Formation and evolution of carbonaceous asteroid Ryugu: Direct evidence from returned samples.

Samples of the carbonaceous asteroid Ryugu were brought to Earth by the Hayabusa2 spacecraft. We analyzed 17 Ryugu samples measuring 1 to 8 millimeters. Carbon dioxide-bearing water inclusions are present within a pyrrhotite crystal, indicating that Ryugu's parent asteroid formed in the outer Solar System. The samples contain low abundances of materials that formed at high temperatures, such as chondrules and calcium- and aluminum-rich inclusions. The samples are rich in phyllosilicates and carbonates, which formed through aqueous alteration reactions at low temperature, high pH, and water/rock ratios of <1 (by mass). Less altered fragments contain olivine, pyroxene, amorphous silicates, calcite, and phosphide. Numerical simulations, based on the mineralogical and physical properties of the samples, indicate that Ryugu's parent body formed ~2 million years after the beginning of Solar System formation.

Impactor material records the ancient lunar magnetic field in antipodal anomalies.

The Moon presently has no dynamo, but magnetic fields have been detected over numerous portions of its crust. Most of these regions are located antipodal to large basins, leading to the hypothesis that lunar rock ejected during basin-forming impacts accumulated at the basin antipode and recorded the ambient magnetic field. However, a major problem with this hypothesis is that lunar materials have low iron content and cannot become strongly magnetized. Here we simulate oblique impacts of 100-km-diameter impactors at high resolution and show that an ~700 m thick deposit of potentially iron-rich impactor material accumulates at the basin antipode. The material is shock-heated above the Curie temperature and therefore may efficiently record the ambient magnetic field after deposition. These results explain a substantial fraction of the Moon's crustal magnetism, and are consistent with a dynamo field strength of at least several tens of microtesla during the basin-forming epoch.

Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: P<0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia.

Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 (FLT3) and rat sarcoma viral oncogene homolog (RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3-ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain (FLT3-TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-α (40%) mutations. However, epigenetics-modifying gene (DNMT3a, TET2 and IDH1/2) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3-ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them (P=0.001). Moreover, the high frequency of FLT3-ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations (P<0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3-ITD, leading to resistance to therapy and relapse.

Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia.

Recently, c-kit mutations have been reported as a novel adverse prognostic factor of acute myeloid leukemia with t(8;21)(q22;q22) translocation (t(8;21) AML). However, much remains unclear about its clinical significance. In this study, we developed a highly sensitive mutation detection method known as mutation-biased PCR (MB-PCR) and investigated the relationship between c-kit mutations and prognosis. When c-kit mutations were analyzed for 26 cases of t(8;21) AML using the direct sequence (DS) and MB-PCR, the latter had a much higher detection rate of c-kit mutations at initial presentation (DS 5/26(19.2%) vs MB-PCR 12/26(46.2%)). Interestingly for the three cases, in which c-kit mutations were observed only at relapse with the DS, c-kit mutations were detected at initial presentation using the MB-PCR. This result suggests that a minor leukemia clone with c-kit mutations have resistance to treatment and are involved in relapse. In univariate analyses, the presence of a c-kit mutation using DS was not an adverse prognostic factor (P = 0.355), but was a factor when using MB-PCR (P = 0.014). The presence of c-kit mutations with MB-PCR was also an independent adverse prognostic factor by multivariate analyses (P = 0.006). We conclude that sensitivity of c-kit mutation detection method is important to predict prognosis for t(8;21) AML.

A non-acromegalic case of multiple endocrine neoplasia type 1 accompanied by a growth hormone-releasing hormone-producing pancreatic tumor.

Cases of acromegaly due to GHRHproducing pancreatic endocrine tumors have been reported. Here we present a case of a 31-yr-old nonacromegalic man with hyperparathyroidism and elevated serum IGF-I with normal serum GH levels. Serum GH was not suppressed below 1 ng/ml by the glucose tolerance test and increased in response to TR H and GHRH administration. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia and an abdominal computed tomography (CT ) scan showed a tumor in the pancreatic tail. Plasma concentration of GHRH was elevated. Based on these clinical data, multiple endocrine neoplasia (MEN) type 1 was suspected. Three enlarged parathyroid glands were removed and a distal pancreatectomy was performed. Pathological examination of the parathyroid glands and pancreatic tumor showed nodular hyperplasia and a well-differentiated endocrine tumor, respectively, both compatible with MEN features. Immunohistochemistry revealed positive immunoreactivity for GHRH, SS , insulin, glucagon, chromogranin A, and pancreatic polypeptide in the pancreatic tumor. After pancreatic surgery, elevated levels of GHRH and IGF-I were normalized and pituitary hyperplasia definitely decreased in size. In cases of pituitary hyperplasia with elevated IGF-I, ectopic GHRH syndrome must be considered even if physical features of acromegaly are absent. It is also important to measure plasma GHRH concentrations in order to give a diagnosis.

Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats.

Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic renal insufficiency (CRI). We proposed that changes in serum PTH and FGF23 levels might be associated with changes in serum phosphorus levels caused by the phosphate binder sevelamer hydrochloride (sevelamer, i.e. crosslinked poly[allylamine hydrochloride]). Rats were fed a diet containing adenine for 4 weeks to establish CRI. Animals were then offered either a normal diet or a diet containing 1 or 3% sevelamer for 8 weeks continuously, or intermittently with sevelamer diet or a normal diet offered for alternating 2-week periods. Changes in the serum levels of phosphorus, calcium, PTH, FGF23, and 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) were monitored over time. Adenine-treated rats developed severe CRI, with markedly elevated serum levels of phosphorus, PTH and FGF23, and reduced levels of serum 1,25(OH)(2)D(3). Continuous treatment with sevelamer suppressed these increases throughout the study period. Serum phosphorus, PTH, and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, the changes in serum FGF23 levels began after the onset of changes in serum phosphorus and PTH levels. In conclusion, circulating PTH, and FGF23 levels can be promptly manipulated through the control of serum phosphorus levels. Moreover, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CRI.

Surgical correction of cryptotia with superiorly based superficial mastoid fascia and skin paddle.

An approach for the correction of cryptotia using a superiorly based superficial mastoid fascial flap and a skin paddle is introduced. The buried portion of the auricle was exposed through an incision made along the upper part of the helix, followed by an appropriate correction of the deformed cartilage. Protrusion of the upper portion of the auricle was accomplished using anchoring sutures. A small skin paddle was elevated from the caudal portion of the auricular sulcus with the superiorly based superficial mastoid fascia as the nutrient pedicle and transferred to the temporal skin defect. The procedure was performed in eight auricles in a total of seven patients with cryptotia. A satisfactory contour and protrusion of the auricle were maintained postoperatively, leaving the scar within the auricular sulcus.

Evaluation of flow characteristics of soft-tissue vascular malformations using technetium-99m labelled red blood cells.

The estimation of intralesional haemodynamics is crucial in determining appropriate treatment for soft-tissue vascular malformations. The aim of this study was to develop a method to evaluate the flow characteristics of soft-tissue vascular malformations using technetium-99m labelled red blood cells (99mTc-RBCs). Seventy-nine soft-tissue vascular malformations, including 20 arteriovenous malformations and 59 venous malformations, in 57 patients were examined. Following the intravenous injection of 99mTc-RBCs, dynamic imaging was performed for 30 min with the lesion in the field of view (99mTc-RBC flow study). A time-activity curve was generated for the lesion, and the lesion was categorized as a high-flow or low-flow lesion by visual inspection of the curve. In low-flow lesions, mean vascular transit time (MTT) was calculated by curve fitting based on a two-compartment model. Twenty-nine lesions in 19 patients were examined twice, and reproducibility was assessed. In 23 venous malformations in 16 patients, 99mTc-Sn colloid was percutaneously injected into the intravascular space of the lesion, and dynamic data of 5-min duration were acquired (direct puncture scintigraphy). MTT was estimated from the washout curve and compared with MTT estimated by 99mTc-RBC flow study. 99mTc-RBC flow study classified all 20 arteriovenous malformations as high-flow lesions and all 59 venous malformations as low-flow lesions. In the low-flow lesions, MTT estimated by 99mTc-RBC flow study ranged from 61.2 to 2174.9 s. In the reproducibility study, complete concordance in classification and high correlation in MTT were shown between the first and second examinations. MTT estimated by 99mTc-RBC flow study was significantly correlated with that estimated by direct puncture scintigraphy. In summary, 99mTc-RBC flow study provides a quantitative indicator of intralesional haemodynamics in low-flow lesions in addition to accurate distinction between high-flow and low-flow lesions. The results of this study suggest the feasibility of detailed evaluation of flow characteristics in soft-tissue vascular malformations using 99mTc-RBCs.

