Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously ...shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression.
We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point.
The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period.
The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.
Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance ...(IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM
exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM
exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM
exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM
exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.
The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The ...endogenously produced molecule acetyl-L-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.
Abstract
Background
Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a ...tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder.
Methods
Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes.
Results
Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score.
Conclusions
Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted.
The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).
Significance StatementAnxiety and trauma-related disorders are among the most prevalent medical conditions in the United States. Posttraumatic stress disorder (PTSD) in particular is a debilitating disorder that develops in a subset of individuals exposed to extreme stress. Drug discovery for PTSD and anxiety disorders has been largely stagnant, contributing to a substantial disease burden and continued patient suffering. A large body of evidence implicates neuropeptide Y (NPY) in the regulation of stress-related behaviors, and preclinical data suggest that enhancing NPY signaling may reduce anxiety and symptoms of PTSD. Herein, we conducted phase Ib double-blind, randomized, placebo-controlled, dose-ranging study of intranasal administration of NPY in subjects with PTSD. We found that NPY was well tolerated at all tested doses and that high, but not low, doses of NPY were associated with reduced anxiety on some measures. The NPY system may represent a promising target for treatment development for anxiety and trauma-related disorders.
A search for CP and P violation in charmless four-body B0 → ppK¯ þπ− decays is performed using
triple-product asymmetry observables. It is based on proton-proton collision data collected by the LHCb
...experiment at center-of-mass energies of 7, 8 and 13 TeV, corresponding to a total integrated luminosity of
8.4 fb−1. The CP- and P-violating asymmetries are measured both in the integrated phase space and in
specific regions. No evidence is seen for CP violation. P-parity violation is observed at a significance of 5.8
standard deviations.
A simultaneous analysis of the Bþ → Kþlþl− and B0 → K 0lþl− decays is performed to test muonelectron universality in two ranges of the square of the dilepton invariant mass, q2. The measurement uses ...a
sample of beauty meson decays produced in proton-proton collisions collected with the LHCb detector
between 2011 and 2018, corresponding to an integrated luminosity of 9 fb−1. A sequence of multivariate
selections and strict particle identification requirements produce a higher signal purity and a better
statistical sensitivity per unit luminosity than previous LHCb lepton universality tests using the same decay
modes. Residual backgrounds due to misidentified hadronic decays are studied using data and included in
the fit model. Each of the four lepton universality measurements reported is either the first in the given q2
interval or supersedes previous LHCb measurements. The results are compatible with the predictions of the
Standard Model.
Effects of supplementing direct-fed microbial agents (DFM) to dairy cows during the transition period were evaluated. Forty-four Holstein cows were fed close-up and lactating diets that did or did ...not contain 2g of DFM/cow per d. Direct-fed microbial supplementation contained approximately 5×109 cfu of yeast and 5×109 cfu of bacteria (2 specific Enterococcus faecium strains) incorporated into a cornmeal carrier. Supplemented cows were fed the DFM 21 d prior to expected calving date through 10 wk postpartum. Cows supplemented with DFM had higher estimated ruminally available dry matter (DM) for both corn silage and haylage than did control cows. Supplemented cows consumed more DM during both the pre- and postpartum periods. In addition, those supplemented with DFM produced 2.3kg more milk/cow per d than did nonsupplemented cows. There was no difference in 3.5% fat-corrected milk. Milk fat percentage was lower, but not depressed (4.76 vs. 4.44%) for cows receiving DFM. There were no differences in milk fat yield or milk protein percentage and yield. Cows consuming DFM had higher blood glucose postpartum, as well as lower β-hydroxybutyrate levels both prepartum and on d 1 postpartum. Plasma nonesterified fatty acid concentration was not statistically affected by DFM, but was numerically lower prepartum and higher postpartum for supplemented cows. This study demonstrated that targeted DFM supplementation enhanced ruminal digestion of forage DM. Early lactation cows receiving supplemental DFM produced more milk and consumed more DM during the pre- and postpartum periods. Cows consuming DFM, however, experienced a lower, but not depressed, fat percentage compared with nonsupplemented cows.
Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and ...effective treatment for improving arm function after stroke.
In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20–35 vs 36–50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 μs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960.
Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0–4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6–41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group.
Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke.
MicroTransponder.
Motor impairment is the most common deficit after stroke. Our aim was to evaluate whether diffusional kurtosis imaging can detect corticospinal tract microstructural changes in the acute phase for ...patients with first-ever ischemic stroke and motor impairment and to assess the correlations between diffusional kurtosis imaging-derived diffusion metrics for the corticospinal tract and motor impairment 3 months poststroke.
We evaluated 17 patients with stroke who underwent brain MR imaging including diffusional kurtosis imaging within 4 days after the onset of symptoms. Neurologic evaluation included the Fugl-Meyer Upper Extremity Motor scale in the acute phase and 3 months poststroke. For the corticospinal tract in the lesioned and contralateral hemispheres, we estimated with diffusional kurtosis imaging both pure diffusion metrics, such as the mean diffusivity and mean kurtosis, and model-dependent quantities, such as the axonal water fraction. We evaluated the correlations between corticospinal tract diffusion metrics and the Fugl-Meyer Upper Extremity Motor scale at 3 months.
Among all the diffusion metrics, the largest percentage signal changes of the lesioned hemisphere corticospinal tract were observed with axial kurtosis, with an average 12% increase compared with the contralateral corticospinal tract. The strongest associations between the 3-month Fugl-Meyer Upper Extremity Motor scale score and diffusion metrics were found for the lesioned/contralateral hemisphere corticospinal tract mean kurtosis (ρ = -0.85) and axial kurtosis (ρ = -0.78) ratios.
This study was designed to be one of hypothesis generation. Diffusion metrics related to kurtosis were found to be more sensitive than conventional diffusivity metrics to early poststroke corticospinal tract microstructural changes and may have potential value in the prediction of motor impairment at 3 months.
PDF
