Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune condition characterized by recurrent episodes of optic neuritis (ON) and transverse myelitis. This case report aims to highlight the importance of considering atypical presentations of NMOSD when confronted with MRI-detected Wernicke's encephalopathy. The primary target in NMOSD is the aquaporin-4 (AQP4) protein, predominantly located on astrocyte surfaces. Antibodies binding to AQP4 can lead to astrocyte dysfunction and damage, contributing to NMOSD's distinctive pathology. The associated immune response and inflammation can cause secondary harm to various components of the central nervous system, including oligodendrocytes and neuronal axons. This inflammatory process results in perivascular demyelination and axonal injury, further aggravating neurological deficits in NMOSD. In this case, we present a 39-year-old female with no prior medical or surgical history who sought medical attention due to a three-week history of progressive eyelid heaviness and somnolence. NMOSD is an autoimmune condition primarily targeting the AQP4 protein, resulting in recurrent ON and transverse myelitis. The patient was initially misdiagnosed with myasthenia gravis due to somnolence and ptosis. Due to concerns about myasthenia gravis due to diffuse fatigue and bilateral ptosis, the patient was initially treated with intravenous immunoglobulin (IVIG) and admitted to the neurology service. On the first day of her hospitalization, MRI with and without contrast revealed extensive, non-enhancing T2-weighted-fluid-attenuated inversion recovery (T2-FLAIR) hyperintensities surrounding the third ventricle and affecting the periaqueductal grey, medial thalami, and mammillary bodies. There was also an interval increase in T2-FLAIR hyperintensity within the right medial temporal lobe, extending more posteriorly and inferiorly, abutting the temporal horn. Subsequent CSF encephalitis panel results showed positive West Nile virus (WNV) IgG but negative WNV IgM, and AQP4 antibodies were positive. Given the high specificity of AQP4 antibodies, the patient was diagnosed with neuromyelitis optica (NMO) encephalitis. This case underscores the importance of considering atypical presentations of NMO when confronted with MRI-detected Wernicke's encephalopathy. Since our patient primarily displayed somnolence and eye-related symptoms, neither NMO nor Wernicke's encephalopathy were initially considered in the differential diagnosis. Furthermore, despite MRI findings suggestive of Wernicke's encephalopathy, it was considered less likely due to the absence of thiamine deficiency and consistent denials by family members regarding alcohol use, gastrointestinal issues, or inadequate oral intake. This case underscores the importance of considering NMOSD in patients with atypical symptoms, even when initial presentations suggest other conditions. Timely diagnosis is crucial to prevent mismanagement and improve patient outcomes. Clinicians should maintain a high level of suspicion for NMOSD, especially when MRI findings do not align with the initial diagnosis, as early recognition and treatment can significantly impact patient care and prognosis.

Recent Advancements in Epidural Etanercept for Pain Management in Radiculopathy: A Literature Review.

The most common etiology of low back and neck pain is associated with spinal cord pathologies. Regardless of origin, low back and neck pain are some of the most common causes of disability worldwide. Mechanical compression due to spinal cord diseases, such as degenerative disc disorders, can lead to radiculopathy, which manifests as numbness or tingling and can progress to loss of muscle function. Conservative management, such as physical therapy, has not been proven effective in treating radiculopathy, and surgical treatments have more risks than benefits for most patients. Epidural disease-modifying medications, such as Etanercept, have been recently explored due to their minimal invasiveness and direct effects on inhibiting tumor necrosis factor-α (TNF-α). Therefore, this literature review aims to evaluate epidural Etanercept's effect on radiculopathy caused by degenerative disc diseases. Epidural Etanercept has been shown to improve radiculopathy in patients with lumbar disc degeneration, spinal stenosis, and sciatica. Further research is needed to compare the effectiveness of Etanercept with commonly used treatments such as steroids and analgesia.

The Potential Role of Etanercept in the Management of Post-stroke Pain: A Literature Review.

Strokes are the second leading cause of death and disability worldwide. The brain injury resulting from stroke produces a persistent neuroinflammatory response in the brain, resulting in a spectrum of neurologic dysfunction affecting stroke survivors chronically, also known as post-stroke pain. Excess production of tumor necrosis factor alpha (TNF alpha) in the cerebrospinal fluid (CSF) of stroke survivors has been implicated in post-stroke pain. Therefore, this literature review aims to assess and review the role of perispinal etanercept in the management of post-stroke pain. Several studies have shown statistically significant evidence that etanercept, a TNF alpha inhibitor, can reduce symptoms present in post-stroke syndrome by targeting the excess TNF alpha produced in the CSF. Studies have also shown improvements in not only post-stroke pain but also in traumatic brain injury and dementia. Further research is needed to explore the effects of TNF alpha on stroke prognosis and determine the optimal frequency and duration of etanercept treatment for post-stroke pain.

