Social threat exposure in juvenile mice promotes cocaine-seeking by altering blood clotting and brain vasculature

Childhood maltreatment is associated with increased severity of substance use disorder and frequent relapse to drug use following abstinence. However, the molecular and neurobiological substrates that are engaged during early traumatic events and mediate the greater risk of relapse are poorly understood and knowledge of risk factors is to date extremely limited. In this study, we modeled childhood maltreatment by exposing juvenile mice to a threatening social experience (social stressed, S-S). We showed that S-S experience influenced the propensity to reinstate cocaineseeking after periods of withdrawal in adulthood. By exploring global gene expression in blood leukocytes we found that this behavioral phenotype was associated with greater blood coagulation. In parallel, impairments in brain microvasculature were observed in S-S mice. Furthermore, treatment with an anticoagulant agent during withdrawal abolished the susceptibility to reinstate cocaine-seeking in S-S mice. These findings provide novel insights into a possible molecular mechanism by which childhood maltreatment heightens the risk for relapse in cocaine-dependent individuals

Experimental and modeling investigation of the laminar flame speeds for ammonia with various oxygen and diluent mixtures

The study utilizes two spherical bombs to explore the Laminar Flame Speed (LFS) and Markstein length of oxygen-enriched ammonia flames and ammonia combined with different oxidizers (N 2 with 21% and 30% O 2 and He with 21% O 2 ). The experiments cover a range of initial conditions, exploring temperatures from 309 K to 423 K and an equivalence ratio spanning from 0.8 to 1.3, all at an initial pressure of 1 bar. At the same time, three established literature mechanisms (Stagni, Shrestha, and Zhang) are used to simulate the data and perform kinetic analysis. A detailed analysis focuses on how the radius of the domain affects LFS, highlighting the importance of a larger domain, in contrast with findings from previous literature. The findings highlighted that, although LFS increased (as expected) with the increase in the initial temperature, the Markstein length remains largely unaffected in oxygen-enriched ammonia flames. This was also calculated using Bechtold and Matalon 's approach, and the results were in a good agreement with the experimental values. The study determines alpha exponents across an equivalence ratio range of 0.8 to 1.3, and also found that the inert gas has varying effects on both LFS and Markstein length. Buoyancy effects were noticeable in the ammonia/air experiments, particularly at lower temperatures, challenging existing literature heavily focused on ammonia blends at temperatures below 400 K, potentially contributing to data discrepancies observed in prior studies

Rediscovering Trazodone for the Treatment of Major Depressive Disorder

Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). The drug is approved and marketed in several countries worldwide for the treatment of major depressive disorder (MDD) in adult patients. In clinical studies, trazodone has demonstrated comparable antidepressant activity to other drug classes, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Moreover, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (i.e. insomnia, anxiety and sexual dysfunction). Recent focus has been placed on the development of a new prolonged-release once-a-day formulation of trazodone (TzCOAD), which may provide improved tolerability over the conventional immediate-release formulation of trazodone. Clinical studies have led to the recent approval in the USA of TzCOAD (as Oleptro™; Angelini Labopharm LLC, Princeton, NJ, USA), which may see resurgence of interest in the drug for the management of patients with MDD. Although trazodone is approved for the treatment of depression, evidence supports the use of low-dose trazodone as an off-label hypnotic for the treatment of sleep disorders in patients with MDD. The most common adverse effects reported with trazodone are drowsiness (somnolence/sedation), headache, dizziness and dry mouth. Other events reported, albeit with low incidence, include orthostatic hypotension (particularly in elderly patients or those with heart disease), minimal anticholinergic activity, corrected QT interval prolongation and torsade de pointes, cardiac arrhythmias, and rare occurrences of priapism and suicidal ideation. Overall, trazodone is an effective and well tolerated antidepressant (SARI) with an important role in the current treatment of MDD both as monotherapy and as part of a combination strategy. Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance

Prediction of flammable range of benzene/N2/O2/H2O mixtures using detailed kinetics

This research introduces an innovative approach to predict benzene Lower and Upper Flammability Limits (LFL and UFL). The focus of this study is on predicting the flammable range of benzene/air/steam mixtures utilizing a freely -propagating flame method, incorporating an optically -thin approximation to model soot radiation. The investigation delves into the consequences of dilution by inert gases (N 2 and steam), along with the impacts of pressure and initial temperature. Soot is recognized as essential not only for its role in flame chemistry under rich conditions but also for its influence on radiation, thereby affecting the flammable region of hydrocarbons especially at higher temperatures and pressures. To address the significant formation of soot during benzene combustion near the UFL, the study integrates the kinetic model for benzene combustion with a recently developed soot mechanism based on the discrete sectional method, which has been validated extensively against a large database of sooting flames, encompassing various hydrocarbons, including benzene. To limit the computational effort associated with predicting flammability limits, a skeletal version (with 136 species and 4788 reactions) of the overall kinetic model covering benzene combustion and soot formation is developed and validated in this work. The kinetic model was first validated against new and existing benzene flame speed data at different pressures and initial temperatures. Then it was used to investigate the flammable range. The model predictions align remarkably well with the available experimental data in the literature for the LFL, for the effect of dilution with inert gases, and with some experimental measurements for the UFL. An extensive review of these experimental data revealed significant uncertainty in characterizing benzene ' s UFL experimentally, both in terms of absolute value and effect of initial temperature. The comprehensive model predictions provide valuable insights, enabling differentiation among various UFL datasets for benzene

Response to Cummins and Finaret (2019)

We thank Joseph Cummins and Amelia Finaret for their interest in our article (Comandini et al., 2019) and their insightful comments, which allowed us to further discuss the issue of age imprecision in nutritional studies. In this response, we aim to stress some points that interfere with the analysis of the three major concerns highlighted by the authors

