Protocol for treating lumbar spinal canal stenosis with a combination of ultrapurified, allogenic bone marrow-derived mesenchymal stem cells and in situ-forming gel: a multicentre, prospective, double-blind randomised controlled trial.

INTRODUCTION: In patients with combined lumbar spinal canal stenosis (LSCS), a herniated intervertebral disc (IVD) that compresses the dura mater and nerve roots is surgically treated with discectomy after laminoplasty. However, defects in the IVD after discectomy may lead to inadequate tissue healing and predispose patients to the development of IVD degeneration. Ultrapurified stem cells (rapidly expanding clones (RECs)), combined with an in situ-forming bioresorbable gel (dMD-001), have been developed to fill IVD defects and prevent IVD degeneration after discectomy. We aim to investigate the safety and efficacy of a new treatment method in which a combination of REC and dMD-001 is implanted into the IVD of patients with combined LSCS. METHODS AND ANALYSIS: This is a multicentre, prospective, double-blind randomised controlled trial. Forty-five participants aged 20-75 years diagnosed with combined LSCS will be assessed for eligibility. After performing laminoplasty and discectomy, participants will be randomised 1:1:1 into the combination of REC and dMD-001 (REC-dMD-001) group, the dMD-001 group or the laminoplasty and discectomy alone (control) group. The primary outcomes of the trial will be the safety and effectiveness of the procedure. The effectiveness will be assessed using visual analogue scale scores of back pain and leg pain as well as MRI-based estimations of morphological and compositional quality of the IVD tissue. Secondary outcomes will include self-assessed clinical scores and other MRI-based estimations of compositional quality of the IVD tissue. All evaluations will be performed at baseline and at 1, 4, 12, 24 and 48 weeks after surgery. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the institutions involved. We plan to conduct dissemination of the outcome data by presenting our data at national and international conferences, as well as through formal publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCT2013210076.

Considerations on Gated CO2 Adsorption Behavior in One-Dimensional Porous Coordination Polymers Based on Paddlewheel-Type Dimetal Complexes: What Determines Gate-Opening Temperatures?

Low-dimensional coordination polymers such as one-dimensional chains often exhibit gated guest sorption accompanying structural transition at a temperature (TG), which is associated with an external pressure of the guest (PG) characteristic to the material and guest used. This phenomenon can be evaluated using the Clausius-Clapeyron relationship with the equation d(ln PG)/d(1/TG) = ΔHG/R, where ΔHG and R are the transition enthalpy and gas constant, respectively. In this study, gated CO2 adsorption behavior was investigated in a one-dimensional chain based on a benzoate-bridged paddlewheel diruthenium(II,II) complex with a phenazine (phz) linker, [Ru2(p-MeOPhCO2)4(phz)] (1; p-MeOPhCO2- = p-anisate). Surprisingly, 1 underwent gate opening (GO)/closing (GC) at a much higher TG, e.g., 385 K for GC, under PCO2 = 100 kPa than those previously reported for such chain compounds, which usually appeared in the temperature range of 200-270 K. The transition entropy ΔSG in each system plays a key role in shifting TG; 1 results in a much smaller |ΔSG| in the series. Only 1 produced a CO2-accessible two-dimensional topological pore in its CO2-adsorbed phase 1⊃CO2, whereas the others reported previously produced one-dimensional or discrete topological pores for CO2 accommodation, strongly reflecting the degree of freedom of CO2 molecules in pores, which is related to ΔSG.

Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review.

Uterine leiomyosarcoma (uLMS) is the most common subtype of mesenchymal tumors in the uterus. This review aims to summarize the current standard therapies and the molecular properties of uLMS for novel molecular-targeted therapies. Although 65% of uLMS cases are diagnosed in stage I, the 5-year overall survival rate is less than 60%. The only effective treatment for uLMS is complete and early resection, and chemotherapy is the main treatment for unresectable advanced or recurrent cases. No chemotherapy regimen has surpassed doxorubicin monotherapy as the first-line chemotherapy for unresectable advanced or recurrent cases in terms of overall survival in phase 3 trials. As a second-line treatment, pazopanib, trabectedin, and eribulin are used, but their therapeutic effects are not sufficient, highlighting the urgent need for development of novel treatments. Recent developments in gene analysis have revealed that homologous recombination deficiency (HRD), including breast cancer susceptibility gene 2 (BRCA2) mutations, are frequently observed in uLMS. In preclinical studies and several case series, poly(adenosine diphosphate-ribose)polymerase inhibitors showed antitumor effects on uLMS cell lines with BRCA2 mutations or HRD and in recurrent or persistent cases of uLMS with BRCA2 mutations. Thus, HRD, including BRCA mutations, may be the most promising therapeutic target for uLMS.