[Efficacy of immunized milk for preventing viral infection].

This paper investigated the efficacy of passive protection provided by milk (immunized milk) against enterovirus infection in mice experimentally infected with enterovirus. Milk with a high antibody titer against six enterovirus serotypes was prepared from hyperimmunized goat. In vivo and in vitro experiments were performed and the results showed that immunized milk has an antiviral activity against enterovirus infection. Further observation was performed using Coxsackie B 3 virus (CVB 3). When immunized milk was orally applied to mice prior to oral inoculation with CVB 3, preventive effects against viral infection such as reduction of histopathological changes in the heart and reduced detection of the virus genome in the organs were seen. The antiviral effect was also indicated by the increase of CD4+T cells proportion in the i-IEL. The proportion of virus specific CD4+T cells was increased in mice treated with immunized milk, whereas no such increase was detected in control mice. These results suggest that oral application of immunized milk is not only capable of preventing viral infection but also induces specific immunological responses. These phenomena may play an important role in host defense mechanisms.

Exhaled nitric oxide after beta2-agonist inhalation and spirometry in asthma.

Exhaled nitric oxide (ENO) is used increasingly as a surrogate marker of airway inflammation in research protocols that may incorporate standard efficacy measures, such as spirometry before and after bronchodilator, which could affect ENO measurements. In seven healthy volunteers and 11 mild asthmatic subjects, we measured ENO before and serially for 1 h after spirometry. On two additional days in the subjects with asthma, we reexamined the effect of spirometry as before, followed by the serial measurement of ENO for 1 h after two puffs of salbutamol (100 microgram/puff) by metered-dose inhaler or matching placebo. As early as 1 min after spirometry, ENO fell by 13% and 10% in the normal and asthmatic subjects, respectively. In both groups, ENO returned to baseline over 1 h. In the asthmatic subjects, salbutamol caused a significant mean increase of the order of 10 parts per billion in ENO (p < 0.001) for 1 h as compared with placebo inhaler. We conclude that spirometry and beta2-agonist may perturb ENO values and recommend that studies control for these factors.

Scalp localization using a simple algorithm.

We have developed a simple algorithm for scalp localization for craniotomy. Using a series of CT/MRI data, the point on the scalp closest to the center of the lesion (T) is determined by our program. A plane (plane R) is defined by three points: bilateral auditory meati and T. Point S is the intersection of three planes: the plane R, the scalp surface and the midsagittal plane. The distance from either S or the ipsilateral external auditory meatus to T is measured along the scalp surface on the plane R. The distance from the nasion to S along the scalp surface on the midsagittal plane is also measured. To determine the craniotomy site, these distances are measured directly on a patient's scalp in the operating room. This simple and accurate method for scalp localization could be used by installing our program in conventional CT/MR scanners.

Effect of recirculation of 99mTc-Sn colloid in estimating mean transit time of soft-tissue vascular anomalies by direct puncture scintigraphy: a simulation analysis.

We have reported direct puncture scintigraphy, a novel method to estimate mean transit time (MTT) of soft-tissue vascular anomaly. In the examination, 99mTc-Sn colloid is infused percutaneously into the lesion, and MTT is calculated using the time-activity curve for the lesion. Recirculation of 99mTc-Sn colloid is neglected in computing MTT, and this may cause error. The aim of this study was to assess this error by simulation analysis. Data simulating direct puncture scintigraphy were produced for lesions with various blood volumes and various blood flows, considering recirculation and blood clearance of 99mTc-Sn colloid, and MTT was estimated by the same method used in the patient examination. Although MTT was overestimated in large lesions with intermediate or long MTT, the error was small except in extremely large lesions. It was suggested that recirculation of 99mTc-Sn colloid does not cause a serious problem in the clinical use of direct puncture scintigraphy.

Flow characteristics of soft-tissue vascular anomalies evaluated by direct puncture scintigraphy.

Soft-tissue vascular anomalies such as haemangioma and vascular malformation are treated by surgical resection, arterial embolization or sclerotherapy. Because the effect of sclerotherapy, i.e. the percutaneous injection of sclerosing agents, depends on intralesional haemodynamics, estimation of flow characteristics of soft-tissue vascular anomalies is essential when determining appropriate patient management. However, lesions are at present divided into only two groups: high flow and low flow. We have developed a new method, direct puncture scintigraphy, to evaluate in detail the haemodynamics of vascular anomalies under conditions simulating sclerotherapy. Twenty-six soft-tissue vascular anomalies in 21 patients were studied. After 30 MBq of technetium-99m Sn colloid was injected percutaneously into the intravascular space of the lesion, dynamic imaging was performed for 5 min. A time-activity curve for the lesion was generated, with the infiltrated activity on injection subtracted. A monoexponential curve was fitted to the declining phase of the time-activity curve, and mean vascular transit time (MTT) was obtained. The lesions were classified into high-flow and low-flow lesions based on radionuclide angiography with intravenous injection of 99mTc-labelled red blood cells, and estimates of MTT in the two groups were compared. The imaging procedures were carried out with no major complications, and broad intralesional diffusion of 99mTc-Sn colloid was achieved in most lesions. The high-flow lesions (six lesions) had a short MTT, ranging from 1.6 to 3.4 s, while the low-flow lesions (20 lesions) had a longer MTT, with no overlap between the groups. MTT showed a wide range in low-flow lesions: it was less than 30 s in six lesions and more than 10 min in five other lesions. Direct puncture scintigraphy provides a quantitative indicator of the flow characteristics of soft-tissue vascular anomalies, and may aid in determining treatment strategies for patients with vascular anomalies.

Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.

Exhaled nitric oxide (NO) may aid in monitoring pulmonary disease. The single-breath NO profile (subjects with nose clip) was described as a NO peak followed by a plateau (NO(PLAT)). Published exhaled NO values vary greatly, possibly due to contamination with nasal NO and differing respiratory maneuvers. We developed a technique to measure pulmonary NO, without nasal NO, by having the subject maintain a positive expiratory pressure (ensuring vellum closure), and we examined the variation in NO(PLAT) over a range of expiratory flows (4.2 to 1,550 ml/s). NO(PLAT) values rose almost 35-fold (3.2 +/- 1.4 ppb to 110.5 +/- 54.8 ppb) with decreasing flow, described by NO(PLAT) = 208.6795 x (flow rate)(-0.5995). However, NO excretion showed an almost 11-fold rise as flow increased. In summary, we present a simple technique for measuring exhaled NO without contamination by nasal NO. There is a marked flow dependence of exhaled NO concentration and excretion. Exhaled pulmonary NO is best measured at very low flow rates to amplify the signal and must be related to the expiratory flow employed.

Use of whole-body imaging using Tc-99m RBC in patients with soft-tissue vascular lesions.

We investigated the usefulness of whole-body imaging as an adjunct to spot imaging in soft-tissue vascular lesions, such as hemangiomas and vascular malformations. Spot imaging of the known lesion and whole-body imaging were performed 1-3 hours after the injection of Tc-99m RBC in 42 patients with soft-tissue vascular lesions. Whole-body imaging was considered to be useful in only two patients, who had multiple distant occult lesions in addition to large known lesions. It was suggested that the routine addition of whole-body imaging is not cost effective in patients with soft-tissue vascular lesions, although it may be beneficial for detecting occult lesions in patients with hemangiomas.

Haloperidol-induced blockade of induction of long-term potentiation in perforant path-dentate gyrus pathway in chronically prepared rabbits.

We investigated the effects of the representative neuroleptic and dopamine receptor antagonist haloperidol (HPD) on the induction of long-term potentiation (LTP) or on the previously induced LTP in the perforant path-dentate gyrus pathway in chronically prepared rabbits. The IP HPD injection of 0.8 mg/kg blocked the induction of LTP when it was given before LTP-inducing tetanic stimulations, although this dose showed virtually no effect on the baseline control responses in the perforant path-dentate gyrus pathway to single shocks. However, neither 0.8-mg/kg nor 1.6-mg/kg HPD doses affected the previously induced LTP. The possible mechanisms underlying these results, notably the HPD-induced blockade of LTP induction, are discussed, especially in association with the inhibitory action of HPD on calmodulin-mediated events rather than dopaminergic function.