PYY3-36 infused systemically or directly into the VTA attenuates fentanyl seeking in male rats.

More effective treatments for fentanyl use disorder are urgently needed. An emerging literature indicates that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate voluntary opioid taking and seeking in rodents. However, GLP-1R agonists produce adverse malaise-like effects that may limit patient compliance. Recently, we developed a dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) that attenuates fentanyl taking and seeking at doses that do not produce malaise-like effects in opioid-experienced rats. Whether activating Y2Rs alone is sufficient to reduce opioid taking and seeking, however, is not known. Here, we investigated the efficacy of the Y2R ligand PYY3-36 to reduce fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, a model of relapse in humans. Male rats were allowed to self-administer fentanyl (2.5 µg/kg, i.v.) for 21 days on a fixed-ratio 5 (FR5) schedule of reinforcement. Rats were then pretreated with vehicle or PYY3-36 (50 µg/kg s.c.; 0.1 and 1.0 µg/100 nL intra-VTA) prior to fentanyl self-administration test sessions. There were no effects of systemic or intra-VTA PYY3-36 on intravenous fentanyl self-administration. Opioid taking was then extinguished. Prior to subsequent reinstatement test sessions, rats were pretreated with vehicle or PYY3-36 (50 µg/kg s.c.; 0.1 and 1.0 µg/100 nL intra-VTA). Both systemic and intra-VTA administration of PYY3-36 attenuated fentanyl reinstatement in male rats at doses that did not affect food intake or produce adverse malaise-like effects. These findings indicate that Y2R agonism alone is sufficient to decrease fentanyl-seeking behavior during abstinence in opioid-experienced rats and further support strategies aimed at targeting Y2Rs for treating opioid use disorders.

ECM-transmitted shear stress induces apoptotic cell extrusion in early breast gland development.

Epithelial cells of human breast glands are exposed to various mechanical ECM stresses that regulate tissue development and homeostasis. Mechanoadaptation of breast gland tissue to ECM-transmitted shear stress remained poorly investigated due to the lack of valid experimental approaches. Therefore, we created a magnetic shear strain device that enabled, for the first time, to analyze the instant shear strain response of human breast gland cells. MCF10A-derived breast acini with basement membranes (BM) of defined maturation state and basoapical polarization were used to resemble breast gland morphogenesis in vitro. The novel biophysical tool was used to apply cyclic shear strain with defined amplitudes (≤15%, 0.2 Hz) over 22 h on living spheroids embedded in an ultrasoft matrix (<60 Pa). We demonstrated that breast spheroids gain resistance to shear strain, which increased with BM maturation and basoapical polarization. Most intriguingly, poorly developed spheroids were prone to cyclic strain-induced extrusion of apoptotic cells from the spheroid body. In contrast, matured spheroids were insensitive to this mechanoresponse-indicating changing mechanosensing or mechanotransduction mechanisms during breast tissue morphogenesis. Together, we introduced a versatile tool to study cyclic shear stress responses of 3D cell culture models. It can be used to strain, in principle, all kinds of cell clusters, even those that grow only in ultrasoft hydrogels. We believe that this approach opens new doors to gain new insights into dynamic shear strain-induced mechanobiological regulation circuits between cells and their ECM.

Intrinsic cell rheology drives junction maturation.

A fundamental property of higher eukaryotes that underpins their evolutionary success is stable cell-cell cohesion. Yet, how intrinsic cell rheology and stiffness contributes to junction stabilization and maturation is poorly understood. We demonstrate that localized modulation of cell rheology governs the transition of a slack, undulated cell-cell contact (weak adhesion) to a mature, straight junction (optimal adhesion). Cell pairs confined on different geometries have heterogeneous elasticity maps and control their own intrinsic rheology co-ordinately. More compliant cell pairs grown on circles have slack contacts, while stiffer triangular cell pairs favour straight junctions with flanking contractile thin bundles. Counter-intuitively, straighter cell-cell contacts have reduced receptor density and less dynamic junctional actin, suggesting an unusual adaptive mechano-response to stabilize cell-cell adhesion. Our modelling informs that slack junctions arise from failure of circular cell pairs to increase their own intrinsic stiffness and resist the pressures from the neighbouring cell. The inability to form a straight junction can be reversed by increasing mechanical stress artificially on stiffer substrates. Our data inform on the minimal intrinsic rheology to generate a mature junction and provide a springboard towards understanding elements governing tissue-level mechanics.

