Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation.

Ferroptosis is a form of regulated non-apoptotic cell death that has been implicated in several disease contexts. A better understanding of the ferroptotic death mechanism could lead to the development of new therapeutics for degenerative diseases, and a better understanding of how to induce ferroptosis in specific tumor contexts. We performed an unbiased genome-wide siRNA screen to find genetic suppressors of ferroptosis. We determined that loss of CARS, the cysteinyl-tRNA synthetase, suppresses ferroptosis induced by erastin, which inhibits the cystine-glutamate antiporter known as system xc(-). Knockdown of CARS inhibited erastin-induced death by preventing the induction of lipid reactive oxygen species, without altering iron homeostasis. Knockdown of CARS led to the accumulation of cystathionine, a metabolite on the transsulfuration pathway, and upregulated genes associated with serine biosynthesis and transsulfuration. In addition, inhibition of the transsulfuration pathway resensitized cells to erastin, even after CARS knockdown. These studies demonstrate a new mechanism of resistance to ferroptosis and may lead to strategies for inducing and suppressing ferroptosis in diverse contexts.

Cerebellar hemangioendothelioma.

We report a 26-year-old woman with cellular hemangioendothelioma that may be the third case diagnosed as cerebellar hemangioendothelioma. The tumor was composed of numerous vascular channels lined by endothelial cells and aggregates of large round endothelial cells. Transitional cells were also present. The large round cells were positive for CD34 and vimentin in their abundant cytoplasm that contained 1 or some red blood cells, revealing intracytoplasmic lumina. The patient remains free of disease over 5 years after tumor resection.

Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF.

We investigated gene expression profiles of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in differentiated and non-differentiated retinal pigment epithelial (RPE) cells during oxidative stress. Human RPE cells were grown in culture on laminin-coated flasks to obtain differentiated features. Cells cultured on plastic were used as non-differentiated controls. After confluence, hydrogen peroxide (H2O2) was added for 48 h, then, total RNA was extracted and used for RT-PCR and Northern blot analysis. Medium conditioned by RPE was used for ELISA, Western blotting, and in vitro angiogenesis assay. As a result, differentiated RPE cells expressed significantly higher levels of VEGF protein, as compared to their non-differentiated counterparts. The expression pattern remained consistent even after cellular exposure to H2O2. Conversely, while elevated levels of PEDF transcript and protein were seen in differentiated RPE cells, compared to non-differentiated cells, a marked decrease at both PEDF mRNA and protein levels was seen after treatment with H2O2. Moreover, this decrease in PEDF expression was dosage dependent. In in vitro angiogenesis assay, conditioned medium from differentiated human RPE cells after exposure to H2O2 showed a dramatic increase in tubular formation and migratory activity of microvascular endothelial cells. These data suggest that, in physiological conditions, a critical balance between PEDF and VEGF exists, and PEDF may counteract the angiogenic potential of VEGF. Under oxidative stress, PEDF decreases disrupting this balance. This equilibrium shift may be significant in promoting a pathological condition of RPE cells and contributing to choroidal neovascularization in age-related macular degeneration.

The right ventricular outflow tract as an unusual location for an implantable defibrillator electrode in a patient with arrhythmogenic right ventricular dysplasia.

A 41-year-old woman with arrhythmogenic right ventricular dysplasia (ARVD) underwent the implantation of an implantable cardioverter-defibrillator (ICD), in which the defibrillator electrode was unusually located in the right ventricular (RV) outflow tract. Although fractionated electrograms were demonstrated in the RV apex, which is the usual site for ICD electrodes, normal electrograms were recorded in the RV outflow tract during an electrophysiologic study. An electrode with a screw-in tip was used to fix the implant in the RV outflow tract and obtain successful defibrillation. If normal electrograms are recorded in the RV outflow tract, the site may prove to be an alternative location for an ICD electrode even for ARVD patients.

Chordoid meningioma. A case report.

