Addictive behavior as molar behavioral allocation: Distinguishing efficient and final causes in translational research and practice.

OBJECTIVE: Translational research on addictive behaviors viewed as molar behavioral allocation is critically reviewed. This work relates rates of behavior to rates of reinforcement over time and has been fruitfully applied to addictive behaviors, which involve excessive allocation to short-term rewards with longer term costs. METHOD: Narrative critical review. RESULTS: This approach distinguishes between final and efficient causes of discrete behaviors. The former refers to temporally extended behavior patterns into which the act fits. The latter refers to environmental stimuli or internal psychological mechanisms immediately preceding the act. Final causes are most clear when addictive behaviors are studied over time as a function of changing environmental circumstances. Discrete acts of addictive behavior are part of an extended/molar behavior pattern when immediate constraints on engagement are low and few rewarding alternatives are available. Research framed by efficient causes often use behavioral economic simulation tasks as individual difference variables that precede discrete acts. Such measures show higher demand for addictive commodities and steeper discounting in various risk groups, but whether they predict molar addictive behavior patterning is understudied. CONCLUSIONS: Although efficient cause analysis has dominated translational research, research supports viewing addictive behavior as molar behavioral allocation. Increasing concern with rate variables underpinning final cause analysis and considering how study methods and temporal units of analysis inform an efficient or final cause analysis may advance understanding of addictive behaviors that occur over time in dynamic environmental contexts. This approach provides linkages between behavioral science and disciplines that study social determinants of health. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Matching, behavioral economics, and teleological behaviorism: Final cause analysis of substance use and health behavior.

Howard Rachlin and his contemporaries pioneered basic behavioral science innovations that have been usefully applied to advance understanding of human substance use disorder and related health behaviors. We briefly summarize the innovations of molar behaviorism (the matching law), behavioral economics, and teleological behaviorism. Behavioral economics and teleological behaviorism's focus on final causes are especially illuminating for these applied fields. Translational and applied research are summarized for laboratory studies of temporal discounting and economic demand, cohort studies of alcohol and other drug use in the natural environment, and experimental behavioral economic modeling of health behavior-related public health policies. We argue that the teleological behavioral perspective on health behavior is conducive to and merges seamlessly with the contemporary socioecological model of health behavior, which broadens the contextual influences (e.g., community, economic, infrastructure, health care access and policy) of individuals' substance use and other health risk behaviors. Basic-to-applied translations to date have been successful and bode well for continued applications of basic science areas pioneered by Howard Rachlin and his contemporaries.

Validation of Diaporthe toxica resistance markers in European Lupinus angustifolius germplasm and identification of novel resistance donors for marker-assisted selection.

The fungus, Diaporthe toxica, anamorph Phomopsis sp., previously classified as P. leptostromiformis, is a plant endophyte and occasional pathogen, causing Phomopsis stem blight. This disease is damaging not only to lupins but also to the animals grazing on infected plants, due to the toxic secondary metabolites called phomopsins. The aim of this work was to validate markers for resistance to Phomopsis stem blight in narrow-leafed lupins and identify novel germplasm with increased levels of resistance to the disease. Plant inoculations were performed using ten isolates of D. toxica, originating from Australia and Poland. The European core collection of L. angustifolius was evaluated both in a controlled environment and with field experiments to classify the accessions based on their resistance to the disease. Simultaneously, the accessions were assayed with disease resistance markers to identify donors of hypothetical resistance alleles. We have found that the European lupin germplasm collection preserves wild and domesticated donors of at least two resistance genes to Phomopsis stem blight, including Phr1 and PhtjR. Molecular markers PhtjM7, InDel2, and InDel10, tagging PhtjR gene, were applicable for marker-assisted selection targeting the European gene pool with an expected accuracy of 95%. None of diagnostic markers for the Phr1 locus was found useful for European breeding programs; two existing markers Ph258M1 and Ph258M2 were unreliable, due to a high percentage of false-positive results (up to 58%) and a high recombination rate between markers (~ 30%).

Interrelationships of child appetite, weight and snacking among Hispanic preschoolers.

BACKGROUND: Snacking among US preschoolers has increased in recent decades, raising questions about whether snacking contributes to dietary excess. OBJECTIVES: This research aimed to characterize snacking contributions to dietary excess and to evaluate associations with appetite and weight among preschool-aged children. METHODS: This study is a cross-sectional, observational study of 187 Hispanic low-income preschoolers. Three 24-h dietary recalls were used to assess snacking frequency and parameters of dietary excess including energy, saturated fat, trans fats and added sugars. Parental reports of child satiety responsiveness, food responsiveness, and enjoyment of food were obtained. Child height and weight were measured. RESULTS: Children consumed 28% (395 kcal) of daily energy from snacks eaten at 2.3 ± 1.0 occasions per day. Greater snacking frequency was associated with greater daily intakes of energy (p < 0.05) and added sugars (p < 0.001). Among overweight/obese children, higher enjoyment of food was associated with more frequent snacking and greater energy intake from snacks (p = 0.01). Inverse associations of enjoyment of food with snacking frequency and energy intake were seen among normal weight children (p < 0.05). CONCLUSIONS: More frequent snacking among low-income Hispanic preschoolers may contribute to excessive intakes of energy and added sugars, particularly among overweight/obese children with greater motivation to eat.

Catalytic enantioselective acyl transfer: the case for 4-PPY with a C-3 carboxamide peptide auxiliary based on synthesis and modelling studies.

A series of 4-pyrrolidinopyridine (4-PPY) C-3 carboxamides containing peptide-based side chains have been synthesised and evaluated in the kinetic resolution of a small library of chiral benzylic secondary alcohols. A key design element was the incorporation of a tryptophan residue in the peptide side chain for promoting π-stacking between peptide side chain and the pyridinium ring of the N-acyl intermediate, in which modelling was used as a structure-based guiding tool. Together, a catalyst containing a LeuTrp-N-Boc side chain (catalyst 8) was identified that achieved s-values up to and in slight excess of 10. A transition-state model based on the modelling is proposed to explain the origin of enantioselectivity. This study establishes the usefulness of modelling as a structure-based guiding tool for enantioselectivity optimization as well as the potential for developing scalable peptide-based DMAP-type catalysts for large-scale resolution work.

A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation.

The use of fibrinolytic agents to prevent new thrombus formation is limited by an increased risk of bleeding due to lysis of hemostatic clots that prevent hemorrhage in damaged blood vessels. We sought to develop an agent that provides thromboprophylaxis without carrying a significant risk of causing systemic fibrinolysis or disrupting hemostatic clots. We previously showed that platelet (PLT) α granule-delivered urokinase plasminogen activator (uPA) is highly effective in preventing thrombosis, while being associated with little systemic fibrinolysis or bleeding. Here, we generated a chimeric prodrug composed of a single-chain version of the variable region of an anti-αIIbß3 mAb fused to a thrombin-activatable, low-molecular-weight pro-uPA (PLT/uPA-T). PLT/uPA-T recognizes human αIIbß3 on both quiescent and activated platelets and is enzymatically activated specifically by thrombin. We found that this prodrug binds tightly to human platelets even after gel filtration, has a prolonged half-life in mice transgenic for human αIIb compared with that of uPA-T, and prevents clot formation in a microfluidic system. Importantly, in two murine injury models, PLT/uPA-T did not lyse preexisting clots, even when administration was delayed by as little as 10 minutes, while it concurrently prevented the development of nascent thrombi. Thus, PLT/uPA-T represents the prototype of a platelet-targeted thromboprophylactic agent that selectively targets nascent over preexisting thrombi.

A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.

Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

Identification of common variants associated with human hippocampal and intracranial volumes.

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

Limiting activity at beta1-subunit-containing GABAA receptor subtypes reduces ataxia.

GABA(A) receptor (R) positive allosteric modulators that selectively modulate GABA(A)Rs containing beta(2)- and/or beta(3)- over beta(1)-subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"beta(2/3)-selective" GABA(A)R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show alpha-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA(A)R positive allosteric modulators that demonstrate differential beta-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other beta(2/3)-subunit selective, alpha-subunit isoform-selective, BZ and nonBZ GABA(A) positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at beta(1)-subunit-containing GABA(A)Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA(A)R with BZ-like anxiolytic efficacy by reducing or eliminating activity at beta(1)-subunit-containing GABA(A)Rs.

Toward cost-effective initial care for substance-abusing homeless.

