Self-excitation of Leidenfrost drops and consequences on their stability.

Volatile liquids (water, alcohol, etc.) poured on hot solids levitate above a layer of vapor. Unexpectedly, these so-called Leidenfrost drops often suddenly start to oscillate with star shapes, a phenomenon first reported about 140 y ago. Similar shapes are known to be triggered when a liquid is subjected to an external periodic forcing, but the unforced Leidenfrost case remains unsolved. We show that the levitating drops are excited by an intrinsic periodic forcing arising from a vibration of the vapor cushion. We discuss the frequency of the vibrations and how they can excite surface standing waves possibly amplified under geometric conditions of resonance-an ensemble of observations that provide a plausible scenario for the origin, mode selection, and sporadic nature of the Leidenfrost stars.

Safety and activity of anti-CD14 antibody IC14 (atibuclimab) in ALS: Experience with expanded access protocol.

INTRODUCTION/AIMS: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 in an acute treatment setting. We provided long-term treatment with IC14 to individuals with ALS via an expanded access protocol (EAP) and documented target engagement, biomarker, safety, and disease endpoints. METHODS: Participants received intravenous IC14 every 2 weeks. Consistent with United States Food and Drug Administration guidelines, participants were not eligible for clinical trials and the EAP was inclusive of a broad population. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), IC14 levels, and antidrug antibodies. Ex vivo T-regulatory functional assays were performed in a subset of participants. RESULTS: Seventeen participants received IC14 for up to 103 weeks (average, 30.1 weeks; range, 1 to 103 weeks). Treatment-emergent adverse events (TEAEs) were uncommon, mild, and self-limiting. There were 18 serious adverse events (SAEs), which were related to disease progression and unrelated or likely unrelated to IC14. Three participants died due to disease progression. Monocyte CD14 RO increased for all participants after IC14 infusion. One individual required more frequent dosing (every 10 days) to achieve over 80% RO. Antidrug antibodies were detected in only one participant and were transient, low titer, and non-neutralizing. DISCUSSION: Administration of IC14 in ALS was safe and well-tolerated in this intermediate-size EAP. Measuring RO guided dosing frequency. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

INTRODUCTION/AIMS: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. METHODS: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. RESULTS: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. CONCLUSION: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

Accelerating diagnosis of Parkinson's disease through risk prediction.

BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.

A Ketogenic Diet Is Acceptable in Women with Ovarian and Endometrial Cancer and Has No Adverse Effects on Blood Lipids: A Randomized, Controlled Trial.

Ketogenic diets (KDs) are emerging as effective therapies for several chronic diseases, including cancer. However, concerns regarding safety and adherence may prevent clinicians from prescribing KDs. We hypothesized that a KD does not negatively affect blood lipid profile compared to a lower-fat diet in ovarian and endometrial cancer patients, and that KD subjects would demonstrate acceptable adherence. Subjects were randomized to either a KD (70% fat, 25% protein, 5% carbohydrate), or the American Cancer Society diet (ACS; high-fiber and lower-fat). Blood lipids and ketones were measured at baseline and after 12 weeks of the assigned intervention. Adherence measures included urinary ketones in the KD and 4 days' diet records. Diet records were also examined to identify general patterns of consumption. Differences between the diets on blood lipids and dietary intake were assessed with Analysis of covariance and independent t-tests. Correlation analyses were used to estimate associations between dietary intake and serum analytes. At 12 weeks, there were no significant differences between diet groups in blood lipids, after adjusting for baseline values and weight loss. Adherence among KD subjects ranged from 57% to 80%. These findings suggest that KDs may be a safe and achievable component of treatment for some cancer patients.

On the shape of giant soap bubbles.

We study the effect of gravity on giant soap bubbles and show that it becomes dominant above the critical size [Formula: see text], where [Formula: see text] is the mean thickness of the soap film and [Formula: see text] is the capillary length ([Formula: see text] stands for vapor-liquid surface tension, and [Formula: see text] stands for the liquid density). We first show experimentally that large soap bubbles do not retain a spherical shape but flatten when increasing their size. A theoretical model is then developed to account for this effect, predicting the shape based on mechanical equilibrium. In stark contrast to liquid drops, we show that there is no mechanical limit of the height of giant bubble shapes. In practice, the physicochemical constraints imposed by surfactant molecules limit the access to this large asymptotic domain. However, by an exact analogy, it is shown how the giant bubble shapes can be realized by large inflatable structures.

A Ketogenic Diet Reduces Central Obesity and Serum Insulin in Women with Ovarian or Endometrial Cancer.

Background: The glycolytic nature of cancer cells presents a potential treatment target that may be addressed by a ketogenic diet (KD). Objective: We hypothesized that a KD would improve body composition and lower serum insulin and insulin-like growth factor-I (IGF-I) in women with ovarian or endometrial cancer. Methods: In this randomized controlled trial, women with ovarian or endometrial cancer [age: ≥19 y; body mass index (kg/m2): ≥18.5] were randomly assigned to a KD (70:25:5 energy from fat, protein, and carbohydrate) or the American Cancer Society diet (ACS; high-fiber, low-fat). Body composition (DXA) and fasting serum insulin, IGF-I, and ß-hydroxybutyrate were obtained at baseline and at 12 wk; urinary ketones were also measured throughout the intervention. We assessed differences between the diets with ANCOVA and independent t tests. We used correlation analyses to estimate associations between changes in serum analytes and body composition. Results: After 12 wk, the KD (compared with ACS) group had lower adjusted total (35.3 compared with 38.0 kg, P < 0.05) and android (3.0 compared with 3.3 kg, P < 0.05) fat mass. Percentage of change in visceral fat was greater in the KD group (compared with the ACS group; -21.2% compared with -4.6%, P < 0.05). Adjusted total lean mass did not differ between the groups. The KD (compared with ACS) group had lower adjusted fasting serum insulin (7.6 compared with 11.2 µU/mL, P < 0.01). There was a significant inverse association between the changes in serum ß-hydroxybutyrate and IGF-I concentrations (r = -0.57; P < 0.0001). Conclusions: In women with ovarian or endometrial cancer, a KD results in selective loss of fat mass and retention of lean mass. Visceral fat mass and fasting serum insulin also are reduced by the KD, perhaps owing to enhanced insulin sensitivity. Elevated serum ß-hydroxybutyrate may reflect a metabolic environment inhospitable to cancer proliferation. This trial was registered at www.clinicaltrials.gov as NCT03171506.

Capillary muscle.

The contraction of a muscle generates a force that decreases when increasing the contraction velocity. This "hyperbolic" force-velocity relationship has been known since the seminal work of A. V. Hill in 1938 [Hill AV (1938) Proc R Soc Lond B Biol Sci 126(843):136-195]. Hill's heuristic equation is still used, and the sliding-filament theory for the sarcomere [Huxley H, Hanson J (1954) Nature 173(4412):973-976; Huxley AF, Niedergerke R (1954) Nature 173(4412):971-973] suggested how its different parameters can be related to the molecular origin of the force generator [Huxley AF (1957) Prog Biophys Biophys Chem 7:255-318; Deshcherevskii VI (1968) Biofizika 13(5):928-935]. Here, we develop a capillary analog of the sarcomere obeying Hill's equation and discuss its analogy with muscles.

Lifestyle Intervention for the Prevention of Cardiovascular Disease.

Lifestyle medicine is a cornerstone of cardiovascular disease prevention and early disease intervention. A leading cause of death in developed countries, modifiable risk factors of cardiovascular disease like diet, exercise, substance use, and sleep hygiene have significant impacts on population morbidity and mortality. One should address these amendable risks in all patients, independently, and stress the importance of intervention adherence while avoiding the sacrifice of patient trust. One must also understand a patient's psychological well-being can be compromised by organic chronic disease states, and poor psychological well-being can have a negative impact on patient compliance and overall health.

Individualized physiology-based digital twin model for sports performance prediction: a reinterpretation of the Margaria-Morton model.

