Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats.

The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRA consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lungs, kidneys, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.

Molecular Basis and Diagnostic Approach to Isolated and Syndromic Lateralized Overgrowth in Childhood.

OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. and STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum (BWSp), PIK3CA-Related Overgrowth Spectrum (PROS), vascular overgrowth (VO) , or isolated (ILO), based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield. RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions and 11% reclassified. BWSp was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PROS had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. VO demonstrated significant clinical overlap with other syndromes. Molecular diagnosis of ILO proved challenging, with only 21% of cases classifiable into a specific condition. CONCLUSION: Despite, LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which would be crucial for addressing potential cancer predisposition, enabling precision medicine treatments, or guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.

Immunonutrition, Metabolism, and Programmed Cell Death in Lung Cancer: Translating Bench to Bedside.

Lung cancer presents significant therapeutic challenges, motivating the exploration of novel treatment strategies. Programmed cell death (PCD) mechanisms, encompassing apoptosis, autophagy, and programmed necrosis, are pivotal in lung cancer pathogenesis and the treatment response. Dysregulation of these pathways contributes to tumor progression and therapy resistance. Immunonutrition, employing specific nutrients to modulate immune function, and metabolic reprogramming, a hallmark of cancer cells, offer promising avenues for intervention. Nutritional interventions, such as omega-3 fatty acids, exert modulatory effects on PCD pathways in cancer cells, while targeting metabolic pathways implicated in apoptosis regulation represents a compelling therapeutic approach. Clinical evidence supports the role of immunonutritional interventions, including omega-3 fatty acids, in augmenting PCD and enhancing treatment outcomes in patients with lung cancer. Furthermore, synthetic analogs of natural compounds, such as resveratrol, demonstrate promising anticancer properties by modulating apoptotic signaling pathways. This review underscores the convergence of immunonutrition, metabolism, and PCD pathways in lung cancer biology, emphasizing the potential for therapeutic exploration in this complex disease. Further elucidation of the specific molecular mechanisms governing these interactions is imperative for translating these findings into clinical practice and improving lung cancer management.

Lower levels of plasma syndecan-4 are associated with loss of body weight and fat-free mass after bariatric surgery.

OBJECTIVE: Bariatric surgery induces a significant loss of both fat mass (FM) and fat-free mass (FFM). The proteoglycan receptor syndecan-4 (SDC4) plays a crucial role in adipose tissue and skeletal muscle functions. Thus, this study was performed (i) to assess plasma SDC4 levels after both Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) surgeries, and (ii) to explore potential associations with changes in body composition variables. RESULTS: Twenty-six patients (17 females) with severe obesity underwent SG (n = 13) or RYGB (n = 13) and were followed up to 1 year (1Y). Body weight, FM, FFM, and SCD4 were measured at baseline (BL), and at week 11 (W11) and 1Y after surgery. Independently of procedure, there was a significant body weight loss at W11, with an average FM and FFM reduction of 13.7 ± 0.6 kg and 5.3 ± 0.5 kg, respectively. Participants continued to lose weight afterwards, with a total weigth loss of 38.2 ± 1.5 kg at 1Y. No associations were found at BL between SDC4 levels and any anthropometric variable; however, SDC4 levels were lower than BL at both W11 and 1Y, independently of type of surgery. Additionally, changes in SDC4 between BL and 1Y were positively correlated with weight and FFM loss during the same period. TRIAL REGISTRATION: ClinicalTrials.gov NCT04051190 on 09/08/2019.

Health technology assessment in musculoskeletal radiology: the case study of EOSedge™.

OBJECTIVES: Health technology assessment (HTA) is a systematic process used to evaluate the properties and effects of healthcare technologies within their intended use context. This paper describes the adoption of HTA process to assess the adoption of the EOSedge™ system in clinical practice. METHODS: The EOSedge™ system is a digital radiography system that delivers whole-body, high-quality 2D/3D biplanar images covering the complete set of musculoskeletal and orthopedic exams. Full HTA model was chosen using the EUnetHTA Core Model® version 3.0. The HTA Core Model organizes the information into nine domains. Information was researched and obtained by consulting the manufacturers' user manuals, scientific literature, and institutional sites for regulatory aspects. RESULTS: All nine domains of the EUnetHTA Core Model® helped conduct the HTA of the EOSedge, including (1) description and technical characteristics of the technology; (2) health problem and current clinical practice; (3) safety; (4) clinical effectiveness; (5) organizational aspects; (6) economic evaluation; (7) impact on the patient; (8) ethical aspects; and (9) legal aspects. CONCLUSIONS: EOS technologies may be a viable alternative to conventional radiographs. EOSedge has the same intended use and similar indications for use, technological characteristics, and operation principles as the EOS System and provides significant dose reduction factors for whole spine imaging compared to the EOS System without compromising image quality. Regarding the impact of EOS imaging on patient outcomes, most studies aim to establish technical ability without evaluating their ability to improve patient outcomes; thus, more studies on this aspect are warranted.

