The Role of Glutamate and Blood-Brain Barrier Disruption as a Mechanistic Link between Epilepsy and Depression.

Epilepsy is associated with substantial neuropsychiatric impairments that persist long after the onset of the condition, significantly impacting quality of life. The goal of this review was to uncover how the pathological consequences of epilepsy, such as excessive glutamate release and a disrupted blood-brain barrier (BBB), contribute to the emergence of neuropsychiatric disorders. We hypothesize that epilepsy induces a dysfunctional BBB through hyperexcitation, which then further amplifies post-ictal glutamate levels and, thus, triggers neurodegenerative and neuropsychiatric processes. This review identifies the determinants of glutamate concentration levels in the brain and explores potential therapeutic interventions that restore BBB integrity. Our focus on therapeutic BBB restoration is guided by the premise that it may improve glutamate regulation, consequently mitigating the neurotoxicity that contributes to the onset of neuropsychiatric symptoms.

Methemoglobinemia screening and treatment in tank warfare survivors.

INTRODUCTION: Methemoglobinemia, characterized by the conversion of functional hemoglobin to methemoglobin, can significantly impede tissue oxygenation. Prompt diagnosis and treatment of methemoglobinemia are critical to optimizing clinical outcomes. Although the underlying etiology of methemoglobinemia is often attributed to a medication reaction or chemical exposure, its association with battlefield trauma remains underexplored. This case series explores the presence of methemoglobinemia in nine soldiers evacuated from tanks targeted by explosives, shedding new light on screening needs and treatment strategies. CASES DESCRIPTION: Nine combat trauma patients with methemoglobinemia were admitted to Soroka Medical Center over a two-month period. Detailed case descriptions illustrate the diverse presentations and treatment responses. Notably, the administration of methylene blue resulted in rapid methemoglobin reductions and an improvement in oxygenation without any observed side effects. DISCUSSION: This series highlights an unexpected consequence of an explosion within an armored fighting vehicle and the challenges related to standard pulse oximetry interpretation and accuracy in the presence of methemoglobinemia, emphasizing the need for vigilant monitoring and co-oximetry utilization. Additionally, the coexistence of carboxyhemoglobin further warrants attention due to its synergistic and deleterious effects on oxygen delivery. Collaborative efforts with military authorities should aim to explore the underlying mechanisms associated with trauma and methemoglobinemia and optimize battlefield care. CONCLUSION: This case series underscores the significance of methemoglobinemia screening in combat trauma patients, and advocates for systematic co-oximetry utilization and methylene blue availability in combat zones. Early detection and intervention of methemoglobinemia in combat soldiers are often difficult in the context of battlefield injuries but are necessary to mitigate the potentially fatal consequences of this condition.

Establishing a 3-Tesla Magnetic Resonance Imaging Method for Assessing Diffuse Axonal Brain Injury in Rats.

Traumatic brain injury (TBI) significantly contributes to death and disability worldwide. However, treatment options remain limited. Here, we focus on a specific pathology of TBI, diffuse axonal brain injury (DABI), which describes the process of the tearing of nerve fibers in the brain after blunt injury. Most protocols to study DABI do not incorporate a specific model for that type of pathology, limiting their ability to identify mechanisms and comorbidities of DABI. In this study, we developed a magnetic resonance imaging (MRI) protocol for DABI in a rat model using a 3-T clinical scanner. We compared the neuroimaging outcomes with histologic and neurologic assessments. In a sample size of 10 rats in the sham group and 10 rats in the DABI group, we established neurological severity scores before the intervention and at 48 h following DABI induction. After the neurological evaluation after DABI, all rats underwent MRI scans and were subsequently euthanized for histological evaluation. As expected, the neurological assessment showed a high sensitivity for DABI lesions indicated using the ß-APP marker. Surprisingly, however, we found that the MRI method had greater sensitivity in assessing DABI lesions compared to histological methods. Out of the five MRI parameters with pathological changes in the DABI model, we found significant changes compared to sham rats in three parameters, and, as shown using comparative tests with other models, MRI was the most sensitive parameter, being even more sensitive than histology. We anticipate that this DABI protocol will have a significant impact on future TBI and DABI studies, advancing research on treatments specifically targeted towards improving patient quality of life and long-term outcomes.