Role of intramolecular hydrogen bonding in the redox chemistry of hydroxybenzoate-bridged paddlewheel diruthenium(II,II) complexes.

The synthesis of a series of trans-heteroleptic paddlewheel diruthenium(II,II) complexes with various hydroxy-substituted benzoate ligands, [Ru2((OH)xPhCO2)2(2,6-(CF3)2PhCO2)2(THF)2] ([RuII,II2]) as tetrahydrofuran (THF) adducts is reported, where (OH)xPhCO2- stands for o-hydroxybenzoate (o-OH), m-hydroxybenzoate (m-OH), p-hydroxybenzoate (p-OH), 2,3-dihydroxybenzoate (2,3-(OH)2), 2,4-dihydroxybenzoate (2,4-(OH)2), 2,5-dihydroxybenzoate (2,5-(OH)2), 2,6-dihydroxybenzoate (2,6-(OH)2), or 3,4-dihydroxybenzoate (3,4-(OH)2), and 2,6-(CF3)2PhCO2- represents 2,6-bis(trifluoromethyl)benzoate. In this heteroleptic series, the redox potential (E1/2) of the [RuII,II2]/[RuII,III2]+ couple in THF varies over a wide range, from -18 mV (vs. Ag/Ag+) for p-OH to 432 mV for 2,6-(OH)2. The redox properties are linearly dependent on the acidity (pKa) of the OH-substituted benzoic acids, but do not depend on the number of ortho-substituted hydroxy (o-OH) groups. This indicates that the steric effect of o-substituents is irrelevant in the case of hydroxyl groups, owing to the formation of intramolecular hydrogen bonds between the o-OH group and carboxylate oxygens. The value of the Hammett constant σo for the o-OH substituent was determined to be 0.667, indicating a strongly electron-withdrawing character, contrary to the expectation of electron-donating character for an OH group. The redox properties of the compounds were well explained in a framework of Hammett analyses and were also consistent with their HOMO energy levels evaluated by DFT calculations based on the atomic coordinates. The unexpected electron-withdrawing character of the o-OH groups could be attributed to the direct effect of intramolecular hydrogen bonding on the charge density on the carboxylate oxygen.

Lipid Droplet Accumulation Independently Predicts Poor Clinical Prognosis in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSOC) is an epithelial cancer that accounts for most ovarian cancer deaths. Metabolic abnormalities such as extensive aerobic glycolysis and aberrant lipid metabolism are well-known characteristics of cancer cells. Indeed, accumulation of lipid droplets (LDs) in certain types of malignant tumors has been known for more than 50 years. Here, we investigated the correlation between LD accumulation and clinical prognosis. In 96 HGSOC patients, we found that high expression of the LD marker adipophilin was associated with poor progression-free and overall survival (p = 0.0022 and p = 0.014, respectively). OVCAR-3 ovarian carcinoma cells accumulated LDs in a glucose-dependent manner, which suggested the involvement of aerobic glycolysis and subsequently enhanced lipogenesis, with a result being LD accumulation. The acyl-CoA: cholesterol acyltransferase 1 inhibitor K604 and the hydroxymethylglutaryl-CoA reductase inhibitor pitavastatin blocked LD accumulation in OVCAR-3 cells and reduced phosphorylation of the survival-related kinases Akt and ERK1/2, both of which have been implicated in malignancy. Our cell-based assays thus suggested that enhanced aerobic glycolysis resulted in LD accumulation and activation of survival-related kinases. Overall, our results support the idea that cancers with lipogenic phenotypes are associated with poor clinical prognosis, and we suggest that adipophilin may serve as an independent indicator of a poor prognosis in HGSOC.

Quantitative examination of isolated finger flexion associated with function of the flexor digitorum superficialis.