We report on a 62-year-old woman without Castleman's syndrome diagnosed with chordoid meningioma. A white, encapsulated brain tumor was located in the parietal lobe of the left hemisphere of the cerebrum, adhered to the dura, and was separated from the cerebrum. The tumor revealed a multilobular arrangement of two types of neoplastic cells, and the surrounding myxoid stroma was separated by incomplete fibrous septa. Neoplastic cells consisted of myxomatous and meningothelial cells. The former made up about four-fifths of the tumor, had a vacuolar cytoplasm, and were arranged in a chordoma-like cord pattern. They were floating in myxoid stroma. The latter had an eosinophilic spindle or epithelioid cytoplasm and were disposed in lobules. Coarse eosinophilic materials positive for periodic acid-Schiff stain were deposited among them. Transitional cells between two types of cells were also observed. Both neoplastic cells were positive for vimentin and Leu-7 (CD57) in their cytoplasm, and were consistently negative for epithelial membrane antigen, S-100 protein, and cytokeratin.

Double ventricular response via dual atrioventricular nodal pathways resulting with nonreentrant supraventricular tachycardia and successfully treated with radiofrequency catheter ablation.

We report a patient with a complex nonreentrant supraventricular tachycardia because of double ventricular response resulting from antegrade dual atrioventricular (AV) nodal pathways. We could induce double ventricular response and confirm dual AV nodal pathways by AV simultaneous pacing during basic stimulation proceeding with programmed atrial single extrastimulation. As far as we know, it is the first report about the application of the AV simultaneous basic stimulation to prove the sustained nonreentrant tachycardia because of simultaneous conduction over dual AV nodal pathways. This was also confirmed by absence of the arrhythmia immediately after the elimination of the slow pathway conduction by radiofrequency ablation.

Left ventricular aneurysm without coronary artery disease, incidence and clinical features: clinical analysis of 11 cases.

OBJECTIVE: To examine the incidence, underlying disease and clinical features of left ventricular aneurysm (LVA) not related to coronary artery occlusion. METHODS: Retrospective review of consecutive patients who underwent both left ventriculography and coronary angiography. PATIENTS: LVA was confirmed in 11 of 2,348 consecutive patients (0.47%). RESULTS: The location of LVA was mainly in the apical region (81.8%). In five of the 11 patients (45.5%), the underlying heart disease was hypertrophic cardiomyopathy (HCM), including 4 patients of dilated phase and one patient of midventricular type. The serial ECG changes from left ventricular hypertrophy to abnormal Q wave and endomyocardial biopsy were useful for the differential diagnosis of these cases against myocardial infarction. The underlying disease of the remaining patients was: myocarditis (2 patients), arrhythmogenic right ventricular dysplasia (1 patient), Chagas' disease (1 patient), glycogen storage disease (1 patient), and sarcoidosis (1 patient). Ventricular tachycardia appeared in 9 of 11 cases (81.8%) including 2 patients with sustained ventricular tachycardia. CONCLUSION: LVA formation without coronary artery disease was a rare phenomenon. The underlying disease was varied but the incidence of hypertrophic cardiomyopathy in the dilated phase was comparatively high. Ventricular tachycardia was a significant complication in these patients.

[Endoscopic resection of the thoracic sympathetic trunk for the treatment of frequent syncopal attack of idiopathic long QT syndrome].

A 22 year old man was diagnosed as having Jervell and Lange-Nielsen syndrome (JLNS), which includes a prolonged QTc, congenital neural deafness, and syncopal attacks or sudden death. In spite of medication with beta blocker, syncopal attack increased in frequency since his sister suddenly had died of JLNS. Because left stellate ganglion block improved the QTc dispersion, left cardiac sympathectomy was scheduled under the video-assisted thoracic surgery. After the premedication with midazolam, anesthesia was induced with thiamylal, and maintained with nitrous oxide, sevoflurane, and fentanyl. Serious arrhythmias were not observed throughout the perioperative period. Sympathetic trunk was successfully resected from the top of 1st ganglion to the bottom of 4th ganglion of left thoracic sympathetic trunk. Horner's sign did not appear after the surgery. Although the shortening of QTc was not significant, QTc dispersion during exercise was improved, and syncopal attack was not observed until 6 months after the surgery.

Temporal lobe lesion demonstrating features of dysembryoplastic neuroepithelial tumor and ganglioglioma: a transitional form?

We report an unusual multimodular glioneuronal lesion found in a temporal lobe from a 17-year-old boy with complex partial seizure. Histologically, this lesion was located within the cortex of the middle temporal gyrus and consisted of multinodular foci and the surrounding cortical dysplasia, resembling dysembryoplastic neuroepithelial tumor (DNT). However, it was quite different in the following respects from usual DNT: 1 nodule found in the subpial area consisted entirely of mature atypical neuronal cells separated by a reticulin fiber network connecting to the pia mater and the area around and between the above nodule, whereas another neighboring nodule, which contained many oligodondroglia-like round cells as well as occasional neuronal cells and fibrillary astrocytic cells, showed scattered neuronal cells in the well-differentiated fibrillary astrocytic stroma, the histological features being those of ganglioglioma (GG). We consider that the present case is a good example of the transitional form between DNT and GG. At 25 months following total lesion extirpation, the patient is healthy and free from seizures.

Melanotic cerebral astrocytoma: case report and literature review.

We describe the case of 47-year-old man with a cystic, melanotic temporal lobe astrocytoma who had a history of complex partial seizures. The tumor mass was made up of two histologically different regions: one consisted of spindle-shaped and pleomorphic cells often with foamy or vacuolated cytoplasm, while the other consisted of fairly uniform spindle-shaped cells, many of which contained dark-brown intracytoplasmic pigment. Desmoplasia was also noted in the latter region of the tumor. No features suggestive of malignancy, such as mitotic figures, necrotic foci or endothelial vascular proliferation, were observed throughout the tumor. Immunohistochemically, the tumor cells in both regions were positive for glial fibrillary acidic protein. Ultrastructural examination of the pigmented region showed the presence of melanosomal melanin in the tumor cells. Apart from the partial pigmentation, the entire histological picture resembled a pleomorphic xanthoastrocytoma. To our knowledge, only two cases of similar melanotic astrocytic tumors have been described previously. Interestingly, the astrocytic tumors in both of these patients were also clinically associated with epilepsy, were located in the temporal lobe, and were histologically benign.

[Signal transduction system in cardiac cells].

The electrical excitation and conduction in the heart is due to ionic events via ion channels and gap junctions. Function of these channels and gap junctions is regulated by intracellular milieu, which is regulated by many kinds of receptors through intracellular second messengers i.e.; GTP binding proteins, protein kinases, Ca2+ concentrations, H+ concentration, cyclic nucleotides and triphosphate nucleotides. In this paper, we focus on signal transduction systems in cardiac myocytes. Subsequently, some of interactions between signal transduction systems are introduced.

Dose-response relationship between urinary cadmium concentration and beta2-microglobulinuria using logistic regression analysis.

Logistic regression analysis was used to investigate the dose-response relationship for environmental cadmium exposure and to consider the effect age had on this association. The target population comprised 3178 inhabitants of Japan who were more than 50 y of age and who lived in a cadmium-polluted area and 1134 inhabitants who lived in nonpolluted areas of Japan. Logistic regression analysis was completed on the dose-response relationship between urinary cadmium concentration (i.e., an indicator of cadmium body burden) and beta2-microglobulinuria (i.e., an index of renal tubular dysfunction caused by exposure to cadmium). Both age and urinary cadmium concentration were associated significantly with beta2-microglobulinuria. Based on the relationship that was determined, we calculated, by age and sex, the values of urinary cadmium concentration that corresponded to the prevalence rates of beta2-microglobulinuria in the nonpolluted population. The resulting values were 1.6-3.0 micrograms/g creatinine for men and 2.3-4.6 micrograms/g creatinine for women.

Significance of elevated urinary human intestinal alkaline phosphatase in Japanese people exposed to environmental cadmium.

Urinary human intestinal alkaline phosphatase (IAP), beta 2-microglobulin (beta 2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) were analyzed in 40 Japanese environmental-cadmium (Cd)-exposed and 40 non-exposed subjects to evaluate early biological markers for Cd-induced renal damage. All urinary indicators were significantly higher in the Cd-exposed subjects than non-exposed subjects. A fourth-order function was fitted for the relationship between beta 2-MG and IAP or NAG. The beta 2-MG concentration corresponding to the inflexion point for IAP was smaller than that for NAG. This result may support the contention that the cells containing IAP are damaged earlier than those containing NAG, and that IAP is a useful marker for detecting renal tubular dysfunction in people moderately exposed to Cd. However, in the stage of severe renal damage, the combination of IAP and beta 2-MG is considered to be more useful.

[A case of distal aneurysms of bilateral posterior inferior cerebellar arteries].

A case of aneurysms of bilateral distal posterior inferior cerebellar arteries (PICAs) is reported. A 61-year-old man experienced a sudden onset of headache and nausea and was admitted to a hospital immediately. His neurological examination showed no abnormalities, but headache and nausea continued in spite of conservative treatment. The patient was referred to our hospital two days after the onset and the neurological examination revealed slight dysmetria of the right upper extremity. A computed tomography (CT) scan demonstrated a round and heterogeneous high density mass at the cerebellar vermis and some blood coagula at the fourth ventricle and vermis. Angiography showed two aneurysms of the bilateral distal PICAs: The right aneurysm was at the cortical segment and the left one was at the telovelotonsillar segment. The patient underwent a suboccipital craniectomy and both aneurysms were clipped successfully. Sleepiness and headache continued postoperatively due to hydrocephalus. After ventricular drainage he soon recovered without having V-P shunt and was discharged with no neurological deficits. Aneurysms of bilateral distal PICAs are very rare and only three cases have been reported in the literature. The etiology, clinical symptom, CT finding and prognosis in the literature reviewed were briefly discussed.

The renal handling of calcium and phosphorus in environmental cadmium-exposed subjects with renal dysfunction.

Clearance methods were used to clarify the renal handling of calcium (Ca) and phosphorus (P) in a population with renal dysfunction induced by exposure to environmental cadmium (Cd). Seventy-six Cd-exposed subjects (32 men and 44 women) and 36 non-exposed subjects (18 men and 18 women) took part in this study. Fractional excretion of P was higher in the Cd-exposed subjects than in the non-exposed subjects, while that of Ca was equal to that of the non-exposed subjects. The urinary excretion rates of Ca and P tended to be lower in the Cd-exposed subjects than in the non-exposed subjects. The urinary excretion rate of Ca was closely related to creatinine clearance, while that of P was related to creatinine clearance and the percentage tubular reabsorption of phosphorus. It is thought that in Cd-induced renal dysfunction the urinary excretion of Ca depends on glomerular function, and no increased excretion of urinary Ca was observed by these clearance methods. It is also clarified that the parallelism in the urinary excretion of Ca and Na persists in Cd-exposed subjects with renal dysfunction.

[Clinical studies of 16 cases of carcinomatous pericarditis].

We studied the effects of local therapy on cardiac tamponade caused by carcinomatous pericarditis in 16 cases. Five out of 16 cases (drainage group) received treatment by only drainage of pericardial effusion, and the remaining 11 cases (infusion group) had local infusion of antineoplastic agents into the pericardium after drainage. The median survival time was 16 weeks in the infusion group and 19 weeks in the drainage group. There was no statistically significant difference. Reaccumulation of pericardial effusion was recognized in 3 patients in the drainage group (60%), and in 3 patients in the infusion group (18%). Our conclusion was that local infusion had no effect on prolongation of the survival time, but had a suppressive effect on reaccumulation of pericardial effusion.

[Olfactory neuroblastoma complicated by postirradiation pneumocephalus. Case report].

A 56-year-old male was admitted with the complaints of nasal bleeding, gait disturbance, and disturbance of consciousness. Neurological examination revealed drowsiness, right hemiparesis, and choked discs. Computed tomography scan showed an enhanced mass at the frontal base, which extended to the left nasal and paranasal cavities. Angiography showed a tumor stain with a mass sign. The intracranial part of the tumor was removed completely and he was discharged ambulatorily. Two months after surgery, however, he was admitted again for the regrowth of the tumor. Ventriculoperitoneal shunting was placed and radiation therapy was given to the brain and nasal cavity. After 3000 rad irradiation the clinical condition suddenly became worse because of pneumocephalus. The cranial tumor disappeared after irradiation but he died of metastases and general prostration. Clinically this case was diagnosed as an olfactory groove meningioma at first, but immunohistochemical diagnosis was olfactory neuroblastoma.

Meningioma in the tela choroidea of the third ventricle: CT and angiographic correlations.

A meningioma of the tela choroidea of the third ventricle is rare. CT and detailed analysis of angiographic findings in such a case are presented. Ct facilitated the detection of rough location of the tumor and the prediction of its histological features. Carotid and vertebral angiographies were utilized in detailing the three-dimensional, gross anatomical relationship between tumor and the surrounding brain structures. Vertebral angiography also contributed to predicting the histology of the tumor.