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1.
Mol Pharm ; 18(3): 878-888, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33492961

RESUMO

This study describes the development of lipid nanoparticles (LNPs) for the efficient and selective delivery of plasmid DNA (pDNA) to the lungs. The GALA peptide was used as a ligand to target the lung endothelium and as an endosomal escape device. Transfection activity in the lungs was significantly improved when pDNA was encapsulated in double-coated LNPs. The inner coat was composed of dioleoylphsophoethanolamine and a stearylated octaarginine (STR-R8) peptide, while the outer coat was largely a cationic lipid, di-octadecenyl-trimethylammonium propane, mixed with YSK05, a pH-sensitive lipid, and cholesterol. Optimized amounts of YSK05 and GALA were used to achieve an efficient and lung-selective system. The optimized system produced a high gene expression level in the lungs (>107 RLU/mg protein) with high lung/liver and lung/spleen ratios. GALA/R8 modification and the double-coating design were indispensable for efficient gene expression in the lungs. Despite the fact that NPs prepared with 1-step or 2-step coating have the same lipid amount and composition and the same pDNA dose, the transfection activity was dramatically higher in the lungs in the case of 2-step coating. Surprisingly, 1-step or 2-step coatings had no effect on the amount of nanoparticles that were delivered to the lungs, suggesting that the double-coating strategy substantially improved the efficiency of gene expression at the intracellular level.


Assuntos
DNA/administração & dosagem , Lipídeos/química , Pulmão/efeitos dos fármacos , Nanopartículas/química , Peptídeos/química , Plasmídeos/administração & dosagem , Animais , Linhagem Celular , Feminino , Expressão Gênica/efeitos dos fármacos , Técnicas de Transferência de Genes , Humanos , Concentração de Íons de Hidrogênio , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Oligopeptídeos/administração & dosagem , Transfecção/métodos
2.
Biol Pharm Bull ; 43(4): 584-595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238701

RESUMO

The last few years have witnessed a great advance in the development of nonviral systems for in vivo targeted delivery of nucleic acids. Lipid nanoparticles (LNPs) are the most promising carriers for producing clinically approved products in the future. Compared with other systems used for nonviral gene delivery, LNPs provide several advantages including higher stability, low toxicity, and greater efficiency. Additionally, systems based on LNPs can be modified with ligands and devices for controlled biodistribution and internalization into specific cells. Efforts are ongoing to improve the efficiency of lipid-based gene vectors. These efforts depend on the appropriate design of nanocarriers as well as the development of new lipids with improved gene delivery ability. Several ionizable lipids have recently been developed and have shown dramatically improved efficiency. However, enhancing the ability of nanocarriers to target specific cells in the body remains the most difficult challenge. Systemically administered LNPs can access organs in which the capillaries are characterized by the presence of fenestrations, such as the liver and spleen. The liver has received the most attention to date, although targeted delivery to the spleen has recently emerged as a promising tool for modulating the immune system. In this review, we discuss recent advances in the use of LNPs for cell-specific targeted delivery of nucleic acids. We focus mainly on targeting liver hepatocytes and spleen immune cells as excellent targets for gene therapy. We also discuss the potential of endothelial cells as an alternate approach for targeting organs with a continuous endothelium.


Assuntos
Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Ácidos Nucleicos/administração & dosagem , Animais , Células Endoteliais/metabolismo , Técnicas de Transferência de Genes , Hepatócitos/metabolismo , Humanos , Baço/metabolismo
3.
J Hum Genet ; 62(2): 159-166, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27829678

RESUMO

GNE myopathy is an autosomal recessive distal myopathy caused by loss-of-function mutations in the GNE gene, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in sialic-acid biosynthesis. By comprehensive screening of manifesting patients using a fine-mapped targeted next-generation sequencing (NGS), we identified copy number variations (CNVs) in 13 patients from 11 unrelated families. The nine unique CNVs largely vary in size from 0.3 to 72 kb. Over half of the cases carry different deletions spanning merely exon 2, which contains the 5' untranslated region (5'UTR) of the muscle major transcript hGNE1. Of most unique CNVs, either the telomeric or the centromeric breakpoint locates within intron 2, indicating rearrangement hotspots. Haplotype analysis suggested the existence of a founder allele with exon 2 deletion. The breakpoints for all CNVs were determined by long-range PCR and sequencing. All of the breakpoints of gross deletion/duplications reside within directly oriented pairs of Alu repeats. The results of this study firstly widen the spectra of mutations to CNVs encompassing 5'UTR, underscoring the pivotal role of the hGNE1 transcript. Alu-mediated non-recurrent CNVs may have been overlooked in a wide variety of recessive phenotypes, especially in those associated with genomic Alu-rich genes such as GNE.


