Considerations for radiotherapy in Bloom Syndrome: A case series.

Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.

Coherent Beam Splitting of Flying Electrons Driven by a Surface Acoustic Wave.

We develop a coherent beam splitter for single electrons driven through two tunnel-coupled quantum wires by surface acoustic waves (SAWs). The output current through each wire oscillates with gate voltages to tune the tunnel coupling and potential difference between the wires. This oscillation is assigned to coherent electron tunneling motion that can be used to encode a flying qubit and is well reproduced by numerical calculations of time evolution of the SAW-driven single electrons. The oscillation visibility is currently limited to about 3%, but robust against decoherence, indicating that the SAW electron can serve as a novel platform for a solid-state flying qubit.

NOVEL ANALYTICAL STUDY FOR REACTION INTERMEDIATES IN THE PRIMARY RADIATION INTERACTION OF DNA USING A SYNCHROTRON RADIATION-INDUCED LUMINESCENCE SPECTROSCOPY.

To identify the precise molecular processes to induce DNA lesions, we attempt a novel spectroscopy of X-ray induced luminescence (XIL) using soft X-ray synchrotron radiation, which is a non-destructive analysis of the reaction intermediates in the elementary reaction pathway of damage induction and self-organized restoration. Using a liquid micro-jet technique to introduce aqueous samples in a vacuum chamber, we measure UV-visible luminescence from nucleotide solution as a function of the soft X-ray energy from the nitrogen to oxygen K-edge region. The XIL intensities for the nucleotide solutions are significantly enhanced in the soft X-ray region (410-530 eV) which is ascribed to the K-shell excitation/ionization of nitrogen atoms in the nucleobases. Furthermore, the XIL spectra do not show any signature of X-ray absorption near-edge structure (XANES) of the nucleobases. This is because the luminescence intensities collected from the integral area of the micro-jet only reflect the quantum yield of luminescence of the absorbed X-ray into UV-visible light irrespective of the absorption cross sections, i.e. of XANES. Thus the present result is the first evidence of luminescence as a result of X-ray absorption of aqueous nucleotides.

Sigmoid-vaginal fistula during bevacizumab treatment diagnosed by fistulography.

WHAT IS KNOWN AND OBJECTIVE: There have been several reports describing rectovaginal fistula development after bevacizumab treatment, and these fistulas were diagnosed by CT scan or colonoscopy. We report a case of sigmoid-vaginal fistula diagnosed by fistulography. CASE DESCRIPTION: The case is a 53-year-old woman who was treated for chronic myelogenous leukaemia and gynaecological cancers 8 years previously. At 52 years of age, she was diagnosed with colon cancer and had a partial colectomy performed. One year after surgery, colon cancer recurred, and she was treated with anticancer agents, including bevacizumab. During chemotherapy, she complained of a foul smelling discharge from the vagina. Fistulography revealed a sigmoid-vaginal fistula. WHAT IS NEW AND CONCLUSION: This is the first report of vaginal fistulography performed on a patient who was treated with bevacizumab. Fistulography may be useful for detecting sigmoid-vaginal fistula.

Fast spin information transfer between distant quantum dots using individual electrons.

Transporting ensembles of electrons over long distances without losing their spin polarization is an important benchmark for spintronic devices. It usually requires injecting and probing spin-polarized electrons in conduction channels using ferromagnetic contacts or optical excitation. In parallel with this development, important efforts have been dedicated to achieving control of nanocircuits at the single-electron level. The detection and coherent manipulation of the spin of a single electron trapped in a quantum dot are now well established. Combined with the recently demonstrated control of the displacement of individual electrons between two distant quantum dots, these achievements allow the possibility of realizing spintronic protocols at the single-electron level. Here, we demonstrate that spin information carried by one or two electrons can be transferred between two quantum dots separated by a distance of 4 µm with a classical fidelity of 65%. We show that at present it is limited by spin flips occurring during the transfer procedure before and after electron displacement. Being able to encode and control information in the spin degree of freedom of a single electron while it is being transferred over distances of a few micrometres on nanosecond timescales will pave the way towards 'quantum spintronics' devices, which could be used to implement large-scale spin-based quantum information processing.

Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory.

Neonatal anoxia in rodents has been used to understand brain changes and cognitive dysfunction following asphyxia. This study investigated the time-course of cellular and subcellular changes and hippocampal cell death in a non-invasive model of anoxia in neonatal rats, using Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL) to reveal DNA fragmentation, Fluoro-Jade® B (FJB) to show degenerating neurons, cleaved caspase-3 immunohistochemistry (IHC) to detect cells undergoing apoptosis, and transmission electron microscopy (TEM) to reveal fine ultrastructural changes related to cell death. Anoxia was induced by exposing postnatal day 1 (P1) pups to a flow of 100% gaseous nitrogen for 25 min in a chamber maintained at 37 °C. Control rats were similarly exposed to this chamber but with air flow instead of nitrogen. Brain changes following anoxia were evaluated at postnatal days 2, 14, 21 and 60 (P2, P14, P21 and P60). In addition, spatial reference memory following anoxia and control treatments was evaluated in the Morris water maze, starting at P60. Compared to their respective controls, P2 anoxic rats exhibited (1) higher TUNEL labeling in cornus ammonis (CA) 1 and the dentate gyrus (DG), (2) higher FJB-positive cells in the CA2-3, and (3) somato-dendritic swelling, mitochondrial injury and chromatin condensation in irregular bodies, as well as other subcellular features indicating apoptosis, necrosis, autophagy and excitotoxicity in the CA1, CA2-3 and DG, as revealed by TEM. At P14, P21 and P60, both groups showed small numbers of TUNEL-positive and FJB-positive cells. Stereological analysis at P2, P14, P21 and P60 revealed a lack of significant differences in cleaved caspase-3 IHC between anoxic and control subjects. These results suggest that the type of hippocampal cell death following neonatal anoxia is likely independent of caspase-3 activation. Neonatal anoxia induced deficits in acquisition and performance of spatial reference memory in the Morris water maze task. Compared to control subjects, anoxic animals exhibited increased latencies and path lengths to reach the platform, as well as decreased searching specifically for the platform location. In contrast, no significant differences were observed for swimming speeds and frequency within the target quadrant. Together, these behavioral results indicate that the poorer performance by anoxic subjects is related to spatial memory deficits and not to sensory or motor deficits. Therefore, this model of neonatal anoxia in rats induces hippocampal changes that result in cell losses and impaired hippocampal function, and these changes are likely related to spatial memory deficits in adulthood.

Transmission phase in the Kondo regime revealed in a two-path interferometer.

We report on the direct observation of the transmission phase shift through a Kondo correlated quantum dot by employing a new type of two-path interferometer. We observed a clear π/2-phase shift, which persists up to the Kondo temperature TK. Above this temperature, the phase shifts by more than π/2 at each Coulomb peak, approaching the behavior observed for the standard Coulomb blockade regime. These observations are in remarkable agreement with two-level numerical renormalization group calculations. The unique combination of experimental and theoretical results presented here fully elucidates the phase evolution in the Kondo regime.

Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.

Haploidentical stem cell transplantation for acute leukemia patients who experienced early relapse within one year after the first transplantation.

To assess the safety and efficacy of allogeneic stem cell transplantation from haploidentical related donors (haplo-SCT) as 2nd transplantation for patients with early relapsed disease, we retrospectively evaluated 7 consecutive patients (median age, 42 years; range, 29-63 years) who experienced relapse within 1 year of the 1st transplantation and received haplo-SCT as a 2nd transplantation. Among the 7 patients who received haplo-SCT, 2 who were in morphologically complete remission (CR) at transplantation were conditioned with a reduced-intensity regimen, and the 5 non-CR patients were conditioned with a myeloablative regimen. Both conditioning regimens included antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methylprednisolone. Sustained neutrophil engraftment was achieved in all 7 patients. One patient developed severe acute GVHD. Notably, only 1 patient experienced relapse, and each patient achieved longer CR duration than after the 1st transplantation. Three of the 7 patients died from treatment-related causes: acute GVHD, post-transplantation lymphoproliferative disorder, and bacterial pneumonia. At the time of analysis, the 2-year overall survival rate of these 7 patients was 42.9%. This suggests that use of haploidentical related donors is a viable alternative for 2nd transplantation and should be confirmed in larger cohorts.