MRI of total hip arthroplasty: technical aspects and imaging findings.

Total hip arthroplasty (THA) is the best surgical approach for treating advanced hip degeneration, providing pain relief, and improved function in most cases. In the past, MR imaging quality has been highly compromised by in-plane distortions, inadequate fat saturation, and other artifacts due to metal components of THA. Technological advancements have made pathologic conditions, which were previously hidden by periprosthetic artifacts, outstanding features due to the optimization of several sequences. To date, several short and long-term complications involving bony and soft-tissue structures may be detected through magnetic resonance imaging (MRI). The use of MRI with adapted sequences and protocols may drastically reduce artifacts thereby providing essential pre-operative elements for planning revision surgery of failed THA. This review has the purpose of conveying new insights to musculoskeletal radiologists about the techniques to suppress metal-related artifacts and the hallmark MRI findings of painful THA. CRITICAL RELEVANCE STATEMENT: Advancements in metal-suppression have given radiologists the opportunity to play an emerging role in THA management. This article provides technical and imaging insights into challenges that can be encountered in cases of THA, which may present complications and characteristic imaging findings. KEY POINTS: Imaging total hip arthroplasty requires adapted MRI protocol and awareness of the common complications. We have reported the available metal-suppression sequences for evaluating total hip arthroplasty. Many structures and conditions should be considered when dealing with painful aseptic or septic arthroplasty.

Discovering Inflammation in Atherosclerosis: Insights from Pathogenic Pathways to Clinical Practice.

This comprehensive review explores the various scenarios of atherosclerosis, a systemic and chronic arterial disease that underlies most cardiovascular disorders. Starting from an overview of its insidious development, often asymptomatic until it reaches advanced stages, the review delves into the pathophysiological evolution of atherosclerotic lesions, highlighting the central role of inflammation. Insights into clinical manifestations, including heart attacks and strokes, highlight the disease's significant burden on global health. Emphasis is placed on carotid atherosclerosis, clarifying its epidemiology, clinical implications, and association with cognitive decline. Prevention strategies, lifestyle modifications, risk factor management, and nuanced antithrombotic treatment considerations are critical to managing cardiovascular complications, thus addressing a crucial aspect of cardiovascular health.

Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.

Concordance in Intraoperative Surgeons' Opinion in the Diagnosis and Management of Acute Appendicitis: The Role of Training.

OBJECTIVE: Acute appendicitis is a wide spectrum disease, from simple inflammation to evident intestinal perforation. The correct interpretation of the degree of inflammation is crucial to guarantee appropriate treatment and adherence to protocols and guidelines. In order to investigate this concordance, the authors compared the definition of appendicitis and the predicted treatment among all surgeons affiliated to a single Pediatric Surgery School (consisting of 8 different centers). DESIGN: Twenty-two short recordings of intra-operative manipulation of appendices were shown to 56 surgeons, blindly to clinical information. Four items were collected and analyzed: classification of appendicitis, type and length of predicted antibiotic therapy, day of re-alimentation. Data were analyzed to identify the concordance kappa coefficient, stratified according to expertise of the responding surgeon. RESULTS: The 1232 evaluations obtained in all valued items low overall concordance. Subgroup analysis identified a good agreement between younger surgeons only in the choice of antibiotic (k 0.47). However, if the centers were divided between University and non-University Hospitals, a strong agreement was found in the former both for classification (k 0.45 vs 0.32) and type of antibiotic (k 0.42 vs 0.24). CONCLUSIONS: The overall concordance between surgeons in different centers in the diagnostic classification and predicted treatment of appendicitis is quite low. University Hospital have a highest concordance in both items at all levels of expertise; it might be postulated that teaching to younger surgeon increase the comparison between experts and finally the concordance and adherence to protocols within the center.

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry.

