Diagnostic performance of deep-learning-based virtual chromoendoscopy in gastric neoplasms.

BACKGROUNDS: Cycle-consistent generative adversarial network (CycleGAN) is a deep neural network model that performs image-to-image translations. We generated virtual indigo carmine (IC) chromoendoscopy images of gastric neoplasms using CycleGAN and compared their diagnostic performance with that of white light endoscopy (WLE). METHODS: WLE and IC images of 176 patients with gastric neoplasms who underwent endoscopic resection were obtained. We used 1,633 images (911 WLE and 722 IC) of 146 cases in the training dataset to develop virtual IC images using CycleGAN. The remaining 30 WLE images were translated into 30 virtual IC images using the trained CycleGAN and used for validation. The lesion borders were evaluated by 118 endoscopists from 22 institutions using the 60 paired virtual IC and WLE images. The lesion area concordance rate and successful whole-lesion diagnosis were compared. RESULTS: The lesion area concordance rate based on the pathological diagnosis in virtual IC was lower than in WLE (44.1% vs. 48.5%, p < 0.01). The successful whole-lesion diagnosis was higher in the virtual IC than in WLE images; however, the difference was insignificant (28.2% vs. 26.4%, p = 0.11). Conversely, subgroup analyses revealed a significantly higher diagnosis in virtual IC than in WLE for depressed morphology (41.9% vs. 36.9%, p = 0.02), differentiated histology (27.6% vs. 24.8%, p = 0.02), smaller lesion size (42.3% vs. 38.3%, p = 0.01), and assessed by expert endoscopists (27.3% vs. 23.6%, p = 0.03). CONCLUSIONS: The diagnostic ability of virtual IC was higher for some lesions, but not completely superior to that of WLE. Adjustments are required to improve the imaging system's performance.

Three weeks of exercise therapy altered brain functional connectivity in fibromyalgia inpatients.

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain. Therefore, we investigated functional connectivity changes and their relationship with clinical improvement in patients with FM after exercise therapy to investigate the underlying mechanisms in the brain using resting-state fMRI (rs-fMRI) and functional connectivity (FC) analysis. Methods: Seventeen patients with FM participated in this study. They underwent a 3-week exercise therapy on in-patient basis and a 5-min rs-fMRI scan before and after the exercise therapy. We compared the FC strength of sensorimotor regions and the mesocortico-limbic system between two scans. We also performed a multiple regression analysis to examine the relationship between pre-post differences in FC strength and improvement of patients' clinical symptoms or motor abilities. Results: Patients with FM showed significant improvement in clinical symptoms and motor abilities. They also showed a significant pre-post difference in FC of the anterior cingulate cortex and a significant correlation between pre-post FC changes and improvement of clinical symptoms and motor abilities. Although sensorimotor regions tended to be related to the improvement of general disease severity and depression, brain regions belonging to the mesocortico-limbic system tended to be related to the improvement of motor abilities. Conclusion: Our 3-week exercise therapy could ameliorate clinical symptoms and motor abilities of patients with FM, and lead to FC changes in sensorimotor regions and brain regions belonging to the mesocortico-limbic system. Furthermore, these changes were related to improvement of clinical symptoms and motor abilities. Our findings suggest that, as predicted by previous animal studies, spontaneous brain activities modified by exercise therapy, including the mesocortico-limbic system, improve clinical symptoms in patients with FM.

ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation.

Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations.

Induction of glioblastoma cell ferroptosis using combined treatment with chloramphenicol and 2-deoxy-D-glucose.

Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-D-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.

Intratracheally injected human-induced pluripotent stem cell-derived pneumocytes and endothelial cells engraft in the distal lung and ameliorate emphysema in a rat model.

