[Thoracoscopic Resection of Schwannoma Using Intraoperative Neurophysiological Monitoring: Report of a Case].

A 28-year-old right-handed woman had been diagnosed with a tumor of 30 mm in a diameter at the right first intercostal space adjacent to brachial nerve plexus. It was incidentally detected by medical checkup examination five years ago. Because the tumor enlarged to 36 mm in five years without any symptoms, thoracoscopic tumor resection was planned for diagnosis. Intraoperative neurophysiological monitoring (IONM) was performed to prevent brachial plexus nerve injury. The tumor was totally removed via thoracoscopic approach without postoperative neurological deficit. Histopathological diagnosis was schwannoma. In order to reduce the risk of neural injury, IONM is useful in thoracoscopic removal of the peripheral nerve tumor.

Amino acid transporter Asc-1 (SLC7A10) expression is altered in basal ganglia in experimental Parkinsonism and L-dopa-induced dyskinesia model mice.

In Parkinson's disease (PD), a decrease in dopamine levels in the striatum causes abnormal circuit activity in the basal ganglia, resulting in increased output via the substantia nigra pars reticulata (SNr). A characteristic feature of glutamatergic synaptic transmission in the basal ganglia circuitry under conditions of dopamine depletion is enhanced synaptic activity of NMDA receptors. However, the cause of this NMDA receptor hyperactivity is not fully understood. We focused on Asc-1 (SLC7A10), an alanine-serine-cysteine transporter, as one of the factors that regulate NMDA receptor activity by modulating D-serine and glycine concentration in synaptic clefts. We generated PD model mice by injection of 6-hydroxydopamine into the unilateral medial forebrain bundle and analyzed the expression level of Asc-1 mRNA in the nuclei of basal ganglia (the external segment of the globus pallidus (GPe), subthalamic nucleus (STN), and SNr) compared to control mice. Each nucleus was dissected using laser microdissection, and RNA was extracted and quantified by quantitative PCR. Asc-1 mRNA expression was significantly higher in the GPe and lower in the SNr under the PD state than that in control naïve mice. The STN showed no change in Asc-1 mRNA expression. We further modeled L-dopa-induced dyskinesia by administering L-dopa continuously for 14 days to the PD model mice and found that Asc-1 mRNA expression in the GPe and SNr became close to that of control mice, regardless of the presence of abnormal involuntary movements. The present study revealed that Asc-1 mRNA expression is differentially regulated in the basal ganglionic nuclei in response to striatal dopamine concentration (depleted or replenished) and suggests that Asc-1 can be a therapeutic target for the amelioration of motor symptoms of PD.

Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures.

BACKGROUND: The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. METHODS: Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. RESULTS: Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. CONCLUSION: The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Characterization of Glial Populations in the Aging and Remyelinating Mouse Corpus Callosum.

Cells in the white matter of the adult brain have a characteristic distribution pattern in which several cells are contiguously connected to each other, making a linear array (LA) resembling pearls-on-a-string parallel to the axon axis. We have been interested in how this pattern of cell distribution changes during aging and remyelination after demyelination. In the present study, with a multiplex staining method, semi-quantitative analysis of the localization of oligodendrocyte lineage cells (oligodendrocyte progenitors, premyelinating oligodendrocytes, and mature oligodendrocytes), astrocytes, and microglia in 8-week-old (young adult) and 32-week-old (aged) corpus callosum showed that young adult cells still include immature oligodendrocytes and that LAs contain a higher proportion of microglia than isolated cells. In aged mice, premyelinating oligodendrocytes were decreased, but microglia continued to be present in the LAs. These results suggest that the presence of microglia is important for the characteristic cell localization pattern of LAs. In a cuprizone-induced demyelination model, we observed re-formation of LAs after completion of cuprizone treatment, concurrent with remyelination. These re-formed LAs again contained more microglia than the isolated cells. This finding supports the hypothesis that microglia contribute to the formation and maintenance of LAs. In addition, regardless of the distribution of cells (LAs or isolated cells), astrocytes were found to be more abundant than in the normal corpus callosum at 24 weeks after cuprizone treatment when remyelination is completed. This suggests that astrocytes are involved in maintaining the functions of remyelinated white matter.

Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice.

Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload. Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.

