Swallowing improvement surgeries.

PURPOSE: To discuss the different swallowing improvement surgeries that address one or more dysfunctional pharyngolaryngeal structures causing dysphagia. These surgeries reduce the risk of aspiration without sacrificing vocal function. METHODS: We searched the PubMed database and used Google Scholar search engine to find studies discussing the different swallowing improvement surgeries. A manual search of references in selected articles and reviews was done as well. No chronologic limitation was set for the studies; however, only articles written in English and Japanese were considered. Due to the nature of this article, no particular inclusion or exclusion criteria were set when searching for studies to be used as references; however, all relevant studies were reviewed and agreed upon by the authors for inclusion in this review article. RESULTS/DISCUSSION: Surgeries to improve swallowing function can be categorized into those that reinforce nasopharyngeal closure or pharyngeal contraction, improve laryngeal elevation or pharyngoesophageal segment opening, and those that improve vocal fold closure to protect the airway during swallowing. They are an effective alternative treatment that may significantly improve these patients' quality of life. Swallowing rehabilitation with the altered pharyngolaryngeal structures is required post-operatively to significantly improve patients' dysphagia. CONCLUSIONS: Surgeries to improve swallowing function address specific dysfunctional sites involved in the swallowing mechanism. Choosing the most appropriate surgery for each patient requires knowledge of the pathophysiology for their dysphagia and detailed pre-operative work-up.

Differences in residual volume above different tracheostomy tube cuffs depending on tube structure, tube tilt angle, and liquid viscosity.

INTRODUCTION: Proper management of aspirated material above the tracheostomy tube cuff is crucial to prevent complications, such as aspiration pneumonia. This study aimed to thoroughly examine the effects of aspirated liquid viscosity, suction port positioning, and tube tilt angle on residual volume above the cuff (RVAC). METHODS: Five types of tracheostomy tubes (approximately 9 mm outer diameter) were placed through a transparent cylinder with an inner diameter of 18 mm. The cuff was inflated to completely seal the interior of the cylinder. Four liquids with different viscosities were poured onto the cuff, and the liquid above the cuff was suctioned from the side port. The cylinder was angled at 90° and 20°, and each test was performed thrice to determine the average RVAC. RESULTS: After side-port suctioning, some liquid residue was observed on the cuff of all tracheostomy tubes. The RVAC increased with higher liquid viscosity. The tubes with a longer distance from the suction port opening to the cuff top exhibited more RVAC. Moreover, the RVAC was almost the same regardless of the cylinder angle for tubes with a suction port on the lateral side. However, tubes with backside ports showed a decreased RVAC with cylinder tilt. CONCLUSIONS: This study underscores the persistence of residual material on cuffed tracheostomy tubes even with regular subglottic secretion drainage. This emphasizes the need for specialized tracheostomy tube development aimed at reducing post-suction RVAC. Improved designs can potentially minimize complications associated with residue accumulation.

Hearing and Hearing Loss Progression in Patients with GJB2 Gene Mutations: A Long-Term Follow-Up.

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.

Characteristics of pregnancy complicated with type 1 and type 2 diabetes.

OBJECTIVE: Diabetes in pregnancy is a major risk factor for adverse perinatal outcomes such as congenital anomalies, hypertensive disorders of pregnancy (HDP), and macrosomia. For the mechanism of onset of type 1 and type 2 diabetes are different, we focused on the difference in perinatal outcomes between the type 1 and type 2 diabetes groups. MATERIALS AND METHODS: We retrospectively reviewed 22 pregnancies with type 1 diabetes and 15 pregnancies with type 2 diabetes, who were managed in our single center, with regard to maternal diabetes conditions during pregnancy and neonatal birthweight and blood glucose level. Furthermore, we checked the effect of continuous glucose monitoring and continuous subcutaneous insulin injection in pregnancies with type 1 diabetes. RESULTS: Type 1 diabetes in pregnancy was less controllable and increased neonatal birth weight and neonatal hypoglycemia within 2 h after birth after neonatal care unit admission. Continuous glucose monitoring and continuous subcutaneous insulin injection that are convenient to use, had a similar effect in the management of type 1 diabetes during pregnancy, compared with conventional diabetes treatment. In contrast, maternal BMI and HDP were increased in women with type 2 diabetes. CONCLUSION: In the management of pregnancy with diabetes, we should pay attention to the difference in pregnancy prognosis between type 1 and type 2 diabetes.