OBJECTIVES: Pulmonary emphysema is characterized by the destruction of alveolar units and reduced gas exchange capacity. In the present study, we aimed to deliver induced pluripotent stem cell-derived endothelial cells and pneumocytes to repair and regenerate distal lung tissue in an elastase-induced emphysema model. METHODS: We induced emphysema in athymic rats via intratracheal injection of elastase as previously reported. At 21 and 35 days after elastase treatment, we suspended 80 million induced pluripotent stem cell-derived endothelial cells and 20 million induced pluripotent stem cell-derived pneumocytes in hydrogel and injected the mixture intratracheally. On day 49 after elastase treatment, we performed imaging, functional analysis, and collected lungs for histology. RESULTS: Using immunofluorescence detection of human-specific human leukocyte antigen 1, human-specific CD31, and anti--green fluorescent protein for the reporter labeled pneumocytes, we found that transplanted cells engrafted in 14.69% ± 0.95% of the host alveoli and fully integrated to form vascularized alveoli together with host cells. Transmission electron microscopy confirmed the incorporation of the transplanted human cells and the formation of a blood-air barrier. Human endothelial cells formed perfused vasculature. Computed tomography scans revealed improved vascular density and decelerated emphysema progression in cell-treated lungs. Proliferation of both human and rat cell was higher in cell-treated versus nontreated controls. Cell treatment reduced alveolar enlargement, improved dynamic compliance and residual volume, and improved diffusion capacity. CONCLUSIONS: Our findings suggest that human induced pluripotent stem cell-derived distal lung cells can engraft in emphysematous lungs and participate in the formation of functional distal lung units to ameliorate the progression of emphysema.

Neuroport® makes brain biopsy less invasive and easy even in eloquent areas.

Tissue diagnosis of brain tumours in eloquent is often done via needle biopsy but this method yields small samples that may not be representative of the whole tumour. The Neuroport® system enables a larger tumour biopsy to be taken via a burr hole. We report our experience on 5 cases October 2017 and June 2018. Brainlab® navigation was used. The diagnosis in all patients was made without worsening of their modified Rankin scale scores.

Mitochondrial dysfunction and impaired growth of glioblastoma cell lines caused by antimicrobial agents inducing ferroptosis under glucose starvation.

Glioblastoma is a difficult-to-cure disease owing to its malignancy. Under normal circumstances, cancer is dependent on the glycolytic system for growth, and mitochondrial oxidative phosphorylation (OXPHOS) is not well utilized. Here, we investigated the efficacy of mitochondria-targeted glioblastoma therapy in cell lines including U87MG, LN229, U373, T98G, and two patient-derived stem-like cells. When glioblastoma cells were exposed to a glucose-starved condition (100 mg/l), they rely on mitochondrial OXPHOS for growth, and mitochondrial translation product production is enhanced. Under these circumstances, drugs that inhibit mitochondrial translation, called antimicrobial agents, can cause mitochondrial dysfunction and thus can serve as a therapeutic option for glioblastoma. Antimicrobial agents activated the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 pathway, resulting in increased expression of heme oxygenase-1. Accumulation of lipid peroxides resulted from the accumulation of divalent iron, and cell death occurred via ferroptosis. In conclusion, mitochondrial OXPHOS is upregulated in glioblastoma upon glucose starvation. Under this condition, antimicrobial agents cause cell death via ferroptosis. The findings hold promise for the treatment of glioblastoma.

Effects of Acupuncture Therapy on Drug-Resistant Fibromyalgia: An Exploratory Single-Arm Nonrandomized Trial.

