Observation of New Isotopes in the Fragmentation of

Five previously unknown isotopes (^{182,183}Tm, ^{186,187}Yb, ^{190}Lu) were produced, separated, and identified for the first time at the Facility for Rare Isotope Beams (FRIB) using the Advanced Rare Isotope Separator (ARIS). The new isotopes were formed through the interaction of a ^{198}Pt beam with a carbon target at an energy of 186 MeV/u and with a primary beam power of 1.5 kW. Event-by-event particle identification of A, Z, and q for the reaction products was performed by combining measurements of the energy loss, time of flight, magnetic rigidity Bρ, and total kinetic energy. The ARIS separator has a novel two-stage design with high resolving power to strongly suppress contaminant beams. This successful new isotope search was performed less than one year after FRIB operations began and demonstrates the discovery potential of the facility which will ultimately provide 400 kW of primary beam power.

Extreme low pH, not Al3+ , is a key abiotic stressor for the extremophyte Carex angustisquama (Cyperaceae) in highly acidic solfatara fields.

Volcanic acidification creates extreme soil conditions, where rhizotoxicity from extremely low pH (2-3) and high Al3+ strongly inhibit plant growth. C. angustisquama is a dominant extremophyte in highly acidic solfatara fields, where no other vascular plants can survive. Here we investigated the key abiotic stressor determining survival of this extremophyte. Soil analyses and topographic surveys were conducted to examine the effects of low pH and Al3+ , two major abiotic stressors in acidic soils, on the occurrence of C. angustisquama in solfatara fields. Hydroponic culture experiments were also performed to test its growth responses to these stressors. In field surveys, the spatial distribution of soil pH was consistent with vegetation zonation within a solfatara field. In contrast, soil exchangeable Al content was overall low due to strong eluviation. Statistical analysis also supported the significant role of soil pH in determining the distribution of C. angustisquama in a solfatara field. Furthermore, hydroponic culture experiments revealed a higher tolerance of C. angustisquama to low pH than a sister species, especially in the range pH 2-3, corresponding to the pH values of the actual habitats of C. angustisquama. Conversely, no significant interspecific difference was detected in Al3+ tolerance, indicating that both species had high Al3+ tolerance. This study suggests that low pH is a critical abiotic stressor leading to formation of the extremophyte in highly acidic solfatara fields. In contrast, C. angustisquama displayed high tolerance to Al3+ toxicity, probably acquired prior to speciation.

First clinical evaluation of the QIAreachTM QuantiFERON-TB for tuberculosis infection and active pulmonary disease.

OBJECTIVE: 1) to compare the QIAreachTM QuantiFERON-TB (QIAreach QFT) vs. QuantiFERON®-TB Gold Plus assay (QFT-Plus) to detect tuberculosis (TB) infection; 2) to evaluate diagnostic sensitivity of QIAreach QFT using active TB as surrogate for TB infection; 3) to preliminarily evaluate QIAreach QFT in immunocompromised individuals. METHODS: QIAreach QFT measures the level of interferon-γ (IFN-γ) in plasma specimens from blood stimulated by ESAT-6 and CFP-10 peptides in one blood collection tube (equivalent to the TB2 tube of the QFT-Plus). QIAreach QFT was applied to plasma samples from 41 patients with pulmonary TB and from 42 healthy or low-TB-risk individuals. RESULTS: Sensitivity and specificity of QIAreach QFT vs. QFT-Plus were 100% (41/41) and 97.6% (41/42), respectively; overall concordance was 98.8% (82/83). All samples were measured within 20 min. The time to result of each sample was significantly correlated with IFN-γ level with a natural logarithmic scale (r = -0.913, p < 0.001). Seven cases in the active TB group were immunocompromised (CD4 <200/µL) and tested positive by QIAreach QFT. CONCLUSIONS: QIAreach QFT provides an objective readout with a minimum blood sample volume (1 mL/subject), potentially being a useful point-of-care screening test for TB infection in high-TB-burden, low-resource countries and for immunocompromised patients.

