24 Apr

Non-invasive therapeutic drug monitoring: LC-MS validation for lamotrigine quantification in dried blood spot and oral fluid/saliva

Epilepsy, affecting over 50 million people globally, presents a significant neurological challenge. Effective prevention of epileptic seizures relies on proper administration and monitoring of Anti-Seizure Medication (ASMs). Therapeutic Drug Monitoring (TDM) ensures optimal dosage adjustment, minimizing adverse effects and potential drug interactions. While traditional venous blood collection for TDM may be stressful, emerging alternative sampling methods, particularly Dried Blood Spot (DBS) or oral fluid offer less invasive way of sampling. This study aimed to develop and validate an analytical method for the determination of lamotrigine in such alternative samples. The sample, either DBS or oral fluid, was subjected to extraction, evaporation, and reconstitution in 15 % acetonitrile containing 0.1 % formic acid. A Kinetex C18 Polar column was used for liquid chromatographic separation and MS in ESI+ mode was used for detection and quantitation of lamotrigine using an isotopically labelled internal standard according to EMA guidelines. The calibration range of the developed method enables the determination of lamotrigine in the concentration range of 1-30 μg/mL in DBS and 0.5-20 μg/mL in oral fluid. Oral fluid and DBS samples from patients treated with lamotrigine analysed by the developed method were compared to plasma concentrations measured by the hospital's accredited laboratory. 

24 Apr

Repeated Administrations of Polyphenolic Extracts Prevent Chronic Reflexive and Non-Reflexive Neuropathic Pain Responses by Modulating Gliosis and CCL2-CCR2/CX3CL1-CX3CR1 Signaling in Spinal Cord-Injured Female Mice

Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study's end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. 

24 Apr

FGFR2 residence in primary cilia is necessary for epithelial cell signaling

Primary cilium projects from cells to provide a communication platform with neighboring cells and the surrounding environment. This is ensured by the selective entry of membrane receptors and signaling molecules, producing fine-tuned and effective responses to the extracellular cues.

In this study, we focused on one family of signaling molecules, the fibroblast growth factor receptors (FGFRs), their residence within cilia, and its role in FGFR signaling. We show that FGFR1 and FGFR2, but not FGFR3 and FGFR4, localize to primary cilia of the developing mouse tissues and in vitro cells. For FGFR2, we demonstrate that the ciliary residence is necessary for its signaling and expression of target morphogenic genes. We also show that the pathogenic FGFR2 variants have minimal cilium presence, which can be rescued for the p.P253R variant associated with the Apert syndrome by using the RLY-4008 kinase inhibitor.

Finally, we determine the molecular regulators of FGFR2 trafficking to cilia, including IFT144, BBS1, and the conserved T429V430 motif within FGFR2.

24 Apr

Dietary inflammatory index during pregnancy and its relationship with gyrification and IQ in young adult offspring

24 Apr

Enhancing stroke response in school children: Efficacy of the HOBIT program - a cluster randomized trial

Keywords: Children; Cluster randomized trial; Health education; Intervention; School; Stroke awareness.

11 Apr

Virtual Waiting Room: The New Narrative of Waiting in Oncology Care

This conceptual study introduces the "virtual waiting room," an innovative, interactive, web-based platform designed to enhance the waiting experience in oncology by providing personalized, educational, and supportive content. Central to our study is the implementation of the circular entry model, which allows for non-linear navigation of health information, empowering patients to access content based on their immediate needs and interests. This approach respects the individual journeys of patients, acknowledging the diverse pathways through which they seek understanding and manage their health. The virtual waiting room is designed not only to support patients but also to facilitate stronger communication and shared understanding between patients, caregivers, and families. By providing a shared digital space, the platform enables caregivers and family members to access the same information and resources, thereby promoting transparency and collective knowledge. This shared access is crucial in managing the emotional complexities of oncology care, where effective communication can significantly impact treatment outcomes and patient well-being. Furthermore, the study explores how the circular entry model within the virtual waiting room can enhance patient autonomy and engagement by offering customized interactions based on user feedback and preferences. This personalized approach aims to reduce anxiety, improve health literacy, and prepare patients more effectively for clinical interactions. 

11 Apr

Noninvasive Temporal Interference Stimulation of the Subthalamic Nucleus in Parkinson's Disease Reduces Beta Activity

Background: Temporal interference stimulation (TIS) is a novel noninvasive electrical stimulation technique to focally modulate deep brain regions; a minimum of two high-frequency signals (f₁ and f₂ > 1 kHz) interfere to create an envelope-modulated signal at a deep brain target with the frequency of modulation equal to the difference frequency: Δf = |f₂ - f₁|.

Objective: The goals of this study were to verify the capability of TIS to modulate the subthalamic nucleus (STN) with Δf and to compare the effect of TIS and conventional deep brain stimulation (DBS) on the STN beta oscillations in patients with Parkinson's disease (PD).

Methods: DBS leads remained externalized after implantation, allowing local field potentials (LFPs) recordings in eight patients with PD. TIS was performed initially by two pairs (f₁ = 9.00 kHz; f₂ = 9.13 kHz, 4 mA peak-peak per pair maximum) of scalp electrodes placed in temporoparietal regions to focus the envelope signal maximum (Δf = 130 Hz) at the motor part of the STN target.

Results: The comparison between the baseline LFPs and recordings after TIS and conventional DBS sessions showed substantial suppression of high beta power peak after both types of stimulation in all patients.

24 Mar

A Controlled Single-Centre Pilot Study to Evaluate the Effect of Prophylactic Surgery in Asymptomatic Degenerative Cervical Cord Compression

Study DesignSingle-centre controlled pilot study.ObjectivesTo evaluate the effect of prophylactic surgery and to review the biases of a therapeutic trial in asymptomatic degenerative cervical cord compression (ADCC) patients.MethodsPatients with ADCC and at least 1 predictor of progression to symptomatic degenerative cervical cord myelopathy (DCM) were offered either prophylactic surgery or standard structured rehabilitation. Recruited patients were clinically followed to detect the development of symptomatic DCM.ResultsForty-one patients treated surgically and 68 patients treated non-surgically completed the minimum 36 months' follow-up; 3 recruited patients were lost from evaluation. The surgical group had a higher Neck Disability Index score and more severe MRI compression. A matched subgroup of 41 non-surgical patients was created to reduce potential bias. During the follow-up period we observed progression to symptomatic DCM in 1 surgical case (2.4%) compared to 9 patients in the non-surgical group (13.2%, P = 0.054) and 7 cases in the matched non-surgical group (17.1%, P = 0.029). We observed non-serious early postoperative complications in 4 patients, which resolved spontaneously or after surgical revision. In 9 patients with progression to DCM, the myelopathy was mild with mJOA scale 15-17. One patient in the non-surgical group and 1 patient in the surgical group who progressed to DCM underwent surgery with a good outcome.ConclusionsProphylactic surgery led to a significant decrease in proportion of ADCC patients with progression to DCM.