Measuring fast stochastic displacements of bio-membranes with dynamic optical displacement spectroscopy.

Stochastic displacements or fluctuations of biological membranes are increasingly recognized as an important aspect of many physiological processes, but hitherto their precise quantification in living cells was limited due to a lack of tools to accurately record them. Here we introduce a novel technique--dynamic optical displacement spectroscopy (DODS), to measure stochastic displacements of membranes with unprecedented combined spatiotemporal resolution of 20 nm and 10 µs. The technique was validated by measuring bending fluctuations of model membranes. DODS was then used to explore the fluctuations in human red blood cells, which showed an ATP-induced enhancement of non-Gaussian behaviour. Plasma membrane fluctuations of human macrophages were quantified to this accuracy for the first time. Stimulation with a cytokine enhanced non-Gaussian contributions to these fluctuations. Simplicity of implementation, and high accuracy make DODS a promising tool for comprehensive understanding of stochastic membrane processes.

Mechanical strength of specific bonds acting isolated or in pairs: a case study on engineered proteins.

The dynamic strength of multiple specific bonds exposed to external mechanical force is of significant interest for the understanding of biological adhesion. Exploiting the well-established FLAG tag technology, we engineered model proteins exhibiting no, one, or two identical binding sites for a monoclonal antibody. Bonds between these engineered proteins and the antibody were studied with dynamic force spectroscopy. On single bonds between a FLAG-tag and the antibody, we observed two regimes corresponding to two different activated complexes, that is, two intermediate states along the reaction path for bond breakage. Dynamic force spectroscopy on double bonds showed the same two regimes. The actual yield forces of double bonds slightly exceeded those of single bonds. A simplified kinetic model with analytical solutions was developed and used to interpret the measured spectra.

Tube width fluctuations in F-actin solutions.

We determine the statistics of the local tube width in F-actin solutions, beyond the usually reported mean value. Our experimental observations are explained by a segment fluid theory based on the binary collision approximation. In this systematic generalization of the standard mean-field approach, effective polymer segments interact via a potential representing the topological constraints. The analytically predicted universal tube width distribution with a stretched tail is in good agreement with the data.

Effects of stage of lactation and dietary forage level on body composition of Alpine dairy goats.

Multiparous Alpine does (42) were used to determine how stage of lactation and dietary forage level affect body composition. The feeding and body composition portion of the study had a 2 x 3 factorial arrangement of treatments. Eighteen does were fed a 40% forage diet (40F) and 18 received a diet with 60% forage (60F) for approximately 2, 4, or 6 mo of lactation (59 +/- 1.3, 116 +/- 1.0, and 184 +/- 1.4 d, respectively), followed by determination of body composition (6 does per diet at each time of slaughter). Does were assigned sequentially to treatments as kidding occurred. The 60F diet had 20% more dehydrated alfalfa pellets than the 40F diet, with higher levels of corn and soybean meal and inclusion of supplemental fat in the 40F diet. Initial body composition measures were made with 6 other does a few days after kidding (0 mo; 4 +/- 0.6 d). Before parturition, does were fed a 50% concentrate diet free choice. Intake of dry matter was greater for 60F than for 40F, average daily gain tended to be affected by an interaction between diet and month (0, 24, 121, -61, 46, and 73 g), and 4% fat-corrected milk was less in mo 5 to 6 than earlier. Internal fat mass was greatest among times at 6 mo and greater for 40F than for 60F. Mass of the gastrointestinal tract was less for 40F than for 60F and decreased with increasing time in lactation. Concentrations of fat in the carcass (13.8, 13.1, 16.5, 11.2, 11.5, and 14.4%), noncarcass tissues (18.6, 24.2, 33.3, 14.3, 16.5, and 24.5%), and empty body (16.5, 18.7, 25.2, 12.9, 14.1, and 19.5% for 40F at 2 mo, 40F at 4 mo, 40F at 6 mo, 60F at 2 mo, 60F at 4 mo, and 60F at 6 mo, respectively) were affected by stage of lactation and diet. Based on daily change in tissue mass and energy, energy concentration in tissue mobilized or accreted was 16, 20, and 32 MJ/kg in 1 to 2, 3 to 4, and 5 to 6 mo of lactation, respectively. In conclusion, based on tissue mass, more energy was expended by the gastrointestinal tract with 60F than with 40F. Considerable internal fat appeared to be mobilized in early lactation, particularly with the diet moderate to high in forage, with more rapid and a greater magnitude of repletion by does consuming the diet lower in forage. The concentration of energy in tissue mobilized or accreted varied with stage of lactation, being considerably greater at 5 to 6 mo of lactation than earlier.