Assuntos
Regiões 5' não Traduzidas/genética , Variações do Número de Cópias de DNA/genética , Miopatias Distais/genética , Complexos Multienzimáticos/genética , Adulto , Sequência de Bases , Feminino , Predisposição Genética para Doença , Testes Genéticos , Genoma/genética , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Deleção de Sequência/genética , Adulto Jovem
4.
Muscle Nerve ; 55(5): 741-747, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27623743

RESUMO

INTRODUCTION: In this study we aimed to determine whether transforming growth factor-ß (TGF-ß) signaling is dysregulated in sporadic inclusion body myositis (sIBM) muscle samples. METHODS: We examined TGF-ß signaling markers in muscle samples from 24 sIBM patients and compared them with those from 10 dermatomyositis (DM) patients using immunohistochemistry and Western blot analyses. RESULTS: Compared with the DM muscle fibers, the sIBM muscle fibers exhibited greater TGF-ß, TGF-ß receptor type I (TßRI), and TGF-ß receptor type II (TßRII) immunoreactivity in the cytoplasm, as well as greater phosphorylated Smad2 (pSmad2) immunoreactivity in the myonuclei. The signal intensities of TGF-ß, TßRI, and TßRII immunoreactivity correlated significantly with muscle fiber cross-sectional areas. Western blot analyses indicated higher expression levels of TGF-ß, TßRI, TßRII, and pSmad2 in the sIBM muscle samples than in the DM muscle samples. CONCLUSIONS: These data indicate that upregulation of TGF-ß signaling may be an important molecular event in sIBM. Muscle Nerve 55: 741-747, 2017.


Assuntos
Músculo Esquelético/metabolismo , Miosite de Corpos de Inclusão/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima , Dermatomiosite/metabolismo , Dermatomiosite/patologia , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/patologia , Fosforilação , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo
5.
BioDrugs ; 38(2): 259-273, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38345754

RESUMO

Gene therapy for many diseases is rapidly becoming a reality, as demonstrated by the recent approval of various nucleic acid-based therapeutics. Non-viral systems such as lipid-based carriers, lipid nanoparticles (LNPs), for delivering different payloads including small interfering RNA, plasmid DNA, and messenger RNA have been particularly extensively explored and developed for clinical uses. One of the most important issues in LNP development is delivery to extrahepatic tissues. To achieve this, various lipids and lipid-like materials are being examined and screened. Several LNP formulations that target extrahepatic tissues, such as the spleen and the lungs have been developed by adjusting the lipid compositions of LNPs. However, mechanistic details of how the characteristics of LNPs affect delivery efficiency remains unclear. The purpose of this review is to provide an overview of LNP-based nucleic acid delivery focusing on LNP components and their structures, as well as discussing biological factors, such as biomolecular corona and cellular responses related to the delivery efficiency.


Assuntos
Lipídeos , Nanopartículas , Humanos , Lipossomos , Técnicas de Transferência de Genes , RNA Interferente Pequeno/genética , DNA/genética , RNA Mensageiro , Nanopartículas/química
6.
Turk Neurosurg ; 34(1): 160-166, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38282595

RESUMO

AIM: To report mechanical thrombectomy (MT) for internal carotid artery (ICA) occlusion with cross-flow through the communicating artery ("with" group), and to compare it with ICA or middle cerebral artery occlusion without cross-flow ("without" group). MATERIAL AND METHODS: This study included 10 and 57 cases of the "with" and "without" groups, respectively. Cases analyzed by rapid processing of perfusion and diffusion (RAPID) since October 2020 were included. RESULTS: Puncture-to-reperfusion time was 78.5 and 39 min (p=0.0155), the National Institutes of Health Stroke Scale score at discharge was 10.5 and 4 (p=0.0166), decline from pre to post Diffusion-Weighted Image-Alberta Stroke Program Early computed tomography (CT) Score was 0.5 and 0 (p=0.0495), and the modified Rankin Scale score at 90 days was 4 and 2 (p=0.0195) in the "with" and "without" groups, respectively. Furthermore, Tmax values of > 6 s (50 cc vs. 164 cc; p=0.0277) and Tmax > 4 s/Tmax > 6 s ratio (3.23 vs. 1.55) (p=0.0074) were significantly different between the "with" and "without" groups. CONCLUSION: The "with" group may have been affected by the longer treatment time and being at high risk of distal migration of thrombus due to poor prognosis. Although the region with a Tmax of > 6 s tends to be small in patients of the "with" group, it indicates a low-perfusion state that can lead to cerebral infarction, and MT should be performed.


