Potential Central Nervous System Research Articles

Loperamide positive deaths in Sweden 2012–2022 and Finland 2017–2022: Fatal loperamide intoxication exclusively for Sweden

Loperamide, a potent μ-opioid receptor agonist used as an antidiarrheal drug, exhibits increased bioavailability at supratherapeutic doses, causing potential central nervous system effects. Its misuse for opioid withdrawal relief and euphoria can lead to dangerously elevated blood levels, causing severe cardiac dysrhythmias and death. This study aimed to compare loperamide positive autopsy cases in Sweden and Finland after the introduction of postmortem toxicological analysis of loperamide, focusing on loperamide’s role in fatalities and identifying common characteristics among those affected. All cases with detected loperamide in femoral blood at forensic autopsies in Sweden (2012–2022) and Finland (2017–2022) were included. In Sweden, loperamide was detected in 126 individuals, and in Finland, in 111 individuals. The incidence of individuals positive for loperamide in postmortem femoral blood increased steadily over the study duration in both Sweden and Finland. Loperamide related fatalities were observed exclusively in Sweden (n=80), predominantly involving younger males with histories of substance abuse, typically classified as accidental deaths. The group of loperamide nonrelated deaths in Sweden mirrored the entirety of cases in Finland. The concentration of loperamide in postmortem femoral blood was significantly higher in cases where loperamide was considered the cause of death (median 0.140 μg/g) compared to cases where loperamide contributed (median 0.080 μg/g), as well as in deaths unrelated to loperamide in both countries (Sweden: median 0.029 μg/g; Finland: median 0.010 μg/ml). The high limit of quantification for loperamide in Sweden may underestimate therapeutic users in epidemiological assessments. This study underscores the absence of loperamide misuse in Finland and indicates a rising trend of loperamide abuse in Sweden.

New halo-enaminones as potential CNS drugs: Synthesis, characterization, DFT, NLO, molecular docking, and ADMET analysis

Some new halo-enaminones (2b-2g) of (Z)-1-(((2-acetylphenyl)amino)methylene)naphthalen-2(1H)-one (2a) were successfully synthesized in a very good yield. They were characterized by spectroscopic techniques. The single crystal XRD analysis confirmed the structure, stereochemistry, and hydrogen bond interactions of the synthesized enaminones. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) were employed to study theoretical attributes such as Structural analysis, Natural Bond Order analysis (NBO), Frontier molecular Orbital Analysis (FMO), Global and local reactivity descriptors, Molecular Electrostatic Potential (MEP) analysis, Absorption, Emission and Non-Linear Optical (NLO) properties. Molecular docking analysis revealed that all these compounds had an excellent binding energy of ∼ -12 kcal/mol, with the human Sirtuin 2 (SIRT2) protein (PDB ID: 5Y5N), which is predominantly expressed in the brain. In addition, ADMET analysis revealed that all of them have drug-like properties, Blood Brain Barrier (BBB) permeable, and are not P–Glycoprotein substrates, implying that they are potential Central Nervous System (CNS) drugs.

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis.

Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood-brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.

Blood brain barrier permeability and astrocyte-derived extracellular vesicles in children with juvenile idiopathic arthritis: a cross-sectional study

BackgroundJuvenile idiopathic arthritis (JIA) is the most prevalent rheumatic disease in children, and the inflammatory process is widely studied, primarily characterized by its impact on joint health. Emerging evidence suggests that JIA may also affect the central nervous system (CNS). This study investigates the potential CNS involvement in JIA by analyzing the presence of astrocyte-derived extracellular vesicles (EVs) and the S100B protein in plasma, both of which are indicative of astrocyte activity and blood-brain barrier (BBB) integrity.MethodsEDTA plasma from 90 children diagnosed with JIA and 10 healthy controls, matched by age and gender, was analyzed for extracellular vesicles by flow cytometric measurement. Astrocyte-derived EVs were identified using flow cytometry with markers for aquaporin 4 (AQP-4) and glial fibrillary acidic protein (GFAP). Levels of the S100B protein were measured using a commercial ELISA. Disease activity was assessed using the Juvenile Arthritis Disease Activity Score (JADAS27, 0–57), and pain levels were measured using a visual analogue scale (VAS, 0–10 cm).ResultsOur analyses revealed a significantly higher concentration of astrocyte-derived EVs in the plasma of children with JIA compared with healthy controls. Furthermore, children with JADAS27 scores of 1 or higher exhibited notably higher levels of these EVs. The S100B protein was detectable exclusively in the JIA group.ConclusionThe elevated levels of astrocyte-derived EVs and the presence of S100B in children with JIA provide evidence of BBB disruption and CNS involvement, particularly in those with higher disease activity. These findings underscore the importance of considering CNS health in the comprehensive management of JIA. Further research is required to elucidate the mechanisms behind CNS engagement in JIA and to develop treatments that address both joint and CNS manifestations of the disease.