Responses of perivascular macrophages to circulating lipopolysaccharides in the subfornical organ with special reference to endotoxin tolerance.

BACKGROUND: Circulating endotoxins including lipopolysaccharides (LPS) cause brain responses such as fever and decrease of food and water intake, while pre-injection of endotoxins attenuates these responses. This phenomenon is called endotoxin tolerance, but the mechanisms underlying it remain unclear. The subfornical organ (SFO) rapidly produces proinflammatory cytokines including interleukin-1ß (IL-1ß) in response to peripherally injected LPS, and repeated LPS injection attenuates IL-1ß production in the SFO, indicating that the SFO is involved in endotoxin tolerance. The purpose of this study is to investigate features of the IL-1ß source cells in the SFO of LPS-non-tolerant and LPS-tolerant mice. METHODS: We first established the endotoxin-tolerant mouse model by injecting LPS into adult male mice (C57BL/6J). Immunohistochemistry was performed to characterize IL-1ß-expressing cells, which were perivascular macrophages in the SFO. We depleted perivascular macrophages using clodronate liposomes to confirm the contribution of IL-1ß production. To assess the effect of LPS pre-injection on perivascular macrophages, we transferred bone marrow-derived cells obtained from male mice (C57BL/6-Tg (CAG-EGFP)) to male recipient mice (C57BL/6N). Finally, we examined the effect of a second LPS injection on IL-1ß expression in the SFO perivascular macrophages. RESULTS: We report that perivascular macrophages but not parenchymal microglia rapidly produced the proinflammatory cytokine IL-1ß in response to LPS. We found that peripherally injected LPS localized in the SFO perivascular space. Depletion of macrophages by injection of clodronate liposomes attenuated LPS-induced IL-1ß expression in the SFO. When tolerance developed to LPS-induced sickness behavior in mice, the SFO perivascular macrophages ceased producing IL-1ß, although bone marrow-derived perivascular macrophages increased in number in the SFO and peripherally injected LPS reached the SFO perivascular space. CONCLUSIONS: The current data indicate that perivascular macrophages enable the SFO to produce IL-1ß in response to circulating LPS and that its hyporesponsiveness may be the cause of endotoxin tolerance.

The inner mitochondrial membrane protein ANT1 modulates IL-6 expression via the JNK pathway in macrophages.

Mitochondria are increasingly associated with inflammation. Here, we focus on the relationship between inflammation and adenine nucleotide translocator type 1 (ANT1), which is localized in the mitochondrial inner membrane. ANT1 plays an important role in oxidative phosphorylation, and mutations in the ANT1 gene are responsible for mitochondrial diseases. Ample studies have demonstrated that ANT1 has a critical role in cardiomyocytes and neurons, but little has been reported on its functions in immune cells. We knocked down ANT1 expression in macrophages and examined inflammatory cytokine expression after lipopolysaccharide stimulation. ANT1 knockdown reduces the expression of IL-6. JNK, upstream of IL-6, is downregulated, but other MAP kinases and the NF-κB signaling remain unchanged. These results suggest that ANT1 modulates IL-6 expression through JNK in macrophages.

Olig2-Lineage Astrocytes: A Distinct Subtype of Astrocytes That Differs from GFAP Astrocytes.

Astrocytes are the most abundant glia cell type in the central nervous system (CNS), and are known to constitute heterogeneous populations that differ in their morphology, gene expression and function. Although glial fibrillary acidic protein (GFAP) is the cardinal cytological marker of CNS astrocytes, GFAP-negative astrocytes can easily be found in the adult CNS. Astrocytes are also allocated to spatially distinct regional domains during development. This regional heterogeneity suggests that they help to coordinate post-natal neural circuit formation and thereby to regulate eventual neuronal activity. Here, during lineage-tracing studies of cells expressing Olig2 using Olig2CreER; Rosa-CAG-LSL-eNpHR3.0-EYFP transgenic mice, we found Olig2-lineage mature astrocytes in the adult forebrain. Long-term administration of tamoxifen resulted in sufficient recombinant induction, and Olig2-lineage cells were found to be preferentially clustered in some adult brain nuclei. We then made distribution map of Olig2-lineage astrocytes in the adult mouse brain, and further compared the map with the distribution of GFAP-positive astrocytes visualized in GFAPCre; Rosa-CAG-LSL-eNpHR3.0-EYFP mice. Brain regions rich in Olig2-lineage astrocytes (e.g., basal forebrain, thalamic nuclei, and deep cerebellar nuclei) tended to lack GFAP-positive astrocytes, and vice versa. Even within a single brain nucleus, Olig2-lineage astrocytes and GFAP astrocytes frequently occupied mutually exclusive territories. These findings strongly suggest that there is a subpopulation of astrocytes (Olig2-lineage astrocytes) in the adult brain, and that it differs from GFAP-positive astrocytes in its distribution pattern and perhaps also in its function. Interestingly, the brain nuclei rich in Olig2-lineage astrocytes strongly expressed GABA-transporter 3 in astrocytes and vesicular GABA transporter in neurons, suggesting that Olig2-lineage astrocytes are involved in inhibitory neuronal transmission.

