Targeting of nanoparticles to the cerebral vasculature after traumatic brain injury.

Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs to the brain. However, there is a potential solution in targeted drug delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following a TBI, the blood-brain barrier (BBB) becomes permeable, which can last for years and allow the leakage of harmful plasma proteins. Consequently, an appealing approach for TBI treatment involves using drug delivery systems that utilize targeting antibodies and nanocarriers to help restore BBB integrity. In our investigation of this strategy, we examined the efficacy of free antibodies and nanocarriers targeting a specific endothelial surface marker called vascular cell adhesion molecule-1 (VCAM-1), which is known to be upregulated during inflammation. In a mouse model of TBI utilizing central fluid percussion injury, free VCAM-1 antibody did not demonstrate superior targeting when comparing sham vs. TBI brain. However, the administration of VCAM-1-targeted nanocarriers (liposomes) exhibited a 10-fold higher targeting specificity in TBI brain than in sham control. Flow cytometry and confocal microscopy analysis confirmed that VCAM-1 liposomes were primarily taken up by brain endothelial cells post-TBI. Consequently, VCAM-1 liposomes represent a promising platform for the targeted delivery of therapeutics to the brain following traumatic brain injury.

Inflammatory Aseptic Arthropathy in the Setting of COVID-19: A Case Report.

Introduction: COVID-19 is among the most deleterious pandemics that the world has ever faced. It is known that SARS-CoV-2 engenders its effects by triggering a massive immune response identified as a "cytokine storm," but the full extent of clinical manifestations of the disease is still not understood. Case Presentation: We report the first case of a patient with COVID-19 infection who developed inflammatory (IL) aseptic arthropathy. The patient is a South Asian male of Indian origin residing in the United States. Conclusion: This case demonstrates the importance of remaining vigilant about the new and unique manners, in which COVID-19 may present itself. Providers should be aware of the possible development of IL arthropathy in patients with the disease.

Effect of Primary Prophylactic Antiseizure Medication for Seizure Prevention Following Intracerebral Hemorrhage in the ERICH Study.

OBJECTIVES: Intracerebral hemorrhage (ICH) has the highest morbidity and mortality rate of any stroke subtype and clinicians often administer prophylactic antiseizure medications (ASMs) as a means of preventing post-stroke seizures, particularly following lobar ICH. However, evidence for ASM efficacy in preventing seizures and reducing disability is lacking given limited randomized trials. Herein, we report analysis from a large prospective observational study that evaluates the effect of primary prophylactic ASM administration on seizure occurrence and disability following ICH. MATERIALS AND METHODS: Primary analysis was performed on 1630 patients with ICH enrolled in the ERICH study. A propensity score for administration of prophylactic ASM was developed and patients were matched by the closest propensity score (difference < 0.1). McNemar's test was used to compare occurrence of in-hospital seizure and disability, defined by modified Rankin Score (mRS) ≥ 3 at 3 months post ICH. RESULTS: Of the 815 matched pairs of patients treated with primary prophylactic ASM, there was no significant difference in seizure occurrence (p = 0.4631) or disability (p = 0.4653). Subset analysis of 280 matched pairs of patients with primary lobar ICH similarly revealed no significant difference in seizure occurrence (p = 0.1011) or disability (p = 1.00) between prophylactically treated and untreated patients. CONCLUSIONS: Although current guidelines do not recommend primary prophylactic ASM following ICH, clinical use remains widespread. Data from the ERICH study did not find an association between administering primary prophylactic ASM and preventing seizures or reducing disability following ICH, thus providing evidence to influence clinical practice and patient care.

Neuronal uptake of nanoformulated superoxide dismutase and attenuation of angiotensin II-dependent hypertension after central administration.

Excessive production of superoxide (O2(-)) in the central nervous system has been widely implicated in the pathogenesis of cardiovascular diseases, including chronic heart failure and hypertension. In an attempt to overcome the failed therapeutic impact of currently available antioxidants in cardiovascular disease, we developed a nanomedicine-based delivery system for the O2(-)-scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD), in which CuZnSOD protein is electrostatically bound to a poly-l-lysine (PLL50)-polyethylene glycol (PEG) block copolymer to form a CuZnSOD nanozyme. Various formulations of CuZnSOD nanozyme are covalently stabilized by either reducible or nonreducible crosslinked bonds between the PLL50-PEG polymers. Herein, we tested the hypothesis that PLL50-PEG CuZnSOD nanozyme delivers active CuZnSOD protein to neurons and decreases blood pressure in a mouse model of angiotensin II (AngII)-dependent hypertension. As determined by electron paramagnetic resonance spectroscopy, nanozymes retain full SOD enzymatic activity compared to native CuZnSOD protein. Nonreducible CuZnSOD nanozyme delivers active CuZnSOD protein to central neurons in culture (CATH.a neurons) without inducing significant neuronal toxicity. Furthermore, in vivo studies conducted in adult male C57BL/6 mice demonstrate that hypertension established by chronic subcutaneous infusion of AngII is significantly attenuated for up to 7 days after a single intracerebroventricular injection of nonreducible nanozyme. These data indicate the efficacy of nonreducible PLL50-PEG CuZnSOD nanozyme in counteracting excessive O2(-) and decreasing blood pressure in AngII-dependent hypertensive mice after central administration. Additionally, this study supports the further development of PLL50-PEG CuZnSOD nanozyme as an antioxidant-based therapeutic option for hypertension.

Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases.

Cardiovascular diseases, including hypertension and heart failure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a primary effector peptide of the RAS. Through its actions on various cell types and organ systems, ANG II contributes to the pathogenesis of cardiovascular diseases by inducing cardiac and vascular hypertrophy, vasoconstriction, sodium and water reabsorption in kidneys, sympathoexcitation, and activation of the immune system. Cardiovascular research over the past 15-20 years has clearly implicated an important role for elevated levels of reactive oxygen species (ROS) in mediating these pathophysiological actions of ANG II. As such, the use of antioxidants, to reduce the elevated levels of ROS, as potential therapies for various ANG II-associated cardiovascular diseases has been intensely investigated. Although some antioxidant-based therapies have shown therapeutic impact in animal models of cardiovascular disease and in human patients, others have failed. In this review, we discuss the benefits and limitations of recent strategies, including gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol conjugation, and nanomedicine-based technologies, which are designed to deliver antioxidants for the improved treatment of cardiovascular diseases. Although much work has been completed, additional research focusing on developing specific antioxidant molecules or proteins and identifying the ideal in vivo delivery system for such antioxidants is necessary before the use of antioxidant-based therapies for cardiovascular diseases become a clinical reality.

Evaluation of a dynamic ankle foot orthosis in hemiplegic gait: A case report.

This investigation utilized a single case design to evaluate the effects of a dynamic AFO on ambulation in post stroke hemiplegia. A single patient with stroke related hemiplegia using a dynamic AFO underwent gait analysis while walking on level ground. Outcome measures included temporal-spatial gait parameters and bilateral kinematic joint angles at the ankle, knee, and hip with and without AFO. Walking speed, stride length, step length and cadence increased with the dynamic AFO. Step width and double support decreased, while single support remained unchanged on the affected limb with the dynamic AFO. With the dynamic AFO there was increased hip flexion at foot strike and toe-off, increased hip sagittal plane angular velocity during swing, and decreased abduction. The dynamic AFO had a positive effect on the participant's overall gait which included improved temporal-spatial parameters and gait velocity which is likely due to a decrease in the overall energy cost of walking. Kinematic angles at the hip were most notably affected by brace utilization and this effect should be more fully explored. Further research with a larger sample utilizing dynamic AFOs is indicated to explore the generalizability of these findings and to determine the potential utility of these braces as an alternative to the traditionally prescribed solid AFO.

Objective assessment of functional ambulation in adults with hemiplegia using ankle foot orthotics after stroke.

OBJECTIVE: To objectively evaluate the effect of ankle foot orthotics (AFOs) on functional ambulation in individuals with hemiplegia secondary to stroke using quantifiable outcome measures. DESIGN: With-without repeated measures design. SETTING: Rehabilitation research center. PARTICIPANTS: Eighteen adults with stroke-related hemiplegia 6 months using a prescribed AFO. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASUREMENTS: The distance (m) and velocity (m/s) during the 6-Minute Walk Test (6MWT) and total time (s) and velocity (m/s) during the 25-ft walk (25ftW). Secondary analysis evaluated the 6MWT and 25ftW grouped by the time component of the Ambulatory Index (AI). RESULTS: Distance walked during the 6MWT was significantly greater with AFO (228.54 +/- 103.93) than without AFO (197.49 +/- 104.13), P = .002. Time to complete the 25ftW was significantly greater without AFO (21.22 +/- 20.57) than with AFO (15.49 +/- 14.65), P = .010. There was a significant difference in average velocity between the 25ftW and 6MWT during the with AFO condition, P = .010. Secondary analysis grouped by the AI time showed that as level of function decreases, brace effect on functional ambulation increases (Group 3: 25ftW with AFO, P = .040). CONCLUSIONS: AFO usage in hemiplegic stroke patients improves functional ambulation, particularly in individuals with a slower gait velocity. The 25ftW, with and without AFO, may be useful to the patient and clinician when determining the importance of brace utilization. Speed modulation was improved when the AFO was added to the paretic limb, and AI grouping indicated that the AFO was more beneficial in people with a slower gait velocity (>20 seconds for the 25ftW). A more definitive study is needed to more completely address this issue. As an exploratory study, the feasibility of different walking assessments was determined so that future studies can validate which objective measures can be used and easily implemented in clinical settings.