[Purpose] Isolated finger flexion associated with function of the flexor digitorum superficialis has been qualitatively assessed using standard and modified tests. The purpose of this study was to quantify isolated finger flexion in healthy participants. [Participants and Methods] We assessed 100 volunteers (mean age: 44.6 years) without upper limb dysfunction using the standard and modified flexor digitorum superficialis tests. The sum of the isolated active flexion angles of the metacarpophalangeal and proximal interphalangeal joints of the test finger was also calculated, with the other three fingers held in an extended position with our original jig. [Results] The mean isolated flexion angles were, respectively, 152.4° and 154.8° for the right and left index fingers, 161.1° and 160.4° for the middle fingers, 160.6° and 158.2° for the ring fingers, 129.4° and 134.6° for the independent flexor digitorum superficialis function, 85.8° and 74.7° for the common flexor digitorum superficialis function, and 75.8° and 71.2° for absent flexor digitorum superficialis function in the small finger. The functional variations of the flexor digitorum superficialis of the small fingers showed symmetry in 65.0% of the fingers but asymmetry in 35.0%. [Conclusion] The data obtained in this study provide normal reference values for the examination of independent movement disorders of the fingers.

Emergence of Salmonella enterica subsp. enterica serovar Chester in a rural area of Japan.

In Japan, only one outbreak of Salmonella enterica subsp. enterica serovar Chester (S. Chester) has been confirmed in 1999. We performed a single-center retrospective case review of S. Chester infections that occurred in a rural area of Japan in 2016 (n=8). Case 5 and 6 occurred in twin infants who had contact with a pet dog. The dog's stool culture was positive for S. Chester. Pulsed-field gel electrophoresis and cluster analysis of S. Chester strains revealed that all the isolates appeared to be derived from the same genetic clone. Emergence of Salmonella infection can be overlooked if cases are not reported to health authorities; therefore, core hospitals should play a role to alert the occurrence of public health issue.

Miliary cerebrospinal lesions caused by Nocardia beijingensis in an immunocompetent patient.

The genus Nocardia usually infect immunocompromised patients. Pulmonary nocardiosis is the most common Nocardia-induced infection while central nervous system (CNS) is the most common extrapulmonary site to develop nocardial disease. Approximately 54 % cases of previously reported nocardial brain abscesses were solitary lesions, while 38 % cases had multiple lesions; but miliary-like ring enhancing lesions have not been reported previously. We present a case of immunocompetent patient with miliary-like cerebrospinal lesions caused by Nocardia beijingensis. A 68-year-old Japanese man presented with acute-onset headache, vomiting, and progressive disturbance of consciousness. A contrasted magnetic resonance imaging (MRI) scan showed countless miliary-like ring-shaped enhancing lesions on the patient's whole brain, brain stem, and cervical spinal cord. A brain biopsy was performed and Kinyoun stain suggested that the brain lesions were abscesses caused by Nocardia species. 16S ribosomal RNA sequencing identified Nocardia beijingensis as the causative microorganism. The trimethoprim/sulfamethoxazole regimen was continued for 7 months and the patient showed good improvement with recovery of consciousness. Clinical manifestation of Nocardia beijingensis infection is poorly studied. Further cases are needed to be accumulated.

Assessment of the Passive Tension of the First Dorsal Interosseous and First Lumbrical Muscles Using Shear Wave Elastography.

PURPOSE: Quantitative evaluation of passive tension of the intrinsic muscles of the hand is necessary to assess contracture of the intrinsic muscles accurately. The aim of this study was to evaluate the shear modulus, which is related to passive muscle tension, of the first dorsal interosseous (FDI) and first lumbrical (FL) muscles using shear wave elastography. METHODS: Subjects were 18 healthy males. The shear modulus of the FDI and FL muscles was assessed at several proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), and wrist joint positions. The position in which the MCP joint was flexed 60° past 0° with PIP-DIP joint extension and that in which the MCP joint was extended 30° past 0° with PIP-DIP joint flexion were respectively defined as the slack and stretched positions. We analyzed whether the shear modulus was affected by finger position (slack or stretched), wrist position (30° flexion past 0° and 30° extension past 0°), and muscle (FDI or FL). RESULTS: Shear modulus in the stretched position was significantly higher than that in the slack position. The shear modulus of the FL muscle at 30° wrist extension was significantly higher than that at 30° flexion. The shear modulus of the FL muscle was significantly higher than that of the FDI muscle in the stretched position with the wrist at 30° flexion and extension, and in the slack position with the wrist at 30° extension. CONCLUSIONS: The shear modulus of the FDI and FL muscles increased with MCP joint extension and PIP-DIP joint flexion. The difference in the muscle characteristics between the FDI and FL muscles should be considered when evaluating or treating contractures of the intrinsic muscles. CLINICAL RELEVANCE: Shear wave elastography can evaluate the condition of the intrinsic muscles of the hand quantitatively.