Assuntos
Doenças das Artérias Carótidas , Acidente Vascular Cerebral , Trombose , Humanos , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/cirurgia , Trombectomia/métodos , Angiografia Cerebral/métodos , Resultado do Tratamento , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/cirurgia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/cirurgia , Estudos Retrospectivos
7.
J Neuroendovasc Ther ; 18(5): 137-141, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38808016

RESUMO

Objective: The double origin of the posterior inferior cerebellar artery (DOPICA) is a rare variant of PICA. Vertebral artery dissecting aneurysm (VADA) with DOPICA is an extremely rare occurrence. Herein, we report a case of VADA located between DOPICA that was successfully treated with endovascular internal trapping. Case Presentation: A 48-year-old male, found collapsed at his workplace, was admitted to our hospital for emergency medical assistance. Head CT revealed a subarachnoid hemorrhage (Fisher group 3), and cerebral angiography revealed right VADA with DOPICA. The VADA was located distal to the proximal component of the posterior inferior cerebellar artery (PCPICA) and just proximal to the hypoplastic distal component of PICA (DCPICA). Emergency endovascular internal trapping was performed using a total of 13 coils from the distal end of the VADA to just the distal of the branching point of PCPICA. VADA was not visualized, and antegrade flow through DOPICA to the basilar artery was confirmed. Head magnetic resonance angiography (MRA) showed antegrade flow via DOPICA, and the patient was discharged home on Day 46 with a modified Rankin Scale 0. Conclusion: Endovascular internal trapping for VADA with DOPICA was considered useful, especially when VADA is distal to PCPICA and proximal to DCPICA.

8.
Ann Clin Transl Neurol ; 11(2): 508-519, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38152056

RESUMO

BACKGROUND AND OBJECTIVE: Chronic graft versus host disease (GVHD)-associated myositis targeting skeletal muscle is a relatively rare but potentially debilitating complication following allogeneic hematopoietic stem cell transplantation (HSCT). We reviewed the clinicopathological features of GVHD-associated myositis among patients receiving allogeneic HSCT to elucidate the cellular pathogenesis. METHODS: We retrospectively reviewed clinical data and muscle biopsy results from 17 consecutive patients diagnosed with GVHD-associated myositis at our institution between 1995 and 2019. Immunostaining findings of GVHD-associated myositis were compared to those of patients with anti-tRNA-synthetase antibody-associated myopathy (ASM) (n = 13) and dermatomyositis (DM) (n = 12). RESULTS: The majority of patients with GVHD-associated myositis showed subacute or chronic progression of mild to moderate limb weakness together with elevated serum creatine kinase. These patients also exhibited mild C-reactive protein elevation but were negative for myositis-related autoantibodies. Programmed death-1 (PD-1)-positive cells were observed in muscle interstitium adjacent to myofibers expressing human leukocyte antigen (HLA)-DR. The interstitium was also HLA-DR-positive, similar to biopsy samples from ASM patients but not DM patients. The proportions of HLA-DR-positive muscle fibers and PD-1-positive interstitial cells were significantly higher in GVHD and ASM samples than DM samples. The PD-1-positive cells were mostly CD-8-positive lymphocytes. DISCUSSION: GVHD-associated myositis is characterized by HLA-DR-positive myofibers and infiltration of PD-1-positive lymphocytes. These features distinguish GVHD-associated myositis from DM but not from ASM.