ANN multi-layer perceptron for prediction of blood–brain barrier permeable compounds for central nervous system therapeutics

Endothelial cells produce a semipermeable barrier known as the blood–brain barrier (BBB) to keep undesired chemicals out of the central nervous system (CNS). However, this barrier also restricts the exploration of potential new medications due to insufficient exposure. To address this challenge, machine learning (ML) algorithms can be useful to predict the BBB permeability of chemical compounds. Support vector machines, continuous neural networks, and deep learning approaches have been used to identify compounds that can penetrate the BBB. However, predicting BBB permeability based solely on chemical structure can be difficult. In the current research, we developed an ML model using a large dataset to predict BBB permeability, which could be used for early-stage drug screening of potential CNS medications. Our artificial neural network ANN algorithm exhibited an accuracy of 0.94, specificity of 0.83, sensitivity of 0.97, AUC of 0.96, and MCC of 0.83. These metrics suggest that our model has a high accuracy rate in predicting BBB permeability and therefore has the potential to advance drug discovery efforts in the CNS. This study’s outcomes demonstrate the potential for ML models to predict BBB permeability accurately, aiding in the identification of new CNS therapeutic options. Communicated by Ramaswamy H. Sarma

Diagnostic Stewardship in the Evaluation of a Child With a Potential Central Nervous System Infection.

Diagnostic Stewardship in the Evaluation of a Child With a Potential Central Nervous System Infection.

Polymer nanoparticles of [(1-methyl-(S)-4,5-dihydroorotyl)-histidyl-prolinamide] as a potential central nervous system antidepressant formulation and their scale-up studies

Polymer nanoparticles of [(1-methyl-(S)-4,5-dihydroorotyl)-histidyl-prolinamide] as a potential central nervous system antidepressant formulation and their scale-up studies

Navigating the complexities of encephalocraniocutaneous lipomatosis: a case series and review

IntroductionEncephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with complex skin, eye, and central nervous system (CNS) symptoms. Diagnosis and treatment are challenging due to its rarity and diverse manifestations. It often involves issues like porencephalic cysts, cortical atrophy, and low-grade gliomas in the CNS, resulting in developmental delays. The spinal cord is frequently affected, leading to problems like medullary compression and radiculopathy, causing back pain and sensory/motor deficits. Surgical interventions are reserved for symptomatic cases to address hydrocephalus or alleviate spinal lipomas. This article reviews a case series to assess surgical risks and neurological outcomes.Case seriesWe present a case series ECCL, focusing on the diffuse lipomatosis of the spinal cord and the intricate surgical procedures involved. A multi-stage surgical approach was adopted, with continuous neuromonitoring employed to safeguard motor pathways. We discuss clinical characteristics, imaging studies, and indications for neurosurgical interventions.DiscussionECCL is a complex syndrome. Diagnosis is challenging and includes clinical evaluation, neuroimaging, and genetic testing. Treatment targets specific symptoms, often requiring surgery for issues like lipomas or cerebral cysts. Surgery involves laminectomies, spinal fusion, and motor pathway monitoring. Thorough follow-up is crucial due to potential CNS complications like low-grade gliomas. Hydrocephalus occurs in some cases, with endoscopic third ventriculostomy (ETV) preferred over ventriculoperitoneal shunt placement.ConclusionNeurosurgery for ECCL is for symptomatic cases. ETV is preferred for hydrocephalus, while the treatment for lipoma is based on the presence of symptoms; the follow-up should assess growth and prevent deformities.