The Relationship between Post-Traumatic Stress Disorder Due to Brain Injury and Glutamate Intake: A Systematic Review.

There is a growing body of evidence that suggests a connection between traumatic brain injury (TBI) and subsequent post-traumatic stress disorder (PTSD). While the exact mechanism is unknown, we hypothesize that chronic glutamate neurotoxicity may play a role. The consumption of dietary glutamate is a modifiable factor influencing glutamate levels in the blood and, therefore, in the brain. In this systematic review, we explored the relationship between dietary glutamate and the development of post-TBI PTSD. Of the 1748 articles identified, 44 met the inclusion criteria for analysis in this review. We observed that individuals from countries with diets traditionally high in glutamate had greater odds of developing PTSD after TBI (odds ratio = 15.2, 95% confidence interval 11.69 to 19.76, p < 0.01). These findings may support the hypothesis that chronically elevated blood glutamate concentrations caused by high dietary intake invoke neurodegeneration processes that could ultimately result in PTSD. Further studies will clarify whether lowering glutamate via diet would be an effective strategy in preventing or treating post-TBI PTSD.

Incidence and clinical impact of aspiration during cesarean delivery: A multi-center retrospective study.

BACKGROUND: The risk of aspiration during general anesthesia for cesarean delivery has long been thought to be increased due to factors such as increased intra-abdominal pressures and delayed gastric emptying in pregnant patients. However, recent studies have reported normal gastric emptying in pregnant patients, suggesting that the risk of aspiration may not be as high as previously believed. METHODS: We conducted a retrospective study of 48,609 cesarean deliveries, of which 22,690 (46.7%) were performed under general anesthesia at two large tertiary medical centers in Israel. The study aimed to examine the incidence of potentially severe aspiration during cesarean delivery, both under general and neuraxial anesthesia. RESULTS: Among the patients included in the study, three were admitted to the intensive care unit due to suspected pulmonary aspiration. Two of these cases occurred during induction of general anesthesia for emergency cesarean delivery associated with difficult intubation and one under deep sedation during spinal anesthesia. The incidence of aspiration during cesarean delivery during general anesthesia in our study was 1 in 11,345 patients, and the incidence of aspiration during neuraxial anesthesia was 1 in 25,929 patients. No deaths due to aspiration were reported during the study period. CONCLUSIONS: Our findings provide another contemporary analysis of aspiration rates in obstetric patients, highlighting increased risks during the management of difficult airways during general anesthesia and deep sedation associated with neuraxial anesthesia.

Diet's Impact on Post-Traumatic Brain Injury Depression: Exploring Neurodegeneration, Chronic Blood-Brain Barrier Destruction, and Glutamate Neurotoxicity Mechanisms.

Traumatic brain injury (TBI) has a profound impact on cognitive and mental functioning, leading to lifelong impairment and significantly diminishing the quality of life for affected individuals. A healthy blood-brain barrier (BBB) plays a crucial role in guarding the brain against elevated levels of blood glutamate, making its permeability a vital aspect of glutamate regulation within the brain. Studies have shown the efficacy of reducing excess glutamate in the brain as a treatment for post-TBI depression, anxiety, and aggression. The purpose of this article is to evaluate the involvement of dietary glutamate in the development of depression after TBI. We performed a literature search to examine the effects of diets abundant in glutamate, which are common in Asian populations, when compared to diets low in glutamate, which are prevalent in Europe and America. We specifically explored these effects in the context of chronic BBB damage after TBI, which may initiate neurodegeneration and subsequently have an impact on depression through the mechanism of chronic glutamate neurotoxicity. A glutamate-rich diet leads to increased blood glutamate levels when contrasted with a glutamate-poor diet. Within the context of chronic BBB disruption, elevated blood glutamate levels translate to heightened brain glutamate concentrations, thereby intensifying neurodegeneration due to glutamate neurotoxicity.