Assuntos
Doença Enxerto-Hospedeiro , Miosite , Humanos , Estudos Retrospectivos , Receptor de Morte Celular Programada 1 , Miosite/etiologia , Miosite/diagnóstico , Doença Enxerto-Hospedeiro/complicações , Antígenos HLA-DR/metabolismo
9.
J Control Release ; 362: 797-811, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37004796

RESUMO

The era of nucleic acid nanomedicine has arrived, as evidenced by Patisiran, a small interfering RNA (siRNA) encapsulated lipid nanoparticle (LNP), and mRNA-loaded LNPs used in COVID-19 vaccines. The diversity of nano-designs for delivering nucleic acid molecules tested in Phase II/III clinical trials reflects the potential of these technologies. These breakthroughs in non-viral gene delivery, including the use of LNPs, have attracted substantial interest worldwide for developing more effective drugs. A next step in this field is to target tissues other than the liver, which requires significant research efforts and material development. However, mechanistic studies in this area are lacking. This study compares two types of LNPs with different tissue-selectivity for delivering plasmid DNA (pDNA), one being liver-selective and the other spleen-selective, in an effort to understand the mechanisms responsible for differences in gene expression of delivered genes. We observed little difference in the biodistribution of these two LNPs despite the 100-1000-fold differences in gene expression. We then quantified the amount of delivered pDNA and mRNA expression in each tissue by quantitative real-time PCR (qPCR) to evaluate various intracellular processes, such as nuclear delivery, transcription and translation. The results showed a >100-fold difference in the translation step but there were little differences in amount of pDNA delivered to the nucleus or the amount of mRNA expression for the two LNP deliveries. Our findings suggest that endogenous factors affect gene expression efficiency not the extent of biodistribution.

10.
Surg Neurol Int ; 14: 311, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37810291

RESUMO

Background: Cerebral aneurysms arising from fenestration of the A1 portion of the anterior cerebral artery (ACA) (A1 fenestration) with the accessory middle cerebral artery (MCA) is rare. Herein, we report a ruptured cerebral aneurysm arising from A1 fenestration combined with the accessory MCA that was successfully treated with coil embolization. Case Description: A 51-year-old woman suddenly experienced a severe occipital headache and was admitted to our hospital. Detailed examination revealed subarachnoid hemorrhage due to a cerebral aneurysm arising from A1 fenestration combined with the accessory MCA. Hence, coil embolization was performed, and a favorable outcome was obtained. Conclusion: Coil embolization of the cerebral aneurysm arising from the A1 fenestration of the ACA combined with the accessory MCA is considered to be useful.

11.
Cureus ; 15(5): e39311, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37346212

RESUMO

Delayed onset of facial spasm following surgery for unilateral facial spasm after microvascular decompression (MVD) of the distal facial nerve is rare. We report a case of unilateral facial spasm caused by compression of the distal facial nerve successfully treated with MVD resulting in delayed peripheral facial nerve palsy. A 51-year-old male patient with a left facial spasm showed a gradual worsening of symptoms. Head imaging revealed that the left anterior inferior cerebellar artery (AICA) was in contact with the distal portion of the left facial nerve; hence, MVD was performed. The AICA was pressing on the distal facial nerve, so the AICA was transpositioned. Postoperatively, the facial spasm improved. On the eighth postoperative day, the patient showed left peripheral facial nerve palsy and was given conservative treatment. The patient was discharged home on the sixteenth postoperative day. One month after discharge, the facial palsy was in complete remission. Distal facial nerve compression may cause unilateral facial spasms. Although delayed facial nerve palsy may occur, the prognosis is good.

12.
Brain Behav ; 13(8): e3163, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37469274

RESUMO

OBJECTIVE: Endovascular therapy (EVT) is performed for acute ischemic stroke (AIS) with large vessel occlusion (LVO), however, the treatment strategies and clinical outcomes differ between cardiac embolism (CE) and intracranial arteriosclerosis-derived LVO (ICAS-LVO). We analyzed whether the time-to-max (Tmax) volume derived from perfusion imaging predicted clinical classification in AIS patients before EVT. METHODS: Consecutive AIS patients with anterior circulation LVO evaluated by automated imaging software were retrospectively identified. Patients were classified into a CE group and an ICAS-LVO group, and parameters were compared between groups. RESULTS: Thirty-nine patients were included and Tmax volume and Tmax > 6 s volume/Tmax > 4 s volume were significantly greater in the CE group than in the ICAS-LVO group (Tmax > 4 s volume: 261 mL vs. 149 mL, p = .01, Tmax > 6 s volume: 143 mL vs. 59 mL, p = .001, Tmax > 6 s volume/Tmax > 4 s volume: 0.59 vs. 0.40, p < .001). Multiple logistic regression analysis indicated an association between clinical classification and high Tmax > 6 s volume/Tmax > 4 s volume (p = .04). CONCLUSION: The Tmax volume derived from perfusion imaging predicts the clinical classification of AIS patients before EVT.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/terapia , Estudos Retrospectivos , Trombectomia/métodos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/terapia , Procedimentos Endovasculares/métodos , Resultado do Tratamento
13.
Cureus ; 15(3): e35911, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37033540