[Usefulness of Oxidization-regenerated Cellulose Sheets in Preventing Postoperative Adhesion Confirmed at Second Surgery for Lung Cancer].

The patient was a 42-year-old woman who had been found to have a mixed ground glass opacity in the lung on chest computed tomography, and had underwent right S6 segmentectomy. At surgery, the plain between the upper and lower lobe was covered with a regenerative oxidized cellulose membrane. Two years later, multiple small shadows appeared in the remaining right lower lobe and completion right lower lobectomy was performed by thoracoscopy due to the adhesion to the absence of adhesion. Both of the histological examinations confirmed the diagnosis of minimally invasive adenocarcinoma of the lung. An oxidization regenerated cellulose sheet was effective in preventing postoperative adhesion in pulmonary resection.

[Epidermal Growth Factor Receptor-mutated Advanced Lung Adenocarcinoma with Long-term Tumor-free Survival by Chemotherapy Followed by Tyrosine Kinase Inhibitor Treatment after Reduction Surgery].

A 67-year-old woman was detected stage III B adenocarcinoma of the left lung, with epidermal growth factor receptor(EGFR) -mutation. Since chest computed tomography showed enlarged lymph nodes in stations 7 and 1R-4R, radiochemotherapy was recommended. However, she declined radiochemotherapy and the chemotherapy after tumor reduction surgery was chosen. She underwent resection of the left lower lobe and lingular segment, and mediastinal lymph node dissection through a posterolateral thoracotomy by extended bronchoplasty(type C) due to the extranodal invasion of lymph nodes to the lingular segmental bronchus. At postoperative day 21, she underwent right superior mediastinal lymph node dissection through a median sternotomy. Postoperatively, she received 6 cycles of chemotherapy with carboplatin plus paclitaxel followed by gefitinib. 1.5 years later, gamma knife surgery was done for multiple cerebral metastases, followed by 4 cycles of chemotherapy with cisplatin plus pemetrexed and then erlotinib. Six years after surgery, she is surviving without any evidence of disease recurrence. Tumor reduction surgery, when followed by chemotherapy, for EGFR-mutant lung adenocarcinoma is likely to lead to long-term survival.

Changes in endothelial cell proliferation and vascular permeability after systemic lipopolysaccharide administration in the subfornical organ.

The subfornical organ (SFO) has highly permeable fenestrated vasculature and is a key site for immune-to-brain communications. Recently, we showed the occurrence of continuous angiogenesis in the SFO. In the present study, we found that systemic administration of bacterial lipopolysaccharide (LPS) reduced the vascular permeability and endothelial cell proliferation. In LPS-administered mice, the SFO vasculature showed a significant decrease in the immunoreactivity of plasmalemma vesicle associated protein-1, a marker of endothelial fenestral diaphragms. These data suggest that vasculature undergoes structural change to decrease vascular permeability in response to systemic LPS administration.

Increased Signal Intensity in the Dentate Nucleus of Patients with Multiple Sclerosis in Comparison with Neuromyelitis Optica Spectrum Disorder after Multiple Doses of Gadolinium Contrast.

