Erratum: Quadrupole Order in the Frustrated Pyrochlore Tb_{2+x}Ti_{2-x}O_{7+y} [Phys. Rev. Lett. 116, 217201 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.116.217201.

Quadrupole Order in the Frustrated Pyrochlore Tb_{2+x}Ti_{2-x}O_{7+y}.

A hidden order that emerges in the frustrated pyrochlore Tb_{2+x}Ti_{2-x}O_{7+y} with T_{c}=0.53 K is studied using specific heat, magnetization, and neutron scattering experiments on a high-quality single crystal. Semiquantitative analyses based on a pseudospin-1/2 Hamiltonian for ionic non-Kramers magnetic doublets demonstrate that it is an ordered state of electric quadrupole moments. The elusive spin liquid state of the nominal Tb_{2}Ti_{2}O_{7} is most likely a U(1) quantum spin-liquid state.

Anisotropy of the superconducting state in Sr2RuO4.

Despite intense studies the exact nature of the order parameter in superconducting Sr2RuO4 remains unresolved. We have used small-angle neutron scattering to study the vortex lattice in Sr2RuO4 with the field applied close to the basal plane, taking advantage of the transverse magnetization. We measured the intrinsic superconducting anisotropy between the c axis and the Ru-O basal plane (~60), which greatly exceeds the upper critical field anisotropy (~20). Our result imposes significant constraints on possible models of triplet pairing in Sr2RuO4 and raises questions concerning the direction of the zero spin projection axis.

Cocktail-substrate assay system for mechanism-based inhibition of CYP2C9, CYP2D6, and CYP3A using human liver microsomes at an early stage of drug development.

We established a mechanism-based inhibition cocktail-substrate assay system using human liver microsomes and drug-probe substrates that enabled simultaneous estimation of the inactivation of main cytochrome P450 (CYP) enzymes, CYP2C9, CYP2D6, and CYP3A, in drug metabolism. The inactivation kinetic parameters of typical mechanism-based inhibitors, tienilic acid, paroxetine, and erythromycin, for each enzyme in the cocktail-substrate assay were almost in agreement with the values obtained in the single-substrate assay. Using this system, we confirmed that multiple CYP inactivation caused by mechanism-based inhibitors such as isoniazid and amiodarone could be detected simultaneously. Mechanism-based inhibition potency can be estimated by the determination of the observed inactivation rate constants (k(obs)) at a single concentration of test compounds because the k(obs) of eleven CYP3A inactivators at 10 microM in the assay system nearly corresponded to k(inact)/K(I) values, an indicator of a compound's propensity to alter the activity of a CYP in vivo (R(2) = 0.97). Therefore, this cocktail-substrate assay is considered to be a powerful tool for evaluating mechanism-based inhibition at an early stage of drug development.

Simultaneous loss of interlayer coherence and long-range magnetism in quasi-two-dimensional PdCrO2.

In many layered metals, coherent propagation of electronic excitations is often confined to the highly conducting planes. While strong electron correlations and/or proximity to an ordered phase are believed to be the drivers of this electron confinement, it is still not known what triggers the loss of interlayer coherence in a number of layered systems with strong magnetic fluctuations, such as cuprates. Here, we show that a definitive signature of interlayer coherence in the metallic-layered triangular antiferromagnet PdCrO2 vanishes at the Néel transition temperature. Comparison with the relevant energy scales and with the isostructural non-magnetic PdCoO2 reveals that the interlayer incoherence is driven by the growth of short-range magnetic fluctuations. This establishes a connection between long-range order and interlayer coherence in PdCrO2 and suggests that in many other low-dimensional conductors, incoherent interlayer transport also arises from the strong interaction between the (tunnelling) electrons and fluctuations of some underlying order.

Interplanar coupling-dependent magnetoresistivity in high-purity layered metals.

The magnetic field-induced changes in the conductivity of metals are the subject of intense interest, both for revealing new phenomena and as a valuable tool for determining their Fermi surface. Here we report a hitherto unobserved magnetoresistive effect in ultra-clean layered metals, namely a negative longitudinal magnetoresistance that is capable of overcoming their very pronounced orbital one. This effect is correlated with the interlayer coupling disappearing for fields applied along the so-called Yamaji angles where the interlayer coupling vanishes. Therefore, it is intrinsically associated with the Fermi points in the field-induced quasi-one-dimensional electronic dispersion, implying that it results from the axial anomaly among these Fermi points. In its original formulation, the anomaly is predicted to violate separate number conservation laws for left- and right-handed chiral (for example, Weyl) fermions. Its observation in PdCoO2, PtCoO2 and Sr2RuO4 suggests that the anomaly affects the transport of clean conductors, in particular near the quantum limit.

Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: A study using mice lacking TNF-alpha.

BACKGROUND: It has been reported that tumor necrosis factor-alpha (TNF-alpha) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF-alpha on viral myocarditis, however, have not been fully elucidated. METHODS AND RESULTS: To investigate the role of TNF-alpha in the progression of viral myocarditis, we used TNF-alpha gene-deficient mice (TNF-alpha(-/-)) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-alpha(-/-) mice after EMCV infection was significantly lower than that of TNF-alpha(+/+) mice (0% versus 67% on day 14). Injection of recombinant human TNF-alpha (0.2 to 4.0 microg/mouse IV) improved the survival of TNF-alpha(-/-) mice in a dose-dependent manner, indicating that TNF-alpha is essential for protection against viral myocarditis. The levels of viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-alpha(-/-) than in TNF-alpha(+/+) mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-alpha(-/-) than in TNF-alpha(+/+) mice. Immunohistochemical analysis revealed that the levels of immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the myocardium were decreased in TNF-alpha(-/-) mice compared with TNF-alpha(+/+) mice. CONCLUSIONS: These observations suggested that TNF-alpha is necessary for adhesion molecule expression and to recruit leukocytes to inflammatory sites, and thus, the lack of this cytokine resulted in failure of elimination of infectious agents. We concluded that TNF-alpha plays a protective role in the acute stage of viral myocarditis.

Process of progression of coronary artery lesions from mild or moderate stenosis to moderate or severe stenosis: A study based on four serial coronary arteriograms per year.

BACKGROUND: The process of progression in coronary artery disease is unknown. METHODS AND RESULTS: The subjects were 36 patients with 36 objective vessels with clinically significant progression of coronary artery disease (>/=15% per year) in whom 4 serial coronary arteriograms (CAGs) were performed at intervals of approximately 4 months in a 1-year period. The degree of progression of percent stenosis between each of 2 serial CAGs was classified as marked (M: >/=15%), slight (S: 5% to 14%), and no progression (N: <5%). From the pattern of progression, the 36 vessels were classified as 14 type 1 vessels with marked progression (N-->N-->M in 13 vessels and S-->S-->M in 1 vessel) and 22 type 2 vessels without marked progression (S-->S-->S in 18 vessels, N-->S-->S in 4). Percent stenosis at the first, second, third, and final CAGs was 44+/-14%, 46+/-13%, 46+/-13%, and 88+/-10% (P<0.05 versus first CAG) in type 1 vessels and 44+/-11%, 50+/-9%, 59+/-9%, and 67+/-9% in type 2 vessels (P<0.05 for second, third, and final CAGs versus first CAG). Type 1 vessels featured the sudden appearance of severe stenosis due to marked progression, angina pectoris, or myocardial infarction (71%) and Ambrose type II eccentric lesions indicating plaque rupture or thrombi (57%). Type 2 vessels featured continuous slight progression of stenosis with smooth vessel walls; angina pectoris (14%) occurred when the percent stenosis reached a severe level. An increase in serum C-reactive protein was observed only in the type 2 vessel group, which suggests a relation between continuous slight progression and inflammatory change. CONCLUSIONS: Two types of stenosis progression provide a new insight into the mechanism of coronary artery disease.

Considerable time from the onset of plaque rupture and/or thrombi until the onset of acute myocardial infarction in humans: coronary angiographic findings within 1 week before the onset of infarction.

BACKGROUND: It has been thought that the thrombi and bleeding in plaques that occur after plaque rupture or endothelial damage from vessels with mild stenosis suddenly occlude the lumen and cause acute myocardial infarction (AMI). However, our hypothesis is that thrombi and bleeding may not suddenly occlude the lumen. METHODS AND RESULTS: The study group consisted of 20 patients who had coronary angiograms performed within 1 week (3+/-3 days) before AMI and 20 control patients who had coronary angiograms performed 6 to 18 months (282+/-49 days) before AMI. The features of infarct-related coronary segments (IRCS) at 3 days before AMI were the presence of a significant stenosis of >50% (95% in incidence and 71+/-12% diameter stenosis) and Ambrose's type II eccentric lesions (plus multiple irregularities), an indicator of plaque rupture and/or thrombi (60% [70%]), and the features at 1 year before AMI were mild stenosis of <50% (95% incidence and 30+/-18% diameter stenosis) with rare Ambrose's type II eccentric lesions (plus multiple irregularities) (10% [10%]). The same relation was observed in each of the 4 subgroups with Q-wave infarction, non-Q-wave infarction, preceding effort angina within 1 month before AMI, and no preceding effort angina. CONCLUSIONS: The appearance of marked progression and Ambrose's type II eccentric lesion on coronary angiograms 3 days before AMI suggests the presence of a considerable time from the onset of plaque rupture and/or thrombi until the onset of AMI. These features may be predictors of AMI. The concept provides new insight into the mechanism and prevention of human AMIs.