In a randomized controlled trial, behavioral day treatment, including contingency management (CM+), was compared to contingency management components alone (CM). All 206 cocaine-dependent homeless participants received a furnished apartment with food and work training/employment contingent on drug-negative urine tests. CM+ also received cognitive-behavioral therapy, therapeutic goal management, and other intervention components. Results revealed that CM+ treatment attendance and abstinence were not significantly different from CM during 24 weeks of treatment. After treatment and contingencies ended, however, CM+ showed more abstinence than CM, indicating a delayed effect of treatment from 6 to 18 months. CM+ had more consecutive weeks abstinent across 52 weeks, but not during active treatment. We conclude that CM alone may be viable as initial care for cocaine-dependent homeless persons. That CM+ yields more durable abstinence indicates that it may be appropriate as stepped-up care for clients not responding to CM (Clinical Trials.gov, no. NCT00368524).

Enaminone amides as novel orally active GABAA receptor modulators.

A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma-aminobutyric acidA (GABAA) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [35S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha1beta2gamma2L GABAA receptors. The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervous system depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-dark paradigm.

Late second trimester assessment of pyelectasis (SERP) to predict pediatric urological outcome is improved by checking additional features.

OBJECTIVE: Counseling for pyelectasis in the late 2nd trimester is usually based only upon assessing the antero-posterior (AP) width of the renal pelvis. We hypothesized that checking additional features would better predict postnatal outcome. STUDY DESIGN: Ultrasound (<24 weeks gestational age (GA)) and newborn outcome data collected prospectively since 1986 were analyzed retrospectively. We determined if outcome predictions in kidneys with a sonographically evident renal pelvis (SERP), which had evaluation of additional features (e.g., renal and bladder lengths, presence of a dilated ureter or dilated calyces) are more accurate than those that did not have these features. RESULTS: There were 286 fetuses studied with pediatric follow-up of an average of 6.5 years. There were 338 exams providing 459 ultrasound images with SERP. Additional features were not assessed in 183 fetuses; however 103 fetuses did have evaluation of additional features. These features were categorized as abnormal (92) or as normal (11). Fetuses with SERP and abnormal additional features required extensive urological care or died 6.1 times more often than fetuses in which additional features were not examined (p < 0.001) and 12.9 times more often when additional features were normal (p < 0.001). CONCLUSION: Fetal kidneys with SERP (<24 weeks GA) and an abnormal additional ultrasound feature had extensive pediatric care significantly more often than when such features were not evaluated or were normal.

Significance of a behavioral economic index of reward value in predicting drinking problem resolution.

This study investigated whether a behavioral economic index of the value of rewards available over different time horizons improved prediction of drinking outcomes beyond established biopsychosocial predictors. Preferences for immediate drinking versus more delayed rewards made possible by saving money were determined from expenditures prior to resolution attempts by problem drinkers with different help-seeking experiences (N = 144). As hypothesized, stable resolutions over a 2-year follow-up were associated with proportionally more preresolution discretionary expenditures on savings and less on alcohol compared with unstable resolutions. The relationship held regardless of help-seeking history, and preresolution drinking practices, problems, and income were similar across outcomes. The findings extend experimental work on behavioral economics and indicate that measuring monetary allocation improves prediction of outcomes.

To house or not to house: the effects of providing housing to homeless substance abusers in treatment.

OBJECTIVES: Housing typically is not provided to homeless persons during drug abuse treatment. We examined how treatment outcomes were affected under 3 different housing provision conditions. METHODS: We studied 196 cocaine-dependent participants who received day treatment and no housing (NH), housing contingent on drug abstinence (ACH), or housing not contingent on abstinence (NACH). Drug use was monitored with urine testing. RESULTS: The ACH group had a higher prevalence of drug abstinence than the NACH group (after control for treatment attendance), which in turn had a higher prevalence than the NH group. All 3 groups showed significant improvement in maintaining employment and housing. CONCLUSIONS: The results of this and previous trials indicate that providing abstinence-contingent housing to homeless substance abusers in treatment is an efficacious, effective, and practical intervention. Programs to provide such housing should be considered in policy initiatives.

Using behavioral theories of choice to predict drinking outcomes following a brief intervention.

