Pulmonary embolism after dexamethasone treatment for COVID-19: a case report.

BACKGROUND: Although the RECOVERY trial showed that dexamethasone was efficacious for the treatment of coronavirus disease 2019 (COVID-19), its impact on the risk of pulmonary embolism (PE) and other serious procoagulant events was not assessed. CASE PRESENTATION: Here we report the case of a previously healthy 83-year-old woman with COVID-19, without any genetic predisposition to thrombosis. She developed moderate respiratory distress 12 days after symptom onset and a 10-day course of dexamethasone therapy was initiated. Her clinical condition and imaging findings improved initially; however, they deteriorated after the completion of dexamethasone therapy, despite the improvement in her pneumonia and viral clearance. Laboratory tests showed markedly raised serum D-dimer, ferritin, and sIL-2R levels, and contrast-enhanced computed tomography showed deep vein thrombosis (DVT) in the left iliac vein and PE of the right pulmonary artery. The DVT and PE were successfully treated using intravenous heparin administration. CONCLUSIONS: This case illustrates the potential risk of rebound inflammation and procoagulant events following dexamethasone withdrawal. We believe that COVID-19-induced DVT and PE can be affected by dexamethasone therapy. Although dexamethasone reduces procoagulant factors, increases anticoagulant factors, and modulates cytokines, which can suppress/delay thrombus formation during treatment, it confers the risk for rebound cytokine production after treatment completion, triggering cytokine and coagulation cascades that can lead to thromboembolic diseases. In this critical clinical period, the patient's deteriorating condition may be overlooked because of the masking effects of dexamethasone treatment on fever and other clinical conditions and laboratory changes. Clinicians should follow-up coagulation markers carefully and contrast-enhanced computed tomography is useful for detecting coagulation; and, if PE occurs, therapeutic heparin administration is essential because emboli can also generate cytokines.

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer.

LESSONS LEARNED: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. BACKGROUND: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. METHODS: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.

A Phase II Study of S-1 and Paclitaxel Combination Therapy as a First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small cell lung cancer showed favorable efficacy.Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small lung cancer showed tolerable toxicity. BACKGROUND: Although monotherapy with cytotoxic agents including docetaxel or vinorelbine are recommended for elderly patients with advanced non-small cell lung cancer (NSCLC), the outcome is not satisfactory. We evaluated the efficacy and safety of S-1 and paclitaxel (PTX) as a first-line cotreatment in elderly patients with advanced NSCLC. METHODS: Oral S-1 was administered on days 1-14 every 3 weeks at 80, 100, and 120 mg per day for patients with body surface area < 1.25 m2, 1.25-1.5 m2, and > 1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. The primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Seventeen patients were enrolled with response and disease control rates of 47.1% and 88.2%, respectively. Median PFS and OS were 5.6 and 35.0 months, respectively. Hematological grade 3 or 4 toxicities included leukopenia (55.8%), neutropenia (52.9%), febrile neutropenia (11.8%), and anemia (11.8%). Nonhematological grade 3 toxicities included stomatitis (23.5%), diarrhea (5.9%), and interstitial lung disease (5.9%), and grade 5 toxicities included interstitial lung disease (5.9%). CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Phase I study of S-1 plus paclitaxel combination therapy as a first-line treatment in elderly patients with advanced non-small cell lung cancer.

This phase I study was aimed at determining the maximum tolerated dose (MTD) and recommended dose (RD) for oral S-1 plus paclitaxel combination therapy in elderly patients with non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients (age, >70 years) with stage III/IV NSCLC were treated with paclitaxel intravenously at four dose levels (DLs), 60, 70, 80, and 90 mg/m2, on day 1 and 8, and with S-1 (80 mg/m2) orally on days 1-14 every 3 weeks. MTD was defined as the dose at which two of the initial three patients experienced dose-limiting toxicities (DLTs). Three patients were added when the initial three patients experienced DLTs. The dose administered in three of the six patients with DLTs met the definition of MTD. The RD was defined as a dose 1 DL below the MTD. Fifteen patients including six on DL 1 and three each on DLs 2, 3, and 4 were enrolled. One patient experienced a DLT (febrile neutropenia) at DL 1. The remaining DLTs were noted at DL 4 (in one patient each): febrile neutropenia, grade (G) 3 skin rash, G3 diarrhea, G3 stomatitis, and G3 international normalized ratio (INR) elevation. The MTD of paclitaxel was 90 mg/m2. The RD for both S-1 and paclitaxel was 80 mg/m2 (DL 3). The response rate was 45.5% (8 of 15 patients achieved a partial response). In conclusion, the RD of both S-1 and paclitaxel was 80 mg/m2 in the combination therapy for chemotherapy-naïve patients with advanced NSCLC.