ATM mutation in aggressive uterine adenosarcoma in which systemic chemotherapies had remarkable effects.

Uterine adenosarcoma is a rare gynecologic malignancy, and 10-25% of the cases exhibit clinically aggressive behaviors. Although TP53 mutations are frequently identified in high-grade adenosarcomas of the uterus, definitive gene alterations have not been identified in uterine adenosarcomas. Specifically, no reports have described mutations in homologous recombination deficiency-related genes in uterine adenosarcomas. This study presents a case of uterine adenosarcoma without sarcomatous overgrowth but with TP53 mutation that exhibited clinically aggressive behaviors. The patient had an ATM mutation, which is a gene associated with homologous recombination deficiency, and exhibited a good response against platinum-based chemotherapy and possible therapeutic target by poly(ADP-ribose) polymerase inhibitors.

Aspiration Prevention Surgery: Clinical Factors Associated With Improvements in Oral Status Intake and Suction Frequency.

OBJECTIVE: In recent years, the use of aspiration prevention surgery (APS) for the treatment of severe dysphagia has been on the rise. However, relevant clinical studies have included small samples, and the frequency of, and risk factors for postoperative complications have not been clarified. We investigated the clinical features of patients undergoing APS and whether oral-intake status and suction frequency could be reduced. STUDY DESIGN: A case series. SETTING: Single-institution academic center. METHODS: We retrospectively evaluated medical charts generated from 2010 to 2021. The clinical characteristics of patients undergoing APS, changes in the oral-intake status (Functional Oral Intake Scale, FOIS), suction frequency before and after surgery, risk factors for postoperative complications, and factors contributing to improvements in postoperative oral-intake status were retrieved. RESULTS: We included the data of 100 patients (median age: 65 years, 72 men). Amyotrophic lateral sclerosis was the most common primary disease (28%), and glottis closure was the most common APS (69%). Postoperatively, 78% of patients showed improvements in the FOIS score, and suction frequency decreased in 85% of cases. Postoperative complications were observed in 10 patients (10%), wound infection in 6, and bleeding in 4; all improved. Higher preoperative FOIS scores were significantly associated with postoperative complications (p = 0.02). CONCLUSION: APS contributed to improving the FOIS score and helped reduce the suction frequency in most cases. APS can be performed safely with proper perioperative management, even in patients with poor preoperative general conditions and nutritional status.

Aspiration prevention surgeries: a review.

BACKGROUND: Severe dysphagia can cause intractable pneumonia and lead to life-threatening conditions. Intractable aspiration can occur despite medical management for aspiration prevention. Surgical intervention is indicated for intractable aspiration to prevent potentially life-threatening complications. Since the 1970s, several surgical treatments to prevent aspiration have been reported, and various aspiration prevention surgeries have been introduced, but little is known about them or their benefits. This is a review of the types of aspiration prevention surgery, with the aim of increasing aspiration prevention surgery awareness and their clinical outcomes among medical professionals, which will guide the choices of aspiration prevention surgeries for patients with intractable aspiration. MAIN BODY: Aspiration prevention surgeries can be categorized into three according to their approaches: removal of the larynx, altering the structure of the trachea, and closure of the larynx. Aspiration prevention surgeries to remove the larynx include total and central-part laryngectomy. Aspiration prevention surgeries to alter the structure of the trachea include tracheoesophageal diversion, laryngotracheal separation, and the tracheal flap method. Surgeries to close the larynx can be divided into supraglottic laryngeal closure, glottic laryngeal closure, and subglottic laryngeal closure. Aspiration prevention surgeries prevent aspiration and increase oral intake in 50-80% of patients. Most patients lose vocal function after aspiration prevention surgeries; however, some patients who have undergone total laryngectomy or laryngotracheal separation restored their speech function through tracheoesophageal puncture and use of voice prosthesis. Postoperative suture failure is frequent after epiglottic flap closure and total laryngectomy but rare after central-part laryngectomy, laryngotracheal separation, glottic closure, and subglottic closure. Furthermore, aspiration prevention surgeries improve the quality of life of patients and their caregivers by decreasing suctioning frequency. CONCLUSIONS: In this review, we described the history and development of aspiration prevention surgeries. Medical professionals need to continually improve their knowledge and skills to facilitate appropriate aspiration prevention surgeries according to patient condition.