Vasopressors and Mean Arterial Pressure in Septic Shock: Do We Bend the Rules for Young Adults?

BACKGROUND: Younger patient age and relatively good prognosis have been described as factors that may increase caregiver motivation in treating patients with septic shock in the intensive care unit (ICU). OBJECTIVES: To examine whether clinical teams tended to achieve unnecessarily higher map arterial pressure (MAP) values in younger patients. METHODS: We conducted a population-based retrospective cohort study of patients presenting with septic shock who were treated with noradrenaline and hospitalized in a general ICU between 2006 and 2018. The patients were classified into four age groups: 18-45 (n=129), 46-60 (n=96), 61-75 (n=157), and older than 75 years (n=173). Adjusted linear mixed models and locally weighted scatterplot smoothing (LOWESS) curves were used to assess associations and potential non-linear relationships, respectively, of age group with MAP and noradrenaline dosage. RESULTS: The cohort included 555 patients. An inverse relation was observed between average MAP value and age. Among patients aged 18-45 years, the average MAP was 4.7 mmHg higher (95% confidence interval 3.4-5.9) than among patients aged > 75 years (P-value <0.001) after adjustment for sex, death in the intensive care unit, and Sequential Organ Failure Assessment scores. CONCLUSIONS: Among patients with septic shock, the titration of noradrenaline by staff led to a higher average MAP for younger patients. Although the MAP target is equal for all age groups, staff may administer noradrenaline treatment according to a higher target of MAP due to attitudes toward patients of different ages, despite any evidence that such practice is beneficial.

Prophylactic Administration of Tranexamic Acid Reduces Blood Products' Transfusion and Intensive Care Admission in Women Undergoing High-Risk Cesarean Sections.

Postpartum hemorrhage (PPH) remains a major cause of maternal mortality. Tranexamic acid (TxA) has shown effectiveness in reducing PPH-related maternal bleeding events and deaths. We conducted a cohort study including parturient women at high risk of bleeding after undergoing a cesarean section (CS). Participants were divided into two groups: the treatment group received prophylactic 1-g TxA before surgery (n = 500), while the comparison group underwent CS without TxA treatment (n = 500). The primary outcome measured increased maternal blood loss following CS, defined as more than a 10% drop in hemoglobin concentration within 24 h post-CS and/or a drop of ≥2 g/dL in maternal hemoglobin concentration. Secondary outcomes included PPH indicators, ICU admission, hospital stay, TxA complications, and neonatal data. TxA administration significantly reduced hemoglobin decrease by more than 10%: there was a 35.4% decrease in the TxA group vs. a 59.4% decrease in the non-TxA group, p < 0.0001 and hemoglobin decreased by ≥2 g/dL (11.4% in the TxA group vs. 25.2% in non-TxA group, p < 0.0001), reduced packed red blood cell transfusion (p = 0.0174), and resulted in lower ICU admission rates (p = 0.034) and shorter hospitalization (p < 0.0001). Complication rates and neonatal outcomes did not differ significantly. In conclusion, prophylactic TxA administration during high-risk CS may effectively reduce blood loss, providing a potential intervention to improve maternal outcomes.

Erector Spinae Plane (ESP) Block for Postoperative Pain Management after Open Oncologic Abdominal Surgery.