[A case of mediastinal recurrence of esophageal cancer diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration].

A 63-year-old man was admitted to our hospital for treatment of cervical esophageal cancer and hepatocellular carcinoma. He had undergone subtotal esophagectomy for esophageal cancer and partial hepatectomy for hepatocellular carcinoma after preoperative chemotherapy and transcatheter arterial embolization (TAE). Histologically, esophageal cancer was diagnosed as pT3, pN2, M0, pStage III. Five months after surgery, a 2.2 cm tumor with abnormal uptake of fluorodeoxyglucose (FDG) was found in the upper mediastinum by positron emission tomography-computed tomography (PET-CT). To obtain a definitive diagnosis, we performed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) on the mediastinal tumor. A tumefactive mucosal lesion was present in the main bronchus and the presence of a tumor was confirmed by ultrasonography. We diagnosed the lesion as a mediastinal recurrence of the primary esophageal cancer because squamous cell carcinoma was observed upon cytological examination. Chemoradiotherapy was performed for the mediastinal recurrence. EBUS-TBNA was useful for the diagnosis of metastases and recurrence of esophageal cancer in the mediastinum.

Procaterol-stimulated increases in ciliary bend amplitude and ciliary beat frequency in mouse bronchioles.

The beating cilia play a key role in lung mucociliary transport. The ciliary beating frequency (CBF) and ciliary bend amplitude (CBA) of isolated mouse bronchiolar ciliary cells were measured using a light microscope equipped with a high-speed camera (500 Hz). Procaterol (aß(2)-agonist) increased CBA and CBF in a dose dependent manner via cAMP. The time course of CBA increase is distinct from that of CBF increase: procaterol at 10 nM first increased CBA and then CBF. Moreover, 10 pM procaterol increased CBA, not CBF, whereas 10 nM procaterol increased both CBA and CBF. Concentration-response studies of procaterol demonstrated that the CBA curve was shifted to a lower concentration than the CBF curve, which suggests that CBA regulation is different from CBF regulation. Measurements of microbead movements on the bronchiole of lung slices revealed that 10 pM procaterol increased the rate of ciliary transport by 37% and 10 nM procaterol increased it by 70%. In conclusion, we have shown that increased CBA is of particular importance for increasing the bronchiolar ciliary transport rate, although CBF also plays a role in increasing it.

Impact of ageing on biological features of bone marrow stromal cells (BMSC) in cell transplantation therapy for CNS disorders: functional enhancement by granulocyte-colony stimulating factor (G-CSF).

This study was designed to clarify the effects of donor age on biological features of bone marrow stromal cells (BMSC), one of the candidates for cell transplantation therapy for CNS disorders, because many aged patients might require such therapy. This study was also aimed to test whether ex vivo treatments with granulocyte-colony stimulating factor (G-CSF) could modify biological properties of BMSC from aged donors and enhance its therapeutic effects in an animal model of traumatic brain injury. The BMSC were harvested from young (6-week-old) and aged (100-week-old) rats. The ageing significantly increased the senescence-associated ß-galactosidase (SA-ß-gal) activity of the cultured BMSC, and decreased their proliferative capacity and production of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). As the next step, the rats were subjected to brain freezing injury by applying liquid nitrogen onto the neocortex through the thinned skull. The 6-week BMSC, 100-week BMSC, G-CSF-treated 100-week BMSC or vehicle were stereotactically injected into the ipsilateral striatum at 7 days post-injury. Transplantation of the 6-week BMSC, but not 100-week BMSC, significantly improved locomotor function. However, treatment of the 100-week BMSC with 0.1 µmol of G-CSF significantly improved their proliferation activity and growth factor production, and recovered therapeutic effects in the injured brain. In conclusion, donor age may largely determine biological aspects of BMSC. G-CSF may contribute to improve the outcome of BMSC transplantation therapy for CNS disorders in aged patients.

Transplanted bone marrow stromal cells protect neurovascular units and ameliorate brain damage in stroke-prone spontaneously hypertensive rats.

This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke.

Regulation of epithelial sodium transport via epithelial Na+ channel.

Renal epithelial Na+ transport plays an important role in homeostasis of our body fluid content and blood pressure. Further, the Na+ transport in alveolar epithelial cells essentially controls the amount of alveolar fluid that should be kept at an appropriate level for normal gas exchange. The epithelial Na+ transport is generally mediated through two steps: (1) the entry step of Na+ via epithelial Na+ channel (ENaC) at the apical membrane and (2) the extrusion step of Na+ via the Na+, K+-ATPase at the basolateral membrane. In general, the Na+ entry via ENaC is the rate-limiting step. Therefore, the regulation of ENaC plays an essential role in control of blood pressure and normal gas exchange. In this paper, we discuss two major factors in ENaC regulation: (1) activity of individual ENaC and (2) number of ENaC located at the apical membrane.

