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Intrusive memories of traumatic events are a core feature of post-traumatic stress disorder but little is known about the neurobiological formation of intrusions. The aim of this study was to determine whether the activity of the noradrenergic system during an intrusion-inducing stressor would influence subsequent intrusive memories. We conducted an experimental, double-blind, placebo-controlled study in 118 healthy women. Participants received a single dose of either 10 mg yohimbine, stimulating noradrenergic activity, or 0.15 mg clonidine, inhibiting noradrenergic activity, or placebo. Subsequently, they watched an established trauma film which induced intrusions. The number of consecutive intrusions resulting from the trauma film, the vividness of the intrusions, and the degree of distress evoked by the intrusions were assessed during the following 4 days. Salivary cortisol and α-amylase were collected before and after the trauma film. A significant time × treatment interaction for the number of intrusions and the vividness of intrusions indicated a different time course of intrusions depending on treatment. Post-hoc tests revealed a delayed decrease of intrusions and a delayed decrease of intrusion vividness after the trauma film in the yohimbine group compared with the clonidine and placebo groups. Furthermore, after yohimbine administration, a significant increase in salivary cortisol levels was observed during the trauma film. Our findings indicate that pharmacological activation of the noradrenergic system during an emotionally negative event makes an impact on consecutive intrusive memories and their vividness in healthy women. The noradrenergic system seems to be involved in the formation of intrusive memories.

Insulin-like growth factor-1 (IGF-1) is an endogenous peptide transported across the blood brain barrier that is protective in several brain injury models, including an acute animal model of Parkinson’s disease (PD). Motor deficits in PD are due largely to the progressive loss of nigrostriatal dopaminergic neurons. Thus, we examined the neuroprotective potential of IGF-1 in a progressive model of dopamine deficiency in which 6-hydroxydopamine (6-OHDA) is infused into the striatum. Rats received intrastriatal IGF-1 (5 or 50 µg) 6 h prior to infusion of 4 µg 6-OHDA into the same site and were euthanized 1 or 4 weeks later. Both concentrations of IGF-1 protected tyrosine hydroxylase (TH) immunoreactive terminals in striatum at 4 weeks but not at 1 week, indicating that IGF-induced restoration of the dopaminergic phenotype occurred over several weeks. TH-immunoreactive cell loss was only attenuated with 50 µg IGF-1. We then examined the effect of striatal IGF-1 on the Ras/ERK1/2 and PI3K/Akt pathways to ascertain whether their activation correlated with IGF-1-induced protection. Striatal and nigral levels of phospho-ERK1/2 were maximal 6 h after IGF-1 infusion and, with the exception of an increase in nigral pERK2 at 48 h, returned to basal levels by 7 days. Phospho-Akt (Ser473) was elevated 6-24 h post-IGF-1 infusion in both striatum and substantia nigra concomitant with inhibition of pro-death GSK-3β, a downstream target of Akt. These results suggest that IGF-1 can protect the nigrostriatal pathway in a progressive PD model and that this protection is preceded by activation of key pro-survival signaling cascades.

The objectives of this study were to examine the effects of feedlot production systems with and without the use of a β-adrenergic agonist compared to an all-natural production program on feedlot performance and carcass characteristics. Crossbred beef steers ( = 336; initial BW = 379 ± 8 kg) were randomized to 1 of 3 treatments in a randomized complete block design (RCBD; 14 steers/pen; 8 pens/treatment). Treatments consisted of an all-natural treatment (NAT), a conventional treatment (CONV), and a conventional treatment with a β-agonist (CONV-Z). All treatments were fed the same basal diet with NAT cattle receiving no growth promoting technologies. The CONV and CONV-Z cattle were implanted with 40 mg of estradiol and 200 mg of trenbolone acetate (TBA) on d 0 and were fed 33 and 9 mg/kg of monensin and tylosin daily, respectively. The CONV-Z cattle were fed zilpaterol hydrochloride (ZH) at 6.76 mg/kg (90% DM basis) for the last 20 days on feed (DOF) There was no effect of treatment on DMI ( = 0.83); however, CONV-Z steers gained 3.8% faster (1.64 vs. 1.58 kg/d; < 0.01) and were 5.3% more efficient (0.160 vs. 0.152; < 0.01) than CONV steers, and CONV steers gained 32.8% faster (1.58 vs. 1.19 kg/d; < 0.01) and were 26.7% more efficient (0.152 vs. 0.120; < 0.01) than NAT steers. There was a 35.7% improvement in estimated carcass gain (1.29 vs. 0.95 kg/d; < 0.01) and a 32.6% improvement in carcass efficiency (0.126 vs. 0.095; < 0.01) for CONV-Z steers compared to NAT steers. Hot carcass weight was increased by 8 kg for CONV-Z steers compared to CONV steers (394 vs. 386 kg; = 0.05) and 46 kg compared to NAT steers (394 vs. 348 kg; < 0.01). Longissimus muscle area was increased by 3.6 cm for CONV-Z steers compared to CONV steers (92.29 vs. 88.67 cm; = 0.02) and 12.1 cm for CONV-Z steers compared to NAT steers (92.29 vs. 80.16 cm; < 0.01), resulting in a 9.6% unit increase in USDA yield grade (YG) 1 (15.14 vs. 5.52%; < 0.05) and a 21.6% unit reduction in USDA YG 3 for CONV-Z steers compared to CONV steers (30.70 vs. 52.32%; < 0.05). The CONV-Z steers had a lower marbling score compared to the other treatments (432; 0.01), resulting in an 11.7% unit increase (20.70 vs. 9.03%; < 0.05) in USDA Select carcasses compared to CONV steers. The results of this experiment show that CONV-Z and CONV production results in a significant improvement in feedlot performance and USDA YG compared to NAT.

