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.

Challenging the Interpretation of White Blood Cell Counts in Patients with Sepsis Following Packed Cell Transfusion.

Critically ill patients with sepsis often require packed cell transfusions (PCT). However, PCT may affect white blood cell (WBC) counts. We conducted a population-based retrospective cohort study to trace changes in WBC count following PCT in critically ill patients with sepsis. We included 962 patients who received one unit of PCT while hospitalized in a general intensive care unit, and 994 matched patients who did not receive PCT. We calculated the mean values of WBC count for the 24 h before and 24 h after PCT. Multivariable analyses using a mixed linear regression model were performed. The mean WBC count decreased in both groups, but more in the non-PCT group (from 13.9 × 109/L to 12.2 × 109/L versus 13.9 × 109/L to 12.8 × 109/L). A linear regression model showed a mean decrease of 0.45 × 109/L in WBC count over the 24 h following the start of PCT. Every 1.0 × 109/L increase in the WBC count prior to PCT administration showed a corresponding decrease of 0.19 × 109/L in the final WBC count. In conclusion, among critically ill patients with sepsis, PCT causes only mild and clinically non-prominent changes in WBC count.

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.

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.

Can the Duration of In-Hospital Ventilation in Patients with Sepsis Help Predict Long-Term Survival?

Mechanical ventilation is a cornerstone in the treatment of critical illness, especially sepsis. Prolonged mechanical ventilation, for a duration exceeding 21 days, is associated with higher rates of in-hospital and post-discharge mortality. Our aim was to assess the association between in-hospital ventilation duration and long-term life expectancy in patients ventilated in intensive care units specifically due to sepsis of any origin. We conducted a population-based retrospective cohort study of adults hospitalized in a general intensive care unit for 24 h or more during 2007-2017, who were diagnosed with sepsis or septic shock, treated with invasive mechanical ventilation for a maximum of 60 days and survived hospitalization. The primary exposure was the length of invasive mechanical ventilation. In an adjusted multivariable regression model, survival rates at 1, 2, 3 and 4 years post-hospitalization did not differ significantly between patients who were ventilated for 3-8 days (n = 169), 9-21 days (n = 160) or 22-60 days (n = 170), and those who were ventilated for 1-2 days (n = 192). We concluded that the duration of in-hospital ventilation in patients with sepsis cannot serve as a predictor for long-term survival. Thus, the duration of ventilation in itself should not guide the level of care in ventilated patients with sepsis.

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.

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.

Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model.

Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.

The effect of prophylactic use of tranexamic acid for cesarean section.

AIM: Treatment with tranexamic acid (TxA) significantly reduces maternal death due to postpartum hemorrhage. There is increasing interest in whether it can also be used as prophylaxis for postpartum hemorrhage, especially during cesarean sections (CS). This impact study is aimed to determine the effect of routine prophylactic tranexamic acid during CS on maternal hemorrhage and the rate of the associated side effects. METHODS: This retrospective population-based cohort single-center impact study include 2000 women who delivered by CS divided into two groups with (n = 1000) and without (n = 1000) prophylactic administration of 1gram TxA prior to surgery. Primary outcomes were to determine the: (1) rate of women experiencing >10% or ≥2 g/dL hemoglobin drop from the preoperative concentration within 24 h after CS. (2) incidence of women having a hemoglobin drop of ≥2 g/dL. RESULTS: Women who did not receive TxA prophylactic had a higher rate of >10% hemoglobin decrease and a higher rate of ≥2 g/dL hemoglobin decrease Than those who received TxA prophylaxis (p < .0001, for both). Mean hospital stay (p = .002) and umbilical cord pH (p < .05) were higher among those who received TxA prophylaxis than in those who were not treated. CONCLUSIONS: The finding of our study suggest that prophylactic administration of TxA prior to CS improves maternal and neonatal outcomes.

Assessing Dominant-Submissive Behavior in Adult Rats Following Traumatic Brain Injury.

Competition over resources such as food, territory, and mates significantly influences relationships within animal species and is mediated through social hierarchies that are often based on dominant-submissive relationships. The dominant-submissive relationship is a normal behavioral pattern among the individuals of a species. Traumatic brain injury is a frequent cause of social interaction impairment and the reorganization of dominant-submissive relationships in animal pairs. This protocol describes submissive behavior in adult male Sprague-Dawley rats after the induction of traumatic brain injury using a fluid-percussion model compared to naive rats through a series of dominant-submissive tests performed between 29 days and 33 days after induction. The dominant-submissive behavior test shows how brain injury can induce submissive behavior in animals competing for food. After traumatic brain injury, the rodents were more submissive, as indicated by them spending less time at the feeder and being less likely to arrive first at the trough compared to the control animals. According to this protocol, submissive behavior develops after traumatic brain injury in adult male rats.