Acute onset intramedullary spinal cord abscess with spinal artery occlusion: a case report and review.

Intramedullary spinal cord abscess (ISCA) without meningitis is an extremely rare entity in the central nervous system, and it is often difficult to diagnose immediately, and no definitive imaging findings have been established. We experienced the case of a 61-year-old male who presented with a sudden onset back pain without fever following rapidly worsening paraparesis for 3 days, who subsequently become unable to walk. According to the initial MRI and 3D-CTA, the presumptive diagnosis was spinal infarction due to spinal artery embolism. However, his symptoms did not improve, despite the gradual changes in MRI following antiplatelet therapy. He underwent a biopsy in an attempt to prevent the lesion from progressing toward the upper spinal cord. The pathological examination revealed an intramedullary abscess, so we performed a midline myelotomy and drained the pus from the abscess. After surgery, MRI showed improvement, but the patient's paraplegia persisted. To the best of our knowledge, this is the first case report of spinal cord abscess with the confirmation of spinal artery occlusion on angiography, which could have been caused by a bacterial embolism. We herein discuss its possible etiology and also review recent reports on ISCA.

Clinical characteristics and outcomes in carotid endarterectomy for internal carotid artery stenosis in a Japanese population: 10-year microsurgical experience.

Few studies have explored the significance of carotid endarterectomy (CEA) in long-term prognosis in Japanese patients. In the present study, we precisely elucidated the demographic and radiologic data, surgical morbidity and mortality, and long-term outcome in 135 Japanese patients who underwent a total of 142 CEAs due to 70%-99% stenosis of the internal carotid artery at our hospitals over a 10-year period. The prevalence of risk factors was similar to those found in previous studies in Western countries. Surgical mortality (0.7%) and morbidity (2.8%) were relatively low. Blood flow studies done immediately after CEA revealed postoperative hyperperfusion in 8 patients (5.6%), but none of these patients exhibited related symptoms. Over the mean follow-up period of 38.7 months, a total of 9 patients died (6.7%), due mainly to malignancies. Cerebrovascular events occurred in 12 patients (8.5%), including ipsilateral ischemic stroke in 2 (1.4%). In addition, 11 patients (8.2%) developed vascular disorders in other organs, including coronary artery disease and chronic renal failure. Follow-up radiologic examination revealed restenosis of >50% in 3 carotid arteries (2.1%). Stenosis of the contralateral carotid arteries progressed to >70% in 12 patients (9.2%). This study strongly suggests that microsurgical CEA is feasible and effective in preventing subsequent ipsilateral ischemic stroke in Japanese patients; however, long-term medical and radiologic surveillance is essential to reduce the incidence of ischemic stroke in other areas and of vascular disorders in other organs to improve prognosis.

[Conus perimedullary arteriovenous fistula with multiple shunt points including the cauda equina: a case report].

Perimedullary arteriovenous fistula (AVF) is usually located on the surface of the spinal cord and is fed by the anterior spinal artery and/or the posterior spinal artery. We report a rare case of Conus perimedullary AVF with multiple shunt points including the cauda equina. A 68-year-old man presented with leg pain when walking long distances. Magnetic resonance imaging at the thoracic and lumbar level revealed multiple signal voids with marked cord signal change. Angiography showed the perimedullary AVF fed by the anterior spinal artery from the right T9 intercostal artery at the level of the conus medullaris and the fistula fed by the left lateral sacral artery from the left internal iliac artery at the level of the cauda equina. In the first surgery, we performed surgical interruption of feeding arteries from the filum terminale and coagulated AV shunt of the conus medullaris. However residual perimedullary AVF was found at the conus medullaris in the postoperative angiography. Secondary surgery was carried out to treat residual AVF. Follow-up angiography showed complete disappearance of all AVFs. Postoperatively, the patient`s symptoms were improved. Because the Conus perimedullary AVF has the characteristics of multiple feeding arteies, multiple shunt points, and complex venous drainage, it must be kept in mind that other fistula could exist in the cauda equina or filum terminale.

[Sacral dural arteriovenous fistula: report of 4 cases].