Sex differences in effectiveness of extended-release stimulant medication among adolescents with attention-deficit/hyperactivity disorder.

This study examined whether adolescent females with attention-deficit/hyperactivity disorder (ADHD) are differentially responsive than their male counterparts to extended-release stimulant medications. This investigation may bear special importance for an adolescent (as opposed to child) population, because hormonal and metabolism differences between sexes are most likely to emerge at this time. Male (n = 19) and female (n = 16) adolescents, ages 16-19 with ADHD, participated in a randomized, double-blind crossover study evaluating the effectiveness of osmotic-release methylphenidate, extended release amphetamine salts, placebo, and routine limited medication regimen. Medication efficacy was evaluated using ADHD symptom ratings from adolescent self-report and parent report, along with objective measures of inattention and hyperactivity/impulsivity during driving performance and neuropsychological tasks. Males and females were largely equivalent in impairment, and medication was similarly effective in reducing symptoms. No interactions were found between sex and medication on any measure of effectiveness or side effects. This finding suggests that the efficacy and tolerability of extended-release stimulant medications is equivalent for male and female adolescents with ADHD.

Effects of breed and diet on growth and body composition of crossbred Boer and Spanish wether goats.

Sixty growing 3/4 Boer x 1/4 Spanish (BS) and Spanish (SP) wethers were used to determine influences of diet and breed on growth and body composition. A pelleted 50% concentrate diet (CD) and a diet based on grass hay (HD) were fed for ad libitum intake. Six wethers of each breed were slaughtered at 0 wk (total of 12). Six wethers of each diet-breed combination were slaughtered at 14 and 28 wk (24 per time) after consumption of the CD or HD. Initial BW of fed wethers were 21.6 and 18.8 kg for BS and SP, respectively (SEM = 0.7). Average daily gain during the entire experiment was influenced by an interaction (P < 0.05) between breed and diet (199, 142, 44, and 50 g/d for BS:CD, SP:CD, BS:HD, and SP:HD, respectively). Carcass mass was greater (P < 0.05) for CD vs. HD (56.2, 56.2, 53.2, and 54.0% of empty BW for BS:CD, SP:CD, BS:HD, and SP:HD, respectively). Mass of the liver (2.11, 1.92, 2.00, and 1.98% of empty BW; SEM = 0.05) and gastrointestinal tract (5.50, 4.83, 8.43, and 8.36% of empty BW for BS:CD, SP:CD, BS:HD, and SP:HD, respectively; SEM = 0.16) tended (P < 0.07) to be influenced by an interaction between breed and diet. Mass of internal fat (12.2, 12.1, 3.4, and 3.4% empty BW for BS:CD, SP:CD, BS:HD, and SP:HD, respectively; SEM = 0.3) differed (P < 0.05) between diets. Energy in the carcass (320, 236, 87, and 79 MJ), noncarcass tissues (318, 237, 77, and 72 MJ), and empty body (638, 472, 164, and 150 MJ) ranked (P < 0.05) BS:CD > SP:CD > BS:HD and SP:HD. Empty body concentration of protein was 18.3, 17.5, 18.3, and 19.7% (SEM = 0.3) and of fat was 24.0, 23.4, 10.8, and 10.3% for BS:CD, SP:CD, BS:HD, and SP:HD, respectively (SEM = 0.6). Energy concentration in accreted tissue was 17.0, 18.7, 16.3, and 6.4 MJ/kg for CD:wk 1 to 14, CD:wk 15 to 28, HD:wk 1 to 14, and HD:wk 15 to 28, respectively (SEM = 1.4). In conclusion, relatively high growth potential of growing Boer crossbred goats with a moderate to high nutritional plane does not entail a penalty in realized growth when the nutritional plane is low. Body composition of growing Boer and Spanish goats is fairly similar regardless of growth rate. For growing meat goats other than with a prolonged limited nutritional plane, an average energy concentration in accreted tissue is 17.3 MJ/kg.

Extended field test on the use of visual ear tags and electronic boluses for the identification of different goat breeds in the United States.