Clinical features of children with nontyphoidal Salmonella bacteremia: A single institution survey in rural Japan.

Nontyphoidal Salmonella (NTS) can cause bacterial enterocolitis. Although some children with NTS infection develop bacteremia, its clinical manifestations have not been discussed adequately. Therefore, we examined children with NTS bacteremia. We retrospectively examined the medical records of 15 patients aged less than 15 years. Salmonella spp. were detected in the blood cultures of these patients between 1991 and 2014. We divided an additional sample group of 34 patients diagnosed with an NTS infection between 2005 and 2014, into 2 groups. Group bacteremia (B) included patients in whose blood cultures Salmonella spp. were detected, and group non-bacteremia (NB) included patients in whom Salmonella infection was not detected. We compared each group using Wilcoxon test and Fisher's exact test. The number of patients with fever, diarrhea, or abdominal pain was 15 (100%), 13 (87%), and 9 (60%), respectively, in the first sample of patients. However, vomiting and bloody stool were observed in only 5 patients (33%). More than 70% of patients exhibited a reduced white blood cell count, while C-reactive protein levels were variable in the patients. Salmonella spp. were detected via stool culture in 10 patients (67%). Diarrhea persisted for more than 4 days more frequently in group B than group NB (p = 0.004). The number of patients whose fever persisted for more than 4 days was significantly higher in group B than group NB (p = 0.030). Therefore, if NTS bacteremia is suspected, blood cultures should be collected and antibiotics should be initiated in cases with diarrhea or fever for more than 4 days. Furthermore, a negative stool culture result does not preclude the possibility of NTS bacteremia.

Azithromycin Can Prolong QT Interval and Suppress Ventricular Contraction, but Will Not Induce Torsade de Pointes.

Azithromycin has been reported to increase the risk of death from cardiovascular causes among patients with high baseline risk. Since the information is still limited to bridge the gap between electrophysiological properties of azithromycin in vitro and cardiac death in patients, we initially assessed its electropharmacological effects in doses of 3 and 30 mg/kg, i.v., with the halothane-anesthetized dogs (n = 4). The low dose provided 5.2 times higher than the therapeutic concentration, whereas the high dose attained 17.0 times higher. The high dose delayed the ventricular repolarization in a reverse use-dependent manner, reflecting blockade of the rapid component of delayed rectifier K(+) current, and the potency was relatively weak; namely, maximum change in QTc was +20 ms (+5.6%). The high dose also induced the negative inotropic effect possibly through Ca(2+) channel-independent pathway. In order to clarify proarrhythmic risk, 30 mg/kg, i.v., of azithromycin was examined with the chronic atrioventricular block dogs (n = 4). Azithromycin neither induced torsade de pointes nor affected beat-to-beat variability of repolarization. Thus, azithromycin can be considered to lack proarrhythmic potential, but caution has to be paid on its use for patients with left ventricular dysfunction.

Intravenous Administration of Apomorphine Does NOT Induce Long QT Syndrome: Experimental Evidence from In Vivo Canine Models.

Apomorphine is a non-selective dopamine D1/D2 receptor agonist, which has been used for patients with Parkinson's disease and reported to induce QT interval prolongation and cardiac arrest. To clarify their causal link, we assessed the cardiovascular and pharmacokinetic profile of apomorphine with the halothane-anaesthetized canine model (n = 4), whereas pro-arrhythmic potential of apomorphine was analysed with the chronic atrioventricular block canine model (n = 4). In the halothane-anaesthetized model, 0.01 mg/kg, i.v. of apomorphine hydrochloride over 10 min., providing about 10 times of its therapeutic concentration, increased the heart rate and ventricular contraction; 0.1 mg/kg over 10 min., providing about 100 times of the therapeutic, prolonged the ventricular effective refractory period; and 1 mg/kg over 10 min., providing about 1000 times of the therapeutic, decreased the ventricular contraction, mean blood pressure and cardiac output together with the intraventricular conduction delay and prolongation of the effective refractory period, whereas the left ventricular end-diastolic pressure, atrioventricular nodal conduction or ventricular repolarization were hardly affected. Meanwhile, in the atrioventricular block model, 1 mg/kg, i.v. of apomorphine hydrochloride over 10 min. neither prolonged the QT interval nor induced torsade de pointes. These results suggest that apomorphine may possess a wide margin of cardiovascular safety contrary to our expectations.

