Dose-dependent effects of oral cannabidiol and delta-9-tetrahydrocannabinol on serum anandamide and related N-acylethanolamines in healthy volunteers.

BACKGROUND: The mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual's effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting. METHODS: Liquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ9-THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ9-THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration. RESULTS: CBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (pcorr<0.05) but not 600 mg dosage. Declining AEA was observed with Δ9-THC at 10 mg (-1.3-fold) and 20 mg (-1.4-fold) but restored to baseline levels by 160 min. CBD+Δ9-THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response. CONCLUSION: CBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ9-THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration.

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes.

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized. Our study revealed that patients with biallelic loss of function in CIAO1 developed proximal and axial muscle weakness, fluctuating creatine kinase elevation, and respiratory insufficiency. In addition, they presented with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, mild normocytic to macrocytic anemia, and gastrointestinal symptoms. Mutational analysis revealed reduced stability of the variants compared with WT CIAO1. Functional assays demonstrated failure of the variants identified in patients to recruit Fe-S recipient proteins, resulting in compromised activities of DNA helicases, polymerases, and repair enzymes that rely on the CIA complex to acquire their Fe-S cofactors. Lentivirus-mediated restoration of CIAO1 expression reversed all patient-derived cellular abnormalities. Our study identifies CIAO1 as a human disease gene and provides insights into the broader implications of the cytosolic Fe-S assembly pathway in human health and disease.

Multi-target drugs for the treatment of cognitive impairment and fatigue in post-COVID syndrome: focus on Ginkgo biloba and Rhodiola rosea.

Cognitive impairment, depression and (mental) fatigue represent the most frequent neuropsychiatric symptoms of the post-COVID syndrome. Neuroinflammation, oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological mechanisms underlying these symptoms. Attempts to treat post-COVID-associated cognitive impairment and fatigue with different drugs available for other diseases have not yet been successful. One probable explanation could be that these drugs work by one specific mechanism of action only and not in a broad multi-target way. Therefore, they will not address the broad pathophysiological spectrum possibly responsible for cognitive impairment, depression and fatigue in post-COVID syndrome. Notably, nearly all drugs currently under investigation for fatigue in post-COVID syndrome are rather addressing one single target instead of the several pathomechanisms underlying this condition. Contrary to this approach, herbal drugs often consist of many different ingredients with different pharmacological properties and pharmacological targets. Therefore, these drugs might be a promising approach for the treatment of the broad symptomatic presentation and the pathophysiological mechanisms of cognitive impairment and fatigue following a SARS-CoV-2 infection. Of these herbal drugs, extracts of Ginkgo biloba and Rhodiola rosea probably are the best investigated candidates. Their broad pharmacological spectrum in vitro and in vivo includes anti-oxidative, anti-inflammatory, antidepressant as well as properties reducing cognitive impairment and fatigue. In several studies, both drugs showed positive effects on physical and mental fatigue and impaired cognition. Moreover, depressive symptoms were also reduced in some studies. However, even if these results are promising, the data are still preliminary and require additional proof by further studies.

Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons.

Mitochondrial aminoacyl-tRNA synthetase (mt-ARS) mutations cause severe, progressive, and often lethal diseases with highly heterogeneous and tissue-specific clinical manifestations. This study investigates the molecular mechanisms triggered by three different mt-ARS defects caused by biallelic mutations in AARS2, EARS2, and RARS2, using an in vitro model of human neuronal cells. We report distinct molecular mechanisms of mitochondrial dysfunction among the mt-ARS defects studied. Our findings highlight the ability of proliferating neuronal progenitor cells (iNPCs) to compensate for mitochondrial translation defects and maintain balanced levels of oxidative phosphorylation (OXPHOS) components, which becomes more challenging in mature neurons. Mutant iNPCs exhibit unique compensatory mechanisms, involving specific branches of the integrated stress response, which may be gene-specific or related to the severity of the mitochondrial translation defect. RNA sequencing revealed distinct transcriptomic profiles showing dysregulation of neuronal differentiation and protein translation. This study provides valuable insights into the tissue-specific compensatory mechanisms potentially underlying the phenotypes of patients with mt-ARS defects. Our novel in vitro model may more accurately represent the neurological presentation of patients and offer an improved platform for future investigations and therapeutic development.