Spinal dural arteriovenous fistula (SDAVF) in the sacral region is relatively rare and remains difficult to diagnose because of the uncommon origin of its feeder. It also has higher incidence of recurrence than usual thoraco-lumbar lesion and needs subsequent treatment. We reviewed 51 cases of SDAVF over the past 10 years. Especially in patients with sacral lesion, clinical features and the findings on spinal angiography were analyzed. Four patients (7.8%) had SDAVF in the sacral region. In all cases, SDAVF were supplied by the lateral sacral artery. Multiple feeders were observed in 3 (75%) out of 4 patients and 2 patients (50%) had multiple fistulas. Endovascular embolizations were performed in all patients, and neurological symptoms were improved in two patients (50%) and the other two were stabilized (50%). There was no recurrence during a follow-up period of 3 months to 8 years. We should keep in mind that SDAVF in the sacral region can have multiple shunts and feeders derived from the lateral sacral artery.

[A case of microscopic polyangiitis with silicosis].

A 76-year-old man was admitted to our hospital because of increasing size of lung nodules, while he was under observation for silicosis at another hospital. As the result of bronchoscopic biopsy, it was confirmed that they were silicotic nodules. However, he was hospitalized again about one month later due to left spontaneous pneumothorax. The pneumothorax improved immediately by persistent drainage of the thoracic cavity, but he developed a fever on day 9, and ground-glass opacities in both lungs also became exacerbated in spite of our administration of antibiotics. In addition, the level of MPO-ANCA increased markedly and multiple 3-10mm sized purpurae was seen on the right thigh on day 29. Skin biopsy specimens revealed infiltration of histiocytes and lymphocytes around medium-sized vessels in lower dermis. We diagnosed microscopic polyangiitis, then treated with steroid and immunosuppressive therapy. Fever and radiological findings improved significantly from the day after initiation of steroid administration. The patient was discharged on day 92 because of the improvement of his respiratory condition. We report a case of microscopic polyangiitis with silicosis, which markedly improved by steroid and immunosuppressive therapy.

Reply to Correspondence: Response to a case report: idiopathic hypereosinophilic syndrome in remission with benralizumab treatment after relapse with mepolizumab.

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Two cases of lung cancer with hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors.

We report the cases of two patients with secondary hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors, who were diagnosed using the recently developed HScore. The first patient presented with fever, cytopenia, and elevated liver enzyme levels at 46 days post-pembrolizumab administration. The HScore was 175. The second patient developed an immune-related adverse event at 30 days after the final pembrolizumab dose. The HScore was 185. Hemophagocytic lymphohistiocytosis was confirmed in both patients, and corticotherapy improved their condition. It is challenging to diagnose hemophagocytic lymphohistiocytosis, particularly after development at a late stage. Our patients developed hemophagocytic lymphohistiocytosis late after immune checkpoint inhibitor administration. However, the HScore enabled us to diagnose both cases precisely and in a timely manner.

Intracellular chloride regulates cell proliferation through the activation of stress-activated protein kinases in MKN28 human gastric cancer cells.

Recently, we reported that reduction of intracellular Cl(-) concentration ([Cl(-)](i)) inhibited proliferation of MKN28 gastric cancer cells by diminishing the transition rate from G(1) to S cell-cycle phase through upregulation of p21, cyclin-dependent kinase inhibitor, in a p53-independent manner. However, it is still unknown how intracellular Cl(-) regulates p21 expression level. In this study, we demonstrate that mitogen-activated protein kinases (MAPKs) are involved in the p21 upregulation and cell-cycle arrest induced by reduction of [Cl(-)](i). Culture of MKN28 cells in a low Cl(-) medium significantly induced phosphorylation (activation) of MAPKs (ERK, p38, and JNK) and G(1)/S cell-cycle arrest. To clarify the involvement of MAPKs in p21 upregulation and cell growth inhibition in the low Cl(-) medium, we studied effects of specific MAPKs inhibitors on p21 upregulation and G(1)/S cell-cycle arrest in MKN28 cells. Treatment with an inhibitor of p38 or JNK significantly suppressed p21 upregulation caused by culture in a low Cl(-) medium and rescued MKN28 cells from the low Cl(-)-induced G(1) cell-cycle arrest, whereas treatment with an ERK inhibitor had no significant effect on p21 expression or the growth of MKN28 cells in the low Cl(-) medium. These results strongly suggest that the intracellular Cl(-) affects the cell proliferation via activation of p38 and/or JNK cascades through upregulation of the cyclin-dependent kinase inhibitor (p21) in a p53-independent manner in MKN28 cells.

Chloride ion modulates cell proliferation of human androgen-independent prostatic cancer cell.