Performance in many racing sports depends on the ability of the athletes to produce and maintain the highest possible work i.e., the highest power for the duration of the race. To model this energy production in an individualized way, an adaptation and a reinterpretation (including a physiological meaning of parameters) of the three-component Margaria-Morton model were performed. The model is applied to the muscles involved in a given task. The introduction of physiological meanings was possible thanks to the measurement of physiological characteristics for a given athlete. A method for creating a digital twin was therefore proposed and applied for national-level cyclists. The twins thus created were validated by comparison with field performance, experimental observations, and literature data. Simulations of record times and 3-minute all-out tests were consistent with experimental data. Considering the literature, the model provided good estimates of the time course of muscle metabolite concentrations (e.g., lactate and phosphocreatine). It also simulated the behavior of oxygen kinetics at exercise onset and during recovery. This methodology has a wide range of applications, including prediction and optimization of the performance of individually modeled athletes.

Domestication reduces caterpillar response to auditory predator cues.

Domestication can lead to significant changes in the growth and behavior of organisms. While the threat of predation is a strong selective force in the wild, the relaxation or removal of this threat in captive-rearing environments selects for reduced sensitivity to biotic stressors. Previous work has documented such changes in other taxa, but no work has been done on domestication-related losses of predation risk sensitivity in insects. We exposed both wild and domesticated (>50 generations in captivity) Lymantria dispar dispar (Lepidoptera: Erebidae) larvae to recordings of predators (wasp buzzing), nonpredators (mosquito buzzing), or no sound to compare the effects of predation risk on the two stocks. Wasp buzzing, but not mosquito buzzing, decreased survival of wild caterpillars relative to the control; domesticated caterpillars showed no such response. Domesticated L. dispar larvae appear to have reduced sensitivity to predation risk cues, suggesting that captive-reared insects may not always be analogs to their wild counterparts for risk-related behavioral studies.

Disease progression strikingly differs in research and real-world Parkinson's populations.

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data and recent advances in natural language processing, particularly large language models, allow for a more granular comparison of populations and the methods of data collection describing these populations than previously possible. This study includes two research populations and two real-world data derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using natural language processing with a large language model to extract measurements of PD progression. This extraction process is manually validated for accuracy. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p<0.001; mini-mental state exam median decline 0.28 vs. 0.11, p<0.001; and clinically recognized cognitive decline, p=0.001). In the real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p<0.001). After diagnosis, in real-world cohorts, treatment with PD medications is initiated 2.3 years later on average (95% CI: [2.1-2.4]; p<0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging using existing data. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

Disease progression strikingly differs in research and real-world Parkinson's populations.

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data, and advances in natural language processing, particularly large language models, allow for a more granular comparison of populations than previously possible. This study includes two research populations and two real-world data-derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using a manually validated natural language processing with a large language model to extract measurements of PD progression. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p < 0.001; mini-mental state exam median decline 0.28 vs. 0.11, p < 0.001; and clinically recognized cognitive decline, p = 0.001). In real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p < 0.001). After diagnosis, in real-world cohorts, treatment with PD medications has initiated an average of 2.3 years later (95% CI: [2.1-2.4]; p < 0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real-world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

High- and normal-protein diets improve body composition and glucose control in adults with type 2 diabetes: a randomized trial.

OBJECTIVE: Weight loss of ≥10% improves glucose control and may remit type 2 diabetes (T2D). High-protein (HP) diets are commonly used for weight loss, but whether protein sources, especially red meat, impact weight loss-induced T2D management is unknown. This trial compared an HP diet including beef and a normal-protein (NP) diet without red meat for weight loss, body composition changes, and glucose control in individuals with T2D. METHODS: A total of 106 adults (80 female) with T2D consumed an HP (40% protein) diet with ≥4 weekly servings of lean beef or an NP (21% protein) diet excluding red meat during a 52-week weight loss intervention. Body weight, body composition, and cardiometabolic parameters were measured before and after intervention. RESULTS: Weight loss was not different between the HP (-10.2 ± 1.6 kg) and NP (-12.7 ± 4.8 kg, p = 0.336) groups. Both groups reduced fat mass and increased fat-free mass percent. Hemoglobin A1c, glucose, insulin, insulin resistance, blood pressure, and triglycerides improved, with no differences between groups. CONCLUSIONS: The lack of observed effects of dietary protein and red meat consumption on weight loss and improved cardiometabolic health suggests that achieved weight loss, rather than diet composition, should be the principal target of dietary interventions for T2D management.

Auditory predator cues decrease herbivore survival and plant damage.

The high fitness cost of predation selects prey capable of detecting risk cues and responding in ways that reduce their vulnerability. While the impacts of auditory predator cues have been extensively researched in vertebrate prey, much less is known about invertebrate species' responses and their potential to affect the wider food web. We exposed larvae of Spodoptera exigua, a slow-moving and vulnerable herbivore hunted by aerial predators, to recordings of wasp buzzing (risk cue), mosquito buzzing (no-risk cue), or a no-sound control in both laboratory and field settings. In the laboratory, wasp buzzing (but not mosquito buzzing) reduced survival relative to the control; there was, however, no effect on time to or weight at pupation in survivors. In the field, wasp buzzing reduced caterpillar herbivory and increased plant biomass relative to the control treatment. In contrast, mosquito buzzing reduced herbivory less than wasp buzzing and had no effect on plant biomass. The fact that wasp cues evoked strong responses in both experiments, while mosquito buzzing generally did not, indicates that caterpillars were responding to predation risk rather than sound per se. Such auditory cues may have an important but largely unappreciated impacts on terrestrial invertebrate herbivores and their host plants.

Is the Most Commonly Used Strategy for the First 1,500 m of a 2,000 m Rowing Ergometer Race the Most Appropriate?

This study investigated time-courses of physiological and psychological parameters of rowers during the first 1,500 m of a simulated race on a rowing ergometer using different pacing strategies. This provided a picture of the physiological and psychological state of the rowers at the start of the last 500 m of their race. Investigated strategies corresponded either to a degressive (degr), a progressive (prog), or a stable (stab) power output over the traveled distance. Thirteen French rowers (4 oarswomen and 9 oarsmen) of national and ex-international levels volunteered to participate. Handle force and velocity, oxygen uptake, heart rate, blood lactate concentration, and peripheral oxygen saturation were measured during the trials. Power output, generated energy [by O 2 consumption (E oxi ) and blood lactate accumulation (E non-oxi )] and efficiency were computed. Rowers also rated their perceived exertion (RPE) and protocol preference. In the explored strategies, no significant differences were found for E oxi . Final blood lactate concentration ([La] blood ) and RPE were similar for all strategies. However, the increase in [La] blood and RPE occurred sooner for degr than for stab and prog. Therefore, the time spent at higher [La] blood and RPE was longer for degr than for stab and prog. According to the questionnaire, degr was the least preferred protocol. While during 2000 m races, the first 1500 m are usually and empirically often conducted in a degr way, the present results indicate that this strategy was the least preferred by the rowers and led to a higher time spent at high [La] blood and RPE.

Do outcomes from a behavioral weight loss intervention differ in Alabama versus Colorado?