A total of 295 goats from 4 breeds (Alpine, n = 74; Angora, n = 75; Boer-cross, n = 73; Spanish, n = 73) were used to assess the retention of 3 types of electronic ruminal boluses (B1, 20 g, n = 95; B2, 75 g, n = 100; and B3, 82 g, n = 100) according to breed and feeding conditions. Time for bolus administration, reading with a handheld reader, and animal data recording (goat identification, breed, and bolus type) were registered. Each goat was also identified with 1 flag-button plastic ear tag (4.6 g, 51 x 41 mm). Retention of boluses and ear tags was regularly monitored for 1 yr. Ruminal fluid in 5 goats from each breed and management group was obtained with an oro-ruminal probe at 2 h after feeding. Ruminal pH was measured at 24 h and at wk 1, 2, 3, and 4 and used as an indicator of feeding conditions on rumen environment. Time for bolus administration differed by bolus type (B1, 14 +/- 2 s; B2, 24 +/- 2 s; B3, 27 +/- 2 s; P < 0.05) and goat breed (Alpine, 34 +/- 3 s; Angora, 17 +/- 2 s; Boer-cross, 16 +/- 1 s; Spanish, 19 +/- 2 s; P < 0.05), although differences were due to greater times for B2 and B3 in Alpine goats. Time for bolus administration averaged 22 +/- 1 s, and overall time for bolusing, reading, and data typing was 49 +/- 1 s on average. Ruminal pH differed according to breed and feeding management (lactating Alpine, 6.50 +/- 0.07; yearling Alpine, 6.73 +/- 0.07; Angora, 6.34 +/- 0.06; Boer-cross, 6.62 +/- 0.04; Spanish, 6.32 +/- 0.08; P < 0.05), but no early bolus losses occurred; rumen pH did not differ according to bolus type (B1, 6.45 +/- 0.05; B2, 6.39 +/- 0.07; B3, 6.49 +/- 0.05; P > 0.05). At 6 mo, electronic boluses showed greater retention than ear tags (99.7 vs. 97.2%; P < 0.05). At 12 mo, bolus retention was 96.3, 100, and 97.8% for B1, B2, and B3, respectively, not differing between B1 and B3 (P = 0.562). No effect of breed and bolus type on bolus retention was detected. No goat losing, at the same time, both bolus and ear tag was observed. Ear tag retention (91.7%) was less (P < 0.05) than all types of bolus (98.1%) on average. Ear tag retention in Boer-cross (98.6%) and Alpine (96.9%) goats was greater (P < 0.05) than in Spanish (88.7%) and Angora (82.9%) and tended to differ (P = 0.095) between Spanish and Alpine. In conclusion, unlike flag-button visual ear tags and mini-boluses used here, properly designed boluses (e.g., standard bolus) met International Committee for Animal Recording and National Animal Identification System retention requirements for goat identification under US conditions and are recommended in practice.

ASAS Centennial Paper: Impact of animal science research on United States goat production and predictions for the future.

Goat research in the United States has increased but at a rate less than that in production. Research on goat meat includes nutritional quality, packaging, color, sensory characteristics, and preslaughter management. Goat skins have value for leather, but quality of goat leather has not been extensively studied. Research in the production, quality, antibiotic residues, and sensory characteristics of goat milk and its products has aided development of the US dairy goat industry. Limited progress has been made in genetic improvement of milk or meat production. There is need to explore applications of genomics and proteomics and improve consistency in texture and functionality of goat cheeses. New goat meat and milk products are needed to increase demand and meet the diverse tastes of the American public. Despite research progress in control of mohair and cashmere growth, erratic prices and sale of raw materials have contributed to further declines in US production. Innovative and cooperative ventures are needed for profit sharing up to the consumer level. Internal parasites pose the greatest challenge to goat production in humid areas largely because of anthelmintic resistance. Study of alternative controls is required, including immunity enhancement via nutrition, vaccination, pasture management such as co-grazing with cattle, and genetic resistance. Similarly, the importance of health management is increasing related in part to a lack of effective vaccines for many diseases. Nutrition research should address requirements for vitamins and minerals, efficiencies of protein utilization, adjusting energy requirements for nutritional plane, acclimatization, and grazing conditions, feed intake prediction, and management practices for rapid-growth production systems. Moreover, efficient technology transfer methods are needed to disseminate current knowledge and that gained in future research.

Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder.