First Simultaneous Acceleration of Multiple Charge States of Heavy Ion Beams in a Large-Scale Superconducting Linear Accelerator.

Experimental studies of the simultaneous acceleration of three-charge-state ^{129}Xe^{49+,50+,51+} beam from 17 to 180 MeV/nucleon in a superconducting linear accelerator are presented. The beam parameters for each individual- and multiple-charge-state beam were measured and compared with the particle tracking simulations. Detailed measurements were performed to characterize the multiple-charge-state beam's recombination after a second-order achromat and isopath 180° bending system. As a result of the recombination of three charge states in the six-dimensional phase space, the xenon beam intensity was increased by 2.5-fold compared to the single-charge-state beam. The results presented in the Letter fully validate the possibility to produce and utilize high-quality multiple-charge-state heavy-ion beams in a large-scale superconducting linac to increase the available beam power on an isotope production target.

Effect of two different pre-anaesthetic omeprazole protocols on gastroesophageal reflux incidence and pH in dogs.

OBJECTIVES: Gastroesophageal reflux can occur during anaesthesia and may lead to esophagitis and occasionally oesophageal stricture formation. The aim of the study is to assess two omeprazole protocols on gastroesophageal reflux incidence and pH in anaesthetised dogs. MATERIALS AND METHODS: Fifty-five dogs undergoing elective ovariectomy were randomly assigned to: omeprazole single dose 1 mg/kg orally the evening before anaesthesia (20 dogs), omeprazole two doses 1 mg/kg orally the evening and 3 hours before anaesthesia (15 dogs), and control group that did not receive omeprazole (20 dogs). An oesophageal impedance/pH probe was used to measure gastroesophageal reflux incidence and pH during anaesthesia. RESULTS: Gastroesophageal reflux was observed in 55% (11/20) of control dogs, 55% (11/20) of dogs receiving omeprazole once and 47% (7/15) of dogs receiving omeprazole twice. The incidence was not statistically significant different between groups. Gastroesophageal reflux pH (mean ± sd) was higher in dogs receiving omeprazole twice (6.3 ± 1.5), when compared to either control dogs (3.8 ± 1.1) or dogs receiving omeprazole once (4.1 ± 1.5). Strongly acidic reflux (pH < 4) was observed in 7% (1/15) of dogs receiving omeprazole twice versus 55% (11/20) and 35% (7/20) of control dogs and dogs receiving omeprazole once, respectively. CLINICAL SIGNIFICANCE: Omeprazole administered the evening and 3 hours before anaesthesia increased gastroesophageal reflux pH and decreased the incidence of strongly acidic reflux in dogs. A single dose of omeprazole given the evening before anaesthesia had no effect on reflux pH.

Screening of hydrogel-based scaffolds for dental pulp regeneration-A systematic review.

OBJECTIVE: The aim of this systematic review was to evaluate the most appropriate hydrogel scaffold type (natural, synthetic or hybrid) to be applied with stem cells for dental pulp regeneration. The findings should help clinicians make an informed choice about the appropriate scaffold to be applied for this approach. DESIGN: Three electronic databases were searched (Medline, Web of Science and Scopus). The review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). RESULTS: From 4990 potentially relevant studies initially identified, 18 papers fulfilled the eligibility criteria and were considered for this review. Natural scaffolds were applied in most studies. Collagen was the most studied scaffold. In 5 of 10 studies, only growth factors were added to the constructs. Even without growth factors, these scaffolds containing stem cells were able to support the formation of dentin. The synthetic scaffolds were the least studied. Only 4 studies were selected, and in 3 of them, the same scaffold (Puramatrix) was evaluated. Puramatrix by itself was unable to form dental pulp when dental pulp stem cells were not present. Synthetic and hybrid hydrogels were unable to attract stem cells from the host. The presence of growth factors in these constructs seems to be of relevance since dental pulp tissue formation was achieved only when the hybrid scaffold was applied with growth factors. CONCLUSION: All types of hydrogel-based scaffolds, when containing mesenchymal stem cells, are able to form connective tissue with different degrees of similarity to dental pulp. However, current data is too heterogeneous to compare and identify the advantages of any specific scaffold.