To determine the echocardiographic changes over time of valvular heart lesions in patients who took the weight loss drugs fenfluramine and phentermine. This prospective cohort study began at the termination of a randomized, double-blind, placebo-controlled weight loss trial of 18 obese women and 13 obese men (mean age, 42 years; mean body mass index, 33.4 kg/m 2) who had been assigned randomly to treatment with fenfluramine and phentermine or to placebo. Echo-cardiograms were obtained at termination of the trial when fenfluramine was withdrawn from the market and 6 months later. They were interpreted independently by 3 cardiologists blinded to treatment assignment and temporal sequence of the echocardiograms. The main outcome measure was the change in drug-related valvular disease over time. One subject assigned to receive the drugs was lost to follow-up, and 3 subjects who did not meet a weight loss goal of 10 kg crossed over from placebo to drug treatment. Echocardiograms were obtained in 19 subjects who received the drugs and 11 subjects who received placebo, and 6-month follow-up echocardiograms were obtained in 15 subjects who received the drugs and 3 who received placebo. Subjects had taken fenfluramine and phentermine a mean of 41 weeks (range, 8-73 weeks). Five of 19 subjects who received the drugs (26%; 95% confidence interval, 7%-46%) and 1 of 11 who received placebo (9%) (odds ratio, 3.6; 95% confidence interval, 0.4-35.6) had findings that met criteria established for drug-related valvular disease. All 5 subjects (4 women and 1 man) receiving the drugs had mild aortic regurgitation, and 1 also had pulmonary hypertension (estimated pulmonary artery pressure, 59 mm Hg). Six months later, the echocardiographic findings had improved in all 5 subjects ( P=.06), and 3 no longer met the criteria for drug-related valvular disease. Pulmonary artery pressures decreased to near normal in the subject with pulmonary hypertension (37 mm Hg). Overall, the echocardiographic valvular features improved in 8 of 15 subjects who received the drugs and had echocardiograms performed at both time periods (P=.008). Valvular heart disease did not appear to progress after cessation of use of fenfluramine and phentermine, and echocardiographic valvular features appeared to improve over time.

