Loco and VSR were significantly associated (Exp 1: r = 0.49, p < 0.00; Exp 2: r = 0.35, p < 0.05). Second, neither Loco (r = .00, p = 0.998) nor VSR (r = -0.12, p = 0.352) predicted acquisition of cocaine SA. Third, in the subgroup of animals that acquired cocaine SA, VSR (r = 0.41, p < 0.01) but not Loco (r = 0.28, p = 0.10) was positively associated with operant responding for cocaine. Both Loco and VSR (Loco: r = 0.37, p < 0.04; VSR: r = 0.51, p < 0.00) were positively associated with operant responding for water reinforcers. CONCLUSIONS: The results indicate that VSR is at least as good a predictor of cocaine reinforced responding as Loco. VSR was predictive of operant responding for both drug and water reinforcers, while Loco was found to be predictive of responding only for water reinforcers. In studies that present visual stimuli in association with drug delivery, Loco may be predicting acquisition of responding for VSR rather than drug.

Between-session progressive ratio performance in rats responding for cocaine and water reinforcers.

RATIONALE: A between-session progressive ratio (BtwPR) procedure was tested in rats responding for cocaine and water reinforcers. OBJECTIVES: Experiment 1 evaluated the sensitivity of the BtwPR procedure to the magnitude of cocaine and water reinforcers. Experiment 2 compared BtwPR performance to within-session progressive ratio (WinPR) performance. METHODS: In experiment 1, rats were tested on a BtwPR procedure with three doses of cocaine (0.1, 0.3, and 1.0 mg/kg/inf) or volumes of water (0.01, 0.03, and 0.1 mL/reinforcer). BtwPR test sessions began with a seeking phase, during which the animal is required to complete a fixed ratio in order to initiate a 2-h consumption phase, where the reinforcer was available according to a fixed ratio 1 (FR1) schedule. Failure to complete the seeking ratio, which was increased after each test session, determined the breakpoint (BP). In experiment 2, the same BtwPR procedure was used except that the consumption phase was a WinPR schedule of reinforcement for cocaine (1.0 mg/kg/inf) or water (0.1 mL) reinforcers. RESULTS AND CONCLUSIONS: BtwPR BPs increased as a function of the magnitude of both cocaine and water reinforcers. The BtwPR produced smaller BPs than the WinPR for cocaine reinforcers. In contrast, the BtwPR produced larger BPs than the WinPR for water reinforcers. One possible explanation is that priming and response activating effects of the cocaine reinforcer increased the WinPR BP. BtwPR and WinPR procedures may measure different aspects of drug-seeking.

Habituation and the reinforcing effectiveness of visual stimuli.

The term "sensory reinforcer" has been used to refer to sensory stimuli (e.g. light onset) that are primary reinforcers in order to differentiate them from other more biologically important primary reinforcers (e.g. food and water). Acquisition of snout poke responding for a visual stimulus (5 s light onset) with fixed ratio 1 (FR 1), variable-interval 1 min (VI 1 min), or variable-interval 6 min (VI 6 min) schedules of reinforcement was tested in three groups of rats (n=8/group). The VI 6 min schedule of reinforcement produced a higher response rate than the FR 1 or VI 1 min schedules of visual stimulus reinforcement. One explanation for greater responding on the VI 6 min schedule relative to the FR 1 and VI 1 min schedules is that the reinforcing effectiveness of light onset habituated more rapidly in the FR 1 and VI 1 min groups as compared to the VI 6 min group. The inverse relationship between response rate and the rate of visual stimulus reinforcement is opposite to results from studies with biologically important reinforcers which indicate a positive relationship between response and reinforcement rate. Rapid habituation of reinforcing effectiveness may be a fundamental characteristic of sensory reinforcers that differentiates them from biologically important reinforcers, which are required to maintain homeostatic balance.

Effects of novelty and methamphetamine on conditioned and sensory reinforcement.

BACKGROUND: Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light. METHODS: The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined. RESULTS: Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs. CONCLUSION: Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.

Association between locomotor response to novelty and light reinforcement: sensory reinforcement as a rodent model of sensation seeking.

BACKGROUND: The human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotor activity in a novel environment (Loco) has been found to predict drug self-administration (SA), and has been hypothesized to be a translational model of human SS. Previously, we reported (Gancarz et al., 2011) that high responder (HR) animals responded more than low responder (LR) animals to produce a response contingent light onset. The primary goal of this paper was a detailed analysis of the association between Loco and light contingent responding in a large sample of rats (n = 93). METHODS: Male rats were pre-exposed to dark operant test chambers for ten 30 min sessions and baseline levels of responding (snout poking) were determined. The pre-exposure phase was followed by 6 sessions during which active responding produced a visual sensory reinforcer (VSR; 5 s light onset) according to a variable interval 1 min schedule of reinforcement. After completion of the VSR phase, Loco was tested. RESULTS: The activating effects (total responding) of light were associated with Loco, but the response guiding effects (proportion of active responding) of the light were not. In addition, HR rats habituated more slowly in both the VSR and Loco tests than LR rats. CONCLUSIONS: These data indicate that VSR measures aspects of the rodent's response to novel sensations and experiences that are not detected by Loco. These data provide some evidence for the use of light reinforcement as an animal model of SS.