Noninvasive quantitative tissue characterization and two-dimensional color-coded map of human atherosclerotic lesions using ultrasound integrated backscatter: comparison between histology and integrated backscatter images.

OBJECTIVES: The purpose of the present study was to define clinicopathologically whether integrated backscatter (IB) combined with conventional two-dimensional echo (2DE) can differentiate the tissue characteristics of calcification (CL), fibrosis (FI), lipid pool (LP) with fibrous cap, intimal hyperplasia (IH) and thrombus (TH) and can construct two-dimensional tissue plaque structure in vivo. BACKGROUND: It is difficult to characterize the components of plaque using conventional 2DE techniques. METHODS: Integrated backscatter values of plaques were measured in the right common carotid and femoral arteries (total 24 segments) both during life and after autopsy in 12 patients (age 68 to 84 years, 10 men and two women). Integrated backscatter values were determined using a 5-12 MHz multifrequency transducer, setting the region of interests (ROIs) (11 x 11 pixels) on the echo tomography of the entire arterial wall (55 +/- 10 ROI/segment) and comparing it with histologic features in the autopsied arterial specimens. RESULTS: Corrected IB values obtained before death and at autopsy were significantly correlated (r = 0.93, p < 0.01). Corresponding to the histologic features, corrected IB values on the rectangle ROIs obtained during life were divided into five categories: category 1 (TH) 4 < IB < or = 6; category 2 (media and IH or LP in the intima) 7 < IB < or = 13; category 3 (FI) 13 < IB < or = 18, category 4 (mixed lesion) 18 < IB < or = 27 and category 5 (CL) 28 < IB < or = 33. In category 2, media and intima were differentiated using conventional 2DE. Under the above procedures, color-coded maps constructed with IB-2DE obtained during life precisely reflected the histologic features of media and intima. CONCLUSIONS: Integrated backscatter with 2DE represents a useful noninvasive tool for evaluating the tissue structure of human plaque.

Modulation of left ventricular iodine-125-MIBG accumulation in cardiomyopathic Syrian hamsters using the renin-angiotensin system.

UNLABELLED: Genetically inbred cardiomyopathic hamsters were examined to investigate the mechanism of reduced myocardial accumulation of metaiodobenzylguanidine (MIBG) in the cardiomyopathic heart. METHODS: Bio 14.6 Syrian hamsters (hypertrophic stage: n = 15, early heart failure stage: n = 17) and control F1b strain golden hamsters (n = 36) were injected with 296 kBq of [125I] MIBG and killed 30 min or 4 hr later. Thirty-three of these hamsters were pretreated with 10 mg/kg of desipramine to determine non-neuronal MIBG accumulation. To evaluate the nonexocytotic MIBG release from nerve endings, desipramine was administered to four Bio 14.6 hamsters 15 min after [125I]MIBG injection. To determine the role of the activated renin-angiotensin system (RAS) in MIBG washout from sympathetic nerve terminals in cardiomyopathy at early heart failure stage, 10 mg/kg/day cilazapril, an angiotensin-converting enzyme inhibitor, was given orally to 7 controls and 16 cardiomyopathic hamsters for 16 wk. RESULTS: In the absence of desipramine pretreatment, left ventricular [125I]MIBG accumulation 4 hr after injection was 0.376% +/- 0.015 %kg dose/g (mean +/- s.e.m.) in the hypertrophic hamsters (versus 0.418 +/- 0.019 in controls of the same age; ns), and 0.195 +/- 0.025 in early heart failure hamsters. Treatment with cilazapril partially restored MIBG accumulation in the Bio 14.6 hamsters but did not affect the controls. CONCLUSION: Decreased [125I]MIBG accumulation in cardiomyopathic hamsters during the early heart failure stage is caused by neuronal release which is partially modulated by the activated RAS.

Cardiac sympathetic denervation from the early stage of Parkinson's disease: clinical and experimental studies with radiolabeled MIBG.