AIMS: No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. METHODS: The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. RESULTS: We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. CONCLUSIONS: Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

This study, from AT-TARGET-IT registry, investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Intensive and early PCSK9i therapy reduce composite major cardiovascular (CV) events in patients in reaching LDL-C target values. A strike early-strike strong strategy is safe and effective.

Artificial intelligence in interventional radiology: state of the art.

Artificial intelligence (AI) has demonstrated great potential in a wide variety of applications in interventional radiology (IR). Support for decision-making and outcome prediction, new functions and improvements in fluoroscopy, ultrasound, computed tomography, and magnetic resonance imaging, specifically in the field of IR, have all been investigated. Furthermore, AI represents a significant boost for fusion imaging and simulated reality, robotics, touchless software interactions, and virtual biopsy. The procedural nature, heterogeneity, and lack of standardisation slow down the process of adoption of AI in IR. Research in AI is in its early stages as current literature is based on pilot or proof of concept studies. The full range of possibilities is yet to be explored.Relevance statement Exploring AI's transformative potential, this article assesses its current applications and challenges in IR, offering insights into decision support and outcome prediction, imaging enhancements, robotics, and touchless interactions, shaping the future of patient care.Key points• AI adoption in IR is more complex compared to diagnostic radiology.• Current literature about AI in IR is in its early stages.• AI has the potential to revolutionise every aspect of IR.

Status (in)consistency in education and violent parenting practices towards children.

Violent childrearing practices represent an invisible threat for global health and human development. Leveraging underused information on child discipline methods, this study explores the relationship between parental educational similarity and violent childrearing practices, testing a new potential pathway through which parental educational similarity may relate to child health and wellbeing over the life course. The study uses data from Multiple Indicator Cluster Surveys (MICS) and Demographic and Health Surveys (DHS) covering 27 sub-Saharan African (SSA) countries. Results suggest that couples where partners share the same level of education (homogamy) are less likely to adopt violent childrearing practices relative to couples where partners face status inconsistency in education (heterogamy), with differences by age of the child, yet less so by sex and birth order. Homogamous couples where both partners share high levels of education are also less (more) likely to adopt physically violent (non-violent) practices relative to homogamous couples with low levels of education. Relationships are stronger in countries characterized by higher GDP per capita, Human Development Index, and female education, yet also in countries with higher income and gender inequalities. Besides stressing the importance of female education, these findings underscore the key role of status concordance vs discordance in SSA partnerships. Tested micro-level mechanisms and country-level moderators only weakly explain result heterogeneity, calling for more research on the topic.

Dual-energy CT in musculoskeletal imaging: technical considerations and clinical applications.

Dual-energy CT stands out as a robust and innovative imaging modality, which has shown impressive advancements and increasing applications in musculoskeletal imaging. It allows to obtain detailed images with novel insights that were once the exclusive prerogative of magnetic resonance imaging. Attenuation data obtained by using different energy spectra enable to provide unique information about tissue characterization in addition to the well-established strengths of CT in the evaluation of bony structures. To understand clearly the potential of this imaging modality, radiologists must be aware of the technical complexity of this imaging tool, the different ways to acquire images and the several algorithms that can be applied in daily clinical practice and for research. Concerning musculoskeletal imaging, dual-energy CT has gained more and more space for evaluating crystal arthropathy, bone marrow edema, and soft tissue structures, including tendons and ligaments. This article aims to analyze and discuss the role of dual-energy CT in musculoskeletal imaging, exploring technical aspects, applications and clinical implications and possible perspectives of this technique.

Posteromedial Corner Injuries of the Knee: Imaging Findings.

The posteromedial corner (PMC) of the knee is an anatomical region formed by ligamentous structures (medial collateral ligament, posterior oblique ligament, oblique popliteal ligament), the semimembranosus tendon and its expansions, the posteromedial joint capsule, and the posterior horn of the medial meniscus. Injuries to the structures of the PMC frequently occur in acute knee trauma in association with other ligamentous or meniscal tears. The correct assessment of PMC injuries is crucial because the deficiency of these supporting structures can lead to anteromedial rotation instability or the failure of cruciate ligaments grafts. This article reviews the anatomy and biomechanics of the PMC to aid radiologists in identifying injuries potentially involving PMC components.

Generation and Validation of Normative, Age-Specific Reference Curves for Bone Strain Index in Women.