AIMS: This study was conducted to compare the effect of linear gadolinium-based contrast agents in the retention in the cerebellar dentate nucleus of patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOsd). METHODS: The signal intensity ratio of the pons to the cerebellar dentate nucleus was measured on T1-weighted MRI scans of the brain in 21 MS patients and 6 NMOsd patients given at least 10 doses of gadolinium. Linear regression analysis of the number of doses was then conducted for each patient. RESULTS: The mean correlation coefficients of the MS and NMOsd patient groups were 0.0029 and -0.0017, respectively, with positive correlations observed in 17 out of 21 patients (81.0%) in the MS group and 2 out of 6 patients (33.3%) in the NMOsd group. Results suggested that significantly high levels of gadolinium accumulate in MS the more doses to the dentate nucleus are increased (p < 0.05). CONCLUSION: Repeated doses of linear gadolinium cause accumulation of gadolinium in the cerebellar dentate nucleus, but differences observed between MS and NMOsd patients suggested that both the structure of gadolinium and differences in disease pathology affect accumulation.

Hedgehog Signaling Modulates the Release of Gliotransmitters from Cultured Cerebellar Astrocytes.

Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family, plays essential roles in the development of the central nervous system. Recent studies suggest that the Hh signaling pathway also functions in mature astrocytes under physiological conditions. We first examined the expression of genes encoding Hh signaling molecules in the adult mouse cerebellum by in situ hybridization histochemistry. mRNA for Patched homolog 1 (Ptch1), a receptor for Hh family members, was expressed in S100ß-positive astrocytes and Shh mRNA was expressed in HuC/D-positive neurons, implying that the Hh signaling pathway contributes to neuro-glial interactions. To test this hypothesis, we next examined the effects of recombinant SHH N-terminal protein (rSHH-N) on the functions of cultured cerebellar astrocytes. rSHH-N up-regulated Hh signal target genes such as Ptch1 and Gli-1, a key transcription factor of the Hh signaling pathway. Although activation of Hh signaling by rSHH-N or purmorphamine influenced neither glutamate uptake nor gliotransmitters release, inhibition of the Hh signaling pathway by cyclopamine, neutralizing antibody against SHH or intracellular Ca(2+) chelation decreased glutamate and ATP release from cultured cerebellar astrocytes. On the other hand, cyclopamine, neutralizing antibody against SHH or Ca(2+) chelator hardly affected D-serine secretion. Various kinase inhibitors attenuated glutamate and ATP release, while only U0126 reduced D-serine secretion from the astrocytes. These results suggested that the Hh signaling pathway sustains the release of glutamate and ATP and participates in neuro-glial interactions in the adult mouse brain. We also propose that signaling pathways distinct from the Hh pathway govern D-serine secretion from adult cerebellar astrocytes.

[Intrapulmonary hematoma masquerading as metastatic carcinoma of lung cancer].

We herein report a case of intrapulmonary hematoma after lobectomy for lung cancer. A 51-year-old male underwent right upper lobectomy for lung cancer in a thoracoscopic procedure. Three months after the operation, chest computed tomography showed a 16-mm well-circumscribed nodule in the right lower lobe suggesting metastatic carcinoma for lung cancer. We performed the partial resection of the right lower lobe. The histological examination confirmed the diagnosis of an intrapulmonary hematoma. When pulmonary shadow appears after lung operations, intrapulmonary hematoma is one of a choice of differential diagnosis. Magnetic resonance imaging may be useful in establishing the diagnosis when intrapulmonary hematoma is suspicious clinically.

Safe stapling technique for pulmonary vessels with the shortened introducers and curved tips in thoracoscopic surgery.

Endo GIA(™) curved tips with Tri-Stapler(™) is more useful for the approach for pulmonary vessels than conventional straight staplers. Unless adequate space is maintained below the vessels, there is a risk of causing damage to the back of vessels with the curved tip without optional introducers. The recommended method involves passing silk thread through the back of the pulmonary vessels and ligating the thread to the introducer. However, the long introducer often applies tension to pulmonary vessels and can be caught in the tissues surrounding vessels. Therefore, we devised a new method. First, the introducer is shortened to a length of approximately 3 cm and attached to a curved tip. Second, a Penrose drain is passed through the back of the vessels. Last, the introducer is inserted into the drain and the stapler is guided. The vessels can be cut without removing the introducers and Penrose drains from staplers.

[Malignant peripheral nerve sheath tumor causing hemothorax; report of a case].