Multicenter study of QuantiFERON®-TB Gold Plus in patients with active tuberculosis.

SETTING: QuantiFERON®-TB Gold Plus (QFT-Plus), recently approved for use in the United States, is a new-generation QuantiFERON assay that differs from its predecessors in that it uses an additional antigen tube containing peptides to elicit both CD8+ and CD4+ T-lymphocyte responses. OBJECTIVE: To assess the sensitivity of QFT-Plus compared with QuantiFERON®-TB Gold In-Tube (QFT-GIT) in participants with active TB. DESIGN: Adult patients with active TB at three US and two Japanese sites were eligible for this study if they had culture-confirmed TB and were either untreated or had received 14 days of anti-tuberculosis treatment. RESULTS: We enrolled 164 participants, nine of whom had indeterminate results. Excluding indeterminate values, there were 150 QFT-GIT-positive results among 159 tests and 146 QFT-Plus-positive results among 157 tests, with sensitivities of respectively 94.3% (95%CI 89.5-97.4) and 93.02% (95%CI 87.8-96.5%). The estimated sensitivities for the two tests were not significantly different (P = 0.16). Overall test agreement was 98.7%, with a κ statistic of 0.89 (95%CI 0.75-1.00). CONCLUSION: In this multisite study, we found that QFT-Plus had similar sensitivity to QFT-GIT in adult patients with active TB.

Bosutinib, an SRC inhibitor, induces caspase-independent cell death associated with permeabilization of lysosomal membranes in melanoma cells.

BACKGROUND: SRC kinase (SRC proto-oncogene, non-receptor tyrosine kinase) is a promising target for the treatment of solid cancers including human melanoma. Bosutinib (Bosu), a SRC inhibitor, has already been applied to the treatment of human chronic myelogenous leukemia and also has been assessed its safety in dogs. AIM: The aim of this study was to clarify a novel anti-tumour mechanism of Bosu in canine and human melanoma cells. MATERIALS AND METHODS: The canine and human melanoma cells were treated with Bosu and its effects were evaluated by the cell viability, the protein expression levels such as caspase-3 and LC3, Annexin V/Propidium iodide staining, and confocal immunostaining. RESULTS: Bosu induced the massive caspase-independent cell death, and blocked autophagy flux, which resulted from lysosomal dysfunction. Lysosomal dysfunction caused by Bosu was due to lysosomal membrane permeabilization (LMP), which resulted in the release of lysosomal hydrolases including cathepsin B. CONCLUSION: Our data suggest that Bosu induces the cell death through induction of LMP in melanoma cells and is a promising therapeutic agent for treatment of melanoma in both dogs and humans.

Endoscopic Cytology for the Diagnosis of Chronic Enteritis and Intestinal Lymphoma in Dogs.