Introduction: Fibromyalgia is a chronic illness that causes symptoms such as pain. In Japan, although pregabalin and duloxetine are the drugs of choice for fibromyalgia, they may be ineffective or may cause side-effects. Studies have reported on the efficacy of acupuncture against fibromyalgia. However, acupuncture is not always effective in clinical practice, and the reason for this is thought to be the dysfunction of the descending pain control system. This study aimed to determine whether the combined use of electro-scalp acupuncture and conventional electroacupuncture reduces fibromyalgia symptoms and drug dosage requirements. Methods: Patients with intractable fibromyalgia (visual analog scale [VAS] score ≥50 mm; Japanese version of the Fibromyalgia Impact Questionnaire [JFIQ] score ≥50) receiving pregabalin were recruited in this single-arm nonrandomized uncontrolled study. They underwent electroacupuncture on four limbs plus electro-scalp acupuncture once a week for 5 weeks. Drug intake, pain (as determined using VAS), quality of life (QOL; as determined using JFIQ), anxiety, depression, catastrophic thoughts, and sleep were assessed. Results: Although there was no increase in drug intake, 42.8% (3/7) of patients reduced pregabalin intake by approximately 10% (a moderate though insignificant effect). Pain levels significantly declined (VAS 75.4 ± 11.7 mm to 64.3 ± 17.3 mm; P = 0.05) and QOL significantly improved (JFIQ 67.0 ± 13.4 to 50.9 ± 18.3; P = 0.02). The parameters for anxiety, depression, catastrophic thoughts, and sleep did not significantly change. Conclusion: The combination of conventional electroacupuncture plus electro-scalp acupuncture may effectively alleviate pain, improve QOL, and reduce pregabalin dosage requirements in patients with fibromyalgia.

Multiple Thrombectomies for Cerebral and Coronary Artery Occlusion in Trousseau Syndrome.

Objective: Trousseau syndrome (TS) is a condition of systemic thrombosis generally associated with an underlying malignancy. An ischemic stroke is a representative thrombotic event. Thrombectomy is a useful procedure for the treatment of cerebral large vessel occlusion, and anticoagulation therapy is the main preventive treatment for TS. This case report describes a woman with terminal pancreatic tumor presenting with repeated occlusions of cerebral and coronary arteries necessitating multiple thrombectomies. Case Presentation: A 67-year-old woman was admitted to our hospital with severe right hemiplegia and global aphasia. MRI revealed left M1 occlusion; therefore, a thrombectomy was performed. Her symptoms recovered completely. Body contrast CT revealed pancreatic cancer with multiple metastases, and she was diagnosed with TS. On day 4 after thrombectomy, the same neurological symptoms occurred and re-occlusion of the left M1 was confirmed. Endothelial injury was suspected, and thrombectomy was repeated. Despite continuing anticoagulation therapy, the coronary artery was occluded and she underwent percutaneous coronary intervention on day 13. To treat the primary pancreatic lesion, she was transferred to the Surgery unit on day 20. Conclusion: Hypercoagulability associated with TS and endothelial damage due to rough procedure resulted in repeated vessel occlusions in this case. Careful thrombectomy and anticoagulation therapy with strict monitoring are needed in TS patients.

Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro.

Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.

ERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes.

One of the earliest maturation steps in cardiomyocytes (CMs) is the sarcomere protein isoform switch between TNNI1 and TNNI3 (fetal and neonatal/adult troponin I). Here, we generate human induced pluripotent stem cells (hiPSCs) carrying a TNNI1EmGFP and TNNI3mCherry double reporter to monitor and isolate mature sub-populations during cardiac differentiation. Extensive drug screening identifies two compounds, an estrogen-related receptor gamma (ERRγ) agonist and an S-phase kinase-associated protein 2 inhibitor, that enhances cardiac maturation and a significant change to TNNI3 expression. Expression, morphological, functional, and molecular analyses indicate that hiPSC-CMs treated with the ERRγ agonist show a larger cell size, longer sarcomere length, the presence of transverse tubules, and enhanced metabolic function and contractile and electrical properties. Here, we show that ERRγ-treated hiPSC-CMs have a mature cellular property consistent with neonatal CMs and are useful for disease modeling and regenerative medicine.

Weather sensitivity associated with quality of life in patients with fibromyalgia.

BACKGROUND: Fibromyalgia is characterized by chronic widespread pain, and more than half of patients with fibromyalgia report that weather-related variables aggravate their symptoms. However, the differences in actual symptoms have not been measured between those with and without weather sensitivity. The present study aimed to investigate whether weather sensitivity associated with the minimal clinically important difference values of quality of life in patients with fibromyalgia, between those with and without weather sensitivity. METHODS: Sixty-four consecutive outpatients with fibromyalgia on their first visit to our tertiary center were included. Weather sensitivity was measured using self-perceived symptoms. Pain intensity was measured using the 0-10 Numerical Rating Scale (NRS). Quality of life was measured using the Euro Quality of life-5 Dimensions-3 level (EQ-5D-3L) scale. The variables were subjected to univariable and multivariable analysis using the EQ-5D-3L scale. RESULTS: The mean age of the patients was 50 years. Forty-eight patients (75%) were women. The mean EQ-5D-3L score was 0.55. Thirty-seven patients (58%) reported weather sensitivity. In univariable analysis, the welfare recipient, weather sensitivity, and NRS values were associated with EQ-5D-3L scale scores. In multivariable analysis, NRS value and weather sensitivity were independently associated with EQ-5D-3L scale scores. The NRS and EQ-5D-3L scale scores were significantly worse in those with weather sensitivity than those without weather sensitivity. The difference in NRS values was less than 1.5 points between groups. The differences in EQ-5D-3L scale scores were 0.16 points between groups. CONCLUSIONS: Weather sensitivity was significantly associated with quality of life in patients with fibromyalgia. There was an association with weather sensitivity and the minimal clinically important difference values of quality of life in patients with fibromyalgia. The presence of weather sensitivity could have a key role in the quality of life in patients with fibromyalgia.

A Multicenter, Prospective, Randomized, Placebo-Controlled, Double-Blind Study of a Novel Pain Management Device, AT-02, in Patients with Fibromyalgia.

OBJECTIVES: Existing treatments for fibromyalgia have limited efficacy, and only a minority of individuals clinically respond to any single intervention. This study was a prospective, multicenter, randomized, double-blind, controlled clinical trial to evaluate the feasibility of alternating magnetic field therapy in fibromyalgia patients by comparing the Angel Touch device (AT-02) with a sham control (S-01). METHODS: Two sites enrolled 44 subjects with diagnosed fibromyalgia. After informed consent, subjects taking prohibited concomitant drugs underwent a washout period of two or more weeks. All subjects then began a one-week run-in period. Numerical rating scale (NRS) pain scores were collected without device intervention for one day, followed by S-01 application to four or more painful sites for 10 minutes at each site, twice daily for six days. Subjects were then randomized to AT-02 or S-01, applied to four or more painful sites for 10 minutes at each site, twice daily for eight weeks. NRS scores were obtained twice daily during the entire treatment period. RESULTS: The primary end point (change in NRS ± SD at week 8 vs baseline) was -0.94 ± 1.33 in the AT-02 group and -0.22 ± 1.38 in the S-01 group. A trend toward a between-group difference in eight-week NRS scores favored the AT-02 group (-0.73, 95% confidence interval = -1.56 to 0.11, P = 0.086). An adjusted repeated measure analysis detected a significant difference in NRS scores (P = 0.039). CONCLUSIONS: The reduction in NRS scores for AT-02 relative to sham was comparable to reductions observed in meta-analyses of fibromyalgia drug therapy. The unadjusted results and the persistence of the pain score reductions remain encouraging.

Cutoff Value for Short Form of Central Sensitization Inventory.

OBJECTIVES: This study aimed to determine the optimal cutoff score of the 9-item short version of the CSI, the CSI-9, by comparing patients with central sensitivity syndrome (CSS) not only to healthy volunteers as with the original version, but also to patients with musculoskeletal (MSK) disorders. METHODS: All participants filled out the CSI, EuroQol 5-dimension, Brief Pain Inventory, and Pain Catastrophizing Scale questionnaires. To identify a clinically relevant cutoff score, receiver operating characteristic analyses were conducted. The area under the curve was used to examine the ability of the CSI-9 to distinguish patients with fibromyalgia (FM) from patients with MSK disorders and healthy individuals. RESULTS: Twenty-six participants with FM, 30 patients with MSK disorders, and 28 healthy individuals were included. We determined 2 cutoff scores: 20 for distinguishing patients with FM from patients with MSK disorders and 17 for distinguishing patients with FM from healthy individuals. These cutoff scores had good sensitivity (patients with MSK disorders, 92.3%; healthy individuals, 96.2%) and specificity (patients with MSK disorders, 93.3%; healthy individuals, 100%). In addition, the patients who scored above the cutoff of 20 points exhibited worse clinical symptoms (higher pain intensity, higher pain interference, higher Pain Catastrophizing Scale scores, and lower EuroQol 5-dimension scores) than those who scored below it. Furthermore, a significantly higher number of subjects who scored more than 20 on the CSI-9 had a history of 2 or more diagnoses of CSS. CONCLUSION: The optimal CSI-9 cutoff score of 20 is beneficial to clinicians in the evaluation of central sensitization-related symptoms. The cutoff score helps to identify patients who need additional treatments, such as pain neuroscience education and cognitive behavioral therapy.

Rapid growth of metastatic brain tumor from gastric undifferentiated pleomorphic sarcoma: A case report.

BACKGROUND: Brain metastasis from undifferentiated pleomorphic sarcoma (UPS) is a rare occurrence, and its clinical course is little known. In this report, we investigate a case of a rapidly growing brain metastasis from gastric UPS. CASE DESCRIPTION: An 82-year-old man with a known gastric tumor, pathologically compatible with UPS, underwent partial gastrectomy at an outside facility. 3 months later, a 4-cm brain tumor was detected, which was completely resected. The patient was diagnosed with metastatic tumor from previously treated gastric UPS. Within 2 months of the initial resection, a large recurrent mass was detected in the same location, which was again removed. Although the patient underwent radiotherapy and chemotherapy for other metastatic tumors, he died 5 months after the second craniotomy. CONCLUSIONS: Brain metastasis from gastric UPS is rare and difficult to treat. Although aggressive treatment, such as surgical intervention, may improve patient survival in some cases, the timing of treatment is challenging because cerebral metastasis rapidly grows and and patients frequently suffer from synchronous systematic metastasis. Therefore, early detection and close follow-up of rapidly progressing brain metastasis are important to improve treatment outcomes.

Psychological Treatment Strategy for Chronic Low Back Pain.

Studies have indicated that chronic low back pain (LBP) should be approached according to its morphological basis and in consideration of biopsychosocial interventions. This study presents an updated review on available psychological assessments and interventions for patients with chronic LBP. Psychosocial factors, including fear-avoidance behavior, low mood/withdrawal, expectation of passive treatment, and negative pain beliefs, are known as risk factors for the development of chronic LBP. The Örebro Musculoskeletal Pain Questionnaire, STarT Back Screening Tool, and Brief Scale for Psychiatric Problems in Orthopaedic Patients have been used as screening tools to assess the development of chronicity or identify possible psychiatric problems. The Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire, and Injustice Experience Questionnaire are also widely used to assess psychosocial factors in patients with chronic pain. With regard to interventions, the placebo effect can be enhanced by preferable patient-clinician relationship. Reassurance to patients with non-specific pain is advised by many guidelines. Cognitive behavioral therapy focuses on restructuring the negative cognition of the patient into realistic appraisal. Mindfulness may help improve pain acceptance. Self-management strategies with appropriate goal setting and pacing theory have proved to improve long-term pain-related outcomes in patients with chronic pain.

How to Remove a Penetrating Intracranial Large Nail.

BACKGROUND: The incidence of penetrating intracranial foreign bodies is rare, and to date, not many relevant studies have been published worldwide. In particular, a nail penetrating intracranially, just near the superior sagittal sinus (SSS), is extremely rare. We treated the case of a large nail that penetrated the middle of the head and strategized its removal. CASE DESCRIPTION: A 70-year-old man had experienced headache lasting a day. Computed tomography of the brain revealed a nail penetrating the middle of his head; in particular, the tip of the nail had penetrated the right ventricle, causing a slight subarachnoid hemorrhage. Angiography showed that the nail was very close to the SSS and that the venous flow was normal. However, there was a risk of the nail penetrating through the SSS or injuring other arteries, and we removed the nail directly from the intracranial view to stop bleeding from the SSS or other vessels. Fortunately, there was no bleeding, and we washed the hole created by the nail penetration and concluded the surgery. CONCLUSIONS: Our technique is useful and safe for removing large nails penetrating the head.

Methioninase Gene Therapy.

Recombinant methioninase (rMETase) derived from Pseudomonas putida targets the elevated methionine (MET) requirement of cancer cells (methionine dependence) and has shown efficacy against a variety of cancer types in mouse models. To enhance the efficacy of rMETase, we constructed the pLGFP-METSN retrovirus encoding the P. putida methioninase (METase) gene fused with the green fluorescent protein (GFP) gene. pLGFP-METSN or control vector pLGFPSN was introduced into the human lung cancer cell line H460. The retrovirus-mediated METase gene transfer decreased the intracellular MET level of the cancer cells and consequently enhanced the efficacy of treatment with the rMETase protein. The rMETase gene was introduced into an adenovirus. rAd-METase transduction of human OVACAR-8 ovarian cancer cells and human fibrosarcoma HT1080 cells in vitro and in vivo resulted in high levels of METase expression up to 10% or more of the total protein of the cells, depending on the multiplicity of infection. The combination of rAd-METase and rMETase was synergistic to kill these cells. Normal fibroblasts, on the other hand, appeared relatively resistant to the METase gene in the presence of rMETase. Adenoviral METase-transduced cancer cells were used in combination with selenomethionine, releasing highly toxic methylselenol, which killed both the cancer cells containing the METase gene and bystanders. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and cancer-cell apoptosis. Adenoviral METase-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. AdMETase/SeMET therapy was effective against Bcl-2-overproducing A549 lung cancer cells, which were resistant to staurosporine-induced apoptosis, with a strong bystander effect. The combination of Ad-METase/SeMET and doxorubicin (DOX) delayed the growth of the H460 human lung cancer, growing subcutaneously in nude mice. These results demonstrate the potential of methionine restriction (MR) for cancer treatment.

[Two Case Reports of Paroxysmal Sympathetic Hyperactivity Following Craniotomy for Cerebral Hemorrhages].

Paroxysmal sympathetic hyperactivity(PSH)is a clinical condition characterized by abnormal paroxysmal surges in sympathetic nervous system activity. PSH is well known to happen after severe head injury and hypoxic encephalopathy. There are reports of cases of PSH developing after stroke, but PSH is not well recognized in the stroke field in Japan. Case 1 is a 79-year-old woman who became unconscious and suffered a large left mixed-type hemorrhage. Emergency craniotomy was performed. Two months postoperatively, she developed a high fever, tachycardia, tachypnea, and decerebrate posture. After taking clonazepam, her symptoms improved, and she was transferred to another hospital. Case 2 is a 67-year-old man with right hemiplegia, a history of thrombectomy for left M1, occlusion and left carotid artery stenting for asymptomatic left severe carotid artery stenosis performed one year previously. Five hours after right corotid artery stenting, he became restless and hemiplegic on his left side. His computed tomography showed extensive cerebral hemorrhage in the right hemisphere necessitating emergency craniotomy. About a month after surgery, he had a high fever, tachypnea, tachycardia, and decerebrate posture. Taking gabapentin improved his symptoms. Prolonged PSH may be a factor greatly impairing activities of daily living in stroke patients. It is important to diagnose and treat PSH early.