UNLABELLED: Autonomic disorder is not infrequent in patients with akinetic-rigid syndromes, including idiopathic Parkinson's disease. In the advanced stage of Parkinson's disease, abnormal blood pressure responses, such as orthostatic hypotension and abnormal circadian blood pressure rhythm, may occur. Few cases of reduced 123I-metaiodobenzylguanidine (MIBG) accumulation in the heart or limbs of Parkinson's disease patients have been reported. However, whether reduced accumulation is caused by damage to the postganglionic sympathetic nervous system or by central autonomic failure corresponding to abnormalities in blood pressure regulation is unknown. METHODS: We evaluated sympathetic denervation in 32 Parkinson's disease patients using 123I-MIBG cardiac scintigraphy and compared the findings with those for autonomic dysfunction detected by orthostatic hypotension and diurnal blood pressure variation. Cardiac 125I-MIBG accumulation was also determined in an experimental model of Parkinson's disease using mice pretreated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Cardiac 123I-MIBG accumulation 15 min after injection and 4 h after injection was markedly reduced in the Parkinson's disease patients (heart-to-mediastinum ratio: 1.58 +/- 0.37 and 1.33 +/- 0.28, respectively) compared with 7 healthy volunteers (2.42 +/- 0.27 and 2.60 +/- 0.15, respectively). This reduction was observed even at the earlier stages of physical activity or disease duration and also in patients with normal blood pressure response and variation, indicating that the marked decrease in cardiac 123I-MIBG accumulation may be a special feature of Parkinson's disease. Pretreatment with a total dose of 100 mg/kg MPTP, which is the standard dose used to destroy the dopaminergic neurons in models of Parkinson's disease, significantly reduced cardiac 125I-MIBG accumulation in C57BL/6 mice. Interestingly, the reduction of 125I-MIBG accumulation was still significant when MPTP was reduced to 5 mg/kg. These findings indicated that the postganglionic sympathetic nerves may be damaged by MPTP or unknown toxic substrates in experimental or human Parkinson's disease during the early stage, because dopaminergic neurons and sympathetic nerves are substantially similar in their plasma membrane transporters. CONCLUSION: Cardiac scintigraphy with 123I-MIBG may be used as a new imaging approach in the diagnosis and characterization of akinetic-rigid syndromes, especially Parkinson's disease.

Evidence for the in vivo production of interleukin-3 in lethally irradiated mice transplanted with syngeneic murine splenocytes.

We wish to demonstrate new evidence for the in vivo production of interleukin-3 (IL-3). Syngeneic murine splenocytes were transplanted into lethally irradiated mice. The spleen cells in these transplant mice spontaneously produced IL-3 in cultures, and IL-3-like activity was detected in the serum. Chronological changes of the Thy-1 antigen expression on the bone marrow cells, and the number of myeloid progenitors in the bone marrow from post-transplant mice correlated with the amount of IL-3 produced in vivo. These results suggest that IL-3 may be produced by activated T cells during the syngeneic mixed lymphocyte reaction induced in vivo.

Autoantibodies against 70-kDa heat shock proteins (HSP70) in allogeneic bone marrow transplant recipients.

We report that autoantibodies against the 70-kDa heat shock protein family (HSP70) were detected in allogeneic bone marrow transplant recipients. Antibodies to HSP70 family proteins were detected in three out of 14 recipients of an allogeneic marrow graft but in none of the seven patients receiving autologous peripheral blood stem cell transplant (PBSCT). Immunoblotting analysis combined with two-dimensional SDS-PAGE revealed that these patients had antibodies to a constitutive 73-kDa/pI 5.5 heat shock protein (HSP73) and to a stress-inducible 72-kDa/pI 5.6 protein (HSP72). This is the first report, to our knowledge, describing the presence of autoantibody against HSP73 in allogeneic marrow transplant recipients. Our results may provide additional insight into the etiology and the pathophysiology of allogeneic transplant-related disorders.

Identification and characterization of novel isoforms of COP I subunits.

COP I-coated vesicles are involved in vesicular trafficking in the early secretory pathway. The COP I coat is composed of seven subunits, alpha-, beta-, beta'-, gamma-, delta-, epsilon-, and zeta-COPs. Evidence suggests, however, that there may be isoforms of the COP I subunits. In the present study, we identified homologs of gamma-COP (gamma2-COP; original gamma-COP is referred to as gamma1-COP in this paper) and of zeta-COP (zeta2-COP; original zeta-COP is referred to as zeta1-COP). gamma1- and gamma2-COPs, and zeta1- and zeta2-COPs share 80 and 75%, respectively, of amino acids. mRNAs for gamma2-COP and zeta2-COP are expressed ubiquitously, suggesting their fundamental role in cellular function. Immunofluorescence analysis shows that gamma2-COP and zeta2-COP are colocalized with beta-COP in the paranuclear cis-Golgi region. Yeast two-hybrid analysis indicates that gamma1- and gamma2-COPs can directly, albeit promiscuously, interact with zeta1- and zeta2-COPs. Like gamma1-COP, gamma2-COP can form a complex with beta-COP in vivo. The gamma1-COP-containing and gamma2-COP-containing complexes can similarly interact with the cytoplasmic domain of p23. These results indicate that gamma2-COP and zeta2-COP can form a COP I-like complex in place of gamma1-COP and zeta1-COP, respectively, and suggest that the COP I complex and the COP I-like complex are functionally redundant.

Structure and intracellular localization of mouse ADP-ribosylation factors type 1 to type 6 (ARF1-ARF6).

ADP-ribosylation factors (ARFs) are a family of small GTP-binding proteins that are proposed to be involved in the formation of coated transport vesicles. Although six ARF sequences have been reported in mammals to date, it has been unclear how many ARF members are present in a single organism. In this study, we provide the first direct evidence by cDNA cloning for the presence of all six ARF members in mouse. These proteins are highly conserved across mammalian species and Northern blot analysis revealed that mRNAs for all the members were expressed ubiquitously. Transfection of cells with epitope-tagged ARFs revealed that ARFs 1-3 displayed a perinuclear Golgi localization, while ARFs 4-6 appeared to be widely dispersed throughout the cytoplasm. These results suggest that although all the ARF proteins play fundamental and critical roles in cellular function, they are involved in different vesicular transport processes.

Modulation of allogeneic immune responses by filgrastim (recombinant human granulocyte colony-stimulating factor) in bone marrow transplantation.

We examined whether the use of G-CSF would affect the outcome of allogeneic marrow transplantation in humans and mice. Retrospective analysis of 24 patients who had received allogeneic marrow grafts from HLA-identical siblings revealed that the incidence of chronic but not acute graft-versus-host disease (GVHD) was lower in the patients receiving G-CSF than in those not given G-CSF (18% vs. 80%, P = 0.02). There was a difference in serum TNF-alpha levels during the first 3 months after transplant between these two groups. Four out of the ten patients who were not given G-CSF showed elevated serum TNF-alpha levels, whereas there was only one patients with an increased TNF-alpha level among eleven patients who were given G-CSF. With the use of murine acute and chronic GVHD models, we also observed that administration of G-CSF improved the survival of minor GVHD, but not major GVHD, mice. Taken together, these findings suggest that G-CSF down-regulates allogeneic immune responses and is active in modulating alloreactivity in vivo.

Bone and brain involvement in a case of diffuse large B cell lymphoma associated with t(2;3)(p12;q27).

We report a 57-year-old male with non-Hodgkin's lymphoma (NHL) associated with t(2;3)(p12;q27). The patient showed bone lesions at presentation and brain involvement at relapse in addition to systemic lymph node swelling. Histological diagnosis was malignant lymphoma, diffuse, large cell, immunoblastic, plasmacytoid. Chromosome analysis revealed t(2;3) which is a variant type of t(3;14)(q27;q32). Fluorescence in situ hybridization (FISH) analysis disclosed splits of signals of BCL-6 gene. Among the cases reported in the literature, the common feature of t(2;3)(p11 or p12;q27) was diffuse, large cell lymphoma of B cell, kappa phenotype and four patients immunosuppressive state before lymphoma.

New variant t(9;11;14)(p22;q23;q24) suggests a translocation of 9p to 11q as the critical genetic event.

We describe a patient with M5a (FAB classification) associated with a new type of variant translocation (9;11), namely t(9;11;14)(p22;q23;q24). The translocation of chromosome fragment from 9p to 11q is the common feature among the five variant translocations in the literature and our patient.

Amyloid A-type renal amyloidosis in a patient with sarcoidosis: report of a case and review of the literature.

A 53-year-old man developed chronic renal failure during a protracted course of sarcoidosis. A renal biopsy showed Congo red-positive homogenous deposits in the subendothelial space of glomerular capillary walls and arterial walls. On electron microscopy, amyloid fibrils were observed in the deposits. Immunohistochemistry showed positive staining for amyloid A (AA) protein. Treatment with prednisolone resulted in poor response, followed by progressive deterioration of renal function requiring hemodialysis. To our knowledge, there are 5 cases with histologically proven renal amyloidosis accompanied by sarcoidosis. Prognosis in these patients is extremely poor. AA-type amyloidosis should be considered as a rare renal complication in the setting of long-standing sarcoidosis.