Synthetic derivatives of the SUMO consensus sequence provide a basis for improved substrate recognition.

Protein sumoylation is a dynamic posttranslational modification that regulates a diverse subset of the proteome. The mechanism by which sumoylation enzymes recognize their cognate substrates is unclear, and the consequences of sumoylation remain difficult to predict. While small molecule probes of the sumoylation process could be valuable for understanding SUMO biology, few small molecules that modulate this process exist. Here, we report the synthesis and evaluation of over 600 oxime-containing peptide sumoylation substrates. Our work demonstrates that higher modification efficiency can be achieved with non-natural side chains that deviate substantially from the consensus site requirement of a hydrophobic substituent. Furthermore, docking studies suggest that these improved substrates mimic binding interactions that are used by other endogenous protein sequences through tertiary interactions. The development of these high efficiency substrates provides key mechanistic insights toward specific recognition of low molecular weight species in the sumoylation pathway.

A nonpeptidic cathepsin S activity-based probe for noninvasive optical imaging of tumor-associated macrophages.

Macrophage infiltration into tumors has been correlated with poor clinical outcome in multiple cancer types. Therefore, tools to image tumor-associated macrophages could be valuable for diagnosis and prognosis of cancer. Herein, we describe the synthesis and characterization of a cathepsin S-directed, quenched activity-based probe (qABP), BMV083. This probe makes use of an optimized nonpeptidic scaffold leading to enhanced in vivo properties relative to previously reported peptide-based probes. In a syngeneic breast cancer model, BMV083 provides high tumor-specific fluorescence that can be visualized using noninvasive optical imaging methods. Furthermore, analysis of probe-labeled cells demonstrates that the probe primarily targets macrophages with an M2 phenotype. Thus, BMV083 is a potential valuable in vivo reporter for tumor-associated macrophages that could greatly facilitate the future studies of macrophage function in the process of tumorigenesis.

Identification and evaluation of small molecule pan-caspase inhibitors in Huntington's disease models.

Huntington's Disease (HD) is characterized by a mutation in the huntingtin (Htt) gene encoding an expansion of glutamine repeats on the N terminus of the Htt protein. Numerous studies have identified Htt proteolysis as a critical pathological event in HD postmortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD therapeutic targets. We report the use of the substrate activity screening method against caspase-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models these irreversible inhibitors suppressed Hdh(111Q/111Q)-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study, the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.

Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes.

The widespread resistance of malaria parasites to all affordable drugs has made the identification of new targets urgent. Dipeptidyl aminopeptidases (DPAPs) represent potentially valuable new targets that are involved in hemoglobin degradation (DPAP1) and parasite egress (DPAP3). Here we use activity-based probes to demonstrate that specific inhibition of DPAP1 by a small molecule results in the formation of an immature trophozoite that leads to parasite death. Using computational methods, we designed stable, nonpeptidic covalent inhibitors that kill Plasmodium falciparum at low nanomolar concentrations. These compounds show signs of slowing parasite growth in a murine model of malaria, which suggests that DPAP1 might be a viable antimalarial target. Interestingly, we found that resynthesis and activation of DPAP1 after inhibition is rapid, suggesting that effective drugs would need to sustain DPAP1 inhibition for a period of 2-3 hr.

Health literacy among Spanish-speaking Latino parents with limited English proficiency.

BACKGROUND: Health literacy measures the degree to which individuals understand health information. It has not been studied among parents with limited English proficiency (LEP). OBJECTIVE: We aimed to determine how well Spanish-speaking Latino parents with LEP understood the written instructions accompanying a routinely prescribed medication. DESIGN AND METHODS: We conducted a cross-sectional survey of parents of young children. We showed subjects a medicine bottle with an English prescription label and a Spanish drug information sheet (DIS). Subjects demonstrated how much medicine they would give and stated how often they would give it (Medication Dosing). Then they answered 5 questions regarding information from the DIS (DIS comprehension). We coded responses dichotomously as correct or incorrect. We compared Medication Dosing and DIS comprehension by age, comfort with speaking English, birthplace, number of years in the United States, and education. Regression analyses were performed to adjust for these potential confounders. RESULTS: Of 100 participants, 22% correctly dosed the medication; 29% correctly answered all questions regarding the Spanish DIS. Of subjects comfortable speaking English, 50% correctly demonstrated the amount of medicine to give. Overall, higher education and comfort speaking English were associated with better Medication Dosing. Higher education and birth in South America were associated with better DIS comprehension. CONCLUSIONS: Few parents with LEP were able to understand routinely dispensed written medication instructions. Pediatricians should not assume that Spanish-speaking Latino parents who are comfortable speaking English will understand a prescription label written in English, or that Latino parents who speak Spanish will understand drug information written in Spanish.