Bone Strain Index (BSI), based on dual-energy X-ray absorptiometry (DXA), is a densitometric index of bone strength of the femur and lumbar spine. Higher BSI values indicate a higher strain applied to bone, predisposing to higher fracture risk. This retrospective, multicentric study on Italian women reports the BSI normative age-specific reference curves. A cohort of Caucasian Italian women aged 20 to 90 years was selected from three different clinical centres. Bone mineral density (BMD) and BSI measurements were obtained for the lumbar spine vertebrae (L1-L4) and for the femur (neck, trochanter and intertrochanter) using Hologic densitometers scans. The data were compared with BMD normative values provided by the densitometer manufacturer. Then, the age-specific BSI curve for the femur and lumbar spine was generated. No significant difference was found between the BMD of the subjects in this study and BMD reference data provided by Hologic (p = 0.68 for femur and p = 0.90 for lumbar spine). Spine BSI values (L1-L4) increase by 84% between 20 and 90 years of age. The mean BSI of the total femur increases about 38% in the same age range. The BSI age-specific reference curve could help clinicians improve osteoporosis patient management, allowing an appropriate patient classification according to the bone resistance to the applied loads and fragility fracture risk assessment.

Association between Obesity and Atrial Function in Patients with Non-Valvular Atrial Fibrillation: An Echocardiographic Study.

Background: Obesity is a public health problem which prevalence has increased worldwide and is associated with different degrees of hemodynamic alterations and structural cardiac changes. The aim of the study is to investigate the impact of body mass index (BMI) on left atrial function using standard and advanced echocardiography in a population of patients with non-valvular atrial fibrillation (AF). Methods: 395 adult patients suffering from non-valvular AF, divided into three tertiles based on BMI value, carry out a cardiological examination with standard and advanced echocardiography. Results: Peak atrial longitudinal strain (PALS), a measure of left atrial function, is lower in the tertile with highest BMI (14.3 ± 8.2%) compared to both the first (19 ± 11.5%) and the second tertile (17.7 ± 10.6%) in a statistically significant manner (p < 0.002). Furthermore, BMI is significantly associated independent with the PALS by multilinear regression analysis, even after correction of the data for CHA2DS2-VASc score, left ventricular mass index, left ventricular ejection fraction, E/E' ratio and systolic pulmonary arterial pressure (coefficient standardized ß = -0.127, p < 0.02; Cumulative R2 = 0.41, SEE = 0.8%, p < 0.0001). Conclusions: BMI could be considered an additional factor in assessing cardiovascular risk in patients with non-valvular atrial fibrillation, in addition to the well-known CHA2DS2-VASc score.

Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia.

OBJECTIVE: The calcium-sensing receptor (CASR) gene encodes a G protein-coupled receptor crucial for calcium homeostasis. Gain-of-function CASR variants result in hypocalcemia, while loss-of-function variants lead to hypercalcemia. This study aims to assess the functional consequences of the novel nonsense CASR variant [c.2897_2898insCTGA, p.(Gln967*) (Q967*)] identified in adolescent patient with chronic hypocalcemia, a phenotype expected for a gain-of-function variants. DESIGN AND METHODS: To functionally characterize the Q967* mutant receptor, both wild-type (WT) and mutant CASR were transiently transfected into HEK293T cells and calcium-sensing receptor (CaSR) protein expression and functions were comparatively evaluated using multiple read-outs. RESULTS: Western blot analysis revealed that the CaSR mutant protein displayed a lower molecular weight compared with the WT, consistent with the loss of the last 122 amino acids in the intracellular domain. Mitogen-activated protein kinase activation and serum responsive element luciferase assays demonstrated that the mutant receptor had higher baseline activity than the WT. Extracellular-signal-regulated kinase/c-Jun N-terminal kinase phosphorylation, however, remained consistently high in the mutant, without significant modulations following exposure to increasing extracellular calcium (Ca2+o) levels, suggesting that the mutant receptor is more sensitive to Ca2+o compared with the WT. CONCLUSIONS: This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.

Preliminary Investigation towards the Use of Infrared Technology for Raw Milk Treatment.