Characterization of central manifestations in patients with Niemann-Pick disease type C

PurposeNiemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. MethodsWe prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. ResultsPatients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. ConclusionThis deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.

CSF cytology of common primary CNS neoplasms categorized by CNS WHO 2021.

The detection of neoplastic cells in cerebral spinal fluid (CSF) is pivotal for the management of patients with central nervous system (CNS) tumours. This article delves into the CSF cytological characteristics of common CNS neoplasms, aligning with the 2021 World Health Organization (WHO) classification of CNS tumours. A retrospective review of CSF specimens positive for primary CNS neoplasms was performed at three tertiary medical centres. Only cases that had histopathologic confirmation and/or molecular workup were included. Common primary CNS neoplasms seen in CSF cytology specimens include medulloblastoma, (non-WNT/non-SHH as well as SHH-activated and TP53 mutant), pineoblastoma, atypical teratoid/rhabdoid tumour (AT/RT), IDH-wildtype glioblastoma, and primary diffuse large B-cell lymphoma of the CNS. Ependymomas and germinomas can also have CSF involvement but are less common. Although the typical histologic architecture of these tumours may not be preserved in the CSF, unique cytomorphologic features such as nuclear moulding, nuclear pleomorphism, rhabdoid cells, prominent nucleoli and rosette formation can still be appreciated. Adopting the updated terminology and correlating cytologic observations with molecular findings will streamline the diagnostic process, reducing the complexities and ambiguities pathologists often encounter when analysing CSF specimens for potential primary CNS neoplasms.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

Letter to editor regarding "The Efficacy and Safety of Topical Saline Irrigation with Tranexamic Acid on Perioperative Blood Loss in Patients Treated with PELD".

Letter: We have read the recent article published by Zhang et al titled "The Efficacy and Safety of Topical Saline Irrigation with Tranexamic Acid on Perioperative Blood Loss in Patients Treated with Percutaneous Endoscopic Interlaminar Diskectomy: A Retrospective Study". In this retrospective study, authors performed interlaminar endoscopic lumbar discectomy (IELD) for L5-S1 disc herniations, categorizing patients into two groups. One group underwent IELD with saline irrigation fluid containing 0.33 gm of tranexamic acid (TXA) per 1L of saline, while the other group received only saline irrigation fluid. We appreciate the authors' efforts in shedding light on the use of TXA in irrigation fluid, which currently has limited literature available. However, we wish to highlight several points of concern that, in our view, warrant further discussion. Upon reviewing the manuscript, our initial concern centers on the reported amount of blood loss, a crucial outcome in this study. The blood loss figures presented in this study appear significantly higher compared to the existing literature. In both study groups, the authors indicate total blood loss (TBL) exceeding 300 ml and intraoperative blood loss (IBL) surpassing 40 ml. In contrast, a systematic review and meta-analysis by Jitpakdee et al. (1) reported a range of blood loss from 10.9 ml to 23.35 ml for interlaminar endoscopic discectomy without any systemic or local use of tranexamic acid. Accurately assessing blood loss in endoscopic spine surgery poses a challenge, and the accuracy of indirect calculation methods is questionable, particularly when bleeding is minimal. Endoscopic discectomy has been proven benefits by minimal tissue damage and negligible blood loss. Another significant concern we would like to address is related to the safety and efficacy of topical tranexamic acid (TXA) use in endoscopic spine surgery. The existing literature generally accepts the safety profile and efficacy of use of intravenous TXA in open spine surgery where the blood loss incurred is substantial (2, 3). However, when it comes to the safety of topical TXA, it is important to note that TXA is known to have neurotoxic and epileptogenic properties when applied to central nervous system (CNS) tissue (5, 6). This is due to its interference with central GABAA receptors and glycine receptors (7). In endoscopic spine surgeries, small dural tears can sometimes go unnoticed due to continuous irrigation fluid pressure. In such cases, the potential CNS side effects associated with topical TXA could pose a real danger. Furthermore, even when dural tears are identified during surgery, it can be challenging to completely washout all the irrigation fluid containing TXA from the surgical field. The accumulation of excessive epidural or intrathecal TXA, especially after a dural tear, can lead to life-threatening conditions such as seizures or arrhythmias, significantly increasing morbidity and mortality in what is often intended as a day-care procedure. Moreover, the authors have not mentioned any exclusion criteria for patients with conditions that are suspected to elevate risk of developing TXA-related side effects, such as a history of thromboembolic events and/or coagulopathy, convulsive disorders and dural disruption. Lastly, in terms of the efficacy of TXA, there are limited studies demonstrating the use of local TXA in spine surgeries to reduce blood loss. For example, Krohn et al(4) used topical TXA irrigation in open instrumented spinal fusion surgery before wound closure. Their study showed a reduction in postoperative blood loss, with drain output decreasing from 525 ml in the non-TXA group to 252 ml in the TXA group. However, it had no significant effect on intraoperative blood loss. We would like to raise a pertinent question regarding endoscopic discectomy procedures, which are characterized by minimal blood loss and are often conducted as day-care surgeries. It becomes a matter of concern whether the potential advantages of using topical TXA in reducing blood loss outweigh the associated risks of neurological damage to the central nervous system (CNS) and other potentially life-threatening complications.

Comparison of pharmaceutical properties and biological activities of prednisolone, deflazacort, and vamorolone in DMD disease models.

Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.

Topical Cocaine Hydrochloride Nasal Solution: Anesthetic and Surgical Considerations.

Adequate surgical view during various types of nasal procedures is essential for surgical operations to be performed in a safe, efficient, and successful manner. Minimizing bleeding during surgery is an important way of increasing visualization that is commonly achieved by using a vasoconstrictive agent to control intraoperative hemorrhage. Many otolaryngologists choose to employ topical cocaine to minimize bleeding during surgery owing to its vasoconstrictive properties, while simultaneously benefitting from its dual local anesthetic effects. The relative benefit of topical cocaine for otolaryngologic procedures when compared to other topical analgesics and vasoconstrictors remains a topic of discussion due to the multiple potential cardiac and central nervous system side effects associated with cocaine administration. Furthermore, there is not a scientifically backed maximal safe dose published; instead, most of the guidelines for intranasal cocaine use are based on untested clinical practice. Despite this, the short latency, adequate duration of action, and inherent vasoconstrictive and decongestive capabilities make cocaine a valuable anesthetic agent for use in clinical procedures. As the relative benefit of using topical cocaine compared to the use of other vasoconstrictors and analgesics for nasal procedures remains undetermined in the current literature, this leaves the need for a comprehensive review of research that explores the risks and benefits of using topical cocaine in nasal procedures based on clinical trials that compare intranasal cocaine with various other analgesics and vasoconstrictors.

Curcuma latifolia Roscoe extract reverses inflammatory pain in mice and offers a favorable CNS safety profile