Effects of pH on nifekalant-induced electrophysiological change assessed in the Langendorff heart model of guinea pigs.

Since information regarding the effects of pH on the extent of nifekalant-induced repolarization delay and torsades de pointes remains limited, we assessed it with a Langendorff heart model of guinea pigs. First, we investigated the effects of pH change from 7.4 to 6.4 on the bipolar electrogram simulating surface lead II ECG, monophasic action potential (MAP), effective refractory period (ERP), and terminal repolarization period (TRP) and found that acidic condition transiently enhanced the ventricular repolarization. Next, we investigated the effects of pH change from 6.4 to 7.4 in the presence of nifekalant (10 µM) on the ECG, MAP, ERP, TRP, and short-term variability (STV) of MAP90 and found that the normalization of pH prolonged the MAP90 and ERP while the TRP remained unchanged, suggesting the increase in electrical vulnerability of the ventricle. Meanwhile, the STV of MAP90 was the largest at pH 6.4 in the presence of nifekalant, indicating the increase in temporal dispersion of repolarization, which gradually decreased with the return of pH to 7.4.Thus, a recovery period from acidosis might be more dangerous than during the acidosis, because electrical vulnerability may significantly increase for this period while temporal dispersion of repolarization remained increased.

Enantio- and diastereoselective hetero-Diels-Alder reactions between 2-aza-3-silyloxy-1,3-butadienes and aldehydes catalyzed by chiral dirhodium(II) carboxamidates.

The first catalytic asymmetric hetero-Diels-Alder reaction between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described. With dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), the cycloaddition reaction proceeded exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-4-ones in high yields with up to 98% ee.

Lymphatic absorption of choline plasmalogen is much higher than that of ethanolamine plasmalogen in rats.

BACKGROUND: Plasmalogen is a subclass of phospholipids widely distributed in animal tissues and ingested as food; however, the absorptive characteristics of different classes of plasmalogen have not been clarified. AIM OF STUDY: Our object was to compare the lymphatic output of choline and ethanolamine plasmalogens after an administration of phospholipid preparations containing each class of plasmalogens, and to analyze molecular species of plasmalogen absorbed into the lymph. METHODS: A duodenal infusion of 1 ml of 10% emulsion of choline phospholipid (PC) containing 50.6% choline plasmalogen (PlsCho) or ethanolamine phospholipid (PE) containing 52.5% ethanolamine plasmalogen (PlsEtn) was administered in the lymph duct-cannulated rats. Molecular species of plasmalogen absorbed into the lymph were measured by LC-MS/MS. RESULTS: Lymph outputs of PlsCho and PlsEtn increased and reached a peak value at 3 h after PC and PE injection, respectively. The peak value of PlsCho was much higher and remained at a high level until 8 h, whereas PlsEtn output fell to half of the peak value at 7 h. Total lymphatic output of PlsCho was 5-times higher than that of PlsEtn. Compositions of sn-1 in lymph plasmalogens roughly reflected those of the injected lipids, whereas sn-2 in both PlsCho and PlsEtn was rich in arachidonic acid (20:4) regardless of the composition of the administered fatty acid. Both plasmalogen and lysoplasmalogen after PE injection were not released into the portal vein. CONCLUSION: Lymphatic absorption of PlsCho is much higher than that of PlsEtn in rats, and plasmalogens are re-esterified as 20:4-rich forms in the small intestine.

Highly enantioselective hetero-Diels-Alder reactions between Rawal's diene and aldehydes catalyzed by chiral dirhodium(II) carboxamidates.

The first example of a chiral Lewis acid-catalyzed enantioselective hetero-Diels-Alder (HDA) reaction between 1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal's diene) and aldehydes is described. The cycloaddition reaction under the influence of 1 mol% of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), proceeded cleanly and gave, after treatment with acetyl chloride, the corresponding dihydropyranones in up to 99% ee.