RESUMO

Fulminant fat embolism syndrome (FES) occurring within 1 h after trauma is extremely rare. We report a case of fulminant FES that developed hyperacute nature after a traumatic injury. A 66-year-old woman was injured when she fell approximately 1.5 m down the stairs. She was rushed to our hospital. One minute after arrival, which was 49 min after the injury, her consciousness and respiratory status deteriorated. Thoracoabdominal and pelvic computed tomography revealed preexisting interstitial pneumonia, a left femoral neck fracture, and a left sacral fracture. Head magnetic resonance imaging (diffusion-weighted imaging) showed diffuse high-signal areas and susceptibility-weighted imaging showed diffuse small perivascular of perivascular hemorrhages. She was diagnosed with fulminant FES. After conservative treatment, she was transferred to a rehabilitation hospital with a Glasgow Coma Scale (GCS) of 8 and a modified Rankin Scale of 5 on Day 45. The possibility of fulminant FES should be considered a cause of early impaired consciousness after a fracture.

14.
Sci Rep ; 13(1): 2644, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36788314

RESUMO

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region.


Assuntos
Neoplasias Encefálicas , Cirurgia Assistida por Computador , Humanos , Cirurgia Assistida por Computador/métodos , Decúbito Ventral , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia
15.
Pharmaceuticals (Basel) ; 15(8)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36015165

RESUMO

mRNA delivery has recently gained substantial interest for possible use in vaccines. Recently approved mRNA vaccines are administered intramuscularly where they transfect antigen-presenting cells (APCs) near the site of administration, resulting in an immune response. The spleen contains high numbers of APCs, which are located near B and T lymphocytes. Therefore, transfecting APCs in the spleen would be expected to produce a more efficient immune response, but this is a challenging task due to the different biological barriers. Success requires the development of an efficient system that can transfect different immune cells in the spleen. In this study, we report on the development of mRNA-loaded lipid nanoparticles (LNPs) targeting immune cells in the spleen with the goal of eliciting an efficient immune response against the antigen encoded in the mRNA. The developed system is composed of mRNA loaded in LNPs whose lipid composition was optimized for maximum transfection into spleen cells. Dendritic cells, macrophages and B cells in the spleen were efficiently transfected. The optimized LNPs produced efficient dose-dependent cytotoxic T lymphocyte activities that were significantly higher than that produced after local administration. The optimized LNPs encapsulating tumor-antigen encoding mRNA showed both prophylactic and therapeutic antitumor effects in mice.

16.
Cureus ; 14(11): e31797, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36569697

RESUMO

The presentation of abducens nerve palsy after each occurrence of subarachnoid hemorrhage (SAH) is rare. Herein, we report the case of a patient with a ruptured microaneurysm at the tip of the basilar artery who presented with right abducens nerve palsy at the time of the initial rupture and rerupture during an outpatient follow-up. A 52-year-old woman developed SAH with right abducens nerve palsy, which was treated with coil embolization. One year after the initial SAH, there was a relapse of the SAH and paresis of the right abducent nerve palsy. This may have been caused by the location of the abducens nerve in relation to the surrounding structures, which were susceptible to the effects of hematoma or intracranial pressure fluctuations. Stent-assisted coil embolization is an effective treatment for regrowth that appears after endovascular therapy of microaneurysms.

17.
J Neuroendovasc Ther ; 16(3): 152-156, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-37502278

RESUMO

Objective: We report a case of a ruptured aneurysm at the posterior inferior temporal artery (PITA) of the posterior cerebral artery (PCA) treated by intra-aneurysmal coil embolization. Case Presentation: A 93-year-old man presented with disturbance of consciousness. Angiography revealed a 3-mm aneurysm in the distal PITA of the left PCA. He was diagnosed with subarachnoid hemorrhage and intracerebral hemorrhage due to a ruptured aneurysm. This aneurysm was occluded by intra-aneurysmal coil embolization with preservation of the PITA. Conclusion: Distal PITA aneurysm of the PCA is rare. Complete occlusion and preservation of the parent artery were achieved by intra-aneurysmal coil embolization, which may be an effective therapeutic option for such aneurysms.