Serratus Anterior Block for Long-Term Post-Thoracoscopy Pain Management.

PURPOSE: Neuropathic, chronic pain is a common and severe complication following thoracic surgery, known as post-thoracotomy pain syndrome (PTPS). Here we evaluated the efficacy of an ultrasound-guided serratus anterior plane block (SAPB) on pain control compared to traditional pain management with intravenous opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) six months after thoracic surgery. PATIENTS AND METHODS: In this retrospective observational study, we analyzed data from a questionnaire survey. We interviewed all patients who underwent elective video-assisted thoracoscopy surgery (VATS) at Soroka University Medical Center between December 2016 and January 2018. The responses of ninety-one patients were included. RESULTS: Participants reported PTPS in both groups, 43% of patients in the SAPB group and 57% of patients in the standard group, which failed to reach significance. However, we demonstrated that the percentage of pain occurrence trended lower in the SAPB group. There was significantly less burning/stitching or shooting, shocking, pressure-like, and aching pain in SAPB patients compared to the standard protocol group. Patients in the SAPB group had significantly less pain located in the upper and lower posterior thorax anatomical regions compared to the standard protocol group. Moreover, we found a significant difference in occurrence of PTPS depending on the type of thoracic surgery. From both study groups, 69% of patients who underwent lobectomy reported pain, compared with 41.9% of those in the segmental (wedge resection) procedure, and 42.1% of patients in other procedures. CONCLUSION: While the present study did not demonstrate a statistically significant reduction of PTPS after SAPB concerning postoperative pain control, there was a trend of a decrease. We also found significance in the type of pain and location of pain after thoracic surgery between the two groups, as well as a significant difference between pain occurrence in types of thoracic surgeries from both groups.

A Novel Histological Technique to Assess Severity of Traumatic Brain Injury in Rodents: Comparisons to Neuroimaging and Neurological Outcomes.

Here we evaluate an alternative protocol to histologically examine blood-brain barrier (BBB) breakdown, brain edema, and lesion volume following traumatic brain injury (TBI) in the same set of rodent brain samples. We further compare this novel histological technique to measurements determined by magnetic resonance imaging (MRI) and a neurological severity score (NSS). Sixty-six rats were randomly assigned to a sham-operated, mild TBI, moderate TBI, or severe TBI group. 48 h after TBI, NSS, MRI and histological techniques were performed to measure TBI severity outcome. Both the histological and MRI techniques were able to detect measurements of severity outcome, but histologically determined outcomes were more sensitive. The two most sensitive techniques for determining the degree of injury following TBI were NSS and histologically determined BBB breakdown. Our results demonstrate that BBB breakdown, brain edema, and lesion volume following TBI can be accurately measured by histological evaluation of the same set of brain samples.

A Retrospective Investigation of Neuraxial Anesthesia Rates for Elective Cesarean Delivery Before and During the SARS-CoV-2 Pandemic.

BACKGROUND: Our hospital used to perform cesarean delivery under general anesthesia rather than neuraxial anesthesia, mostly because of patient refusal of members of the conservative Bedouin society. According to recommendations implemented by the Israeli Obstetric Anesthesia Society, which were implemented due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, we increased the rate of neuraxial anesthesia among deliveries. OBJECTIVES: To compare the rates of neuraxial anesthesia in our cesarean population before and during SARS-CoV-2 pandemic. METHODS: We included consecutive women undergoing an elective cesarean delivery from two time periods: pre-SARS-CoV-2 pandemic (15 February 2019 to 14 April 2019) and during the SARS-CoV-2 pandemic (15 February 2020 to 15 April 2020). We collected demographic data, details about cesarean delivery, and anesthesia complications. RESULTS: We included 413 parturients undergoing consecutive elective cesarean delivery identified during the study periods: 205 before the SARS-CoV-2 pandemic and 208 during SARS-CoV-2 pandemic. We found a statistically significant difference in neuraxial anesthesia rates between the groups: before the pandemic (92/205, 44.8%) and during (165/208, 79.3%; P < 0.0001). CONCLUSIONS: We demonstrated that patient and provider education about neuraxial anesthesia can increase its utilization. The addition of a trained obstetric anesthesiologist to the team may have facilitated this transition.

A Complex Diving-For-Food Task to Investigate Social Organization and Interactions in Rats.