Swallowing computed tomography and virtual reality as novel imaging modalities for the diagnosis of clicking larynx: Two case reports.

Globus sensation and pain causes are difficult to identify by conventional examination methods. With technology advances, new imaging methods including swallowing computed tomography (CT) and virtual reality (VR) have emerged and are contributing to definite diagnoses. We report two cases of cervical discomfort diagnosed as clicking larynx using swallowing CT/VR . Case 1 is a 55-year-old man. There were no findings on laryngoscopy or swallowing examinations, but swallowing CT/VR showed that the thyroid cartilage collided with the hyoid bone during swallowing, leading to the diagnosis of a clicking larynx. The patient was obese and is under observation hoping that weight loss will improve symptoms. Case 2 is a 32-year-old transgender man. He is receiving male hormones for gender identity disorder. He was diagnosed with a clicking larynx using swallowing CT/VR. Hormonal therapy may have increased the size of the thyroid cartilage, likely causing the symptoms. As they didn't choose surgical treatment, no symptomatic relief was achieved, but identifiying the cause contributed to improved patient satisfaction. Swallowing CT/VR is useful not only for evaluating the swallowing function, but also the underlying etiology of globus sensation and pain upon swallowing. Further clinical applications of this technique are expected for motion induced cervical symptoms.

Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: An Experimental Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause long-lasting anosmia, but the impact of SARS-CoV-2 infection, which can spread to the nasal cavity via the oral route, on the olfactory receptor neuron (ORN) lineage and olfactory bulb (OB) remains undetermined. Using Syrian hamsters, we explored whether oral SARS-CoV-2 inoculation can lead to nasal viral infection, examined how SARS-CoV-2 affects the ORN lineage by site, and investigated whether SARS-CoV-2 infection can spread to the OB and induce inflammation. On post-inoculation day 7, SARS-CoV-2 presence was confirmed in the lateral area (OCAM-positive) but not the nasal septum of NQO1-positive and OCAM-positive areas. The virus was observed partially infiltrating the olfactory epithelium, and ORN progenitor cells, immature ORNs, and mature ORNs were fewer than in controls. The virus was found in the olfactory nerve bundles to the OB, suggesting the nasal cavity as a route for SARS-CoV-2 brain infection. We demonstrated that transoral SARS-CoV-2 infection can spread from the nasal cavity to the central nervous system and the possibility of central olfactory dysfunction due to SARS-CoV-2 infection. The virus was localized at the infection site and could damage all ORN-lineage cells.

Risk Factors for Aspiration Pneumonia After Receiving Liquid-Thickening Recommendations.

OBJECTIVE: We examined the influence of liquid thickness levels on the frequency of liquid penetration-aspiration in patients with dysphagia and evaluated the clinical risk factors for penetration-aspiration and aspiration pneumonia development. STUDY DESIGN: A case series. SETTING: Single-institution academic center. METHODS: We reviewed medical charts from 2018 to 2019. First, we evaluated whether liquid thickness levels influence the frequency of liquid penetration-aspiration in patients with dysphagia. Penetration-aspiration occurrence in a videofluoroscopic swallowing study was defined as Penetration-Aspiration Scale (PAS) scores ≥3. Second, the association between liquid thickness level and penetration-aspiration was analyzed, and clinical risk factors were identified. Moreover, clinical risk factors for aspiration pneumonia development within 6 months were investigated. RESULTS: Of 483 patients, 159 showed penetration-aspiration. The thickening of liquids significantly decreased the incidence of penetration-aspiration (P < .001). Clinical risk factors for penetration-aspiration were vocal fold paralysis (odds ratio [OR], 1.99), impaired laryngeal sensation (OR, 5.01), and a history of pneumonia (OR, 2.90). Twenty-three patients developed aspiration pneumonia while undertaking advised dietary changes, including liquid thickening. Significant risk factors for aspiration pneumonia development were poor performance status (OR, 1.85), PAS score ≥3 (OR, 4.03), and a history of aspiration pneumonia (OR, 7.00). CONCLUSION: Thickening of liquids can reduce the incidence of penetration-aspiration. Vocal fold paralysis, impaired laryngeal sensation, and history of aspiration pneumonia are significant risk factors of penetration-aspiration. Poor performance status, PAS score ≥3, and history of aspiration pneumonia are significantly associated with aspiration pneumonia development following recommendations on thickening liquids. LEVEL OF EVIDENCE: 3.