Patients undergoing abdominal oncologic surgical procedures require particular surgical and anesthesiologic considerations. Traditional pain management, such as opiate treatment, continuous epidural analgesia, and non-opioid drugs, may have serious side effects in this patient population. We evaluated erector spinae plane (ESP) blocks for postoperative pain management following elective oncologic abdominal surgeries. In this single-center, prospective, and randomized study, we recruited 100 patients who underwent elective oncological abdominal surgery between December 2020 and January 2022 at Soroka University Medical Center in Beer Sheva, Israel. We compared postoperative pain levels in patients who were treated with a preincisional ESP block in addition to traditional pain management with intravenous opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen, compared to patients who were only given traditional pain management (control). Patients who were treated with a preincisional ESP block demonstrated significantly lower Visual Analog Scale scores at 60 minutes and 4, 8, and 12 hours following the surgery, compared to the control group (p < 0.001). Accordingly, patients in the ESP group required less morphine from 60 minutes to 12 hours after surgery, but they required increased non-opioid postoperative analgesia management at 4, 8, and 12 hours after surgery (p from 0.002 to <0.001) compared to the control group. In this study, we found ESP blocks to be a safe, technically simple, and effective treatment for postoperative pain management after elective oncologic abdominal procedures.

BODY TEMPERATURE VARIATION AFTER PACKED CELL TRANSFUSION IN ADULT PATIENTS WITH SEPSIS-WHERE WILL THE PENDULUM STOP?

ABSTRACT: Background : Critically ill patients with sepsis often require packed cell transfusions (PCTs). Packed cell transfusion causes changes in body's core temperature. Objective : To trace the course and amplitude of body core temperature after PCT in adults with sepsis. Methods : We conducted a population-based retrospective cohort study of patients with sepsis who received one unit of PCT during their hospitalization in a general intensive care unit during 2000-2019. A control group was established by matching each of these patients to a patient who did not receive PCT. We calculated the mean values of urinary bladder temperature for the 24 h before and 24 h after PCT. To evaluate the effect of PCT on body core temperature, multivariable analyses using a mixed linear regression model were performed. Results : The study comprised 1,100 patients who received one unit of PCT and 1,100 matched patients. The mean temperature before PCT was 37.3°C. Immediately from initiation of PCT, body temperature decreased, to a minimum of 37.0°C. During the 24 subsequent hours, the temperature increased gradually and consistently, until a peak temperature of 37.4°C. In a linear regression model, body core temperature increased by a mean 0.06°C in the first 24 h after PCT and decreased by a mean 0.65°C for every 1.0°C increase before PCT. Conclusions : Among critically ill patients with sepsis, PCT itself causes only mild and clinically insignificant temperature changes. Thus, significant changes in core temperature during the 24 h after PCT may indicate an unusual clinical event that requires clinicians' immediate attention.

The Integrity of the Blood-Brain Barrier as a Critical Factor for Regulating Glutamate Levels in Traumatic Brain Injury.

A healthy blood-brain barrier (BBB) shields the brain from high concentrations of blood glutamate, which can cause neurotoxicity and neurodegeneration. It is believed that traumatic brain injury (TBI) causes long-term BBB disruption, subsequently increasing brain glutamate in the blood, in addition to increased glutamate resulting from the neuronal injury. Here, we investigate the relationship between blood and brain glutamate levels in the context of BBB permeability. Rats exposed to BBB disruption through an osmotic model or TBI and treated with intravenous glutamate or saline were compared to control rats with an intact BBB treated with intravenous glutamate or saline. After BBB disruption and glutamate administration, the concentrations of glutamate in the cerebrospinal fluid and blood and brain tissue were analyzed. The results showed a strong correlation between the brain and blood glutamate concentrations in the groups with BBB disruption. We conclude that a healthy BBB protects the brain from high levels of blood glutamate, and the permeability of the BBB is a vital component in regulating levels of glutamate in the brain. These findings bring a new approach to treating the consequences of TBI and other diseases where long-term disruption of the BBB is the central mechanism of their development.

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment.