British and British x Continental steers (n = 560; initial BW = 339.4 ± 1.76 kg) were used in a serial slaughter study with a completely random design to evaluate effects of zilpaterol hydrochloride (ZH; 8.33 mg/kg of dietary DM basis) on performance and carcass characteristics. Treatments were arranged in a 4 x 4 factorial (112 pens; 7 pens/treatment; 5 steers/pen) and included duration of ZH feeding (0, 20, 30, or 40 d before slaughter plus a 3-d ZH withdrawal period) and days on feed (DOF) before slaughter (136, 157, 177, and 198 d). No duration of ZH feeding x slaughter group interactions were detected for the performance measurements (P > 0.10). Final BW did not differ (P = 0.15) between the 0-d group and the average of the 3 ZH groups, but ADG was greater for the average of the 3 ZH groups during the period in which ZH diets were fed (P < 0.01) and for the overall feeding period (P = 0.05). As duration of ZH feeding increased, DMI decreased (P = 0.01) and G:F increased linearly (P < 0.01). With the exception of KPH (P = 0.022), no duration of ZH feeding x slaughter group interactions (P > 0.10) were detected for carcass characteristics. Regardless of the duration of ZH feeding, cattle fed ZH had greater HCW (P < 0.01), greater dressing percent (P < 0.01), less 12th-rib fat (P < 0.01), larger LM area (P < 0.01), less KPH (P = 0.03), and lower yield grade (P < 0.01) than the 0-d cattle. The 0-d group had greater marbling scores (P < 0.01) than cattle fed ZH diets, with a tendency for a linear decrease in marbling score (P = 0.10) as duration of ZH feeding was extended. A greater percentage of carcasses in the 0-d group graded USDA Choice or greater (P < 0.01) than in the 3 ZH groups, whereas the percentage of Select carcasses was greater (P = 0.01) for the 3 ZH groups. From d 0 to end (P = 0.04) and during the last 43 d on feed (P < 0.01), ADG responded quadratically to DOF before slaughter. No differences were detected among slaughter groups for DMI for the entire trial period; however, a quadratic response (P = 0.02) was observed for the final 43 d before slaughter. A quadratic response was also detected for the final 43 d before slaughter (P < 0.01) and from d 0 to end (P = 0.02) for G:F. Final BW, HCW, dressing percent, and 12th-rib fat increased linearly (P < 0.01) as DOF before slaughter increased. Our results indicate that no substantial effects on performance and carcass measurements were observed when ZH was fed for 30 or 40 d as opposed to 20 d, and that effects of ZH generally did not interact with DOF before slaughter.

Four trials, each with a randomized complete block design, were conducted with 8,647 beef steers (initial BW = 346 ± 29.6 kg) in 3 different locations in the United States to evaluate the effects of zil-paterol hydrochloride (ZH) on performance and carcass characteristics of feedlot cattle. Treatments consisted of feeding ZH (8.33 mg/kg of dietary DM) for 0, 20, 30, or 40 d, at the end of the feeding period, followed by a 3-d withdrawal period before slaughter. Cattle were weighed on d 0 and 50 before slaughter (in 3 of the 4 studies), and on the day of slaughter. Data from the 4 trials were pooled for statistical analyses. No differences (P greater-than-or-equal 0.78) were detected among treatments for ADG and G:F from the start of the study until the final 50 d on feed. Final BW was greater for the average of the 3 ZH-treated groups (P < 0.01) than for the 0-d group. Average daily gain was greater for ZH-treated vs. control cattle during the final 50 d on feed (P < 0.01) and for the entire feeding period (P < 0.01). No differences in DMI were noted for any periods of the experiment (P greater-than-or-equal 0.42) for ZH-treated cattle vs. controls. No differences were noted for DMI among the ZH-treated groups for the final 50 d on feed (P = 0.81) or for the overall feeding period (P = 0.31). Feeding ZH for any length of time increased G:F (P < 0.01) for the final 50 d and overall compared with 0-d cattle. In addition, a linear increase with more days of ZH feeding was observed for G:F during the period that ZH was fed (P = 0.01), as well as for the overall feeding period (P = 0.01). The ZH-treated cattle had heavier HCW (P < 0.01), greater dressing percent (P < 0.01), reduced marbling scores (P < 0.01), less 12th-rib fat (P < 0.01), larger LM area (P < 0.01), less KPH (P = 0.01), and a lower USDA yield grade (P < 0.01) than the 0-d cattle, regardless of the duration of ZH feeding. Dressing percent increased linearly (P < 0.01) with increased duration of ZH feeding, whereas 12th-rib fat (P = 0.07), marbling scores (P < 0.01), and USDA calculated yield grade (P = 0.01) decreased linearly with increased duration of ZH feeding. Feeding ZH increased ADG and G:F and decreased overall carcass fatness. In addition, effects of ZH on measures of carcass fatness were enhanced by feeding the product for a greater length of time.

Rationale Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established. Objectives In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or parachloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed. Methods In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high-pressure liquid chromatography. Results Exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance. Conclusions These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions.

Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old. The results showed enhanced amphetamine self-administration in PE animals. In PE animals, we observed a persistent augmentation in calcium-permeable AMPA receptor (CP-AMPAR) expression, indicated by increased rectification and reduced decay time of AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), enhanced depression of AMPAR-EPSCs by NASPM (a selective CP-AMPAR antagonist), and increased GluA3 subunits in VTA DA neuron dendrites. Increased CP-AMPAR expression in PE animals led to enhanced excitatory synaptic strength and the induction of CP-AMPAR-dependent long-term potentiation (LTP), an anti-Hebbian form of LTP. These observations suggest that, in PE animals, increased excitatory synaptic strength in VTA DA neurons might be susceptible to further strengthening even in the absence of impulse flow. The PE-induced persistent increase in CP-AMPAR expression, the resulting enhancement in excitatory synaptic strength, and CP-AMPAR-dependent LTP are similar to effects observed after repeated exposure to drugs of abuse, conditions known to increase addiction risk. Therefore, these mechanisms could be important neuronal substrates underlying PE-induced enhancement in amphetamine self-administration and increased addiction risk in individuals with fetal alcohol spectrum disorders.

Parkinson’s disease (PD) is a disorder characterized by a progressive loss of the dopaminergic neurons in the substantia nigra and a depletion of the neurotransmitter dopamine in the striatum. Our published results indicate that fasciculation and elongation protein zeta-1 (FEZ1) plays a role in the astrocyte-mediated protection of dopamine neurons and regulation of the neuronal microenvironment during the progression of PD. In this study, we examined the effects of engrafted type-2 astrocytes (T2As) with high expression of FEZ1 on the improvement of the symptoms and functional reconstruction of PD rats. T2As were stereotactically transplanted into the striatum of rats with PD induced by 6-hydroxydopamine (6-OHDA). An examination of apomorphine (APO)-induced rotations was performed to evaluate dopamine neuron damage and motor functions. Remarkably, the grafted cells survived in the lesion environment for six weeks or longer after implantation. In addition, the transplantation of T2As decrease the average velocity and the duration time of the APO-induced rotations, and increase the actuation time, as measured in the rotation behavioural tests. In the substantia nigra, the transplantation of T2As reduced the PD-induced GFAP, TH and FEZ1 downregulation. The grafted cells exclusively migrated to other regions near the injection site in the striatum and differentiated into GFAP+ astrocytes or TH+ neurons. Furthermore, by detecting monoamine neurotransmitters through high-performance liquid chromatography, we found that the nigrostriatal pathway had been repaired to some extent. Taken together, these results suggest that engrafted T2As with high expression of FEZ1 improved the symptoms and functional reconstruction of PD rats, providing a theoretical basis for FEZ1 as a potential target and engraftment of T2As as a therapeutic strategy in the treatment of PD.

Serial harvests were conducted using Holstein steers ( = 110) fed zilpaterol hydrochloride (ZH) for 0 or 20 d prior to harvest. Steers were harvested in 28-d increments beginning at 254 d on feed (DOF) and ending at 534 DOF. After harvest and a 36-h chill period, carcasses were evaluated using grading methods standard for the United States (USDA), Canada (Canadian Beef Grading Association [CBGA]), and Japan (Japanese Meat Grading Agency [JMGA]). No ZH treatment differences ( = 0.81) were detected for 12th-rib fat thickness; however, additional DOF resulted in a daily linear increase ( < 0.01) of 12th-rib fat thickness by 0.004 cm/d. Longissimus muscle area was increased ( < 0.01) by 8.7 cm with ZH supplementation and linearly increased ( < 0.01) 0.08 cm2/d with additional DOF. Calculated USDA yield grade (YG) decreased ( < 0.01) 0.33 units due to ZH treatment and linearly increased ( < 0.01) 0.009 units/d. Steers supplemented with ZH exhibited increased ( < 0.01) CGBA LM width; however, no difference ( = 0.37) was detected in CGBA LM length. No ZH treatment differences ( = 0.64) were observed for CBGA fat class; however, CGBA fat class linearly increased ( < 0.01) by 0.01 units/d. No ZH differences ( ≥ 0.17) were detected for the CBGA estimated lean percentage or YG equations. Evaluation for JMGA occurs at the sixth and seventh rib interface; LM area was 4.6 cm2 greater ( = 0.02) for cattle supplemented with ZH and linearly increased ( < 0.01) by 0.07 cm2/d with additional DOF. Subcutaneous fat thickness was not different among ZH treatments ( = 0.10) but linearly ( < 0.04) increased ( < 0.01) by 0.005 cm/d with additional DOF using the JMGA grading method. No difference ( ≥ 0.21) was calculated between ZH treatments or DOF for JMGA estimated yield. No ZH treatment differences ( = 0.85) were detected in USDA marbling score; however, marbling linearly increased ( < 0.01) 0.07 units/d. These data illustrate the impact of ZH and increasing DOF on economically important carcass grading outcomes used in the USDA, CBGA, and JMGA grading programs.