Infrared (IR) technology offers a promising solution for reducing microbiological loads in various food types while preserving their quality traits, such as flavour. However, research on IR's application in complex matrices is limited. Therefore, our preliminary study aimed to evaluate its effectiveness in sanitizing bovine raw milk. We assessed the bacterial count before and after IR treatment by comparing volatile organic compound profiles via headspace extraction and GC/MS analysis. Our findings showed that higher energy levels led to a greater bacterial reduction. IR85 was the most effective in reducing Coliforms and Enterobacteriaceae in non-homogenised samples, with a reduction ranging from -1.01 to >-2.99 and from -1.66 to -3.09 Log CFU/mL, respectively. IR60 and 70 showed no efficacy, while IR80 had intermediate but still satisfactory effect. IR85 notably affected volatile compounds, particularly increasing hexanal (from 0.08 to 4.21 ng g-1) and dimethyl sulphone (from 10.76 to 26.40 ng g-1), while IR80 better preserved the aroma profile. As a result, only IR80 was tested with homogenised raw milk, demonstrating significant bacterial reduction (from >2.39 to 3.06 Log CFU/mL for Coliforms and from 1.90 to >2.45 Log CFU/mL for Enterobacteriaceae) and maintaining the aroma profile quality.

High incidence of RAMP lesions and a nonnegligible incidence of anterolateral ligament and posterior oblique ligament rupture in acute ACL injury.

PURPOSE: The purpose of this study was to assess the frequency of medial collateral ligament (MCL), posterior oblique ligament (POL) and anterolateral ligament (ALL) tears and different types of RAMP lesions of patients with verified acute anterior cruciate ligament (ACL) tears by magnetic resonance imaging (MRI). METHODS: MRI was performed on patients with a clinical diagnosis of acute ACL injury. Patients were eligible for inclusion if they had an initially clinically noted ACL tear confirmed on MRI within 30 days of trauma. RESULTS: A total of 146 patients were included in the study, 42 (28.8%) females and 104 (71.2%) males. The mean age at MRI was 27.2 ± 9.4 years, and the mean time from injury to MRI was 15.7 ± 7.8 days. Thirty-four (23.3%) patients had a complete MCL lesion, 32 (21.9%) had a complete POL lesion and 28 (19.2%) had a complete ALL lesion. One hundred and fourteen patients (78.1%) presented with RAMP lesions, while 20 (13.7%) patients reported other meniscal lesions. The mean medial and lateral tibial slopes were 4.0° ± 2.7° and 4.0° ± 3.1°, respectively. Only 10 (6.8%) patients reported no lesions associated with ACL rupture. The most common injuries were isolated RAMP type 3 (18-12.3%) and isolated RAMP type 1 (17-11.6%). Thirteen (8.9%) patients had a combination of MCL, POL and ALL rupture. CONCLUSIONS: Isolated lesions of the ACL are extremely rare. In most cases, a single RAMP lesion should be investigated. In the presence of MCL injury, POL injury should always be suspected as well, while nearly 20% of patients present a rupture of the ALL. About one in 10 patients had three lesions (MCL, ALL and POL), and most of them had a combined RAMP lesion. LEVEL OF EVIDENCE: Level IV.

Immune and glial cell alterations in the rat brain after repeated exposure to the synthetic cannabinoid JWH-018.

The use of synthetic cannabinoid receptor agonists (SCRAs) poses major psychiatric risks. We previously showed that repeated exposure to the prototypical SCRA JWH-018 induces alterations in dopamine (DA) transmission, abnormalities in the emotional state, and glial cell activation in the mesocorticolimbic DA circuits of rats. Despite growing evidence suggesting the relationship between substance use disorders (SUD) and neuroinflammation, little is known about the impact of SCRAs on the neuroimmune system. Here, we investigated whether repeated JWH-018 exposure altered neuroimmune signaling, which could be linked with previously reported central effects. Adult male Sprague-Dawley (SD) rats were exposed to JWH-018 (0.25 mg/kg, i.p.) for fourteen consecutive days, and the expression of cytokines, chemokines, and growth factors was measured seven days after treatment discontinuation in the striatum, cortex, and hippocampus. Moreover, microglial (ionized calcium-binding adaptor molecule 1, IBA-1) and astrocyte (glial fibrillary acidic protein, GFAP) activation markers were evaluated in the caudate-putamen (CPu). Repeated JWH-018 exposure induces a perturbation of neuroimmune signaling specifically in the striatum, as shown by increased levels of cytokines [interleukins (IL) -2, -4, -12p70, -13, interferon (IFN) γ], chemokines [macrophage inflammatory protein (MIP) -1α, -3α], and growth factors [macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF)], together with increased IBA-1 and GFAP expression in the CPu. JWH-018 exposure induces persistant brain region-specific immune alterations up to seven days after drug discontinuation, which may contribute to the behavioral and neurochemical dysregulations in striatal areas that play a role in the reward-related processes that are frequently impaired in SUD.