Although cytology is a rapid diagnostic procedure in dogs, the cytologic criteria of endoscopic biopsies for chronic enteritis and intestinal lymphoma are not well defined. An immediate diagnosis using cytology would benefit patients by enabling prompt initiation of therapy. The objective of this study was to investigate the correlation between the results of endoscopic cytology and histopathology. In this study, 167 dogs with clinical signs of chronic gastrointestinal disease were included. On the basis of histopathology, the following diagnoses were determined: lymphocytic-plasmacytic enteritis in 93 dogs; eosinophilic enteritis in 5 dogs; small cell intestinal lymphoma in 45 dogs; and large cell intestinal lymphoma in 24 dogs. Two clinical pathologists retrospectively evaluated the endoscopic cytology of squash-smear preparations. The cytologic diagnoses of inflammation, small cell lymphoma, and large cell lymphoma were based on the severity of lymphocyte infiltration, the size of infiltrated lymphocytes, and eosinophil/mast cell infiltration. The clinical severity score was significantly increased along with the degree of lymphocyte infiltration evaluated by cytology. The cytologic diagnosis was in complete agreement with the histopathologic diagnosis in 136 of 167 (81.4%) cases. For the differentiation between enteritis and lymphoma, endoscopic cytology had a sensitivity of 98.6%, a specificity of 73.5%, a positive predictive value of 72.3%, and a negative predictive value of 98.6%. The log-rank test and Cox regression analysis showed that the results of cytology predicted the prognosis. These results suggest that endoscopic cytology is a useful technique to aid diagnosis of intestinal inflammation and lymphoma in dogs.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.

Analysis of serum corticosteroid-induced alkaline phosphatase isoenzyme in dogs with hepatobiliary diseases.

OBJECTIVE: To reveal the relationship between canine corticosteroid-induced alkaline phosphatase isoenzyme activity and hepatobiliary diseases. MATERIALS AND METHODS: Retrospective analysis of the relationship between serum corticosteroid-induced alkaline phosphatase activity and diagnosis, serum cortisol concentration and alanine transferase activity in dogs with hepatobiliary diseases. Dogs with a history of glucocorticoid administration were excluded. RESULTS: Seventy-two dogs with hepatobiliary diseases were analysed. The serum corticosteroid-induced alkaline phosphatase concentration was increased in dogs with hepatobiliary diseases. There was no correlation between serum cortisol concentration and serum corticosteroid-induced alkaline phosphatase percentage or activity. CLINICAL SIGNIFICANCE: Dogs with hepatobiliary disease can exhibit high serum alkaline phosphatase activity even if the dogs have not been administrated glucocorticoids and the serum cortisol concentration is normal.

Plasma matrix metalloproteinase-9 activity in cats with lymphoma.

In this study, plasma MMP-9 activity was evaluated in cats with lymphoma. Plasma samples were obtained from 26 cats with lymphoma before treatment. From 13 of the included 26 cats, plasma samples were obtained 4 weeks after the initiation of treatment. Plasma samples were also obtained from 10 healthy cats as a control. Plasma MMP-9 activity was examined by gelatin zymography and semi-quantitative value (arbitrary unit; a.u.) for each sample was calculated. Relatively high levels of MMP-9 were observed in cats with lymphoma compared with those in healthy control cats. MMP-9 quantification through zymography showed significantly higher activity in cats with lymphoma (median, 0.63 a.u.; range, 0.23-3.24 a.u.) than in healthy controls (0.22 a.u.; 0.12-0.46 a.u.; P < 0.01). MMP-9 activities were significantly different before (0.73 a.u.; 0.30-3.24 a.u.) and after treatment (0.50 a.u.; 0.14-1.32 a.u.; P = 0.017). Measuring plasma MMP-9 activity in cats with lymphoma may become an appropriate monitoring tool for feline lymphoma.

Recommendation for severity assessment following liver resection and liver transplantation in rats: Part I.

Score sheets were first introduced 30 years ago to assess pain, distress and suffering in animals. To date, however, there is still no general agreement on their use in research practice, and only a few publications can be found on this topic. In the present work, we demonstrate the use of a special score sheet for severity assessment in the first three postoperative days in two showcased studies performed on Wistar and Lewis rats undergoing liver resection or orthotopic liver transplantation, respectively. Scoring of different criteria and the total score were evaluated within each intervention. Additionally, both procedures were compared regarding their degree of severity. Suitability of these score sheets was evaluated for assessing severity of the procedures and these showed a minor severity within each investigated study. A comparison of both studies showed slightly higher scores involving liver transplantation. In contradiction to the common classification of these procedures as a moderate severity grade the score sheets applied here indicates a minor severity grade within each investigated study. Also, limitations and possible improvements in the design of our score sheets for defined interventions are reconsidered.