Traumatic brain injury (TBI) is a serious condition that is associated with an increased risk of severe, long-term psychiatric consequences. Drugs that target the glutamatergic system have proven successful in treating both TBI and many of its psychiatric sequelae. Blood glutamate scavengers (BGS) cause a decrease in blood glutamate levels, leading to a reduction in glutamate's concentration gradient from the brain to the blood and decreased levels of brain glutamate. This study evaluated the BGS pyruvate as a treatment for TBI-related neuropsychiatric conditions in a rat model. 213 rats were divided into four groups in a 2 × 2 design: Sham or TBI rats treated with pyruvate or control treatment. Magnetic resonance imaging, neurological status, brain glutamate and blood glutamate levels were assessed following the injury. Four weeks after the start of treatment, all rats underwent behavioral tests to assess anxious behavior and social impairment (aggressive and hierarchical behavior). Rats responded positively to pyruvate in several tasks, lowering brain glutamate levels and reducing anxiety and depression, as well as modulating TBI-related changes in social behavior. Glutamate scavenging with pyruvate may be an effective therapeutic option for post-TBI behavioral changes by reducing associated elevations in brain glutamate levels.

On Regularized Systems of Equations for Gas Mixture Dynamics with New Regularizing Velocities and Diffusion Fluxes.

We deal with multidimensional regularized systems of equations for the one-velocity and one-temperature inert gas mixture dynamics consisting of the balance equations for the mass of components and the momentum and total energy of the mixture, with diffusion fluxes between the components as well as the viscosity and heat conductivity terms. The regularizations are kinetically motivated and aimed at constructing conditionally stable symmetric in space discretizations without limiters. We consider a new combined form of regularizing velocities containing the total pressure of the mixture. To confirm the physical correctness of the regularized systems, we derive the balance equation for the mixture entropy with the non-negative entropy production, under generalized assumptions on the diffusion fluxes. To confirm nice regularizing properties, we derive the systems of equations linearized at constant solutions and provide the existence, uniqueness and L2-dissipativity of weak solutions to an initial-boundary problem for them. For the original systems, we also discuss the related Petrovskii parabolicity property and its important corollaries. In addition, in the one-dimensional case, we also present the special three-point and symmetric finite-difference discretization in space of the regularized systems and prove that it inherits the entropy correctness property. We also give results of numerical experiments confirming that the discretization is able to simulate well various dynamic problems of contact between two different gases.

Pathophysiology and Current Drug Treatments for Post-Stroke Depression: A Review.

Post-stroke depression (PSD) is a biopsychosocial disorder that affects individuals who have suffered a stroke at any point. PSD has a 20 to 60 percent reported prevalence among stroke survivors. Its effects are usually adverse, can lead to disability, and may increase mortality if not managed or treated early. PSD is linked to several other medical conditions, including anxiety, hyper-locomotor activity, and poor functional recovery. Despite significant awareness of its adverse impacts, understanding the pathogenesis of PSD has proved challenging. The exact pathophysiology of PSD is unknown, yet its complexity has been definitively shown, involving mechanisms such as dysfunction of monoamine, the glutamatergic systems, the gut-brain axis, and neuroinflammation. The current effectiveness of PSD treatment is about 30-40 percent of all cases. In this review, we examined different pathophysiological mechanisms and current pharmacological and non-pharmacological approaches for the treatment of PSD.

Glutamate Neurotoxicity and Destruction of the Blood-Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies.

Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients' lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood-brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae.

The effect of timing of intravenous paracetamol on perioperative pain and cytokine levels following laparoscopic bariatric surgery, a randomized controlled trial.

OBJECTIVE: Bariatric surgeries involve manipulation of the viscera and are associated with significant postoperative pain. Paracetamol is a nonopioid analgesic with a rapid onset, and it is effective and safe. The study compared the effects of pre- and postincisional intravenous paracetamol administration for optimal postoperative pain management in patients undergoing bariatric surgeries. METHODS: This is a prospective, double-blinded, placebo-controlled randomized clinical trial of adult patients, admitted electively for laparoscopic bariatric surgery. The patients were randomly divided into two groups. One group of patients was given paracetamol at the beginning of the operation, prior to the surgical incision, the other group of patients received the same treatment at the end of the operation. RESULTS: Patients who were given preincisional intravenous paracetamol presented significantly lower visual analog scale (VAS) scores following the surgery compared with patients who were given intravenous paracetamol in the last 30 minutes of the operation (VAS, median [IQR] = 2 [2-3] vs. 5 [3-6]; p < 0.001). They also required fewer postoperative opioids and tramadol (in milligrams, respectively, 1 [0-5] vs. 7.5 [5-10] and 300 [100-400] vs. 400 [200-500]) compared with later analgesia administration (p < 0.001 and p = 0.03). The levels of inflammatory markers measured at fixed intervals from paracetamol administration were not statistically different between the study groups. CONCLUSION: Early analgesia with intravenous paracetamol, given before the surgical incision, may result in lower VAS scores postoperatively compared with the same treatment administered toward the end of the operation.