Prevalence of COVID-19 and Psychotropic Drug Treatment in Psychiatric In-patients in Germany in 2020: Results from a Nationwide Pilot Survey.

INTRODUCTION: In patients with a pre-existing mental disorder, an increased risk for a first manifestation of a psychiatric disorder in COVID-19 patients, a more severe course of COVID-19 and an increased mortality have been described. Conversely, observations of lower COVID-19 incidences in psychiatric in-patients suggested protective effects of psychiatric treatment and/or psychotropic drugs against COVID-19. METHODS: A retrospective multi-center study was conducted in 24 German psychiatric university hospitals. Between April and December 2020 (the first and partly second wave of COVID-19), the effects of COVID-19 were assessed on psychiatric in-patient care, the incidence and course of a SARS-CoV-2 infection, and treatment with psychotropic drugs. RESULTS: Patients (n=36,322) were admitted to the hospitals. Mandatory SARS-CoV-2 tests before/during admission were reported by 23 hospitals (95.8%), while 18 (75%) conducted regular testing during the hospital stay. Two hundred thirty-two (0.6%) patients were tested SARS-CoV-2-positive. Thirty-seven (16%) patients were receiving medical treatment for COVID-19 at the psychiatric hospital, ten (4.3%) were transferred to an intermediate/intensive care unit, and three (1.3%) died. The most common prescription for SARS-CoV-2-positive patients was for second-generation antipsychotics (n=79, 28.2%) and antidepressants (SSRIs (n=38, 13.5%), mirtazapine (n=36, 12.9%) and SNRIs (n=29, 10.4%)). DISCUSSION: Contrary to previous studies, our results showed a low number of infections and mortality in SARS-CoV-2-positive psychiatric patients. Several preventive measures seem effective to protect this vulnerable group. Our observations are compatible with the hypothesis of a protective effect of psychotropic drugs against COVID-19 as the overall mortality and need for specific medical treatment was low.

Resistance, Motor Control, and Mindfulness-Based Exercises Are Effective for Treating Chronic Nonspecific Neck Pain: A Systematic Review With Meta-Analysis and Dose-Response Meta-Regression.

OBJECTIVE: We aimed to analyze the effects and dose-response relationship of the most effective exercises for improving pain and disability in people with chronic nonspecific neck pain. DESIGN: Intervention systematic review with meta-analysis. LITERATURE SEARCH: We searched the PubMed, PEDro, and CENTRAL databases from their inception to September 30, 2022. STUDY SELECTION CRITERIA: We included randomized controlled trials that involved people with chronic neck pain adopting a longitudinal exercise intervention and assessed one pain and/or disability outcome. DATA SYNTHESIS: Restricted maximum-likelihood random-effects meta-analyses were modeled separately for resistance, mindfulness-based, and motor control exercises; standardized mean differences (Hedge's g, standardized mean difference [SMD]) were effect estimators. Meta-regressions (dependent variable: effect sizes of the interventions; independent variables: training dose and control group effects) were conducted to explore the dose-response relationship for therapy success of any exercise type. RESULTS: We included 68 trials. Compared to true control, effects on pain and disability were significantly larger for resistance exercise (pain: SMD, -1.27; 95% confidence interval [CI]: -2.26, -0.28; |2 = 96%; disability: SMD, -1.76; 95% CI: -3.16, -0.37; |2 = 98%), motor control exercise (pain: SMD, -2.29; 95% CI: -3.82, -0.75; |2 = 98%; disability: SMD, -2.42; 95% CI: -3.38, -1.47; |2 = 94%), and Yoga/Pilates/Tai Chi/Qui Gong exercise (pain: SMD, 1.91; 95% CI:-3.28, -0.55; |2 = 96%; disability: SMD, -0.62; 95% CI: -0.85, -0.38; |2 = 0%). Yoga/Pilates/Tai Chi/Qui Gong exercise was more effective than other exercises (SMD, -0.84; 95% CI: -1.553, -0.13; |2 = 86%) for reducing pain. For disability, motor control exercise was superior to other exercises (SMD, -0.70; 95% CI: -1.23, -0.17; |2 = 98%). There was no dose-response relationship for resistance exercise (R2 = 0.32). Higher frequencies (estimate = -0.10) and longer durations (estimate = -0.11) of motor control exercise had larger effects on pain (R2 = 0.72). Longer sessions (estimate = -0.13) of motor control exercise had larger effects on disability (R2 = 0.61). CONCLUSION: Resistance, mindfulness-based, and motor control exercises were effective for reducing neck pain (very low- to moderate-certainty evidence). Higher frequencies and longer duration of sessions had a significant effect on pain for motor control exercise. J Orthop Sports Phys Ther 2023;53(8):1-41. Epub: 20 June 2023. doi:10.2519/jospt.2023.11820.

