Mechanistic Insights into the Neurotoxicity of 2,5-Dimethoxyphenethylamines (2C) and Corresponding N-(2-methoxybenzyl)phenethylamine (NBOMe) Drugs.

Substituted phenethylamines including 2C (2,5-dimethoxyphenethylamines) and NBOMe (N-(2-methoxybenzyl)phenethylamines) drugs are potent psychoactive substances with little to no knowledge available on their toxicity. In the present in vitro study, we explored the mechanisms underlying the neurotoxicity of six substituted phenethylamines: 2C-T-2, 2C-T-4, 2C-T-7 and their corresponding NBOMes. These drugs were synthesized and chemically characterized, and their cytotoxicity (0-1000 µM) was evaluated in differentiated SH-SY5Y cells and primary rat cortical cultures, by the NR uptake and MTT reduction assays. In differentiated SH-SY5Y cells, mitochondrial membrane potential, intracellular ATP and calcium levels, reactive oxygen species production, and intracellular total glutathione levels were also evaluated. All the tested drugs exhibited concentration-dependent cytotoxic effects towards differentiated SH-SY5Y cells and primary rat cortical cultures. The NBOMe drugs presented higher cytotoxicity than their counterparts, which correlates with the drug's lipophilicity. These cytotoxic effects were associated with mitochondrial dysfunction, evident through mitochondrial membrane depolarization and lowered intracellular ATP levels. Intracellular calcium imbalance was observed for 2C-T-7 and 25T7-NBOMe, implying a disrupted calcium regulation. Although reactive species levels remained unchanged, a reduction in intracellular total GSH content was observed. Overall, these findings contribute to a deeper understanding of these drugs, shedding light on the mechanisms underpinning their neurotoxicity.

Normative modelling of molecular-based functional circuits captures clinical heterogeneity transdiagnostically in psychiatric patients.

Advanced methods such as REACT have allowed the integration of fMRI with the brain's receptor landscape, providing novel insights transcending the multiscale organisation of the brain. Similarly, normative modelling has allowed translational neuroscience to move beyond group-average differences and characterise deviations from health at an individual level. Here, we bring these methods together for the first time. We used REACT to create functional networks enriched with the main modulatory, inhibitory, and excitatory neurotransmitter systems and generated normative models of these networks to capture functional connectivity deviations in patients with schizophrenia, bipolar disorder (BPD), and ADHD. Substantial overlap was seen in symptomatology and deviations from normality across groups, but these could be mapped into a common space linking constellations of symptoms through to underlying neurobiology transdiagnostically. This work provides impetus for developing novel biomarkers that characterise molecular- and systems-level dysfunction at the individual level, facilitating the transition towards mechanistically targeted treatments.

Tips and tricks for a proper radiological assessment of abdominal and pelvic lymph nodes.

The assessment of lymph node dimensions is a commonly used criterion in analyzing lymphatic involvement related to inflammatory or neoplastic diseases. However, it is important to understand that the interpretation of lymph nodes goes beyond simply considering their size. A pathologic lymph node can present with enlarged dimensions, a heterogeneous appearance, increased cortex thickness, irregular contours, or a lobulated shape. In this context, it is essential to consider not only the dimensions but also the morphology, attenuation, and enhancement of lymph nodes on imaging exams. This article aims to demonstrate how characteristics of lymph nodes, beyond their size, can provide crucial insights that assist in diagnostic reasoning, focusing on computed tomography. By emphasizing different enhancement patterns, attenuation, and the potential contents related to these patterns, the study seeks to show how these features can indicate possible differential diagnoses and guide more accurate clinical assessments.

Diffuse and focal liver fat: advanced imaging techniques and diagnostic insights.

The fatty liver disease represents a complex, multifaceted challenge, requiring a multidisciplinary approach for effective management and research. This article uses conventional and advanced imaging techniques to explore the etiology, imaging patterns, and quantification methods of hepatic steatosis. Particular emphasis is placed on the challenges and advancements in the imaging diagnostics of fatty liver disease. Techniques such as ultrasound, CT, MRI, and elastography are indispensable for providing deep insights into the liver's fat content. These modalities not only distinguish between diffuse and focal steatosis but also help identify accompanying conditions, such as inflammation and fibrosis, which are critical for accurate diagnosis and management.