In the present study, we investigated if the intracellular Cl(-) affects cell growth and cell cycle progression of androgen-independent prostate cancer PC3 cells. PC3 cells cultured in a medium containing 113 mM Cl(-) for 96 h grew up 9-fold in cell number, while PC3 cells cultured in an 8 mM-Cl(-)-containing culture medium showed complete arrest of cell growth even after culture for 96 h. Exposure of cells to the 8 mM-Cl(-) culture medium diminished phosphorylation levels of Rb and cdc2, which are respectively key accelerators of transition from G(1) to S phase and G(2) to M phase in cell cycle progression. Culturing cells in the 8 mM-Cl(-)-containing culture medium upregulated the protein expression level of p21 (a CDK inhibitor) inhibiting transition of G(1) to S phase, and diminished the incorporation of 5-ethynyl-2'-deoxyuridine (EdU; a thymidine analogue) into DNA. These results suggest that cells cultured in the low Cl(-) medium prolonged the duration of all phases of the cell cycle (G(1), S, and G(2)/M), thereby abolishing overall cell cycle progression. Effects of culturing cells in the low Cl(-) culture medium on cell cycle progression would be mediated via a change in the intracellular Cl(-) concentration ([Cl(-)](i)), since [Cl(-)](i) was decreased under a low Cl(-) culture medium. To clarify this possibility, we studied effects of furosemide and bumetanide, Na+/K+/2Cl(-) cotransporter (NKCC) inhibitors, on proliferation of PC3 cells. Furosemide and bumetanide decreased [Cl(-)](i) and cell growth of PC3 cells. These results suggest that a change in [Cl(-)](i) would play a critical role in this growth mechanism.

Overexpression of mitochondrial transcription factor A (TFAM) ameliorates delayed neuronal death due to transient forebrain ischemia in mice.

Mitochondrial transcription factor A (TFAM) is an important regulator to maintain mitochondrial DNA copy number. However, no studies have denoted its roles in cerebral ischemia. Therefore, this study was aimed to assess whether the forced overexpression of TFAM ameliorates delayed neuronal death following transient forebrain ischemia. We have established human TFAM-transgenic (Tg) mice. Wild type (WT) and TFAM-Tg mice were subjected to 20-min bilateral common carotid artery occlusion (BCCAO). Immunostaining against cytochrome c was performed to estimate its release from mitochondria at 24 h after 20-min BCCAO. Histological analysis was performed to evaluate the effect of TFAM overexpression on delayed neuronal death at 72 h after 20-min BCCAO. The number of cytochrome c-positive neurons in the hippocampal CA1 sector was significantly smaller in TFAM-Tg mice than in WT mice (P = 0.005). The percentage of viable neurons in the hippocampal CA1 sector was significantly higher in TFAM-Tg mice than in WT mice (P < 0.001), and the number of TUNEL-positive neurons was significantly smaller in TFAM-Tg mice than in WT mice (P < 0.001). Our data strongly suggest that TFAM overexpression can reduce mitochondrial permeability transition and ameliorate delayed neuronal death in the hippocampus after transient forebrain ischemia.

Synergistic effects of bone marrow stromal cells and a Rho kinase (ROCK) inhibitor, fasudil on axon regeneration in rat spinal cord injury.

Transplanted bone marrow stromal cells (BMSC) promote functional recovery after spinal cord injury (SCI) through multiple mechanisms. A Rho kinase inhibitor, Fasudil also enhances axonal regeneration. This study was aimed to evaluate whether combination therapy of BMSC transplantation and Fasudil further enhances axonal regeneration and functional recovery in rats subjected to SCI. Fasudil or vehicle was injected for 2 weeks. BMSC or vehicle transplantation into the rostral site of SCI was performed at 7 days after injury. Neurological symptoms were assessed throughout the experiments. Fluoro-Ruby was injected into the dorsal funiculus of the rostral site of SCI at 63 days after injury. The fate of the transplanted BMSC was examined using immunohistochemistry. BMSC transplantation significantly increased the number of Fluoro-Ruby -labeled fibers of the dorsal corticospinal tracts at the caudal site of SCI, enhancing functional recovery of the hind limbs. Some of the engrafted BMSC were positive for Fluoro-Ruby, neuronal specific nuclear protein and microtubule-associated protein-2, suggesting that they acquired neuronal phenotypes and built synaptic connection with the host's neural circuits. Fasudil treatment also improved axonal continuity, but did not promote functional recovery. Combination therapy dramatically increased the number of Fluoro-Ruby-labeled fibers of the dorsal corticospinal tracts at the caudal site of SCI, but did not further boost the therapeutic effects on locomotor function by BMSC transplantation. The findings suggest that BMSC transplantation and Fasudil provide synergistic effects on axon regeneration after SCI, although further studies would be necessary to further enhance functional recovery.