This study investigated whether OROS methylphenidate (OROS MPH, Concerta) or extended-release mixed amphetamine salts (se-AMPH ER, Adderall XR) were associated with worsening of driving performance, or drug rebound, relative to placebo 16-17 hours post-ingestion. Nineteen male adolescent drivers aged 17-19 with attention-deficit/hyperactivity disorder (ADHD) were compared on a virtual reality driving simulator and an on-road drive after taking 72 mg of OROS MPH, 30 mg of se-AMPH ER, or placebo. Medication was taken at 08:00 in a randomized, double-blind, placebo-controlled, crossover study. Participants drove a simulator at 17:00, 20:00, 23:00, and 01:00, and drove their own cars over a 16-mile road course at 24:00. The main outcome measures were composite scores of driving performance. Neither OROS MPH nor se-AMPH ER was associated with significant worsening of simulator performance relative to placebo 17 hours post-ingestion in group comparisons. However, inattentive on-road driving errors were significantly more common on se-AMPH ER relative to placebo at midnight (p = 0.04), suggesting possible rebound. During both late simulator and on-road testing, driving performance variance was approximately 300% greater during the se-AMPH ER compared to the OROS MPH condition.

The contribution of chevon from Africa to global meat production.

Africa's goat population increased by 75% between 1980 and 2005 and constitutes 30% of the world goat population. Although Africa produces about 20% of the world's chevon, its share of world chevon market has been declining. Exports from Africa represent less than 5% of the total world trade. Most goats are raised by smallholder farmers for subsistence and trading in informal markets. The world renowned Boer, Kalahari Red and Savanna goats are meat breeds that were developed in South Africa. Information on most African goat breeds is scanty, but there seems to be large variations in the breed characteristics, which suggests a potential for selective breeding for more and meat breeds. Recommendations for enhancing goat production in Africa include, prioritizing research and technology transfer on meat goat production, development of more chevon breeds, devising methods to enhance the quality of African chevon through pre- and post-harvest interventions, and improved support from government institutions and policy.

Toward physiological conditions for cell analyses: forces of heart muscle cells suspended between elastic micropillars.

Almost each mammalian cell permanently applies forces to its environment. These forces are essential for many vital processes such as tissue formation or cell movement. In turn, the environmental conditions of cells strongly affect force production. Here we report on the development of an array of elastomeric micropillars as cellular environment. Within these micropillar arrays, we cultivated rat heart muscle cells (cardiac myocytes). For lattice constants between 20 and 30 mum, cells strongly preferred spanning between the elastic micropillars over adhering to the underlying flat substrate. In addition, the architectures of the cytoskeleton and of protein complexes formed for adhesion were strongly dependent on the environment of the cell. On flat parts of the substrates, we observed prominent stress fibers and focal adhesion sites. In contrast, cells suspended between micropillars exhibited well organized myofibers and costameric adhesions at the locations of Z-bands. These observations argue for close-to-nature environmental conditions within micropillar arrays. Resting as well as contraction forces of myocytes resulted in measurable pillar bending. Using an approximate theoretical treatment of elastically founded micropillars, we calculated average cell forces of 140 nN in the relaxed and 400 nN in the contracted state.

Manual transmission enhances attention and driving performance of ADHD adolescent males: pilot study.

OBJECTIVE: Inattention is a major contributor to driving mishaps and is especially problematic among adolescent drivers with ADHD, possibly contributing to their 2 to 4 times higher incidence of collisions. Manual transmission has been demonstrated to be associated with greater arousal. This study tests the hypotheses that manual transmission, compared to automatic transmission, would be associated with better attention and performance on a driving simulator. METHOD: Ten adolescent drivers with ADHD practice driving on the simulator in the manual and automatic mode. Employing a single-blind, cross-over design, participants drive the simulator at 19:30 and 22:30 hr for 30 min in both transmissions and rate their attention to driving. RESULTS: Subjectively, participants report being more attentive while driving in manual transmission mode. Objectively, participants drive safer in the manual transmission mode. CONCLUSION: Although in need of replication, this pilot study suggests a behavioral intervention to improve driving performance among ADHD adolescents.