Neuroinflammation in the prefrontal-amygdala-hippocampus network is associated with maladaptive avoidance behaviour.

Maladaptive avoidance behaviour is often observed in patients suffering from anxiety and trauma- and stressor-related disorders. The prefrontal-amygdala-hippocampus network is implicated in learning and memory consolidation. Neuroinflammation in this circuitry alters network dynamics, resulting in maladaptive avoidance behaviour. The two-way active avoidance test is a well-established translational model for assessing avoidance responses to stressful situations. While some animals learn the task and show adaptive avoidance (AA), others show strong fear responses to the test environment and maladaptive avoidance (MA). Here, we investigated if a distinct neuroinflammation pattern in the prefrontal-amygdala-hippocampus network underlies the behavioural difference observed in these animals. Wistar rats were tested 8 times and categorized as AA or MA based on behaviour. Brain recovery followed for the analysis of neuroinflammatory markers in this network. AA and MA presented distinct patterns of neuroinflammation, with MA showing increased astrocyte, EAAT-2, IL-1ß, IL-17 and TNF-ɑ in the amygdala. This neuroinflammatory pattern may underlie these animals' fear response and maladaptive avoidance. Further studies are warranted to determine the specific contributions of each inflammatory factor, as well as the possibility of treating maladaptive avoidance behaviour in patients with psychiatric disorders with anti-inflammatory drugs targeting the amygdala.

Ligand Effects on the Spin Relaxation Dynamics and Coherent Manipulation of Organometallic La(II) Potential Qudits.

We present pulsed electron paramagnetic resonance (EPR) studies on three La(II) complexes, [K(2.2.2-cryptand)][La(Cp')3] (1), [K(2.2.2-cryptand)][La(Cp″)3] (2), and [K(2.2.2-cryptand)][La(Cptt)3] (3), which feature cyclopentadienyl derivatives as ligands [Cp' = C5H4SiMe3; Cp″ = C5H3(SiMe3)2; Cptt = C5H3(CMe3)2] and display a C3 symmetry. Long spin-lattice relaxation (T1) and phase memory (Tm) times are observed for all three compounds, but with significant variation in T1 among 1-3, with 3 being the slowest relaxing due to higher s-character of the SOMO. The dephasing times can be extended by more than an order of magnitude via dynamical decoupling experiments using a Carr-Purcell-Meiboom-Gill (CPMG) sequence, reaching 161 µs (5 K) for 3. Coherent spin manipulation is performed by the observation of Rabi quantum oscillations up to 80 K in this nuclear spin-rich environment (1H, 13C, and 29Si). The high nuclear spin of 139La (I = 7/2), and the ability to coherently manipulate all eight hyperfine transitions, makes these molecules promising candidates for application as qudits (multilevel quantum systems featuring d quantum states; d >2) for performing quantum operations within a single molecule. Application of HYSCORE techniques allows us to quantify the electron spin density at ligand nuclei and interrogate the role of functional groups to the electron spin relaxation properties.

Mitigating jaw osteonecrosis: bioactive glass and pericardial membrane combination in a rat model.

Objectives: Bisphosphonates (BFs) show clinical effectiveness in managing osteoporosis and bone metastases but pose risks of bisphosphonate-related jaw osteonecrosis (BRONJ). With no established gold standard for BRONJ treatment, our focus is on symptom severity reduction. We aimed to assess the preventive effects of bioactive glass and/or pericardial membrane in a preclinical BRONJ model, evaluating their potential to prevent osteonecrosis and bone loss post-tooth extractions in zoledronic acid (ZA)-treated animals. Methods: Rats, receiving ZA or saline biweekly for four weeks, underwent 1st and 2nd lower left molar extractions. Pericardial membrane alone or with F18 bioglass was applied post-extractions. Microarchitecture analysis and bone loss assessment utilized computerized microtomography (CT) and positron emission tomography (PET) with 18F-FDG and 18F-NaF tracers. Histological analysis evaluated bone injury. Results: Exclusive alveolar bone loss occurred post-extraction in the continuous ZA group, inducing osteonecrosis, osteolysis, osteomyelitis, and abscess formation. Concurrent pericardial membrane with F18 bioglass application prevented these outcomes. Baseline PET/CT scans showed no discernible uptake differences, but post-extraction 18F-FDG tracer imaging revealed heightened glucose metabolism at the extraction site in the ZA-treated group with membrane, contrasting the control group. Conclusion: These findings suggest pericardial membrane with F18 bioglass effectively prevents BRONJ in the preclinical model.

Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.

Enhancing nerve regeneration in infraorbital nerve injury rat model: effects of vitamin B complex and photobiomodulation.

Orofacial nerve injuries may result in temporary or long-term loss of sensory function and decreased quality of life in patients. B vitamins are required for DNA synthesis and the repair and maintenance of phospholipids. In particular, vitamins B1, B6, and B12 are essential for neuronal function. Deficiency in vitamin B complex (VBC) has been linked to increased oxidative stress, inflammation and demyelination. Photobiomodulation (PBM) has antioxidant activity and is neuroprotective. In addition, a growing literature attests to the positive effects of PBM on nerve repair. To assess the effect of PBM and VBC on regenerative process we evaluated the expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), myelin basic protein (MBP), laminin and neurofilaments (NFs) using Western blotting to identify regenerative pattern after chronic constriction injury of the infraorbital nerve (CCI IoN) treated by PBM, VBC or its combination. After CCI IoN, the rats were divided into six groups naive, sham, injured (CCI IoN), treated with photobiomodulation (904 nm, 6.23 J/cm2, CCI IoN + PBM), treated with VBC (containing B1, B6 and B12) 5 times, CCI IoN + VBC) and treated with PBM and VBC (CCI IoN + VBC + PBM). The treatments could revert low expression of BDNF, MBP and laminin. Also reverted the higher expression of neurofilaments and enhanced expression of NGF. PBM and VBC could accelerate injured infraorbital nerve repair in rats through reducing the expression of neurofilaments, increasing the expression of BDNF, laminin and MBP and overexpressing NGF. These data support the notion that the use of PBM and VBC may help in the treatment of nerve injuries. This finding has potential clinical applications.

Influence of diimine bidentate ligand in the nitrosyl and nitro terpyridine ruthenium complex on the HSA/DNA interaction and antiviral activity.

Nitric oxide (NO) acts in different physiological processes, such as blood pressure control, antiparasitic activities, neurotransmission, and antitumor action. Among the exogenous NO donors, ruthenium nitrosyl/nitro complexes are potential candidates for prodrugs, due to their physicochemical properties, such as thermal and physiological pH stability. In this work, we proposed the synthesis and physical characterization of the new nitro terpyridine ruthenium (II) complexes of the type [RuII(L)(NO2)(tpy)]PF6 where tpy = 2,2':6',2″-terpyridine; L = 3,4-diaminobenzoic acid (bdq) or o-phenylenediamine (bd) and evaluation of influence of diimine bidentate ligand NH.NHq-R (R = H or COOH) in the HSA/DNA interaction as well as antiviral activity. The interactions between HSA and new nitro complexes [RuII(L)(NO2)(tpy)]+ were evaluated. The Ka values for the HSA-[RuII(bdq)(NO2)(tpy)]+ is 10 times bigger than HSA-[RuII(bd)(NO2)(tpy)]+. The sites of interaction between HSA and the complexes via synchronous fluorescence suppression indicate that the [RuII(bdq)(NO2)(tpy)]+ is found close to the Trp-241 residue, while the [RuII(bd)(NO2)(tpy)]+ complex is close to Tyr residues. The interaction with fish sperm fs-DNA using direct spectrophotometric titration (Kb) and ethidium bromide replacement (KSV and Kapp) showed weak interaction in the system fs-DNA-[RuII(bdq)(NO)(tpy)]+. Furthermore, fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+ system showed higher intercalation constant. Circular dichroism spectra for fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+, suggest semi-intercalative accompanied by major groove binding interaction modes. The [RuII(bd)(NO2)(tpy)]+ and [RuII(bd)(NO)(tpy)]3+ inhibit replication of Zika and Chikungunya viruses based in the nitric oxide release under S-nitrosylation reaction with cysteine viral.

Prognostic impact of thrombocytosis in gastric cancer-A retrospective study.

