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A 46-year-old man with neck pain and impaired physical mobility called for emergency medical services. The patient was able to communicate with the emergency medical team upon their arrival. However, he went into cardiopulmonary arrest 5 minutes later. Cardiopulmonary resuscitation was immediately performed, and the patient was admitted to our hospital with a Glasgow Coma Scale score of E1V1M1. His respiratory rate was 5 breaths/minute and his partial pressure of carbon dioxide in arterial blood (PaCO 2 ) was 127 ‍mmHg, necessitating intubation and ventilation. His consciousness improved as the PaCO 2 level decreased. However, he was unable to be weaned off the ventilator and breathe independently. Neurological examination revealed flaccid quadriplegia, pain sensation up to the C5 level, absence of deep tendon reflexes, indifferent plantar responses, and absence of the rectoanal inhibitory reflex. Magnetic resonance imaging showed a hyperintense lesion with slight enlargement of the anterior two-thirds of the spinal cord at the C2-C4 level on both T 2 -weighted and diffusion-weighted images, consistent with a diagnosis of spinal cord infarction. Although the quadriplegia and sensory loss partially improved, the patient was unable to be weaned from the ventilator. Cervical cord infarction of the anterior spinal artery can cause rapid respiratory failure leading to cardiopulmonary arrest. Therefore, cervical cord infarction should be included as a differential diagnosis when examining patients after cardiopulmonary resuscitation.

Objective: Studies that evaluate YouTube videos on hydrocephalus often exclude non-English-language videos, even though hydrocephalus is more prevalent in low- and middle-income countries where English may not be widely understood. This study had two aims: to analyze the engagement, content, and quality of YouTube videos on hydrocephalus in the Filipino language, and to determine whether the videos' content matched the information needs of caregivers of children with hydrocephalus in the Philippines., Methods: The authors conducted an online survey among caregivers of patients with hydrocephalus, recruited through the Facebook page of the Hydrocephalus Foundation of the Philippines Inc. Data on demographics, social media use, and language and content preferences were collected. In parallel, the authors systematically evaluated the engagement and content of three groups of YouTube videos on hydrocephalus: 1) most viewed Filipino-language videos, 2) most viewed English-language videos, and 3) same-age English-language videos, matched to the first group based on upload date. The quality of the Filipino-language videos was assessed using the DISCERN criteria., Results: Among 280 respondents, 91% watched videos on hydrocephalus online and 89% preferred videos in Filipino. Compared with same-age English videos, Filipino videos had greater engagement, indicated by a higher median number of likes (40 vs 8, p = 0.005) and comments (8.5 vs 1, p = 0.007). English and Filipino videos emphasized similar topics on hydrocephalus, but the latter were more likely to discuss treatment cost and to solicit donations. Caregivers were most interested in the long-term care of patients with hydrocephalus, discussed only in 10 of 72 videos (14%) overall. The mean DISCERN score for Filipino videos was 30.1 ± 7.7, indicating poor quality., Conclusions: There is a gap between the information needs of Filipino caregivers and the content of YouTube videos on hydrocephalus. Neurosurgeons can serve as creators, resource persons, or curators of content, ensuring that up-to-date, accurate, and credible health information on hydrocephalus is available to caregivers in their preferred language.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Here, we identified a novel function of HLA class II in the transport of intracellular α-synuclein to the outside of cells. HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB5∗01:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB5∗01:01. Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, shedding light on the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/μL at administration to 121,000/μL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.

The pathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) cases is the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein. Several studies have attributed disease processes of ALS to abnormal RNA metabolism. However, dysregulated biogenesis of RNA, especially non-coding RNA (ncRNA), is poorly understood. To resolve it, RNA-Seq, biochemical, and immunohistochemical analyses were performed on the pyramidal tract of the medulla oblongata of sporadic ALS (sALS) and control postmortem brain samples. Here, we report perturbation of ncRNA biogenesis in PIWI-interacting RNA (piRNA) in several sALS brain samples associated with TDP-43 pathology. In addition, we confirmed the dysregulation of two PIWI homologs, PIWI-like-mediated gene silencing 1 (PIWIL1) and PIWIL4, which bind to piRNAs to regulate their expression. PIWIL1 was mislocalized and co-localized with TDP-43 in motor neurons of sporadic ALS lumbar cords. Our results imply that dysregulation of piRNA, PIWIL1, and PIWIL4 is linked to pathogenesis of ALS. Based on these results, piRNAs and PIWI proteins are potential diagnostic biomarkers and therapeutic targets of ALS., (© 2022. The Author(s).)

Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.

Pectin is a plant cell wall constituent that is mainly composed of polygalacturonic acid (PGA), a linear α1,4-d-galacturonic acid (GalUA) backbone. Polygalacturonase (PG) hydrolyzes the α1,4-linkages in PGA. Nearly all plant PGs identified thus far are secreted as soluble proteins. Here we describe the microsomal PG activity in pea (Pisum sativum) epicotyls and present biochemical evidence that it was localized to the Golgi apparatus, where pectins are biosynthesized. The microsomal PG was purified, and it was enzymatically characterized. The purified enzyme showed maximum activity towards pyridylaminated oligogalacturonic acids with six degrees of polymerization (PA-GalUA6), with a Km value of 11 μM for PA-GalUA6. The substrate preference of the enzyme was complementary to that of PGA synthase. The main PG activity in microsomes was detected in the Golgi fraction by sucrose density gradient ultracentrifugation. The activity of the microsomal PG was lower in rapidly growing epicotyls, in contrast to the high expression of PGA synthase. The role of this PG in the regulation of pectin biosynthesis or plant growth is discussed., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size. The dissolution curves of the cilostazol suspensions were in good agreement with the simulation based on the Noyes-Whitney equation. The bioavailability of cilostazol after oral administration to dogs was increased with reducing the particle size. While positive food effect on the absorption was observed for the suspensions made of the hammer-milled and the jet-milled crystals, no significant food effect was found for the suspension made of the NanoCrystal cilostazol spray-dried powder. These results could be qualitatively predicted from the in vitro dissolution data using the bio-relevant media, FaSSIF and FeSSIF. In conclusion, the NanoCrystal technology is found to be efficient to improve the oral bioavailability of cilostazol and to avoid the food effect on the absorption.

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate (J(total)) of PX was measured in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl sulfate (SLS) using the rotating disk apparatus. Solubility (c(total)) was also measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX <--> H(+) + PX(-)) and two micellar solubilization equilibria (PX + micelle <--> [PX](micelle), PX(-) + micelle <--> [PX(-)](micelle)) were considered in the convective diffusion reaction model. J(total) and c(total) of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed that observed experimental data were well described with the proposed model (r(2) = 0.86, P < 0.001 for J(total) and r(2) = 0.98, P < 0.001 for c(total)). The pK(a) value of 5.63 +/- 0.02 estimated from c(total) agreed well with the reported value. The micellar solubilization equilibrium coefficient for the unionized drug was estimated to be 348 +/- 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients of the species PX, PX(-), and [PX](micelle) were estimated from the experimental results as (0. 93 +/- 0.35) x 10(-5), (1.4 +/- 0.30) x 10(-5), and (0.59 +/- 0.21) x 10(-5) cm(2)/s, respectively. The total flux enhancement is less than the total solubility enhancement due to the smaller diffusion coefficients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and surfactant and for establishing in vitro-in vivo correlations, IVIVC, for maintaining bioequivalence of drug products., (Copyright 2000 Wiley-Liss, Inc.)

ESR and optical spectra ascribed to be the hemoprotein-butylperoxide complex were detected for the frozen aqueous solution containing whale met-Mb and t- or n-butylhydroperoxide at pH 10. The observed ESR and optical parameters of the complex were characteristic to those of six coordinate ferric low-spin complexes, having the butylperoxide anion at the axial position of heme. pH dependent ESR measurements demonstrated the formation of the complex in the biological pH regions (7.0). Time dependent ESR and optical measurements indicated that the complex may be one of the intermediate species in the processes of heme degradation reaction induced by butylperoxide.

OPC-14117 is a potent drug which has both brain function activating effect and protective effect against cerebral ischemia. Occurrences of these effects might be expected due to superoxide dismutase-like activity of OPC-14117. The present study has been conducted to evaluate the active oxygen scavenging activity of OPC-14117 and to explain the mechanisms of its pharmacological activities. The reaction of OPC-14117 and superoxide anion, generated in potassium superoxide, was examined by electron spin resonance technique at both liquid nitrogen (77 K) and room (22 degrees C) temperatures. OPC-14117 showed a higher superoxide scavenging activity than that of alpha-tocopherol in an aprotic solvent system. The active moiety of OPC-14117 to provide the scavenging effect was found due to the phenolic hydroxyl group of its indan skeleton.