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.

Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis.

OBJECTIVE: To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (NONMEM) in Japanese patients treated with oral therapy. METHOD: Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured. RESULTS: Estimates generated using NONMEM indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0*16 * TBW * 0.53(AGE >or= 65 ) * 0*78(BMI >or= 25) * DD(0.51), V(d) (L) = 10*2 * TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) >or=65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m(2)) >or=25 = 1 for patient was 25 kg/m(2) or over and 0 otherwise and V(d) is apparent volume of distribution. The clearance of AMD decreased significantly by 22.3% with a BMI higher than 25 kg/m(2). The clearance of AMD also decreased significantly by 46.9% when patient age was more than 65 years. CONCLUSION: Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD.

Spleen enlargement and genetic diversity of Plasmodium falciparum infection in two ethnic groups with different malaria susceptibility in Mali, West Africa.

The high resistance to malaria in the nomadic Fulani population needs further understanding. The ability to cope with multiclonal Plasmodium falciparum infections was assessed in a cross-sectional survey in the Fulani and the Dogon, their sympatric ethnic group in Mali. The Fulani had lower parasite prevalence and densities and more prominent spleen enlargement. Spleen rates in children aged 2-9 years were 75% in the Fulani and 44% in the Dogon (P<0.001). There was no difference in number of P. falciparum genotypes, defined by merozoite surface protein 2 polymorphism, with mean values of 2.25 and 2.11 (P=0.503) in the Dogon and Fulani, respectively. Spleen rate increased with parasite prevalence, density and number of co-infecting clones in asymptomatic Dogon. Moreover, splenomegaly was increased in individuals with clinical malaria in the Dogon, odds ratio 3.67 (95% CI 1.65-8.15, P=0.003), but not found in the Fulani, 1.36 (95% CI 0.53-3.48, P=0.633). The more susceptible Dogon population thus appear to respond with pronounced spleen enlargement to asymptomatic multiclonal infections and acute disease whereas the Fulani have generally enlarged spleens already functional for protection. The results emphasize the importance of spleen function in protective immunity to the polymorphic malaria parasite.

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.

The prevalence, incidence and prognostic value of the Brugada-type electrocardiogram: a population-based study of four decades.

OBJECTIVES: We sought to demonstrate the prevalence, incidence and prognostic value of the Brugada-type electrocardiogram (ECG) in a general population. BACKGROUND: The Brugada syndrome is characterized by evidence of right bundle branch block and ST segment elevation in the right precordial leads, as well as sudden death caused by ventricular fibrillation. However, the natural history of the Brugada-type ECG remains unclear. METHODS: We investigated 4,788 subjects (1,956 men and 2,832 women) who were <50 years old in 1958 and had undergone biennial health examinations, including electrocardiography, through 1999. The Brugada-type ECG was defined as a terminal r' wave in lead V(1) and ST segment elevation > or =0.1 mV in leads V(1) and V(2). Unexpected death was defined as sudden death or unexplained accidental death. RESULTS: There were a total of 32 Brugada-type ECG cases; the prevalence and incidence were 146.2 in 100,000 persons and 14.2 persons per 100,000 person-years, respectively. The incidence was nine times higher among men than women, and the average age at presentation was 45 +/- 10.5 years. The Brugada-type ECG appeared intermittently in most cases and was found in 26% of subjects who died unexpectedly. Cox survival analysis revealed that mortality from unexpected death was significantly higher in subjects with a Brugada-type ECG than in control subjects (p < 0.01). Unexpected deaths were more frequent among subjects with the Brugada-type ECG who had a history of syncope (p < 0.05). CONCLUSIONS: The Brugada-type ECG is not a very rare condition in the adult Japanese population. Subjects with a Brugada-type ECG have an increased risk of unexpected death.

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.

Cavernous sinus thrombophlebitis caused by sphenoid sinusitis--report of autopsy case.

A 34-year-old man developed fever, headache, nausea, double vision, exophthalmus, ptosis, disturbance of vision and oculomotor nerve palsy. Magnetic resonance imaging and cerebral angiography led to the clinical diagnoses of cavernous sinus thrombophlebitis and suspicion of bacterial aneurysm of the left internal carotid artery, respectively. Peptostreptococcus was detected in blood culture analysis. He died 15 days after admission. Systemic organs showed several septic changes. In particular, the bilateral cavernous sinuses were enlarged and showed severe neutrophilic leukocyte infiltration of the walls and organization, recanalization and abscesses in thrombi. In anterior to the middle cranial fossa, abscess-forming, necrotic, hemorrhagic meningitis, purulent sphenoid sinusitis, pyogenic osteomyelitis of the sphenoid bone, suppurative encephalitis, and inflammatory necrosis of the hypophysis were seen. Based on these findings, we diagnosed the patient with cavernous sinus thrombophlebitis caused by sphenoid sinusitis.

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.

A 15-year longitudinal follow-up study of heart rate and heart rate variability in healthy elderly persons.

BACKGROUND: Few researchers have conducted heart rate (HR) studies in healthy very elderly subjects aged 70 years or older, and there are no longitudinal follow-up studies in this population. The objective of this study was to evaluate long-term changes in HR and heart rate variability (HRV) with aging in healthy elderly persons by means of comparison between two Holter monitor recordings obtained at an interval of 15 years. METHODS: The study population consisted of 15 healthy elderly persons (10 women and 5 men) aged 64 to 80 years (mean 70 +/- 4.1) at the first recording, and 79 to 95 years old (mean 85 +/- 4.1 years) at the second recording 15 years later. Nighttime (midnight to 5 AM) and daytime (noon to 5 PM) HR and HRV were obtained, and paired t tests were performed to assess the differences in each parameter of nighttime and daytime HR and HRV between the two (15-year interval) Holter monitor recordings. RESULTS: The results of the t-test comparisons were as follows: there was a significant increase in minimal, maximal, and average HRs (nighttime, p < .01; daytime, p < .05, respectively). On the other hand, with regard to HRV, there was a significant nighttime decrease in the SDNN index (mean of standard deviations of normal RR intervals between adjacent QRS complexes resulting from sinus node depolarizations for all 5-minute segments) (p = .0086), and a significant daytime increase in the NN50 (number of adjacent normal RR intervals >50 milliseconds) per hour (p = .0425). Moreover, there was a significant decrease in the low-frequency (LF) component (nighttime, p = .0151; daytime, p = .0032), and a significant decrease in the LF/HF ratio (nighttime, p = .0270; daytime, p = .0371), but there was no significant change in the nighttime or daytime high-frequency (HF) component. CONCLUSIONS: HR increased with age over the 15-year period in the healthy elderly persons. As for concurrent changes in HRV, however, the parameters of sympathetic modulation decreased, and the parameters of parasympathetic modulation were unchanged or slightly increased.

Expression of chemokine receptors on CD4+ T cells in peripheral blood from HIV-infected individuals in Uganda.

CXCR4, a coreceptor for T cell (T)-tropic HIV-1, is preferentially expressed on naive T cells, whereas CCR5, a coreceptor for macrophage (M)-tropic HIV-1, is preferentially expressed on previously activated memory T cells and the Th1 subset of CD4+ T cells. CCR4 is preferentially expressed on the Th2 subset of CD4+ T cells. A cross-sectional flow cytometry study was conducted to evaluate the expression of CXCR4, CCR5, and CCR4 on the peripheral blood CD4+ T cells from African HIV-1-infected and uninfected Ugandan adults. The plasma viral load in HIV-1-infected individuals was also examined. Upregulation of CCR4 and CCR5 expression but no decrease in CXCR4 expression on CD4+ T cells were obtained in peripheral blood from African adults with progression of the disease. Plasma HIV-1 viremia significantly and inversely correlated with the peripheral CD4+ T cell count but did not correlate with the degree of CCR4 and CCR5 expression on the peripheral CD4+ T cells in HIV-1-infected individuals. Our present data suggest an increase in percentage of activated memory CD4+ T cells in the advanced stage of HIV-1 infection among African adults. There was no evidence of a Th1 to Th2 shift in terms of chemokine receptor expression profile with advancing disease in the peripheral blood of these subjects.

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.

Radiofrequency catheter ablation of a concealed atrioventricular accessory pathway associated with a coronary sinus diverticulum.

A 31-year-old woman underwent radiofrequency catheter ablation of a concealed left posteroseptal accessory pathway associated with a coronary sinus diverticulum. The patient had previously undergone unsuccessful catheter ablation of the posteroseptal region of the mitral annulus. Coronary sinus venography revealed the presence of the diverticulum near the ostium. An electrogram in the neck of the diverticulum showed the shortest ventriculoatrial conduction time and a large accessory pathway potential during atrioventricular reciprocating tachycardia. The pathway was successfully ablated within the neck of the diverticulum. The findings in this case underscore the importance of coronary sinus venography before ablation.

Spontaneous involution of a large retinal arterial macroaneurysm.

BACKGROUND: Acquired retinal macroaneurysms are round dilatations of retinal arterioles that occur in the posterior fundus. They tend to rupture before they grow large and cause a visual decrease. The average diameter of macroaneurysms in the previous reports is 281 micrometer. METHODS: A 63-year-old man complained of a sudden decrease of visual acuity in the left eye. Fundus examination of his left eye revealed a large protruded mass, 2 disc diameters in size, at the first bifurcation of the inferotemporal retinal artery. Preretinal vitreous bleeding and serous retinal detachment were observed around the lesion. Indocyanine green (ICG) angiography showed this mass to be continuous with the inferotemporal retinal artery and ICG dye leaked from the retinal artery into the lumen of the mass, with pulsation. RESULTS: Six months later, the large macroaneurysm underwent spontaneous involution. CONCLUSION: As shown in this patient, retinal macroaneurysms may grow extremely large. ICG angiography was useful to diagnose this large retinal arterial macroaneurysm.

Preserving normal ventricular activation versus atrioventricular delay optimization during pacing: the role of intrinsic atrioventricular conduction and pacing rate.

The purpose of the study was to compare the effects of DDD pacing with optimal AV delay and AAI pacing on the systolic and diastolic performance at rest in patients with prolonged intrinsic AV conduction (first-degree AV block). We studied 17 patients (8 men, aged 69 +/- 9 years) with dual chamber pacemakers implanted for sick sinus syndrome in 15 patients and paroxysmal high degree AV block in 2 patients. Aortic flow and mitral flow were evaluated using Doppler echocardiography. Study protocol included the determination of the optimal AV delay in the DDD mode and comparison between AAI and DDD with optimal AV delay for pacing rate 70/min and 90/min. Stimulus-R interval during AAI (ARI) was 282 +/- 68 ms for rate 70/min and 330 +/- 98 ms for rate 90/min (P < 0.01). The optimal AV delay was 159 +/- 22 ms. AV delay optimization resulted in an increase of an aortic flow time velocity integral (AFTVI) of 16% +/- 9%. At rate 70/min the patients with ARI < or = 270 ms had higher AFTVI in AAI than in DDD (0.214 +/- 0.05 m vs 0.196 +/- 0.05 m, P < 0.01), while the patients with ARI > 270 ms demonstrated greater AFTVI under DDD compared to AAI (0.192 +/- 0.03 m vs 0.166 +/- 0.02 m, P < 0.01). At rate 90/min AFTVI was higher during DDD than AAI (0.183 +/- 0.03 m vs 0.162 +/- 0.03 m, P < 0.01). Mitral flow time velocity integral (MFTVI) at rate 70/min was higher in DDD than in AAI (0.189 +/- 0.05 m vs 0.173 +/- 0.05 m, P < 0.01), while at rate 90/min the difference was not significant in favor of DDD (0.149 +/- 0.05 m vs 0.158 +/- 0.04 m). The results suggest that in patients with first-degree AV block the relative impact of DDD and AAI pacing modes on the systolic performance depends on the intrinsic AV conduction time and on pacing rate.

[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.

Clinical analysis of hypertrophic cardiomyopathy which evolved into dilated phase during long-term follow-up.

The aim of the present study was to analyze the incidence, clinical features and prognosis of patients with hypertrophic cardiomyopathy (HCM) which evolved into dilated phase HCM. The medical records of 43 patients with HCM followed up for at least 10 years were analyzed retrospectively. The patients were divided into two groups: group A consisting of patients with dilated-phase HCM defined by a left ventricular end diastolic dimension (LVDD) of 55 mm or more and a left ventricular ejection fraction (LVEF) of less than 50% obtained by echocardiography, and group B, consisting of patients with HCM that did not evolve into dilated phase HCM. During the mean follow-up of 16.7 years, 10 patients (23.3%) evolved into dilated phase HCM (group A) while the remaining 33 patients (76.7%) did not (group B). Ventricular tachycardia (VT) occurred in 7 of the 10 patients (70.0%) in group A and in 5 of the 33 patients (15.2%) in group B (p < 0.001). An increase in LVDD and decreases in LVEF and SV1 + RV5 in the electrocardiogram were observed during the early phase of the follow-up period in group A, while these changes were gradual in group B. Cardiac death occurred in 5 (50.0%) of the 10 patients in group A and in 2 (6.1%) of the 33 patients in group B (p < 0.001). In conclusion, dilated-phase HCM is characterized by decreases in LVEF and SV + RV5 and an increase in LVDD during the early phase of follow-up period, and is associated with an increased incidence of VT and a poor prognosis.

Electrophysiological properties of the left atrium evaluated by coronary sinus pacing in patients with atrial fibrillation.

Repetitive atrial firing (RAF), marked fragmentation of atrial activity (FAA), and interatrial conduction delay (CD) have been shown to be electrophysiological features of the atrium in patients with atrial fibrillation (AF). Moreover, it has been observed that atrial extrastimuli are more likely to induce AF when delivered from the right atrial appendage (RAA) than from the distal coronary sinus (CSd). We examined the electrophysiological properties of the atrial muscle by CS and RAA stimulation in patients with paroxysmal AF. Patients were divided into two groups: group I, consisting of 18 patients with clinical paroxysmal AF; and group II, consisting of 22 patients with various cardiac arrhythmias in which the substrate does not exist in the atrium. In group I, the following values of electrophysiological parameters of the atrium indicated that AF was more likely to be induced during RAA pacing than CSd pacing: atrial effective refractory period (RAA vs CSd: 201 +/- 28 ms vs 240 +/- 35 ms, P < 0.001), RAF zone (16 +/- 25 ms vs 0 +/- 0 ms, P < 0.03), FAA zone (38 +/- 37 ms vs 5 +/- 19 ms, P < 0.01), maximum interatrial conduction time (144 +/- 19 ms vs 93 +/- 19 ms, P < 0.0001) and CD zone (53 +/- 21 ms vs 9 +/- 18 ms, P < 0.0001). The values of the electrophysiological parameters of the atrium evaluated by CSd pacing in group I patients were not significantly different from those in group II patients. In conclusion, when coronary sinus stimulation is performed, electrophysiological properties of the atrium in patients with AF show a significant decrease in atrial vulnerability compared to stimulation from RAA and also show similar values to those in patients without AF. It might be suggested that the left posterior or posterolateral atrium is electrophysiologically stable even in patients with paroxysmal AF.