Traumatic brain injury-induced submissive behavior in rats: link to depression and anxiety.

Traumatic brain injury (TBI) affects millions of people worldwide, many of whom are affected with post-TBI mood disorders or behavioral changes, including aggression or social withdrawal. Diminished functionality can persist for decades after TBI and delay rehabilitation and resumption of employment. It has been established that there is a relationship between these mental disorders and brain injury. However, the etiology and causal relationships behind these conditions are poorly understood. Rodent models provide a helpful tool for researching mood disorders and social impairment due to their natural tendencies to form social hierarchies. Here, we present a rat model of mental complications after TBI using a suite of behavioral tests to examine the causal relationships between changes in social behavior, including aggressive, hierarchical, depressive, and anxious behavior. For this purpose, we used multivariate analysis to identify causal relationships between the above post-TBI psychiatric sequelae. We performed statistical analysis using principal component analysis, discriminant analysis, and correlation analysis, and built a model to predict dominant-submissive behavior based on the behavioral tests. This model displayed a predictive accuracy of 93.3% for determining dominant-submissive behavior in experimental groups. Machine learning algorithms determined that in rats, aggression is not a principal prognostic factor for dominant-submissive behavior. Alternatively, dominant-submissive behavior is determined solely by the rats' depressive-anxious state and exploratory activity. We expect the causal approach used in this study will guide future studies into mood conditions and behavioral changes following TBI.

Glutamate Efflux across the Blood-Brain Barrier: New Perspectives on the Relationship between Depression and the Glutamatergic System.

Depression is a significant cause of disability and affects millions worldwide; however, antidepressant therapies often fail or are inadequate. Current medications for treating major depressive disorder can take weeks or months to reach efficacy, have troubling side effects, and are limited in their long-term capabilities. Recent studies have identified a new set of glutamate-based approaches, such as blood glutamate scavengers, which have the potential to provide alternatives to traditional antidepressants. In this review, we hypothesize as to the involvement of the glutamate system in the development of depression. We identify the mechanisms underlying glutamate dysregulation, offering new perspectives on the therapeutic modalities of depression with a focus on its relationship to blood-brain barrier (BBB) permeability. Ultimately, we conclude that in diseases with impaired BBB permeability, such as depression following stroke or traumatic brain injury, or in neurogenerative diseases, the glutamate system should be considered as a pathway to treatment. We propose that drugs such as blood glutamate scavengers should be further studied for treatment of these conditions.

The Development of Novel Drug Treatments for Stroke Patients: A Review.

Acute ischemic stroke is a critical condition that can result in disability and death. The consequences of this medical condition depend on various factors, including the size of the stroke, affected brain region, treatment onset, and the type of treatment. The primary objective of stroke treatment is to restart ischemic penumbra tissue perfusion and reduce infarct volume by sustaining blood flow. Recent research on the condition's pathological pathways and processes has significantly improved treatment options beyond restoring perfusion. Many studies have concentrated on limiting injury severity via the manipulation of molecular mechanisms of ischemia, particularly in animal research. This article reviews completed and ongoing research on the development of acute ischemic stroke drugs. This study focuses on three main categories of antithrombotic drugs, thrombolytic drugs, and neuroprotective agents. The paper outlines findings from animal and clinical trials and explores the working mechanisms of these drugs.