Effects of Aspiration Prevention Surgery on the Dynamics of the Pharynx and Upper Esophageal Sphincter.

OBJECTIVE: Oral intake after aspiration prevention surgery (APS) is influenced by postoperative pharyngeal pressure and the dynamics of the upper esophageal sphincter (UES). We examined the effects of less invasive APS combined with UES relaxation techniques (laryngeal closure with cricopharyngeal myotomy [LC-CPM] and central-part laryngectomy [CPL]) on pharyngeal pressure and UES dynamics. STUDY DESIGN: Retrospective, observational study. SETTING: Single center. METHODS: We assessed the high-resolution pharyngeal manometric parameters of patients who underwent APS from 2018 to 2020. Then, we compared the effects of bilateral cricopharyngeal myotomy (combined with LC: LC-CPM group) and total cricoidectomy (CPL group) on both pharyngeal pressure and UES dynamics pre- and postoperatively. RESULTS: Eighteen patients (median age, 68 years; 17 men [94%]) were enrolled. Primary diseases associated with severe aspiration were neuromuscular disorders in 13, stroke in 3, and others in 2 patients. Pharyngeal swallowing pressure did not significantly change before and after APS. UES resting pressure and UES relaxation duration were significantly reduced (P < .001) and prolonged (P < .001), respectively, after APS. Only the CPL group (8 patients: median 62 years, all men) showed an increase in the velopharyngeal closure integral after APS (P < .05). More prolonged UES relaxation duration was recognized postoperatively in the CPL group (P < .01) than in the LC-CPM group. CONCLUSION: Less invasive APS minimally affects pharyngeal swallowing pressure, decreases UES resting pressure, and prolongs UES relaxation duration. CPL may be more effective for postoperative UES relaxation in patients with a short UES relaxation time.

Aspiration Prevention Surgery under Local Anesthesia for Palliative Care in Patients with Head and Neck Cancer: A Report of Two Cases.

Aspiration prevention (AP) surgery may improve the quality of life (QOL) of patients with severe dysphagia. However, not all patients can endure this type of surgery under general anesthesia because of their poor status. Herein, we describe the cases of 2 patients with head and neck cancer (HNC) who underwent AP surgery for palliative care. Although both patients had tracheostomy due to severe dysphagia and respiratory impairment and frequently needed suction, they were successfully managed with AP surgery under local anesthesia. A tracheostoma was reshaped to be sufficiently large for an airway to be secured without a cannula. Their respiratory failure gradually improved, and suction frequency markedly decreased after surgery; thus, they could receive medical treatment at home. When patients with HNC under palliative care have a tracheal cannula and cannot vocalize, AP surgery under local anesthesia is an option to improve their QOL.

Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate.

OBJECTIVE: Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES-), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations. In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES-. METHODS: We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz). RESULTS: In ES+ (n = 10), the OR(FRs) , the number of electrodes with high-rate FRs, and the MI(FRs & 3-4 Hz) in all electrodes were significantly higher than in ES- (n = 14). In both the ES+ and ES- groups, MI(ripples/FRs & 3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR(FRs) and the MI(FRs & 3-4 Hz) in the resected area in ES+ were significantly higher than in ES- (OR[FRs] , P = .04; MI[FRs & 3-4 Hz] , P = .04). SIGNIFICANCE: In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES-. High values of OR(FRs) and MI(FRs & 3-4 Hz) in ES+ compared to ES- are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.

Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats.

Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia. Next, we demonstrated that administration of primary microglia preconditioned by 18 hours of OGD at 7 days prompted functional recovery at 28 days after focal cerebral ischemia compared to control therapies by marked secretion of remodelling factors such as vascular endothelial growth factor, matrix metalloproteinase-9, and transforming growth factor-ß polarized to M2 microglia in vitro/vivo. In conclusion, intravascular administration of M2 microglia preconditioned by optimal OGD may be a novel therapeutic strategy against ischemic stroke.

Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression.

Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.

Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death.

Hypoglycemic encephalopathy (HE) is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG) state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB) staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg) or vehicle (dimethyl sulfoxide; DMSO) was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020). Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.

Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke.

In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (∼88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNA-binding protein-43, respectively.