18.
Adv Drug Deliv Rev ; 188: 114417, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35787389

RESUMO

A new era of nanomedicines that involve nucleic acids/gene therapy has been opened after two decades in 21st century and new types of more efficient drug delivery systems (DDS) are highly expected and will include extrahepatic delivery. In this review, we summarize the possibility and expectations for the extrahepatic delivery of small interfering RNA/messenger RNA/plasmid DNA/genome editing to the spleen, lung, tumor, lymph nodes as well as the liver based on our studies as well as reported information. Passive targeting and active targeting are discussed in in vivo delivery and the importance of controlled intracellular trafficking for successful therapeutic results are also discussed. In addition, mitochondrial delivery as a novel strategy for nucleic acids/gene therapy is introduced to expand the therapeutic dimension of nucleic acids/gene therapy in the liver as well as the heart, kidney and brain.


Assuntos
Nanopartículas , Ácidos Nucleicos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lipossomos , Nanomedicina
19.
J Neurol Sci ; 439: 120317, 2022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35709642

RESUMO

INTRODUCTION: Sporadic inclusion body myositis (sIBM) is often accompanied by signs suggestive of denervation on electromyography (EMG), which mimics neurogenic disorders. Hence, the current study aimed to assess reinnervation after denervation in sIBM and its clinical impllcation. METHODS: We retrospectively examined consecutive muscle biopsy specimens collected from 109 sIBM patients who were referred to our institution for diagnostic muscle biopsy from 2001 to 2018. Reinnervation after denervation in sIBM patients was assessed via muscle biopsy and EMG. The levels of acetylcholine receptor subunit γ (Chrng) and muscle-specific kinase (MuSK) mRNA, which are markers of denervation, were examined using real-time polymerase chain reaction. Response to treatment was defined as an increase of grade 1 or higher in two or more muscle groups as assessed using the Medical Research Council scale. RESULTS: In total, 93 (85.3%) of 109 sIBM patients had reinnervation after denervation on histological examination and/or EMG. The mean disease duration before biopsy was significantly longer in patients with reinnervation after denervation than in those without (p < 0.00001). Patients with denervation had significantly higher levels of Chrng and MuSK mRNA than those without. The proportion of patients who responded to immunosuppressive therapies was smaller in the patients with denervation than those without (p < 0.05). However, there was no significant difference regarding time from onset to using a walking aid between the two groups. DISCUSSION: Reinnervation after denervation is associated with disease duration and short-term response to therapy in individuals with sIBM.


Assuntos
Miosite de Corpos de Inclusão , Denervação , Eletromiografia , Humanos , Miosite de Corpos de Inclusão/diagnóstico , RNA Mensageiro , Estudos Retrospectivos
20.
Ann Clin Transl Neurol ; 9(10): 1602-1615, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36107781

RESUMO

OBJECTIVE: Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy in patients older than 50 years of age. sIBM is hardly responds to any immunosuppressing theraphies, and its pathophysiology remains elusive. This study aims to explore pathogenic pathways underlying sIBM and identify novel therapeutic targets using metabolomic and transcriptomic analyses. METHODS: In this retrospective observational study, we analyzed biopsied muscle samples from 14 sIBM patients and six non-diseased subjects to identify metabolic profiles. Frozen muscle samples were used to measure metabolites with cation and anion modes of capillary electrophoresis time of flight mass spectrometry. We validated the metabolic pathway altered in muscles of sIBM patients through RNA sequencing and histopathological studies. RESULTS: A total of 198 metabolites were identified. Metabolomic and transcriptomic analyses identified specific metabolite changes in sIBM muscle samples. The pathways of histamine biosynthesis and certain glycosaminoglycan biosynthesis were upregulated in sIBM patients, whereas those of carnitine metabolism and creatine metabolism were downregulated. Histopathological examination showed infiltration of mast cells and deposition of chondroitin sulfate in skeletal muscle samples, supporting the results of metabolomic and transcriptomic analyses. INTERPRETATION: We identified alterations of several metabolic pathways in muscle samples of sIBM patients. These results suggest that mast cells, chondroitin sulfate biosynthesis, carnitine, and creatine play roles in sIBM pathophysiology.


Assuntos
Miosite de Corpos de Inclusão , Carnitina/metabolismo , Sulfatos de Condroitina/metabolismo , Creatina/genética , Creatina/metabolismo , Perfilação da Expressão Gênica , Histamina/metabolismo , Humanos , Metaboloma , Músculo Esquelético , Miosite de Corpos de Inclusão/genética
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