Behavioral theories of choice predict that substance use is partly a function of the relative value of drugs in relation to other available reinforcers. This study evaluated this hypothesis in the context of predicting drinking outcomes following an alcohol abuse intervention. Participants (N = 54, 69% female, 31% male) were college student heavy drinkers who completed a single-session motivational intervention. Students completed a baseline measure of substance-related and substance-free activity participation and enjoyment. Only women showed a significant reduction in drinking at the 6-month follow-up, and the ratio of substance-related to substance-free reinforcement accounted for unique variance in their drinking outcomes. Women who at baseline derived a smaller proportion of their total reinforcement from substance use showed lower levels of follow-up drinking, even after the authors controlled for baseline drinking level. Male and female participants who reduced their drinking showed increased proportional reinforcement from substance-free activities.

Fetal bladder sagittal length: a simple monitor to assess normal and enlarged fetal bladder size, and forecast clinical outcome.

PURPOSE: We examined if the parameter of fetal bladder sagittal length (FBSL) could serve as a monitor of normative and enlarged fetal bladder size. MATERIALS AND METHODS: There were 76 consecutive cases examined between 1984 and 2000 that included measurement of fetal bladder size as FBSL and postnatal urological followup. Fetal images used to assess normal bladder size were derived from cases in which the bladder was normal on prenatal imaging and postnatal testing. An enlarged bladder was categorized as being greater than the 95% CI for a given gestational age (GA). The presence and extent of renal pelvic dilatation were also noted and correlated with FBSL. RESULTS: Measuring normal FBSL in 39 fetuses showed an exponential growth pattern (r = 0.76), which could be represented by the approximate linear formula FBSL = GA in weeks -5 (+/- 95% upper/lower CI = 7). An enlarged bladder was diagnosed in 37 fetuses. A dilated bladder in 9 fetuses, defined as FBSL greater than the 95% upper CI of normal (ie between GA + 2 and GA + 12), showed outcomes of posterior urethral valves, vesicoureteral reflux or a normal outcome. Megacystis in 28 fetuses, defined as FBSL greater than 10 mm larger than that of a dilated bladder (ie greater than GA + 12), showed additional outcomes of megacystis megaureter/vesicoureteral reflux or prune-belly syndrome. A normal outcome was significantly more likely in fetuses with a dilated bladder than in those with megacystis (p < or = 0.05). The incidence of azotemia in those with a dilated bladder or megacystis and pyelectasis was significantly lower than that in those with megacystis with hydronephrosis (p < or = 0.03). CONCLUSIONS: Postnatal diagnosis of fetuses that show an enlarged bladder is predicted based on whether the bladder is enlarged as a dilated bladder or megacystis and if the renal pelvis is enlarged as pyelectasis or hydronephrosis.

Transitions during effective treatment for cocaine-abusing homeless persons: establishing abstinence, lapse, and relapse, and reestablishing abstinence.

Data are reported on drug use among cocaine-dependent homeless persons who participated in a clinical trial that compared day treatment only (DT, n = 69) with day treatment plus abstinent-contingent housing and work (DT+, n = 72). Drug use was measured with multiple weekly urine toxicologies. Compared with DT participants, more DT+ participants established abstinence, maintained abstinence for longer durations, were marginally significantly more likely to lapse, and significantly less likely to relapse. Of all participants who established abstinence and then relapsed, DT+ participants relapsed later and were more likely to reestablish abstinence. These analyses yield information on the processes involved in the manner in which drug use changes as a result of abstinent-contingent housing and work.

A comparison of personalized feedback for college student drinkers delivered with and without a motivational interview.

OBJECTIVE: This study evaluated the relative efficacy of personalized drinking feedback (PDF) delivered with and without a motivational interview (MI) for college student drinkers. METHOD: Heavy-drinking college students (N = 54; 691% female) were identified from a large screening sample and randomly assigned either to receive PDF during a single MI session or to receive PDF without an MI. Of these participants, 51 (94%) completed a 6-month follow-up assessment that included measures of alcohol consumption and alcohol-related problems. RESULTS: At 6-months postintervention, participants in both groups showed significant, small to moderate reductions in alcohol consumption, but the groups did not differ. Women showed larger reductions than men. Rates of alcohol-related problems remained relatively unchanged. CONCLUSIONS: The hypothesis that an MI would enhance the efficacy of PDF was not supported.