We herein report a case of malignant peripheral nerve sheath tumor that caused a hemothorax. A 39-year-old male was found to have an abnormal shadow on a chest X-ray. Chest computed tomography showed a 60-mm tumor in the right posterior mediastinum. Fourteen months earlier, he underwent drainage of a hemothorax with a medaistinal tumor but refused to undergo further examinations. We performed a tumor resection combined with the right lower lobectomy and the partial resection of the pericardium because of invasion. The histological examination confirmed the diagnosis of a malignant peripheral nerve sheath tumor. Postoperative radiotherapy was performed. The patient has been well without recurrence for 9 months.

[Pulmonary mucosal associated lymphoid tissue( MALT) lymphoma with 7-year natural history; computed tomography( CT) scan findings and pathological correlations].

A 58-year-old man was found to have an abnormal shadow on chest computed tomography (CT). The size and density of the nodule increased gradually over 7 years. Partial lung resection was performed by a thoracoscopic procedure. The pathological examination and gene analysis revealed that the tumor was primary pulmonary B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). The CT findings showed that the level of substantial shadow with air bronchograms gradually increased in the center of the mass shadow, while a radial filamentous and ground glass shadow increased in the periphery. The pathological findings showed a cellular lymphocytic infiltrate that had expanded without destroying the existing blood vessels and bronchi in the center area of the tumor, while had expanded in the interstitial area along with vessel bundles in the border area. The CT findings were consistent with the pathological findings.

A thymic cyst in the middle mediastinum: report of a case.

BACKGROUND: Thymic cysts are usually located in the neck or anterior mediastinal compartment. Thymic cysts arising in the middle mediastinum are extremely rare, with only 2 previously reported cases. We herein describe the third case of a thymic cyst in the middle mediastinum. CASE: A 41-year-old female was referred to our department because of an incidental mediastinal mass detected on chest X-ray. Computed tomography showed a well-defined 7 cm mass located in the retroinnominate vein area. Magnetic resonance imaging showed a cystic lesion without any soft tissue density in the circumference. The border of the tumor was clear, without any invasion and continuity with the surrounding tissue. We performed thoracoscopic surgery. After aspiration of the serous contents in an end-pouch, the tumor was removed from the thoracic cavity. A pathological examination showed a fibrotic cyst wall containing the thymic cyst, which diagnosed it as thymic cyst. CONCLUSION: Thymic cysts in the middle mediastinum are extremely rare. A surgical resection provided the histological diagnosis of a thymic cyst in the present case.

[Hyperbaric oxygen therapy for air embolism complicating computed tomography (CT)-guided needle marking of the lung].

Preoperative computed tomography( CT)-guided marking with a short hook wire for small sized lung tumors has become popular along with the spread of thoracoscopic surgery. Systemic arterial air embolism is a very rare but potentially fatal complication. The patient was a 79-year-old man who was found to have a mixed ground glass opacity shadow on chest CT. Almost immediately after marking, he lost consciousness and complete atrio-ventricular (AV) block was found on the electrocardiogram (ECG) monitor. Brain CT showed intravascular air bubbles in the right frontal lobe. Two hours later, his conscious level was recovered completely but remained left hemiplegia. Five hours later, he was transported to another hospital for hyperbaric oxygen therapy. After 3 episodes of the treatment, left hemiplegia recovered with slight sense disorder in the left little finger. When neurologic findings are remained after air embolism, hyperbaric oxygen therapy should be arranged immediately.

A case of sclerosing hemangioma forming a pedunculated mass.

We report our experience with an unusual case of sclerosing hemangioma (SH) that formed a pedunculated mass protruding into the thoracic cavity. A pulmonary tumor was found in a 60-year-old female during the medical examination. Computed tomography showed a 19 × 17-mm nodule with a clear border and smooth margin contiguous with the diaphragm in the right S8 segment. Uneven enhancement following contrast medium administration was observed. We performed a 3-port thoracoscopic wedge resection of the right lower lobe. We observed a yellow pedunculated tumor protruding from the diaphragmatic surface of the right lower lobe. The surface of the tumor was smooth and encapsulated. Microscopically, we diagnosed it as a SH. SHs usually exist adjacent to the visceral pleura, but rarely form pedunculated tumors protruding into the cavity as seen in this case. By thoracoscopic surgery, we successfully diagnosed and treated the patient in a minimally invasive manner. Since there have been reported cases of recurrence, we anticipate that periodic follow-up observations will be required.