Behavioral proxies compete by the time courses of their rewards, including endogenous rewards.

Natural selection is slow, so behavioral goals must be based on patterns of reward. Addictions are rewarded in the same way as adaptive choice, so they can be distinguished only by their time course. In addition, the reward process is more plastic than is generally recognized, so abstract goals are shaped by the "legibility" of their proxies.

"Switching" between fast and slow processes is just reward-based branching.

Shortcuts to goals are rewarded by faster attainment and punished by more frequent failure, so selection of the various kinds - heuristics, cached sequences (habits or ), gut instincts - depends on reward history just like other kinds of choice. The speeds of shortcuts lie on continua along with speeds of deliberation, and these continua have no obvious separation points.

Framing is a motivated process.

Frames group choices into categories, thus modifying the incentives for them. This effect makes framing itself a motivated choice rather than a neutral cognition. In particular, framing an inferior choice with a high short-term payoff as part of a broad category of choices recruits incentive to reject it; but this must be motivated by its being a test case.

Behavioral construction of the future.

Objective: To examine Howard Rachlin's hypothetical model of molar choice as a tactic for resisting addictions and to explore how some of its then-radical components can be developed to account for nonphysical and far future rewards.

Method: The history of Rachlin's long dialog with the present author about molar choice is reviewed. The possible implications are described of both authors' proposal that behavior can depend entirely on reward.

Reply to commentaries to willpower with and without effort.

Twenty-six commentators from several disciplines have written on the assumption that choice is determined by comparative valuation in a common denominator of reward, the "competitive marketplace." There was no apparent disagreement that prospective rewards are discounted hyperbolically, although some found that the resulting predictions could come just as well from other models, including the interpretation of delay as risk and analysis in terms of hot versus cold valuation systems. Several novel ideas emerged.

Willpower with and without effort.

Most authors who discuss willpower assume that everyone knows what it is, but our assumptions differ to such an extent that we talk past each other. We agree that willpower is the psychological function that resists temptations - variously known as impulses, addictions, or bad habits; that it operates simultaneously with temptations, without prior commitment; and that use of it is limited by its cost, commonly called effort, as well as by the person's skill at executive functioning. However, accounts are usually not clear about how motivation functions during the application of willpower, or how motivation is related to effort.

Review: Contrast-enhanced magnetic resonance in the diagnosis and management of cardiac sarcoidosis.

Sarcoidosis is a relatively rare inflammatory condition which potentially carries high morbidity and substantial mortality. Due to the fact that it does not subject patients to ionizing radiation, has high temporal, spatial and contrast resolutions, cardiovascular magnetic resonance imaging (CMR) has become an important diagnostic and prognostic modality in the evaluation for cardiac involvement in this condition. This review provides relevant clinical and pathophysiological background on cardiac sarcoidosis, whilst detailing the role of CMR imaging in the diagnosis, and management of this condition.

Microphysiological lung models to evaluate the safety of new pharmaceutical modalities: a biopharmaceutical perspective.

The lung is a complex organ; it is both the initial barrier for inhaled agents and the site of metabolism and therapeutic effect for a subset of systemically administered drugs. Comprised of more than 40 cell types that are responsible for various important functions, the lung's complexity contributes to the subsequent challenges in developing complex in vitro co-culture models (also called microphysiological systems (MPS), complex in vitro models or organs-on-a-chip). Although there are multiple considerations and limitations in the development and qualification of such in vitro systems, MPS exhibit great promise in the fields of pharmacology and toxicology.

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.

The anticonvulsant vigabatrin (VGB; Sabril) irreversibly inhibits GABA transaminase to increase neural GABA, yet its mechanism of retinal toxicity remains unclear. VGB is suggested to alter several amino acids, including homocarnosine, β-alanine, ornithine, glycine, taurine, and 2-aminoadipic acid (AADA), the latter a homologue of glutamic acid. Here, we evaluate the effect of VGB on amino acid concentrations in mice, employing a continuous VGB infusion (subcutaneously implanted osmotic minipumps), dose-escalation paradigm (35-140 mg/kg/d, 12 days), and amino acid quantitation in eye, visual and prefrontal cortex, total brain, liver and plasma.

Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects.

Vigabatrin (VGB; 4-aminohex-5-enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA-T), manifests use-limiting ocular toxicity. Hypothesizing that the active enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6-8 animals/dose) for 12 days. VGB enantiomers, total GABA and β-alanine (BALA), 4-guanidinobutyrate (4-GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC.

Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.

We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option.

Positivity versus negativity is a matter of timing.

"Negative" emotions are never purely negative. They attract attention at the very least and often stay attractive enough to make rehearsing them an addictive activity. As the authors point out, they also counteract a relentless tendency for positive emotions to become boring.

Right ventricular involvement in cardiac sarcoidosis demonstrated with cardiac magnetic resonance.

Aims: Cardiac involvement in sarcoidosis is reported in up to 30% of patients. Left ventricular involvement demonstrated by contrast-enhanced cardiac magnetic resonance has been well validated. We sought to determine the prevalence and distribution of right ventricular late gadolinium enhancement in patients diagnosed with pulmonary sarcoidosis.

In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells.