Clinical evaluation of switching from immediate-release to prolonged-release lithium in bipolar patients, poorly tolerant to lithium immediate-release treatment: A randomized clinical trial

open13Aim: The effect of switching from lithium immediate release (Li-IR) to lithium prolonged release (Li-PR) on lithium-induced tremor after 1 and 12 weeks of treatment was evaluated in a randomized, multicenter, open trial, in bipolar patients from the participating sites with a tremor severity ≥2 (Udvalg for Kliniske Undersøgelser [UKU] rating scale) despite optimal lithium titration. Methods: The primary endpoint was the evaluation of tremor by means of the UKU scale after 1 week of treatment. Secondary endpoints included manic Young Mania Rating Scale (YMRS) and depressive symptoms (Montgomery-Asberg Depression Rating Scale), a global assessment of the patient's status (Clinical Global Impression), polyuria/polydipsia (UKU item 3.8) and patient-reported outcomes. Results: Owing to difficulties in including suitable patients the enrollment phase was closed when 73 patients were randomized. Notwithstanding the lower number of patients, in the modified intention-to-treat population (n = 70) the primary endpoint was statistically significant: tremor improved after 1 week in 62.9% in Li-PR group against 20.0% of patients in Li-IR group (p = .0006; two-tailed Fisher's exact test). The difference remained statistically significant after 4 (p = .0031) and 12 weeks (p = .0128). The same analysis performed in the PP population confirmed these results. Among the secondary endpoints, only the factor convenience of the treatment satisfaction questionnaire showed a statistically significant difference between groups. There were no apparent differences in the safety profile of the two formulations. Conclusions: This study is the first comparative documentation of a potential benefit of the prolonged-release formulation in reducing the symptom tremor, a well-known adverse effect of lithium therapy. Indeed, the study results should be interpreted taking into account the sample size lower than planned.openPelacchi, Federica; Dell'Osso, Liliana; Bondi, Emi; Amore, Mario; Fagiolini, Andrea; Iazzetta, Paolo; Pierucci, Daniela; Gorini, Manuela; Quarchioni, Elisa; Comandini, Alessandro; Salvatori, Enrica; Cattaneo, Agnese; Pompili, MaurizioPelacchi, Federica; Dell'Osso, Liliana; Bondi, Emi; Amore, Mario; Fagiolini, Andrea; Iazzetta, Paolo; Pierucci, Daniela; Gorini, Manuela; Quarchioni, Elisa; Comandini, Alessandro; Salvatori, Enrica; Cattaneo, Agnese; Pompili, Maurizi

A randomized, double-blind study comparing the efficacy and safety of trazodone once-a-day and venlafaxine extended-release for the treatment of patients with major depressive disorder

This double-blind, randomized study evaluated the efficacy and safety of trazodone OAD (once-a-day) in comparison with venlafaxine XR (extended-release) in 324 patients (166 trazodone and 158 venlafaxine) with major depressive disorder (MDD). The primary efficacy endpoint was the mean change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) at week 8. Both treatments were effective in reducing the HAM-D-17 total score at week 8 vs. baseline (intent-to-treat: trazodone -12.9, venlafaxine -14.7; per protocol: trazodone -15.4, venlafaxine -16.4). Patients in the venlafaxine group achieved better results after 8 weeks, whereas the trazodone group achieved a statistically significant reduction in HAM-D-17 following only 7 days of treatment. The most frequent adverse events (AEs) were dizziness and somnolence in the trazodone group, and nausea and headache in the venlafaxine group. Most AEs were mild-to-moderate in severity. This study confirmed that both venlafaxine XR and trazodone OAD may represent a valid treatment option for patients with MDD

Compliance with the breakthrough cancer pain European guidelines and impact on patients' quality of life: an observational prospective study

IntroductionThis study aimed to assess the percentage of patients treated according to the European Society for Medical Oncology (ESMO) 2018 guidelines for breakthrough cancer pain (BTcP) and the impact of guidelines adherence on patients' quality of life (QoL).MethodsAdult opioid-tolerant patients diagnosed with BTcP and locally advanced or recurrent metastatic cancer with a life expectancy of >3 months prospectively were included. Patients were followed up for 28 days.ResultsOf 127 patients included, 37 were excluded due to the impossibility to establish adherence to the ESMO guidelines. Among the evaluable patients [51.1% female; with mean (SD) age of 66.4 (11.8) years], all were adherent. BTcP was diagnosed by the Association for Palliative Medicine algorithm in 47.8% of patients and by clinical experience in 52.2% of patients. The mean number of daily BTcP episodes ranged between 1 and 8, with a mean (95% CI) severity of 7.3 (7.0; 7.6) at week 0 and 6.2 (5.8; 6.6) at week 4. Time to maximum pain intensity was 3–15 min in 52.2% of patients, and BTcP lasted 30–60 min in 14.4% of patients at week 0 and 4.4% of patients at week 4. Mean (95% CI) treatment effectiveness was 6.6 (6.1; 7.1) at week 0 and 7.4 (7.0; 7.8) at week 4. Median (Q1–Q3) patients' global impression of clinical condition was 4.0 (4.0–4.0) at week 0 and 3.0 (2.0–3.0) at week 4.ConclusionA clear BTcP assessment and strict follow-up could be crucial to guidelines adherence and for patient's QoL

Guideline-Based Follow-Up Outcomes in Patients With Gastrointestinal Stromal Tumor With Low Risk of Recurrence: A Report From the Italian Sarcoma Group

Importance: Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure. Objective: To evaluate the outcomes of guideline-based follow-up in low-risk GIST. Design, setting, and participants: This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up. Exposures: All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines. Main outcomes and measures: The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed. Results: A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients. Conclusions and relevance: In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy