Reaction of size-selected iron-oxide cluster cations with methane: a model study of rapid methane loss in Mars' atmosphere.

We report gas-phase reactions of free iron-oxide clusters, FenOm+, and their Ar adducts with methane in the context of chemical processes in Mars' atmosphere. Methane activation was observed to produce FenOmCH2+/FenOmCD2+ and FenOmC+, where the reactivity exhibited size and composition dependence. For example, the rate coefficients of methane activation for Fe3O+ and Fe4O+ were estimated to be 1 × 10-13 and 3 × 10-13 cm3 s-1, respectively. Based on these reaction rate coefficients, the presence of iron-oxide clusters/particles with a density as low as 107 cm-3 in Mars' atmosphere would explain the rapid loss of methane observed recently by the Curiosity rover.

The Resection of Thyroid Cancer Was Associated with the Resolution of Hyporesponsiveness to an Erythropoiesis-stimulating Agent in a Hemodialysis Patient with Aceruloplasminemia.

We herein report the case of a hemodialysis patient whose response to an erythropoiesis-stimulating agent (ESA) improved following the resection of thyroid cancer. Her hemoglobin level remained below 7 g/dL, despite the use of ESA. During the search for the causes of her hyporesponsiveness to ESA, papillary thyroid cancer and aceruloplasminemia were found. The existence of other potential causes, such as iron deficiency, infectious disease, severe hyperparathyroidism and malnutrition were ruled out. Following the resection of the thyroid cancer tumor, her hemoglobin level increased to 10.2 g/dL over a period of 4 months. This is the first report to demonstrate the resolution of hyporesponsiveness to ESA following the resection of a malignant tumor.

The Possible Link between GABAergic Dysfunction and Cognitive Decline in a Patient with Idiopathic Hypoparathyroidism.

Idiopathic hypoparathyroidism (IHP) is accompanied by cognitive impairment. We report the case of a 70-year-old IHP patient with cognitive disturbance. Brain computed tomography showed bilateral calcification in basal ganglia, thalamus, and cerebellum. Neuropsychological assessment revealed low scores for intelligence, memory, and perseverative errors. Brain positron emission tomography showed a significant reduction in [(18)F]-Fludeoxyglucose (FDG) uptake in bilateral frontal, left temporal and parietal cortices, along with a marked reduction in [(11)C]-flumazenil binding in left frontal, temporal, parietal, and bilateral cerebellum. These findings suggest cognitive impairment in IHP may be ascribed to GABAergic dysfunction, thus leading to, or coexisting with, cerebral hypometabolism.

An autopsy case of the Marburg variant of multiple sclerosis (acute multiple sclerosis).

We herein report an autopsy case of the Marburg variant of multiple sclerosis (MS). A 29-year-old woman developed acute and progressive neurological symptoms. A diagnosis of MS was suspected based on the patient's clinical background and brain MRI findings and the lack of evidence of malignancy on a brain biopsy. Despite the administration of typical treatment for MS, a fatal outcome occurred three months after disease onset. The autopsy revealed multiple inflammatory demyelinating lesions in the central nervous system. In addition, two noteworthy histopathological features were observed compared with prototypical MS. We evaluate the pathogenic differences between the Marburg type and prototypical MS by discussing the neuropathology and cerebrospinal fluid (CSF) findings of our case.

Effectiveness of oral iron chelator treatment with deferasirox in an aceruloplasminemia patient with a novel ceruloplasmin gene mutation.

A 59-year-old man presented with refractory anemia, choreoathetosis in the left upper extremity, an unsteady gait and cognitive dysfunction. The laboratory findings showed a marked decrease in ceruloplasmin. Magnetic resonance images revealed iron deposition in the brain and visceral organs. Iron accumulation was also observed in hepatocytes. Genetic analyses of the ceruloplasmin gene revealed a novel homozygous mutation of c.2185 delC in exon 12. The oral chelator deferasirox was effective in treating the left-side choreoathetosis and unsteady gait. Providing early treatment using deferasirox may be useful for preventing the progression of symptomatic neurological dysfunction.

[Surgical treatment in an adult with coronary artery aneurysm at proximal site of left anterior descending artery; report of a case].

A 52-year-old man was admitted to our hospital with complaint of chest pain and abnormal electrocardiogram (ECG) findings showing ST depression in V2-V6. Coronary computed tomography (CT) and coronary arteriography (CAG) showed coronary artery aneurysm at #5 [left main trunk (LMT)] 20 mm, #11 [circumflex artery (Cx)] 8.3 mm, RV branch 4 mm, and severe stenosis at #5 and #11. Therefore, his chest pain was due to thromboembolism from coronary artery aneurysm. In the present case, Kawasaki disease was not diagnosed in childhood. Coronary artery aneurysms were rare in the elderly and were usually found in association with Kawasaki disease. Morphological evaluation findings strongly suggested that the coronary artery aneurysm were related to Kawasaki disease. Resection of coronary artery aneurysm and coronary artery bypass grafting [left internal thoracic artery (LITA) to #8 and saphenous vein graft (SVG): aorta (Ao) to #14] were successfully performed. We report a case of coronary artery aneurysms presumed to be due to childhood Kawasaki disease in an elderly man.

A case of Epstein-Barr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy.

Post-transplant lymphoproliferative disorder (PTLD) with CNS involvement is an uncommon and fatal side effect of immunosuppressants. A 55-year-old man presented with non-fluent aphasia, fever, neck stiffness and disturbance of consciousness. Twenty-one years previously, the patient had undergone kidney transplantation for chronic renal failure. Brain MRI revealed multiple lesions in the bilateral cerebrum, right cerebellum and medulla oblongata. The brain biopsy showed EBV-positive lymphocytes infiltrating into the subarachnoid and Virchow-Robins space. The diagnosis of PTLD was made and the patient received a reduction in immunosuppressants. However, the patient died of massive bleeding from a rectal ulcer 3 months after the onset. An autopsy conducted 1 month after the biopsy revealed a diffuse large B-cell lymphoma at the biopsy site and extracranial PTLD lesions. Moreover, a human cytomegalovirus infection involving the rectum, pancreas, trachea and bladder was confirmed. Comparisons with past cases clarified the characteristics of this case, in particular, the clinicopathological involvement of leptomeninges. In addition, there have so far been only a limited number of such reports demonstrating detailed pathological findings, including both biopsy and autopsy findings. We herein describe the relationship between clinical and pathological findings and demonstrate the way CNS PTLD lesion progresses.

Central diabetes insipidus and hypothalamic hypothyroidism associated with aceruloplasminemia.

Aceruloplasminemia is a rare autosomal recessive disease first reported by Miyajima et al. (Neurology 37: 761-767, 1987); it is clinically characterized by diabetes mellitus, retinal degeneration and neurological abnormalities, such as cerebellar ataxia, extrapyramidal signs and dementia. Aceruloplasminemia is caused by mutations in the ceruloplasmin gene, which results in the absence of serum ceruloplasmin and iron overload in the brain, liver, pancreas and other organ tissues. However, little is known about endocrine diseases associated with aceruloplasminemia. We report herein a case of aceruloplasminemia accompanied by central diabetes insipidus and hypothalamic hypothyroidism.

Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin.

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients.

Reinforced closure of the sternum with absorbable pins for high-risk patients.

We report our result of the reinforced sternal closure in 51 consecutive patients. We applied a new type of absorbable radiopaque pins (Super FIXSORB) composed of poly-lactide acid and hydroxyapatite, in addition to conventional stainless steel wires. The risk scores of our patients were calculated from the simplified risk scoring system for major infection based on the Society of Thoracic Surgeons National Cardiac Database. The expected probability of infection is significantly higher than the actual infection rate in our patients. Our procedure may contribute to minimizing the fatal sternal complication particularly in high-risk patients.

Repeated true lumen collapse after repair of descending thoracic aneurysm in chronic type B dissection.

The patient was 69-year-old man. Dilatation of the descending thoracic aorta in chronic type B dissection was revealed on computed tomography. During replacement of the descending thoracic aorta, distal anastomosis was performed in a double-barreled manner. On postoperative day (POD) 3, the patient complained of paralysis and dysesthesia of both legs, and he developed acute renal dysfunction. Based on the results of emergent aortography, we suspected true lumen collapse resulting from an expanded false lumen; therefore, we stabilized the intimal flap to the aortic wall. However, on POD 7 he complained of coldness in both legs. Emergent aortography revealed that occlusion of the abdominal aorta had recurred, and so right axillobifemoral bypass was performed. Preoperative conventional angiography may be mandatory to confirm reentry. There have been several reports of transcatheter fenestration in acute or chronic aortic dissection. The technique would also be effective for postoperative malperfusion.

Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia.

BACKGROUND/AIMS: Aceruloplasminemia is an inherited iron overload disorder caused by a mutation in the ceruloplasmin gene and characterized by iron accumulation in both the liver and brain. The aim of this study was to elucidate the molecular pathogenesis of aceruloplasminemia by a functional analysis of mutant ceruloplasmin. METHODS: The effects of nonsense mutations including Y694ter, W858ter and R882ter were studied by the expression in cultured cells. RESULTS: A biogenesis study demonstrated that the Y694ter and W858ter mutants showed protein synthesis identical to that of wild type protein, however, the mutants were retained in the endoplasmic reticulum (ER), while R882ter mutant was secreted out. Site-directed mutagenesis analyses suggested that Cys-881 was necessary for the secretion of the truncated ceruloplasmin. The W858ter mutant decreased viability in the transfected cells. The expression and the promoter activity of glucose-regulated protein 78 that is an ER stress sensor protein, were up-regulated in the transfected cells. CONCLUSIONS: The truncated mutant containing Cys-881 was able to pass through the ER and was secreted, while the truncated mutant protein without Cys-881 appeared to accumulate in the ER thus leading to ER stress and eventually resulting in cell death.

Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of aceruloplasminemia.

BACKGROUND & AIMS: Aceruloplasminemia is a novel hereditary iron overload disease caused by a mutation in the ceruloplasmin gene and characterized by a complete deficiency of serum ceruloplasmin and iron accumulation in the liver and brain. METHODS: We herein studied a novel clinical type of aceruloplasminemia in which a low amount of ceruloplasmin was detected in the serum of a patient. The patient presented with an asymptomatic hepatic iron overload, retinal degeneration, and diabetes mellitus. Magnetic resonance imaging of the liver and basal ganglia showed T2-hypointensity signals associated with parenchymal iron accumulation because of an absence of the ferroxidase activity in ceruloplasmin. RESULTS: A gene analysis showed a novel G969S mutation in the ceruloplasmin gene. A biochemical analysis of the patients' serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity. CONCLUSIONS: This novel clinical type of aceruloplasminemia should therefore be considered in the differential diagnosis of unexplained hemochromatosis, which is associated with a decrease in the serum ceruloplasmin level.

Molecular and pathological basis of aceruloplasminemia

Aceruloplasminemia is an autosomal recessive neurodegenerative disease characterized by iron accumulation in the brain as well as visceral organs. It is a loss-of-function disorder caused by mutations in the ceruloplasmin gene. Clinically, this disease consists of the triad of adult-onset neurological disease, retinal degeneration and diabetes mellitus. Massive iron accumulation and extensive loss of neurons are observed in the basal ganglia. The elevated iron concentration is associated with increased lipid peroxidation in the brains of aceruloplasminemia patients. Enlarged or deformed astrocytes and spheroid-like globular structures are characteristic neuropathological findings in aceruloplasminemia. Moreover, deformed astrocytes and globular structures react positively to anti-4-hydroxynonenal antibody, suggesting that increased oxidative stress is involved in neuronal cell death in aceruloplasminemia brain. More than 30 aceruloplasminemia-causing mutations in the ceruloplasmin gene have been identified. We examined the biosynthesis of two missense ceruloplasmin proteins that result from a Japanese P177R mutation and a Dutch G631R mutation, using Chinese hamster ovary cell expression system. The P177R mutant protein is retained in the endoplasmic reticulum. The G631R mutant protein, predicted to alter the interactions at a single type I copper-binding site, prevented incorporation of copper into apoceruloplasmin and resulted in the synthesis and secretion only of apoceruloplasmin. Molecular analysis of missense mutations showed different structure-function relationships in ceruloplasmin protein. The investigation of mutant ceruloplasmin reveals new insights into molecular pathogenesis of aceruloplasminemia as well as biosynthesis, trafficking, and function of ceruloplasmin.

Early results and problems with St. Jude Medical Symmetry bypass system in Japan.

The early results of coronary artery grafting with an aortic connector system were assessed in Japanese patients. From May 2002 through April 2003, 24 consecutive patients underwent off-pump coronary artery bypass using an aortic connector system. Another patient was excluded because the saphenous vein was insufficient for the smallest available aortic connector system. Saphenous veins were harvested from the thigh in 17 (70.8%) patients, and from the lower leg in 7. The size of the aortic connector system was 4.5-5.0 mm in 19 (79.2%) patients. Intraoperative epiaortic echo indicated that a side-clamp was contraindicated in 15 cases. Hemostasis was instantaneous in all patients. There were no hospital deaths and no neurologic morbidity. Pre-discharge angiography revealed 100% patency of the anastomoses. Use of the aortic connector system demonstrated excellent early results with low neurologic morbidity even when employed in the context of an atheromatous ascending aorta. However, smaller sizes of the device are required for some Japanese patients.

Effects of long-term high-altitude hypoxia and troponin I phosphorylation on cardiac myofilament calcium responses in fetal and nonpregnant sheep.

OBJECTIVE: We studied the effects of long-term high-altitude hypoxia and protein kinase A (PKA) phosphorylation on calcium (Ca2+) responses of skinned cardiac papillary muscles from fetal and adult sheep. METHODS: Fetal and nonpregnant adult sheep were exposed to high-altitude (3820 m), long-term (approximately 110 days) hypoxia. Papillary muscles were isolated and mounted in well-oxygenated, temperature-controlled baths. After the papillary muscles were stimulated electrically to establish the diastolic tension that produced the maximum active contraction, the electrical stimulation was stopped, and the muscles were skinned with 1% vol/vol Triton-X-100. In protocol 1, the skinned muscles were exposed to activating solutions containing different calcium concentrations (pCa; from pCa 8.0 to pCa 4.0), which were prepared by varying the Ca-EGTA/EGTA ratio, and the steady-state tension was measured at each pCa. In protocol 2, the skinned muscles were contracted with activating solution containing a pCa of 5.0. After equilibration, the solution in some baths was changed to activating solution at the same pCa of 5.0 but also containing the catalytic subunit of PKA. The other baths were exchanged with activating solution at a pCa of 5.0 containing no PKA. We then measured the degree of tension reduction caused by PKA until tension reached a new steady state. RESULTS: In the long-term hypoxic fetal heart, the maximum tension response of right, but not left, ventricular skinned papillary muscle to Ca2+ was significantly less than that in control muscles. In the long-term hypoxic adult heart, the left ventricle, but not the right ventricle, displayed an increased maximum tension response to Ca2+ compared with control. Phosphorylation of troponin I (TnI) with PKA reduced active tension in both fetal ventricles of the long-term hypoxic group more than in hearts from control fetuses. In the adult, phosphorylation with PKA resulted in a larger decrease in tension in the left ventricle and a smaller decrease in tension in the right ventricle in the long-term hypoxic group, although the differences were small. CONCLUSION: In the long-term hypoxic fetal right ventricle, the decreased maximum tension response to Ca2+ is consistent with the decrease in myofibrillar magnesium-activated adenosine triphosphatase activity observed previously. The larger decrease in tension after PKA phosphorylation of TnI in the long-term hypoxic fetal left ventricle indicates a larger reduction in Ca2+ binding to troponin C.

Autosynchronized systolic unloading during left ventricular assist with a centrifugal pump.

OBJECTIVES: The purpose of this study was to investigate how the inflow cannulation site of the left ventricular assist system with a centrifugal pump would influence cardiac function on failing heart models. METHODS: In 10 sheep, a left ventricular assist system was instituted by an outflow cannula in the descending aorta, two inflow cannulas in the left atrium and the left ventricle, and connecting those cannulas to a magnetically suspended centrifugal pump. A conductance catheter and a tipped micromanometer for monitoring the pressure-volume loop were also inserted into the left ventricle. Myocardial oxygen consumption was directly measured. Heart failure was induced by injection of microspheres into the left main coronary artery. The assist rate was varied from 0% to 100% at each inflow cannulation site. RESULTS: The pump flow with left ventricular cannulation increased during the systolic phase and decreased during the diastolic phase, whereas it was constant with left atrial cannulation. Ejection fraction with left atrial cannulation decreased as the assist rate increased, whereas that with left ventricular cannulation was maintained up to 75% assist. The external work with left atrial cannulation decreased gradually as the assist rate increased, whereas the external work with left ventricular cannulation did not decrease until the assist rate reached 75%. The myocardial oxygen consumption in both cannulations decreased proportionally as the assist rate increased; they were significantly less with left ventricular cannulation at the 100% assist rate than with left atrial cannulation. CONCLUSION: Left ventricular cannulation during left ventricular assistance maintains ejection fraction and effectively reduces oxygen consumption.

Aceruloplasminemia, an inherited disorder of iron metabolism.

Ceruloplasmin, a multi-copper ferroxidase that affects the distribution of tissue iron, has antioxidant effects through the oxidation of ferrous iron to ferric iron. Aceruloplasminemia is an inherited disorder of iron metabolism due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. It is characterized by iron accumulation in the brain as well as visceral organs. Clinically, the disease consists of the triad of retinal degeneration, diabetes mellitus, and neurological disease, which include ataxia, involuntary movements, and dementia. These symptoms reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Twenty-one mutations in the ceruloplasmin gene have been reported in 24 families worldwide. In Japan, the incidence was estimated to be approximately one per 2,000,000 in the case of non-consanguineous marriages. Excess iron functions as a potent catalyst of biologic oxidation. Previously we showed that an increased iron concentration is associated with increased levels of lipid peroxidation in the serum, cerebrospinal fluid, and erythrocyte membranes. The levels of malondialdehyde and 4-hydroxynonenals, indicators of lipid peroxidation, were also elevated in the basal ganglia and cerebral cortex. Positron emission tomography showed diminished brain metabolism of glucose and oxygen. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to approximate 45% and 42%, respectively, for complexes I and IV. These findings suggest that iron-mediated free radicals causes neuronal cell damage through lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains.