Identification of genotype-biochemical phenotype correlations associated with fructose 1,6-bisphosphatase deficiency.

Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.

Cyst-to-Mastoid Antrum Diversion as an Alternate Pathway for Management of Small Symptomatic Petrous Apex Cholesterol Granuloma Without Anteromedial Expansion Using an Extradural Middle Fossa Approach: A Technical Case Report.

BACKGROUND AND IMPORTANCE: Cholesterol granuloma (CG) is the most common petrous apex (PA) cystic lesion. Posterolateral expansion of a PA CG (PACG) compresses the internal auditory canal (IAC), leading to vestibulocochlear (VC) and facial nerve dysfunction. Even small, symptomatic PACGs are managed surgically. The preferred strategy is not complete removal, but drainage and aeration. PACG with anteromedial expansion using an endoscopic endonasal approach provides natural drainage into the nasal sinus without risking VC and facial dysfunction. Endoscopic endonasal approach is inappropriate for small PACGs without anteromedial expansion because of potential damage to the petrous internal carotid artery. Small PACGs without anteromedial expansion are managed using extradural middle fossa (EMF) approach, which lacks a natural drainage pathway, thus necessitating an artificial drainage pathway for PACG aeration to prevent recurrence. We introduced EMF approach for CG decompression and cyst-to-mastoid antrum (MA) diversion for managing small, symptomatic PACGs without anteromedial expansion. CLINICAL PRESENTATION: A 48-year-old woman presented with headache, vertigo, tinnitus, and left hemifacial spasm with preserved hearing because of IAC compression caused by a small PACG without anteromedial expansion. Using the EMF approach, the CG and IAC were safely decompressed. Effective and long-standing artificial drainage for CG aeration was established by anterior petrosectomy and silicone tubing from the CG into the MA. Surgery resolved the symptoms, which have not recurred in 3 years. CONCLUSION: Granuloma decompression and cyst-to-MA diversion using silicone tubing using the EMF approach is a safe and effective surgical management for small, symptomatic PACG without anteromedial expansion.

Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors.

The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein-coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.

Ruptured bilateral middle cerebral artery aneurysms diagnosed based on cerebral vasospasm-associated ischemic symptoms: A case report.

We report a case of subarachnoid hemorrhage presenting with ischemic symptoms due to cerebral vasospasm. A 64-year-old woman with right facial paralysis was referred to our hospital for treatment because of bilateral middle cerebral artery aneurysms observed using magnetic resonance imaging. She had no headache episodes; however, contrast-enhanced magnetic resonance imaging showed contrast enhancement of the aneurysmal wall only on the left side. Therefore, she was considered to have a ruptured aneurysm and underwent craniotomy and aneurysmal neck clipping. The postoperative course was uneventful; however, she developed aphasia and dysphagia 9 months after the surgery and was readmitted. New cerebral infarction and subarachnoid hemorrhage were observed on the right side, and the patient exhibited marked vasospasm. Because of a headache episode one week earlier, coil embolization was performed after the vasospasm. She was discharged home with a modified Rankin scale score of 2 and planned rehabilitation. Aneurysms that enlarge and rupture in a short time period should be treated with caution. Vessel wall imaging was useful in identifying the ruptured aneurysm in the current case.

Superconductivity in In-doped AgSnBiTe3 with possible band inversion.

We investigated the chemical pressure effects on structural and electronic properties of SnTe-based material using partial substitution of Sn by Ag0.5Bi0.5, which results in lattice shrinkage. For Sn1-2x(AgBi)xTe, single-phase polycrystalline samples were obtained with a wide range of x. On the basis of band calculations, we confirmed that the Sn1-2x(AgBi)xTe system is basically possessing band inversion and topologically preserved electronic states. To explore new superconducting phases related to the topological electronic states, we investigated the In-doping effects on structural and superconducting properties for x = 0.33 (AgSnBiTe3). For (AgSnBi)(1-y)/3InyTe, single-phase polycrystalline samples were obtained for y = 0-0.5 by high-pressure synthesis. Superconductivity was observed for y = 0.2-0.5. For y = 0.4, the transition temperature estimated from zero-resistivity state was 2.4 K, and the specific heat investigation confirmed the emergence of bulk superconductivity. Because the presence of band inversion was theoretically predicted, and the parameters obtained from specific heat analyses were comparable to In-doped SnTe, we expect that the (AgSnBi)(1-y)/3InyTe and other (Ag, In, Sn, Bi)Te phases are candidate systems for studying topological superconductivity.

Botulinum toxin injections for Japanese patients with urinary incontinence caused by neurogenic detrusor overactivity: Clinical evaluation of onabotulinumtoxinA in a randomized, placebo-controlled, double-blind trial with an open-label extension.

OBJECTIVE: To assess the efficacy and safety of botulinum toxin treatment (onabotulinumtoxinA 200 units) for Japanese patients with neurogenic detrusor overactivity caused by spinal cord injury or multiple sclerosis. METHODS: Patients with urinary incontinence refractory to pharmacological treatment were enrolled and randomized in a phase III trial. A single dose of onabotulinumtoxinA (n = 11) or placebo (n = 10) was given in the double-blind phase, and repeat injections of onabotulinumtoxinA were given in the subsequent open-label phase. Outcomes included urinary incontinence episodes, urodynamics, patient-reported outcomes and adverse events. RESULTS: The onabotulinumtoxinA group showed a numerically greater reduction in the number of urinary incontinence episodes per day than the placebo group, with the difference between the groups at week 6 of -3.02 (95% confidence interval -5.85 to -0.19). The onabotulinumtoxinA group also showed greater improvements in urodynamic assessments. Adverse events related to onabotulinumtoxinA injections were hematuria, urinary retention, urinary bladder hemorrhage, autonomic dysreflexia and epididymitis. Most events were deemed mild or moderate. CONCLUSIONS: Intradetrusor injections of onabotulinumtoxinA are efficacious and tolerable for Japanese patients with neurogenic detrusor overactivity-related symptoms that are difficult to manage with anticholinergics and/or ß3 -adrenergic receptor agonists.

An efficient way of increasing the total entropy of mixing in high-entropy-alloy compounds: a case of NaCl-type (Ag,In,Pb,Bi)Te1-xSex (x = 0.0, 0.25, 0.5) superconductors.

We propose an efficient way of increasing the entropy of mixing in high-entropy-alloy-type compounds, which can be achieved by multi-site alloying. As an example of this concept, we report the synthesis and observation of polycrystalline samples of new high-entropy-alloy-type metal chalcogenides (Ag,In,Pb,Bi)Te1-xSex (x = 0.0, 0.25, and 0.5) with a NaCl-type structure. The samples were synthesized using high pressure synthesis. Superconductivity with transition temperatures of 2.7, 2.5, and 2.0 K was observed with x = 0.0, 0.25, and 0.5, respectively. To investigate the multi-site alloying effect on the entropy of mixing (ΔSmix) for the examined samples, we calculated the total ΔSmix for two crystallographic sites. For the samples with x = 0.25 and 0.5, ΔSmix reaches 1.89R and 2.00R, respectively, which exceed the ΔSmix of 1.79R for a simple (single-site) high-entropy alloy containing six different elements.

Detection of Hole Pockets in the Candidate Type-II Weyl Semimetal MoTe_{2} from Shubnikov-de Haas Quantum Oscillations.

The bulk electronic structure of T_{d}-MoTe_{2} features large hole Fermi pockets at the Brillouin zone center (Γ) and two electron Fermi surfaces along the Γ-X direction. However, the large hole pockets, whose existence has important implications for the Weyl physics of T_{d}-MoTe_{2}, has never been conclusively detected in quantum oscillations. This raises doubt about the realizability of Majorana states in T_{d}-MoTe_{2}, because these exotic states rely on the existence of Weyl points, which originated from the same band structure predicted by density functional theory (DFT). Here, we report an unambiguous detection of these elusive hole pockets via Shubnikov-de Haas (SdH) quantum oscillations. At ambient pressure, the quantum oscillation frequencies for these pockets are 988 and 1513 T, when the magnetic field is applied along the c axis. The quasiparticle effective masses m^{*} associated with these frequencies are 1.50 and 2.77 m_{e}, respectively, indicating the importance of Coulomb interactions in this system. We further measure the SdH oscillations under pressure. At 13 kbar, we detected a peak at 1798 T with m^{*}=2.86m_{e}. Relative to the oscillation data at a lower pressure, the amplitude of this peak experienced an enhancement, which can be attributed to the reduced curvature of the hole pockets under pressure. Combining our experimental data with DFT+U calculations, where U is the Hubbard parameter, our results shed light on why these important hole pockets have not been detected until now.

Bulk superconductivity in a four-layer-type Bi-based compound La2O2Bi3Ag0.6Sn0.4S5.7Se0.3.

Recently, we reported the observation of superconductivity at ~0.5 K in a La2O2M4S6-type (M: metal) layered compound La2O2Bi3AgS6, which is a layered system related to the BiS2-based superconductor system but possesses a thicker Bi3AgS6-type conducting layer. In this study, we have developed the La2O2Bi3AgS6-type materials by element substitutions to increase the transition temperature (Tc) and to induce bulk nature of superconductivity. A resistivity anomaly observed at 180 K in La2O2Bi3AgS6 was systematically suppressed by Sn substitution for the Ag site. By the Sn substitution, Tc increased, and the shielding volume fraction estimated from magnetization measurements also increased. The highest Tc (=2.3 K) and the highest shielding volume fraction (~20%) was observed for La2O2Bi3Ag0.6Sn0.4S6. The superconducting properties were further improved by Se substitutions for the S site. By the combinational substitutions of Sn and Se, bulk-superconducting phase of La2O2Bi3Ag0.6Sn0.4S5.7Se0.3 with a Tc of 3.0 K (Tconset = 3.6 K) was obtained.

Effectiveness of Low-Dose Intravenous Tissue Plasminogen Activator before Stent Retriever or Aspiration Mechanical Thrombectomy.

PURPOSE: To determine whether thrombolysis with a lower dose of intravenous recombinant tissue plasminogen activator before mechanical thrombectomy is beneficial for functional outcomes compared with mechanical thrombectomy alone. MATERIALS AND METHODS: Data for 100 Japanese patients who underwent mechanical thrombectomy between July 2014 and November 2017 were retrospectively reviewed. These patients were divided into groups according to whether they received intravenous thrombolysis before mechanical thrombectomy, and outcomes were compared. Favorable outcome was defined as a modified Rankin scale score ≤ 2 at 3 months after treatment. RESULTS: Thirty-four patients for the thrombolysis group and 66 patients for the thrombectomy-only group were identified. The thrombolysis and nonthrombolysis groups did not differ significantly in baseline characteristics (mean age, 74.3 y vs 75.7 y [P = .485]; mean preoperative National Institute Health Stroke Scale score, 19.8 vs 19.6 [P = .825]). There were no significant differences in the times required for, or the rates of, successful recanalization. However, the thrombolysis group had a higher rate of complete recanalization (67.6% vs 43.9%; P = .041). Postoperative symptomatic intracranial hemorrhage was not significantly different between groups. Favorable outcomes were observed in 73.5% of patients in the thrombolysis group and 51.5% in the nonthrombolysis group (P = .028). CONCLUSIONS: This single-center retrospective study shows that lower-dose intravenous thrombolysis improves the outcomes of mechanical thrombectomy for Japanese patients with acute anterior-circulation stroke treated within 4.5 hours of onset.

Magnetic, thermal, and neutron diffraction studies of a coordination polymer: bis(glycolato)cobalt(ii).

The two-dimensional quadratic lattice magnet, bis(glycolato)cobalt(ii) ([Co(HOCH2CO2)2]), showed antiferromagnetic ordering at 15.0 K and an abrupt increase in magnetisation at H = 22 600 Oe and 2 K, thereby acting as a metamagnet. Heat capacity measurements revealed that the associated entropy change ΔS around the transition temperature was evaluated to be 6.20 J K-1 mol-1 and that the Co(ii) ion had the total angular momentum of J = 1/2 at low temperatures. Neutron diffraction studies suggested that the magnetic moment vectors of the Co(ii) ions had an amplitude of 3.59µB and were not aligned in a fully antiparallel fashion to those of their neighbours, which caused canting between the magnetic moment vectors in the sheet. The canting angle was determined to be 7.1°. Canting induced net magnetisation in the sheet, but this magnetisation was cancelled between sheets. The magnetisations in the sheets were oriented parallel to the magnetic field at the critical magnetic field.

Na1-xSn2P2 as a new member of van der Waals-type layered tin pnictide superconductors.

Superconductors with a van der Waals (vdW) structure have attracted a considerable interest because of the possibility for truly two-dimensional (2D) superconducting systems. We recently reported NaSn2As2 as a novel vdW-type superconductor with transition temperature (Tc) of 1.3 K. Herein, we present the crystal structure and superconductivity of new material Na1-xSn2P2 with Tc = 2.0 K. Its crystal structure consists of two layers of a buckled honeycomb network of SnP, bound by the vdW forces and separated by Na ions, as similar to that of NaSn2As2. Amount of Na deficiency (x) was estimated to be 0.074(18) using synchrotron X-ray diffraction. Bulk nature of superconductivity was confirmed by the measurements of electrical resistivity, magnetic susceptibility, and specific heat. First-principles calculation using density functional theory shows that Na1-xSn2P2 and NaSn2As2 have comparable electronic structure, suggesting higher Tc of Na1-xSn2P2 resulted from increased density of states at the Fermi level due to Na deficiency. Because there are various structural analogues with tin-pnictide (SnPn) conducting layers, our results indicate that SnPn-based layered compounds can be categorized into a novel family of vdW-type superconductors, providing a new platform for studies on physics and chemistry of low-dimensional superconductors.

Crystal Structure and Superconductivity of Tetragonal and Monoclinic Ce1- xPr xOBiS2.

Ce1- xPr xOBiS2 powders and Ce0.5Pr0.5OBiS2 single crystals were synthesized and their structure and superconductive properties were examined by X-ray diffraction, X-ray absorption, electronic resistivity, and magnetization. While PrOBiS2 was found to be in a monoclinic phase with one-dimensional Bi-S zigzag chains showing no superconductive transition above 0.1 K, CeOBiS2 was in a tetragonal phase with two-dimensional Bi-S planes showing zero resistivity below 1.3 K. In the range x = 0.3-0.9 in Ce1- xPr xOBiS2, both monoclinic and tetragonal phases were formed together with zero resistivity up to a maximum temperature of 2.2 K. A Ce0.5Pr0.5OBiS2 single crystal, which showed both zero resistivity and a decrease in magnetization at ∼2.4 K, presented a tetragonal structure. Short Bi-S bonding in flat two-dimensional Bi-S planes and mixed Ce3+/Ce4+ were characteristic features of the Ce0.5Pr0.5OBiS2 single crystal, which presumably triggered its superconductivity.

Unexpected prominent tension pneumosella five years after endoscopic endonasal transsphenoidal surgery.

Tension pneumosella (TP) is a rare entity reported as the invagination of the sphenoid sinus mucosa into the skull base after endonasal transsphenoidal surgery. Few studies have reported on TP, and in these studies, invagination is confined to either the intrasellar or suprasellar area. We encountered a case of unexpected prominent TP toward the intracranial space 5 years after endoscopic endonasal transsphenoidal surgery (EETS) for a nonfunctioning pituitary adenoma. In addition, we present a hypothesis of the underlying mechanism by a pressure gradient change between the extracranial and intracranial space in TP formation. For repair, a pedicled nasal septal flap was fabricated from the remaining part of the septal mucosa, and a pedicled inferior turbinate flap was created. Moreover, the nasal septal cartilage was used as a rigid support for reconstruction, which was useful for preventing TP recurrence. This is the first report of an unexpected prominent TP after EETS. It is important for otorhinolaryngologists and neurosurgeons to be aware of the possibility of TP following EETS. Laryngoscope, 1798-1801, 2018.

Quadrupole effects in tetragonal crystals PrCu2Si2 and DyCu2Si2.

We have investigated quadrupole effects in tetragonal crystals of PrCu2Si2 and DyCu2Si2 by means of low-temperature ultrasonic measurements. The elastic constant C44 of PrCu2Si2 exhibits pronounced softening below 70 K down to a Néel temperature TN = 20 K, which is described in terms of a quadrupole susceptibility for a Γ5 doublet ground state and a Γ3 singlet first excited state located at 15.6 K in the crystalline electric field scheme. The C44 and C66 of DyCu2Si2 also show softening below 70 K down to TN1 = 9.7 K. A low-lying pseudo-sextet state consisting of three Kramers doublets of Γ6⊕2Γ7 brings about softening of C44 and C66 in DyCu2Si2.

Note: Improved sensitivity of magnetic measurements under high pressure in miniature ceramic anvil cell for a commercial SQUID magnetometer.

Two modifications have been made to a miniature ceramic anvil high pressure cell (mCAC) designed for magnetic measurements at pressures up to 12.6 GPa in a commercial superconducting quantum interference (SQUID) magnetometer [N. Tateiwa et al., Rev. Sci. Instrum. 82, 053906 (2011); ibid. 83, 053906 (2012)]. Replacing the Cu-Be piston in the former mCAC with a composite piston composed of the Cu-Be and ceramic cylinders reduces the background magnetization significantly smaller at low temperatures, enabling more precise magnetic measurements at low temperatures. A second modification to the mCAC is the utilization of a ceramic anvil with a hollow in the center of the culet surface. High pressures up to 5 GPa were generated with the "cupped ceramic anvil" with the culet size of 1.0 mm.

Magnetic measurements at pressures above 10 GPa in a miniature ceramic anvil cell for a superconducting quantum interference device magnetometer.

A miniature ceramic anvil high pressure cell (mCAC) was earlier designed by us for magnetic measurements at pressures up to 7.6 GPa in a commercial superconducting quantum interference magnetometer [N. Tateiwa et al., Rev. Sci. Instrum. 82, 053906 (2011)]. Here, we describe methods to generate pressures above 10 GPa in the mCAC. The efficiency of the pressure generation is sharply improved when the Cu-Be gasket is sufficiently preindented. The maximum pressure for the 0.6 mm culet anvils is 12.6 GPa when the Cu-Be gasket is preindented from the initial thickness of 300-60 µm. The 0.5 mm culet anvils were also tested with a rhenium gasket. The maximum pressure attainable in the mCAC is about 13 GPa. The present cell was used to study YbCu(2)Si(2) which shows a pressure induced transition from the non-magnetic to magnetic phases at 8 GPa. We confirm a ferromagnetic transition from the dc magnetization measurement at high pressure. The mCAC can detect the ferromagnetic ordered state whose spontaneous magnetic moment is smaller than 1 µ(B) per unit cell. The high sensitivity for magnetic measurements in the mCAC may result from the simplicity of cell structure. The present study shows the availability of the mCAC for precise magnetic measurements at pressures above 10 GPa.

Effect of oxidative stress on the pharmacokinetics of clomipramine in rats treated with ferric-nitrilotriacetate.

The effect of oxidative stress (OS) on the pharmacokinetics of clomipramine (CPM), particularly addressing the change of CPM distribution to plasma components, was studied in ferric-nitrilotriacetate-induced oxidative-stress model rats (OS rats). First, CPM pharmacokinetic studies in OS rats were performed using CPM continuous infusion (17.5 µg/min/kg). Plasma concentration of CPM at a steady state in OS rats (0.20 ± 0.02 µg/mL) was significantly lower than that in control rats (0.30 ± 0.02 µg/mL). However, no difference was found in the amounts of CPM in the brains of control rats (1.67 ± 0.13 µg/g) and OS rats (1.63 ± 0.09 µg/g). Both of plasma unbound fraction and distribution to erythrocytes in OS rats were significantly higher than those of control rats. These results suggest that the lower CPM concentration in plasma in OS condition does not induce an inferior pharmacological effect.