How to measure children's feet: 3D foot scanning compared with established 2D manual or digital methods.

BACKGROUND: In infants and young children, a wide heterogeneity of foot shape is typical. Therefore, children, who are additionally influenced by rapid growth and maturation, are a very special cohort for foot measurements and the footwear industry. The importance of foot measurements for footwear fit, design, as well as clinical applications has been sufficiently described. New measurement techniques (3D foot scanning) allow the assessment of the individual foot shape. However, the validity in comparison to conventional methods remains unclear. Therefore, the purpose of this study was to compare 3D foot scanning with two established measurement methods (2D digital scanning/manual foot measurements). METHODS: Two hundred seventy seven children (125 m / 152 f; mean ± SD: 8.0 ± 1.5yrs; 130.2 ± 10.7cm; 28.0 ± 7.3kg) were included into the study. After collection of basic data (sex, age (yrs), body height (cm), body weight (kg)) geometry of the right foot was measured in static condition (stance) with three different measurement systems (fixed order): manual foot measurement, 2D foot scanning (2D desk scanner) and 3D foot scanning (hand-held 3D scanner). Main outcomes were foot length, foot width (projected; anatomical; instep), heel width and anatomical foot ball breadth. Analysis of variances for dependent samples was applied to test for differences between foot measurement methods (Post-hoc analysis: Tukey-Kramer-Test; α=0.05). RESULTS: Significant differences were found for all outcome measures comparing the three methods (p<0.0001). The span of foot length differences ranged from 3 to 6mm with 2D scans showing the smallest and 3D scans the largest deviations. Foot width measurements in comparison of 3D and 2D scans showed consistently higher values for 3D measurements with the differences ranging from 1mm to 3mm. CONCLUSIONS: The findings suggests that when comparing foot data, it is important to consider the differences caused by new measurement methods. Differences of about 0.6cm are relevant when measuring foot length, as this is the difference of a complete shoe size (Parisian point). Hence, correction factors may be required to compare the results of different measurements appropriately. The presented results may have relevance in the field of ergonomics (shoe industry) as well as clinical practice.

Loss of Function of the Cytoplasmic Fe-S Assembly Protein CIAO1 Causes a Neuromuscular Disorder with Compromise of Nucleocytoplasmic Fe-S Enzymes.

Cytoplasmic and nuclear iron-sulfur enzymes that are essential for genome maintenance and replication depend on the cytoplasmic iron-sulfur assembly (CIA) machinery for cluster acquisition. Here we report that patients with biallelic loss of function in CIAO1 , a key CIA component, develop proximal and axial muscle weakness, fluctuating creatine kinase elevation and respiratory insufficiency. In addition, they present with CNS symptoms including learning difficulties and neurobehavioral comorbidities, along with iron deposition in deep brain nuclei, macrocytic anemia and gastrointestinal symptoms. Mutational analysis and functional assays revealed reduced stability of the variants compared to wild-type CIAO1. Loss of CIAO1 impaired DNA helicases, polymerases and repair enzymes which rely on the CIA complex to acquire their Fe-S cofactors, with lentiviral restoration reversing all patient-derived cellular abnormalities. Our study identifies CIAO1 as a novel human disease gene and provides insights into the broader implications of the iron-sulfur assembly pathway in human health and disease.

Acute effects of game-based biofeedback training on trunk motion in chronic low back pain: a randomized cross-over pilot trial.

BACKGROUND: Improving movement control might be a promising treatment goal during chronic non-specific low back pain (CLBP) rehabilitation. The objective of the study is to evaluate the effect of a single bout of game-based real-time feedback intervention on trunk movement in patients with CLBP. METHODS: Thirteen CLBP patients (8female;41 ± 16 years;173 ± 10 cm;78 ± 22 kg) were included in this randomized cross-over pilot trial. During one laboratory session (2 h), participants performed three identical measurements on trunk movement all including: first, maximum angle of lateral flexion was assessed. Secondly, a target trunk lateral flexion (angle: 20°) was performed. Main outcome was maximum angle ([°]; MA). Secondary outcomes were deviation [°] from the target angle (angle reproduction; AR) and MA of the secondary movement planes (rotation; extension/flexion) during lateral flexion. The outcomes were assessed by an optical 3D-motion-capture-system (2-segment-trunk-model). The measurements were separated by 12-min of intervention and/or resting (randomly). The intervention involved a sensor-based trunk exergame (guiding an avatar through virtual worlds). After carryover effect-analysis, pre-to-post intervention data were pooled between the two sequences followed by analyses of variances (paired t-test). RESULTS: No significant change from pre to post intervention for MA or AR for any segment occurred for the main movement plane, lateral flexion (p > .05). The upper trunk segment showed a significant decrease of the MA for trunk extension/flexion from pre to post intervention ((4.4° ± 4.4° (95% CI 7.06-1.75)/3.5° ± 1.29° (95% CI 6.22-0.80); p = 0.02, d = 0.20). CONCLUSIONS: A single bout of game-based real-time feedback intervention lead to changes in the secondary movement planes indicating reduced evasive motion during trunk movement. TRIAL REGISTRATION NO: DRKS00029765 (date of registration 27.07.2022). Retrospectively registered in the German Clinical Trial Register.

Effect of Six-Week Resistance and Sensorimotor Training on Trunk Strength and Stability in Elite Adolescent Athletes: A Randomized Controlled Pilot Trial.

Intervention in the form of core-specific stability exercises is evident to improve trunk stability. The purpose was to assess the effect of an additional 6 weeks sensorimotor or resistance training on maximum isokinetic trunk strength and response to sudden dynamic trunk loading (STL) in highly trained adolescent athletes. The study was conducted as a single-blind, 3-armed randomized controlled trial. Twenty-four adolescent athletes (14f/10 m, 16 ± 1 yrs.;178 ± 10 cm; 67 ± 11 kg; training sessions/week 15 ± 5; training h/week 22 ± 8) were randomized into resistance training (RT; n = 7), sensorimotor training (SMT; n = 10), and control group (CG; n = 7). Athletes were instructed to perform standardized, center-based training for 6 weeks, two times per week, with a duration of 1 h each session. SMT consisted of four different core-specific sensorimotor exercises using instable surfaces. RT consisted of four trunk strength exercises using strength training machines, as well as an isokinetic dynamometer. All participants in the CG received an unspecific heart frequency controlled, ergometer-based endurance training (50 min at max. heart frequency of 130HF). For each athlete, each training session was documented in an individual training diary (e.g., level of SMT exercise; 1RM for strength exercise, pain). At baseline (M1) and after 6 weeks of intervention (M2), participants' maximum strength in trunk rotation (ROM:63°) and flexion/extension (ROM:55°) was tested on an isokinetic dynamometer (concentric/eccentric 30°/s). STL was assessed in eccentric (30°/s) mode with additional dynamometer-induced perturbation as a marker of core stability. Peak torque [Nm] was calculated as the main outcome. The primary outcome measurements (trunk rotation/extension peak torque: con, ecc, STL) were statistically analyzed by means of the two-factor repeated measures analysis of variance (α = 0.05). Out of 12 possible sessions, athletes participated between 8 and 9 sessions (SMT: 9 ± 3; RT: 8 ± 3; CG: 8 ± 4). Regarding main outcomes of trunk performance, experimental groups showed no significant pre-post difference for maximum trunk strength testing as well as for perturbation compensation (p > 0.05). It is concluded, that future interventions should exceed 6 weeks duration with at least 2 sessions per week to induce enhanced trunk strength or compensatory response to sudden, high-intensity trunk loading in already highly trained adolescent athletes, regardless of training regime.

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of "repurposing" drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway.The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients.Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs.

Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers.

The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Emotion, Cognition, and Attention: A Double-Blind, Placebo-Controlled, Randomized Experimental Trial in Healthy Volunteers.

The two main phytocannabinoids-delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)-have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories-more precisely, the performance-related activity and extraversion-, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.

In Vivo Endoscopic Optical Coherence Tomography of the Healthy Human Oral Mucosa: Qualitative and Quantitative Image Analysis.

To date, there is still a lack of reliable imaging modalities to improve the quality of consultation, diagnostic and medical examinations of the oral mucosa in dentistry. Even though, optical technologies have become an important element for the detection and treatment of different diseases of soft tissue, for the case of oral screenings the evidence of the benefit in comparison to conventional histopathology is mostly still pending. One promising optical technology for oral diagnostics is optical coherence tomography (OCT). To prove the potential of OCT, even the amount of freely accessible OCT data is not sufficient to describe the variance of healthy human oral soft tissue in vivo. In order to remedy this deficiency, the present study provides in vivo OCT cross sections of the human oral mucosa of the anterior and posterior oral cavity as well as the oropharynx of 47 adult volunteers. A collection of representative OCT cross sections forms the basis for a randomized blinded image analysis by means of seven criteria to assess the main features of the superficial layers of the human oral mucosa and to determine its correlation to regional features known from hematoxylin and eosin (HE) stained histology.

Dose-response-relationship of stabilisation exercises in patients with chronic non-specific low back pain: a systematic review with meta-regression.

Stabilization exercise (SE) is evident for the management of chronic non-specific low back pain (LBP). The optimal dose-response-relationship for the utmost treatment success is, thus, still unknown. The purpose is to systematically review the dose-response-relationship of stabilisation exercises on pain and disability in patients with chronic non-specific LBP. A systematic review with meta-regression was conducted (Pubmed, Web of Knowledge, Cochrane). Eligibility criteria were RCTs on patients with chronic non-specific LBP, written in English/German and adopting a longitudinal core-specific/stabilising/motor control exercise intervention with at least one outcome for pain intensity and/or disability. Meta-regressions (dependent variable = effect sizes (Cohens d) of the interventions (for pain and for disability), independent variable = training characteristics (duration, frequency, time per session)), and controlled for (low) study quality (PEDro) and (low) sample sizes (n) were conducted to reveal the optimal dose required for therapy success. From the 3,415 studies initially selected, 50 studies (n = 2,786 LBP patients) were included. N = 1,239 patients received SE. Training duration was 7.0 ± 3.3 weeks, training frequency was 3.1 ± 1.8 sessions per week with a mean training time of 44.6 ± 18.0 min per session. The meta-regressions' mean effect size was d = 1.80 (pain) and d = 1.70 (disability). Total R2 was 0.445 and 0.17. Moderate quality evidence (R2 = 0.231) revealed that a training duration of 20 to 30 min elicited the largest effect (both in pain and disability, logarithmic association). Low quality evidence (R2 = 0.125) revealed that training 3 to 5 times per week led to the largest effect of SE in patients with chronic non-specific LBP (inverted U-shaped association). In patients with non-specific chronic LBP, stabilization exercise with a training frequency of 3 to 5 times per week (Grade C) and a training time of 20 to 30 min per session (Grade A) elicited the largest effect on pain and disability.