Severity assessment in rabbits after partial hepatectomy: Part II.

Although the recognition of pain, distress and discomfort has already been described in 1985 by Morton and Griffiths there is still very little known about the establishment of score sheets especially, regarding post-surgical pain and severity assessment for laboratory animals such as rabbits. In this paper we describe the estimation of severity and recovery status of 36 female New Zealand White rabbits (NZW) in a standardized liver resection model using two different adhesive treatments and one control group. Welfare was assessed at 3-4 consecutive days after surgery using a scoring system which included the following criteria: body weight, general state, clinical results, spontaneous behavior and clinical examination. Values could range from 0 to 20 where increasing values indicated increasing severity with a predefined humane endpoint for a score ≥20 points. Documented score points were almost exclusively a result of body weight loss, whereas clinical signs and general health status had no influence on the overall sum of points scored. Behavioral variation was solely observed postoperatively, within the first 24 h, with an average score ≤1. In contrast to the classification of a laparotomy as a moderate procedure in the EU Directive 2010/63 (annex VIII) the assessment herein presented showed a mild burden in all groups according to the scoring system used. The partial hepatectomy itself, as well as the adhesive treatment using either synthetic glue VIVO-107 or fibrin glue, were well tolerated.

Recent developments of ion sources for life-science studies at the Heavy Ion Medical Accelerator in Chiba (invited).

With about 1000-h of relativistic high-energy ion beams provided by Heavy Ion Medical Accelerator in Chiba, about 70 users are performing various biology experiments every year. A rich variety of ion species from hydrogen to xenon ions with a dose rate of several Gy/min is available. Carbon, iron, silicon, helium, neon, argon, hydrogen, and oxygen ions were utilized between 2012 and 2014. Presently, three electron cyclotron resonance ion sources (ECRISs) and one Penning ion source are available. Especially, the two frequency heating techniques have improved the performance of an 18 GHz ECRIS. The results have satisfied most requirements for life-science studies. In addition, this improved performance has realized a feasible solution for similar biology experiments with a hospital-specified accelerator complex.

Development of a compact ECR ion source for various ion production.

There is a desire that a carbon-ion radiotherapy facility will produce various ion species for fundamental research. Although the present Kei2-type ion sources are dedicated for the carbon-ion production, a future ion source is expected that could provide: (1) carbon-ion production for medical use, (2) various ions with a charge-to-mass ratio of 1/3 for the existing Linac injector, and (3) low cost for modification. A prototype compact electron cyclotron resonance (ECR) ion source, named Kei3, based on the Kei series has been developed to correspond to the Kei2 type and to produce these various ions at the National Institute of Radiological Sciences (NIRS). The Kei3 has an outer diameter of 280 mm and a length of 1120 mm. The magnetic field is formed by the same permanent magnet as Kei2. The movable extraction electrode has been installed in order to optimize the beam extraction with various current densities. The gas-injection side of the vacuum chamber has enough space for an oven system. We measured dependence of microwave frequency, extraction voltage, and puller position. Charge state distributions of helium, carbon, nitrogen, oxygen, and neon were also measured.

Poly(trimethylene carbonate)-based polymers engineered for biodegradable functional biomaterials.

Aliphatic polycarbonates have drawn attention as biodegradable polymers that can be applied to a broad range of resorbable medical devices. In particular, poly(trimethylene carbonate) (PTMC), its copolymers, and its derivatives are currently studied due to their unique degradation characteristics that are different from those of aliphatic polyesters. Furthermore, their flexible and hydrophobic nature has driven the application of PTMC-based polymers to soft tissue regeneration and drug delivery. This review presents the diverse applications and functionalization strategies of PTMC-based materials in relation to recent advances in medical technologies and their subsequent needs in clinical settings.