Background: There are well-established regional differences in obesity prevalence in the United States but relatively little is known about why or whether success in weight loss differs regionally. Objective: The objective of this study was to determine whether changes in body weight, engagement in physical activity (PA), and psychosocial factors differed in Alabama (AL) versus Colorado (CO) in response to a 16-week behavioral weight loss program. Design: This is an ancillary study to a weight loss intervention being conducted simultaneously in AL and CO with identical intervention content and delivery in 70 participants (n = 31 AL and n = 39 CO). Body weight, objective (accelerometry) PA, and responses to psychosocial questionnaires (reward-based eating, stress, social support) were collected at baseline and at Week 16. Results: There were no differences in percent weight loss between states (AL: 10.98%; CO: 11.675%, p = 0.70), and weights at Week 16 were not different for participants in AL and CO (AL: 101.54 ± 4.39 kg, CO: 100.42 ± 3.67 kg, p = 0.84). Accelerometry-derived step count, stepping time, and activity score were all greater at Week 16 for participants in AL compared to participants in CO. Hedonic eating scores were more favorable for participants in AL at baseline (AL: 24.08 ± 2.42; CO: 34.99 ± 2.12, p = 0.0023) and at Week 16 (AL: 18.62 ± 2.70; CO: 29.11 ± 2.19, p = 0.0023). Finally, participants in AL presented more favorable social support scores at Week 16 compared to participants in CO. Conclusions: Weight loss did not differ between states, suggesting that factors contributing to higher obesity rates in some regions of the United States may not be barriers to weight loss. Further, participants in AL experienced greater improvements in some factors associated with weight maintenance, indicating the need to study regional differences in weight loss maintenance. National Clinical Trial 03832933.

Diet pattern may affect fasting insulin in a large sample of black and white adults.

OBJECTIVE: Dietary modification of insulin resistance may be a strategy for reducing chronic disease. For this study, we tested the hypothesis that higher fasting insulin, a marker for insulin resistance, would be related to diet patterns with a high proportion of carbohydrates, those with a high glycemic index, and those characterized by added sugar and processed starches. STUDY DESIGN: Data were analyzed on 13,528 nondiabetic participants of the REasons for Geographic and Ethnic Differences in Stroke (REGARDS), an observational study of adults aged ≥45 years residing in 1855 counties across the continental USA. Information on habitual diet was collected using the Block 98 Food Frequency Questionnaire. Percent energy from carbohydrate, glycemic index, and glycemic load were determined for each participant, as well as adherence to five established diet patterns. Logistic regression was used to examine associations of baseline diet characteristics with odds for high fasting insulin [quartiles 3 and 4 (median = 98.9 pmol/L) vs. quartile 1], after adjusting for covariates. RESULT: Greater percent carbohydrate, glycemic index, and glycemic load, and adherence to sweets/fat and southern diet patterns, was associated with greater odds for high insulin (P for trend <0.05 to <0.0001), whereas adherence to the plant-based and alcohol/salad patterns was associated with lower odds for high insulin (P for linear trend <0.0001). CONCLUSION: In conclusion, diet pattern is associated with fasting insulin. Future studies are needed to determine if diet interventions designed to lower insulin, perhaps based on the patterns identified in this study, can improve risk for chronic disease.

Stimulation of the beta3-Adrenoceptor as a novel treatment strategy for anxiety and depressive disorders.

The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.

Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models.

Central tachykinins have been shown to play a role in the modulation of stress-related behaviours. Saredutant, a tachykinin NK2 receptor antagonist, displayed mixed anxiolytic- and antidepressant-like activities in rodents. The present study aimed at further characterizing its psychotropic properties. Saredutant was tested in the rat social interaction test to further confirm its anxiolytic-like activity, and in a variety of behavioural models sensitive to antidepressant drugs. In the rat social interaction test, saredutant (20 mg/kg, i.p.) significantly increased the time spent in interaction, as did the prototypical anxiolytic agents, diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, s.c.), but not the antidepressant, fluoxetine. In a differential reinforcement of low rate-72s task, saredutant (3 mg/kg, i.p.) displayed an antidepressant-like activity by increasing reinforced response rate and percentage of responses emitted in the inter-response time bin [49-96 s]. In bulbectomized rats, saredutant (20 mg/kg, i.p.) restored the deficit of acquisition of passive avoidance. In rat pups separated from their mother, saredutant (3-10 mg/kg, s.c.) reduced ultrasonic distress calls. Finally, in the chronic mild stress paradigm in mice, a 29-day treatment regimen with saredutant (10 mg/kg, i.p.) attenuated stress-induced physical degradation. Importantly, in the depression models, the effects of saredutant were comparable to those obtained under similar experimental conditions by reference antidepressants such as fluoxetine or imipramine. Together, these results suggest further that the NK2 receptor may represent an attractive target for the treatment of both depressive and anxiety disorders.