For many species, where status is a vital motivator that can affect health, social hierarchies influence behavior. Social hierarchies that include dominant-submissive relationships are common in both animal and human societies. These relationships can be affected by interactions with others and with their environment, making them difficult to analyze in a controlled study. Rather than a simple dominance hierarchy, this formation has a complicated presentation that allows rats to avoid aggression. Status can be stagnant or mutable, and results in complex societal stratifications. Here we describe a complex diving-for-food task to investigate rodent social hierarchy and behavioral interactions. This animal model may allow us to assess the relationship between a wide range of mental illnesses and social organization, as well as to study the effectiveness of therapy on social dysfunction.

A Metric Test for Assessing Spatial Working Memory in Adult Rats following Traumatic Brain Injury.

Impairments to sensory, short-term, and long-term memory are common side effects after traumatic brain injury (TBI). Due to the ethical limitations of human studies, animal models provide suitable alternatives to test treatment methods, and to study the mechanisms and related complications of the condition. Experimental rodent models have historically been the most widely used due to their accessibility, low cost, reproducibility, and validated approaches. A metric test, which tests the ability to recall the placement of two objects at various distances and angles from one another, is a technique to study impairment in spatial working memory (SWM) after TBI. The significant advantages of metric tasks include the possibility of dynamic observation, low cost, reproducibility, relative ease of implementation, and low stress environment. Here, we present a metric test protocol to measure impairment of SWM in adult rats after TBI. This test provides a feasible way to evaluate physiology and pathophysiology of brain function more effectively.

Measuring Post-Stroke Cerebral Edema, Infarct Zone and Blood-Brain Barrier Breakdown in a Single Set of Rodent Brain Samples.

One of the most common causes of morbidity and mortality worldwide is ischemic stroke. Historically, an animal model used to stimulate ischemic stroke involves middle cerebral artery occlusion (MCAO). Infarct zone, brain edema and blood-brain barrier (BBB) breakdown are measured as parameters that reflect the extent of brain injury after MCAO. A significant limitation to this method is that these measurements are normally obtained in different rat brain samples, leading to ethical and financial burdens due to the large number of rats that need to be euthanized for an appropriate sample size. Here we present a method to accurately assess brain injury following MCAO by measuring infarct zone, brain edema and BBB permeability in the same set of rat brains. This novel technique provides a more efficient way to evaluate the pathophysiology of stroke.

Laser-Induced Brain Injury in the Motor Cortex of Rats.

A common technique for inducing stroke in experimental rodent models involves the transient (often denoted as MCAO-t) or permanent (designated as MCAO-p) occlusion of the middle cerebral artery (MCA) using a catheter. This generally accepted technique, however, has some limitations, thereby limiting its extensive use. Stroke induction by this method is often characterized by high variability in the localization and size of the ischemic area, periodical occurrences of hemorrhage, and high death rates. Also, the successful completion of any of the transient or permanent procedures requires expertise and often lasts for about 30 minutes. In this protocol, a laser irradiation technique is presented that can serve as an alternative method for inducing and studying brain injury in rodent models. When compared to rats in the control and MCAO groups, the brain injury by laser induction showed reduced variability in body temperature, infarct volume, brain edema, intracranial hemorrhage, and mortality. Furthermore, the use of a laser-induced injury caused damage to the brain tissues only in the motor cortex unlike in the MCAO experiments where destruction of both the motor cortex and striatal tissues is observed. Findings from this investigation suggest that laser irradiation could serve as an alternative and effective technique for inducing brain injury in the motor cortex. The method also shortens the time for completing the procedure and does not require expert handlers.

Inducing Acute Liver Injury in Rats via Carbon Tetrachloride (CCl4) Exposure Through an Orogastric Tube.

Acute liver injury (ALI) plays a crucial role in the development of hepatic failure, which is characterized by severe liver dysfunction including complications such as hepatic encephalopathy and impaired protein synthesis. Appropriate animal models are vital to test the mechanism and pathophysiology of ALI and investigate different hepatoprotective strategies. Due to its ability to perform chemical transformations, carbon tetrachloride (CCl4) is widely used in the liver to induce ALI through the formation of reactive oxygen species. CCl4 exposure can be performed intraperitoneally, by inhalation, or through a nasogastric or orogastric tube. Here, we describe a rodent model, in which ALI is induced by CCl4 exposure through an orogastric tube. This method is inexpensive, easily performed, and has minimal hazard risk. The model is highly reproducible and can be widely used to determine the efficacy of potential hepatoprotective strategies and assess markers of liver injury.