BACKGROUND: Solid tumors are a common cause of secondary thrombocytosis, which has been identified as a prognostic factor in various cancers. However, the impact of thrombocytosis on the prognosis of gastric cancer is not yet well defined. The aim of this study was to assess the prevalence and prognostic value of thrombocytosis in patients with gastric cancer. METHODS: This was a retrospective study of patients with gastric carcinoma treated surgically, with curative intent, in our hospital, Centro Hospitalar Vila Nova de Gaia/Espinho, between January 2009 and December 2019. Clinical files were consulted and clinicopathological characteristics were analyzed. RESULTS: In the present sample (n = 352), the prevalence of pretreatment thrombocytosis was 16.5%. Thrombocytosis was associated with more advanced T stage, greater number of metastatic nodes, and more frequent lymphatic and venous permeation. The presence of thrombocytosis had a negative impact on disease-free survival (hazard ratio [HR] 3.54, 95% confidence interval [CI] 2.35-5.33, P < .001) and overall survival (HR 4.45, 95% CI 2.95-6.71, P < .001). CONCLUSIONS: The presence of pretreatment thrombocytosis had a negative impact on overall survival and disease-free survival and thus could be used as an independent prognostic factor.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Effects of auriculotherapy on anxiety and biomarkers in Primary Health Care: a clinical trial.

OBJECTIVE: to assess the effects of auriculotherapy on anxiety and brain-derived neurotrophic factor (BDNF), neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) serum levels in adults assisted in Primary Health Care. METHODS: a pre-experimental pilot clinical trial. Information was obtained from 19 patients using the State-Trait Anxiety Inventory (STAI) and analysis of BDNF, NSE and S100B serum levels. RESULTS: the pre-intervention anxiety score in the IDATE-Trait was 52.11±6.691 (CV 12.84%) and the assessment after auriculotherapy was significantly lower (43.72±8.141; CV 18.62%; P=0.0007). S100B levels were significantly reduced after auriculotherapy (from 64.03±72.18 to 54.03±68.53 pg/mL; CV 126.8%; P=0.0023). CONCLUSION: auriculotherapy effectively reduced anxiety levels. It proved to be safe and easy to apply, allowing nurses to perform this technique autonomously. A reduction of S100B was also evidenced, demonstrating possible prevention of neuronal damage.

Modulation of functional networks related to the serotonin neurotransmitter system by citalopram: Evidence from a multimodal neuroimaging study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR). AIM: We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge. METHODS: We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography. RESULTS: 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task. CONCLUSIONS: Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.

Electrical stimulation of the auricular branch of the vagus nerve potentiates analgesia induced by physical exercise in mice with peripheral inflammation.

Objective: This study evaluated the antihyperalgesic and anti-inflammatory effects of percutaneous vagus nerve electrical stimulation (pVNS) associated with physical exercise, i.e., swimming, in mice with peripheral inflammation. Methods: The pain model was induced by intraplantar (i.pl.) injection of Freund's complete adjuvant (CFA). Sixty-four male Swiss mice (35-40 g) received an i.pl. of CFA and underwent behavioral tests, i.e., mechanical hyperalgesia, edema, and paw temperature tests. Additionally, cytokine levels, specifically interleukin-6 (IL-6) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay. Mice were treated with swimming exercise for 30 min alone or associated with different time protocols (10, 20, or 30 min) of stimulation in the left ear with random frequency during four consecutive days. Results: pVNS for 20 min prolonged the antihyperalgesic effect for up to 2 h, 24 h after CFA injection. pVNS for 30 min prolonged the antihyperalgesic effect for up to 7 h, 96 h after CFA injection. However, it did not alter the edema or temperature at both analyzed times (24 and 96 h). Furthermore, the combination of pVNS plus swimming exercise, but not swimming exercise alone, reduced IL-6 levels in the paw and spinal cord, as well as IL-10 levels in the spinal cord. Conclusion: pVNS potentiates the analgesic effect induced by swimming, which may be, at least in part, mediated by the modulation of inflammatory cytokines in the periphery (paw) and central nervous system (spinal cord). Therefore, the combination of these therapies may serve as an important adjunctive treatment for persistent inflammatory pain.

Complex Regional Pain Syndrome Type I: Evidence for the CB1 and CB2 Receptors Immunocontent and Beneficial Effect of Local Administration of Cannabidiol in Mice.

Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.