We explored the utility of neural stem cells (NSCs) as an in vitro model for evaluating preclinical therapeutics in succinic semialdehyde dehydrogenase-deficient (SSADHD) mice. NSCs were obtained from aldh5a1+/+ and aldh5a1-/- mice (aldh5a1 = aldehyde dehydrogenase 5a1 = SSADH). Multiple parameters were evaluated including: (1) production of GHB (γ-hydroxybutyrate), the biochemical hallmark of SSADHD; (2) rescue from cell death with the dual mTOR (mechanistic target of rapamycin) inhibitor, XL-765, an agent previously shown to rescue aldh5a1-/- mice from premature lethality; (3) mitochondrial number, total reactive oxygen species, and mitochondrial superoxide production, all previously documented as abnormal in aldh5a1-/- mice; (4) total ATP levels and ATP consumption; and (5) selected gene expression profiles associated with epilepsy, a prominent feature in both experimental and human SSADHD.

Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: Therapeutic implications for SSADH deficiency, a GABA metabolic disorder.

We report the in vitro assessment of pharmacotoxicity for the high-affinity GHB receptor ligand, NCS-382, using neuronal stem cells derived from mice with a targeted deletion of the aldehyde dehydrogenase 5a1 gene (succinic semialdehyde dehydrogenase(SSADH)-deficient mice). These animals represent a phenocopy of the human disorder of GABA metabolism, SSADH deficiency, that metabolically features accumulation of both GABA and the GABA-analog γ-hydroxybutyric acid in conjunction with a nonspecific neurological phenotype. We demonstrate for the first time using MDCK cells that NCS-382 is actively transported and capable of inhibiting GHB transport.

Right ventricular involvement and the extent of left ventricular enhancement with magnetic resonance predict adverse outcome in pulmonary sarcoidosis.

Aims: Cardiac involvement is the main determinant of poor outcomes in sarcoidosis. Right ventricular (RV) dysfunction and left ventricular (LV) late gadolinium enhancement (LGE) have been reported to be predictive of adverse outcome in non-ischaemic cardiomyopathies. The aim of our study was to determine whether delayed RV LGE with cardiovascular magnetic resonance would be predictive of adverse events in addition to LV LGE during the long-term follow-up of pulmonary sarcoidosis patients.

Targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) employing an enzymatic assay for γ-hydroxybutyric acid (GHB) in biofluids.

Hypothesis: An enzymatic assay for quantification of γ-hydroxybutyric acid (GHB) in biofluids can be employed for targeted screening of succinic semialdehyde dehydrogenase deficiency (SSADHD) in selected populations.

Rationale: We used a two-tiered study approach, in which the first study (proof of concept) examined 7 urine samples derived from patients with SSADHD and 5 controls, and the second study (feasibility study) examined a broader sample population of patients and controls, including plasma.

Objective: Split samples of urine and plasma (anonymized) were evaluated by enzymatic assay, gas chromatography alone (proof of concept) and gas chromatography-mass spectrometry, and the results compared.

Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies.

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v.

Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency.

Gamma-hydroxybutyrate (GHB) is a drug of abuse, an approved therapeutic for narcolepsy, an agent employed for facilitation of sexual assault, as well as a biomarker of succinic semialdehyde dehydrogenase deficiency (SSADHD). Our laboratory seeks to identify surrogate biomarkers in SSADHD that can shed light on the developmental course of this neurometabolic disease. Since GHB may be quantified in hair as a potential surrogate to identify victims of drug-related assault, we have opted to examine its level in SSADHD.

Recommendations for the management of idiopathic pulmonary fibrosis in South Africa: a position statement of the South African Thoracic Society.

Idiopathic pulmonary fibrosis (IPF) is a very specific form of a chronic, progressive fibroproliferative interstitial pneumonia of unknown aetiology. The disease is generally associated with a poor prognosis. Several international evidence-based guidelines on the diagnosis and management of IPF and other interstitial lung diseases (ILDs) have been published and updated in the last decade, and while the body of evidence for the use of some treatment modalities has grown, others have been shown to be futile and even harmful to patients.

In vitro toxicological evaluation of NCS-382, a high-affinity antagonist of γ-hydroxybutyrate (GHB) binding.

γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear.

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS-382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication.

Gamma-aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter and precursor of gamma-hydroxybutyric acid (GHB). NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid), a known GHB receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (SSADHD), a heritable neurological disorder featuring chronic elevation of GHB that blocks the final step of GABA degradation. NCS-382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the NCS-382 metabolites formed by mouse and human.

Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity?

Vigabatrin (VGB; γ-vinylGABA) is a unique antiepileptic directly elevating CNS GABA via inactivation of the GABA metabolic enzyme GABA-transaminase. VGB is effective in treating infantile spasms, a rare seizure disorder associated with significant morbidity. The potential for unexplained bilateral constriction of the visual field associated with VGB intervention can severely limit its temporal utility.

mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice.

Background: Gamma-vinyl-γ-aminobutyric acid (GABA) (vigabatrin) is an antiepileptic drug and irreversible GABA transaminase inhibitor associated with visual field impairment, which limits its clinical utility. We sought to relate altered visual evoked potentials associated with vigabatrin intake to transcriptional changes in the mechanistic target of rapamycin (mTOR) pathway and GABA receptors to expose further mechanisms of vigabatrin-induced visual field loss.

Methods: Vigabatrin was administered to mice via an osmotic pump for two weeks to increase GABA levels.

Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.

Aldehyde dehydrogenase 5a1-deficient (aldh5a1) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis that aldh5a1 mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR. We observed that multiple metabolites associated with GABA metabolism (γ-hydroxybutyrate, succinic semialdehyde, D-2-hydroxyglutarate, 4,5-dihydrohexanoate) and oxidative stress were significantly increased in multiple tissues derived from aldh5a1 mice.