Ethnopharmacological relevanceCurcuma latifolia Roscoe, a plant in the Curcuma genus, has been used as a food additive and folk medicine in Thailand to treat pelvic pain and improve premenstrual syndrome. Although it has been used for centuries, no scientific studies have proved its potential effects on inflammatory pain and central nervous system (CNS) safety profiles.Aim of the study: This study aimed to evaluate the potential effects of the ethanolic extract of C. latifolia rhizome on inflammatory pain in mice, together with its CNS safety profiles. Materials and methodsFirst, network pharmacology was employed to identify the role of bioactive constituents in C. latifolia on inflammatory pain. In addition, in vitro pharmacology was also evaluated to confirm the anti-inflammatory activity of C. latifolia extract at cellular levels in activated macrophages and microglia. Furthermore, the efficacy of the plant extract in attenuating formalin-induced pain-like behaviors in mice was evaluated. Mice were orally administered the extract (125, 250, 500 mg/kg) followed by the measurement of formalin-induced pain-like behaviors. The LABORAS automated behavioral analysis and rotarod test were used to assess potential CNS side effects of C. latifolia extract (500 mg/kg) in mice. ResultsThe results demonstrated that major bioactive constituents present in C. latifolia have the ability to regulate multiple targets, biological processes and pathways associated with inflammatory pain as assessed by network pharmacology. C. latifolia modulated peripheral and central immune cells via reducing proinflammatory mediators (NO, TNF-α, and IL-6). C. latifolia extract improved formalin-induced pain-like behaviors in a dose-dependent manner during phase II of the formalin test. The efficacy of the plant extract at doses of 250 and 500 mg/kg was comparable to that of the positive control (indomethacin 10 mg/kg). Furthermore, the highest therapeutic dose of the extract did not affect motor coordination, exploratory behaviors, general behaviors, and overall well-being of mice, indicating no development of potential CNS adverse effects after administration of the extract. ConclusionThese findings provide novel perspectives on using C. latifolia extract for pain management, considering its therapeutic efficacy and CNS safety.

Realgar-Induced Neurotoxicity: Crosstalk Between the Autophagic Flux and the p62-NRF2 Feedback Loop Mediates p62 Accumulation to Promote Apoptosis.

Realgar is a traditional Chinese medicine that contains arsenic. It has been reported that the abuse of medicine-containing realgar has potential central nervous system (CNS) toxicity, but the toxicity mechanism has not been elucidated. In this study, we established an in vivo realgar exposure model and selected the end product of realgar metabolism, DMA, to treat SH-SY5Y cells in vitro. Many assays, including behavioral, analytical chemistry, and molecular biology, were used to elucidate the roles of the autophagic flux and the p62-NRF2 feedback loop in realgar-induced neurotoxicity. The results showed that arsenic could accumulate in the brain, causing cognitive impairment and anxiety-like behavior. Realgar impairs the ultrastructure of neurons, promotes apoptosis, perturbs autophagic flux homeostasis, amplifies the p62-NRF2 feedback loop, and leads to p62 accumulation. Further analysis showed that realgar promotes the formation of the Beclin1-Vps34 complex by activating JNK/c-Jun to induce autophagy and recruit p62. Meanwhile, realgar inhibits the activities of CTSB and CTSD and changes the acidity of lysosomes, leading to the inhibition of p62 degradation and p62 accumulation. Moreover, the amplified p62-NRF2 feedback loop is involved in the accumulation of p62. Its accumulation promotes neuronal apoptosis by upregulating the expression levels of Bax and cleaved caspase-9, resulting in neurotoxicity. Taken together, these data suggest that realgar can perturb the crosstalk between the autophagic flux and the p62-NRF2 feedback loop to mediate p62 accumulation, promote apoptosis, and induce neurotoxicity. Realgar promotes p62 accumulation to produce neurotoxicity by perturbing the autophagic flux and p62-NRF2 feedback loop crosstalk.

Novel USP9X Mutation in A Lebanese Patient with Delay and Microcephaly: Case Report and Review of Literature

Introduction: USP9X gene is located on the X-chromosome and encodes for an enzyme that regulates important substrates involved in neuronal growth and development. Thus, rare USP9X mutations were identified as directly causative of neurodevelopmental disorders (NDDs) and Intellectual Disability (ID) in homozygous males and more rarely in heterozygous females. In males, USP9X variants have been linked to an X-linked mental retardation syndrome that includes; central nervous system (CNS) abnormalities (white matter disturbances, thin corpus callosum, widened ventricles, and cerebellar defects), global delay with significant alteration of speech, language and behavior, hypotonia, joint hypermobility, digital abnormalities, gastro-intestinal symptoms, visual system defects and dysmorphic facial features. Patient Data: We report the rare case of a 3 years old and 8 months male patient presenting with NDD, ID, speech delay, progressive aggressive behavioral changes and CNS abnormalities (microcephaly, left periventricular lesion). He was found to have a USP9X variant carrying a missense mutation: USP9X, c.1870A>T p.(Met624Leu) on Whole-Exome Sequencing (WES). Discussion: Our patient had most of the important features of the previously described X-linked mental retardation syndrome but some were absent such as dysmorphic features, digital or visual abnormalities and hypotonia. Microcephaly rather than macrocephaly was noted, which could be an additional potential CNS malformation, expanding the spectrum of phenotypic characteristics of the USP9X variants. No associated congenital anomalies were noted that are usually more common in female subjects. Conclusion: This is to our knowledge the first reported case of a USP9X variant in Lebanon. The clinical characteristics matched most of the previously described features in the literature. Microcephaly was a new clinical feature not previously described and could be a new possible phenotypic characteristic of the disease.