Effect of extended release stimulant-based medications on neuropsychological functioning among adolescents with Attention-Deficit/Hyperactivity Disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with diminished neuropsychological functioning. This randomized, double-blind, placebo controlled, study is the first comparison of two extended release stimulant-based medications (Adderall XR and Concerta) and placebo on ADHD neuropsychological functioning. Adolescents diagnosed with ADHD (n=35, 19 males) completed three separate assessments (5, 8, 11 p.m.) on three different days and medications (Concerta, Adderall XR and Placebo). The assessments consisted of two different neuropsychological tests, the Delayed Matching-to-Sample and the Go/No-go (GNG), which measure visual memory, attention span, and response inhibition. Results indicated a significant effect of medication on signs of impulsivity and memory. Simple contrasts showed significant improvement in neuropsychological functioning (as measured by commission errors, reaction time, and recall accuracy) when participants were taking Concerta as opposed to placebo. These results suggest that Concerta impacts not only symptomatic behaviors but also cognitive functioning, which has implications for both academic performance and daily functioning.

Relative benefits of stimulant therapy with OROS methylphenidate versus mixed amphetamine salts extended release in improving the driving performance of adolescent drivers with attention-deficit/hyperactivity disorder.

OBJECTIVE: Automobile accidents are the leading cause of death among adolescents, and collisions are 2 to 4 times more likely to occur among adolescents with attention-deficit/hyperactivity disorder. Studies have demonstrated that stimulants improve driving performance. This study compared 2 long-acting stimulant medications during daytime and evening driving evaluations. METHODS: Adolescent drivers with attention-deficit/hyperactivity disorder were compared on a driving simulator after taking 72 mg of OROS methylphenidate, 30 mg of mixed amphetamine salts extended release, or placebo in a randomized, double-blind, placebo-controlled, crossover study design. During laboratory testing, adolescents drove a driving simulator at 5:00 pm, 8:00 pm, and 11:00 pm. Driving performance was rated by adolescents and investigators. RESULTS: The study included 35 adolescent drivers with attention-deficit/hyperactivity disorder (19 boys/16 girls). The mean age was 17.8 years. The overall Impaired Driving Score demonstrated that OROS methylphenidate led to better driving performance compared with placebo and mixed amphetamine salts extended release, whereas mixed amphetamine salts extended release demonstrated no statistical improvement over placebo. Specifically, relative to placebo, OROS methylphenidate resulted in less time driving off the road, fewer instances of speeding, less erratic speed control, more time executing left turns, and less inappropriate use of brakes. OROS methylphenidate and mixed amphetamine salts extended release worked equally well for male and female adolescents and equally as well with teenagers who have combined and inattentive subtypes of attention-deficit/hyperactivity disorder. CONCLUSIONS: This study validates the use of stimulants to improve driving performance in adolescents with attention-deficit/hyperactivity disorder. In the study, OROS methylphenidate promoted significantly improved driving performance compared with placebo and mixed amphetamine salts extended release.

Theoretical analysis of single-molecule force spectroscopy experiments: heterogeneity of chemical bonds.

We show that the standard theoretical framework in single-molecule force spectroscopy has to be extended to consistently describe the experimental findings. The basic amendment is to take into account heterogeneity of the chemical bonds via random variations of the force-dependent dissociation rates. This results in a very good agreement between theory and rupture data from several different experiments.

Controlled-release methylphenidate improves attention during on-road driving by adolescents with attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with a 3- to 4-fold increase in both driving-related accidents and associated injuries. Methylphenidate (MPH) is the most commonly prescribed psychostimulant medication for ADHD. It has been demonstrated to improve performance on a driving simulator. This study investigated whether a once-daily, long-acting, osmotic, controlled-release MPH formulation improves the driving performance of ADHD adolescents while driving their own car on an actual road segment. METHODS: Twelve ADHD-diagnosed male adolescent drivers (mean age, 17.8 years) prescribed a standard dose of 1.0 mg/kg (if they were not already taking methylphenidate) of controlled-release MPH participated in this repeated-measures crossover study. On 2 separate occasions (off/on medication randomized), participants drove a standard 16-mile road course incorporating rural, highway, and urban streets. A rater, blind to medication conditions, sat in the back seat and rated impulsive (eg, "cutting off" another driver) and inattentive (eg, drove past designated turn) driving errors. RESULTS: Impulsive driving errors were observed to occur rarely under both medication and no medication conditions. Inattentive driving errors were more common and were significantly reduced while the subject was on medication (4.6 versus 7.8; P <.01). The improvement in driving performance (change in number of errors recorded) from first to second testing was positively correlated with medication dosage (r = 0.60; P <.01). CONCLUSIONS: Once-daily controlled-release MPH improves real-life driving performance of adolescent males diagnosed with ADHD. In particular, it significantly reduces driving errors arising from inattention.