Sudden gait perturbations elicit sex-specific neuromuscular trunk responses in persons with low back pain.

Persons with low back pain (LBP) exhibit delayed trunk muscle onset and increased co-contractions as a response to quasi-static and dynamic sudden trunk loading in comparison to back-healthy controls. Although LBP is more prevalent in females, sex-specific responses have not been well documented. Therefore, the purpose was to explore sex-specific neuromuscular differences, to gait perturbation, in LBP patients. Twenty-nine LBP patients (12m/17f;31 ± 10yrs; 174 ± 12 cm; 71 ± 16 kg) walked on a split-belt treadmill at 1 m/s, while 15 right-sided random perturbations (treadmill-belt decelerating, 40 m/s2, 50 ms duration; 200 ms after heel contact) were applied. Muscle activity was assessed using a 12-lead surface EMG (6 back/6 abdominal muscles; 4000 Hz). EMG-RMS [%] (0-200 ms after perturbation) was calculated and normalized to RMS of unperturbed gait for each muscle. Furthermore, muscle onsets (ms) were determined. Two-way ANOVA (factors: sex/muscle) was applied to account for sex differences in main outcomes. EMG-RMS (amplitudes; mean) ranged from 356% to 901% in males and 349% to 694% in females representing a significant interaction effect (sex * muscle: p = 0.017). Post-hoc analysis revealed significant differences for EMG-RMS analysis of rectus abdominis left (p = 0.043; f > m) as well as obliques externus right/left (p = 0.018/p = 0.005; f < m). In the time domain, females showed overall, shorter (mean: 90 ± 16 ms) response times compared to males (mean: 98 ± 22 ms, sex effect: p < 0.0001). In this LBP population, abdominal muscle activation discriminated females from males. Specifically, females had higher activity of the rectus abdominis muscles and lower activation of the externus oblique muscles. These different activation strategies might be relevant to the development of sex-specific intervention strategies.

Sustainability effects of motor control stabilisation exercises on pain and function in chronic nonspecific low back pain patients: A systematic review with meta-analysis and meta-regression.

STUDY DESIGN: Systematic review with meta-analysis and meta-regression. BACKGROUND AND OBJECTIVES: We systematically reviewed and delineated the existing evidence on sustainability effects of motor control exercises on pain intensity and disability in chronic low back pain patients when compared with an inactive or passive control group or with other exercises. Secondary aims were to reveal whether moderating factors like the time after intervention completion, the study quality, and the training characteristics affect the potential sustainability effects. METHODS: Relevant scientific databases (Medline, Web of Knowledge, Cochrane) were screened. Eligibility criteria for selecting studies: All RCTs und CTs on chronic (≥ 12/13 weeks) nonspecific low back pain, written in English or German and adopting a longitudinal core-specific/stabilizing sensorimotor control exercise intervention with at least one pain intensity and disability outcome assessment at a follow-up (sustainability) timepoint of ≥ 4 weeks after exercise intervention completion. RESULTS AND CONCLUSIONS: From the 3,415 studies that were initially retrieved, 10 (2 CTs & 8 RCTs) on N = 1081 patients were included in the review and analyses. Low to moderate quality evidence shows a sustainable positive effect of motor control exercise on pain (SMD = -.46, Z = 2.9, p < .001) and disability (SMD = -.44, Z = 2.5, p < .001) in low back pain patients when compared to any control. The subgroups' effects are less conclusive and no clear direction of the sustainability effect at short versus mid versus long-term, of the type of the comparator, or of the dose of the training is given. Low quality studies overestimated the effect of motor control exercises.

Familial abnormalities of endocannabinoid signaling in schizophrenia.

OBJECTIVES: Epidemiological and experimental evidence suggests that the endocannabinoid system plays a pathophysiological role in schizophrenia. This is reflected by elevated cerebrospinal levels of the endocannabinoid anandamide in schizophrenia and its initial prodromal states. METHODS: We analyzed plasma concentrations of anandamide, 2-arachidonoyl-sn-glycerol, palmitoylethanolamide and oleoylethanolamide from 25 twin pairs discordant for schizophrenia, six discordant for bipolar disorder and eight healthy twin pairs to determine hereditary traits. RESULTS: Twin pairs discordant for schizophrenia or bipolar disorder had significantly higher levels of anandamide and palmitoylethanolamide compared to healthy twins (both P < 0.002). Non-affected twins discordant for schizophrenia, who developed a psychotic disorder within 5 years follow-up showed lower anandamide (P = 0.042) and 2-arachidonoyl-sn-glycerol levels (P = 0.049) than twins who remained healthy. CONCLUSIONS: We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism.

Trunk peak torque, muscle activation pattern and sudden loading compensation in adolescent athletes with back pain.

OBJECTIVE: To evaluate trunk peak torque and muscle activation pattern during isokinetic and sudden trunk loading (STL) between adolescent athletes with/without back pain. METHODS: Nine adolescent athletes with back pain (BP) (m/f 2/7; 15.6 ± 1.2 y; 177 ± 9 cm; 67 ± 13 kg; 22.5 ± 9.8 h/week) and nine matched controls (m/f 2/7; 15.7 ± 1.4 y; 177 ± 12 cm; 65 ± 9 kg; 16.5 ± 8.0 h/week training) were included. Trunk strength in rotation and flexion/extension was assessed. Sudden trunk loading was measured during eccentric extension and rotation (30∘/s) with additional perturbation. Trunk muscle activity was measured using a 12 lead-EMG (electromyography). Main outcome measures were peak torque [Nm] and MVC normalized EMG-amplitudes (RMS [%]) for each muscle. Additionally, the mean EMG-RMS for four areas of the trunk was calculated (right/left ventral, right/left dorsal). RESULTS: Back pain showed lower trunk peak torque for all conditions in extension/flexion, but not for rotation. EMG amplitudes were increased for BP athletes with statistical significant differences for dorsal muscles in rotation and extension (p< 0.0042), not for ventral muscles in flexion. CONCLUSIONS: The evaluation of strength and muscle activity in isokinetic and sudden trunk loading presents altered trunk function in adolescent back pain athletes. Training interventions focusing on trunk strength and muscular activation pattern appears reasonable.

Dose-response relationship of core-specific sensorimotor interventions in healthy, well-trained participants: study protocol for a (MiSpEx) randomized controlled trial.

BACKGROUND: Core-specific sensorimotor exercises are proven to enhance neuromuscular activity of the trunk, improve athletic performance and prevent back pain. However, the dose-response relationship and, therefore, the dose required to improve trunk function is still under debate. The purpose of the present trial will be to compare four different intervention strategies of sensorimotor exercises that will result in improved trunk function. METHODS/DESIGN: A single-blind, four-armed, randomized controlled trial with a 3-week (home-based) intervention phase and two measurement days pre and post intervention (M1/M2) is designed. Experimental procedures on both measurement days will include evaluation of maximum isokinetic and isometric trunk strength (extension/flexion, rotation) including perturbations, as well as neuromuscular trunk activity while performing strength testing. The primary outcome is trunk strength (peak torque). Neuromuscular activity (amplitude, latencies as a response to perturbation) serves as secondary outcome. The control group will perform a standardized exercise program of four sensorimotor exercises (three sets of 10 repetitions) in each of six training sessions (30 min duration) over 3 weeks. The intervention groups' programs differ in the number of exercises, sets per exercise and, therefore, overall training amount (group I: six sessions, three exercises, two sets; group II: six sessions, two exercises, two sets; group III: six sessions, one exercise, three sets). The intervention programs of groups I, II and III include additional perturbations for all exercises to increase both the difficulty and the efficacy of the exercises performed. Statistical analysis will be performed after examining the underlying assumptions for parametric and non-parametric testing. DISCUSSION: The results of the study will be clinically relevant, not only for researchers but also for (sports) therapists, physicians, coaches, athletes and the general population who have the aim of improving trunk function. TRIAL REGISTRATION: German Clinical Trials Register, ID: DRKS00012917 . Registered on 22 August 2017.