Third‐line or above anlotinib in relapsed and refractory small cell lung cancer patients with brain metastases: A post hoc analysis of ALTER1202, a randomized, double‐blind phase 2 study

AbstractBackgroundThe prognosis of patients with small cell lung cancer (SCLC) and brain metastases (BM) was poor. This study aimed to explore the efficacy and safety of anlotinib as third‐line or above treatment in SCLC with BM.MethodsThis was a subgroup analysis of the ALTER1202 trial, which was a randomized, placebo‐controlled trial aimed to evaluate the role of anlotinib as third‐line treatment or above in patients with SCLC. This study included patients with BM at baseline. The efficacy and safety outcomes included progression‐free survival (PFS), overall survival (OS), central nervous system (CNS), objective response rate (ORR), CNS disease control rate (DCR), time to CNS progression, and adverse events (AEs).ResultsTwenty‐one and nine patients with BM were included in the anlotinib and placebo groups, respectively. The median PFS and OS were 3.8 months (95% confidence interval [CI]: 1.8–6.1) and 6.1 months (95% CI: 4.1–8.0) in the anlotinib group. Anlotinib was associated with a significant improvement in PFS (hazard ratio [HR] = 0.15, 95% CI: 0.04–0.51, p = 0.0005) and OS (HR = 0.26, 95% CI: 0.09–0.73, p = 0.0061) than placebo. Anlotinib significantly prolonged the time to CNS progression (p < 0.0001). The anlotinib group had a higher CNS DCR than placebo (95.2% vs. 22.2%, p = 0.0001). The most common grade 3 or higher AEs were increased lipase (19.0%), hypertension (14.3%), and hyponatremia (14.3%) in the anlotinib group.ConclusionsAnlotinib proved to have potential CNS activity and a manageable toxicity profile in patients with SCLC and BM, significantly delaying CNS progression.

Clinical Features and Outcomes of Primary Breast Diffuse Large B-Cell Lymphoma: A Matched-Pair Study.

The influence of the breast as the primary site on the outcome of diffuse large B-cell lymphoma (DLBCL) and further changes in therapeutic strategies remain unclear. We aimed to compare the outcomes between primary breast and non-breast DLBCL and analyze the genetic profiles of some of the study cohorts using next-generation sequencing. This matched-pair study reviewed the medical records of 19 patients with stage I and II primary breast DLBCL diagnosed between January 2005 and December 2021 on the basis of the Wiseman and Liao criteria, and we used 1:4 propensity score matching to identify patients with non-breast DLBCL as the control group. The overall response rate, progression-free survival (PFS), and overall survival (OS) were the outcome measures. Patients with primary breast and non-breast DLBCL had a 5-year PFS of 72.6% and 86.9%, respectively (P = .206). These 2 groups also had comparable 5-year OS (86.9% vs 87.8%; P = .772). The breast as the primary site was not associated with inferior PFS (hazard ratio [HR]: 2.14; 95% CI: 0.66-6.96; P = .206) and OS (HR: 1.26; 95% CI: 0.27-5.93; P = .772). Patients with primary breast DLBCL and those with non-breast DLBCL had comparable PFS and OS under rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens. Further investigations of the mutation profile, its clinical impact, potential central nervous system relapse, and prognosis of primary breast DLBCL are required.

Adagrasib: A landmark in the KRASG12C-mutated NSCLC.

Adagrasib: A landmark in the KRASG12C-mutated NSCLC.