Quantification of changes in metamorphopsia and retinal contraction in eyes with spontaneous separation of idiopathic epiretinal membrane.

BACKGROUND: To quantify changes in metamorphopsia and retinal contraction in eyes with idiopathic epiretinal membrane (ERM) before and after a spontaneous separation of ERM. METHODS: Among 92 eyes of 92 patients with idiopathic ERM who were followed up at our hospital, 5 eyes of 5 patients had experienced a spontaneous separation of ERM during the follow-up period. Patient's metamorphopsia was assessed horizontally and vertically by a metamorphopsia chart developed by our group, M-CHARTS, to obtain the horizontal (MH) and vertical (MV) metamorphopsia scores. Difference in the scores before and after the membrane separation represents change in patient's metamorphopsia. Changes in retinal contraction were also evaluated horizontally and vertically with our original software for fundus image analysis. The difference between M-CHARTS scores and distances of retinal vessel movements with before and after membrane separation were measured. RESULTS: All five subjects showed a decrease in the retinal contraction. Improved visual acuity was observed in three subjects, and no change was seen in the other two. Four subjects obtained better metamorphopsia scores after the membrane separation, while the other one was not detected with metamorphopsia by M-CHARTS either before or after the separation. In subjects with an improved MV, horizontal retinal movement was seen larger than the vertical movement. Similarly, the subjects with an improved MH indicated a larger vertical retinal movement than the horizontal movement. CONCLUSIONS: The direction of patient's metamorphopsia closely associated with the direction of retinal contraction before and after a spontaneous separation of ERM.

Prognostic factors influencing clinical outcome of allogeneic hematopoietic stem cell transplantation following imatinib-based therapy in BCR-ABL-positive ALL.

We investigated prognostic factors for the clinical outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. Among 100 adult patients who were prospectively enrolled in the JALSG Ph+ALL202 study, 97 patients obtained complete remission (CR) by imatinib-combined chemotherapy, among whom 60 underwent allo-HSCT in their first CR. The probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years after HSCT were 64% (95% CI, 49-76) and 58% (95% CI, 43-70), respectively. Prognostic factor analysis revealed that the major BCR-ABL transcript was the only unfavorable predictor for OS and DFS after HSCT by both univariate (HR, 3.67 (95% CI 1.49-9.08); P=0.005 and HR, 6.25 (95% CI, 1.88-20.8); P=0.003, respectively) and multivariate analyses (HR, 3.20 (95% CI, 1.21-8.50); P=0.019 and HR, 6.92 (95% CI, 2.09-22.9); P=0.002, respectively). Minimal residual disease status at the time of HSCT had a significant influence on relapse rate (P=0.015). Further study of the BCR-ABL subtype for the clinical impact on outcome of allo-HSCT in Ph+ALL is warranted.

Immunohistochemical investigation of lymphatic vessel formation control in mouse tooth development: lymphatic vessel-forming factors and receptors in tooth development in mice.

The presence of lymphatic vessels in dental pulp has recently been controversial, and no conclusion has been reached. In this study, we investigated the control of lymphangiogenesis with dental pulp development in the mouse mandibular molar using VEGF-C, VEGF-D, and VEGFR-3 as indices of lymphatic vessel-controlling factors. In addition, to distinguish blood and lymphatic vascular epithelial cells, we performed immunohistochemical analysis using von Willebrand factor (vWF) and statistical analysis. In dental papilla in the bell-stage non-calcified period, mesenchymal cells positive for VEGF-C, VEGF-D, and VEGFR-3 increased and lumen-forming endothelial cells were noted, but vWF was negative, suggesting that these were actively forming lymphatic vessels. Positive undifferentiated mesenchymal cells, an increase in endothelial cells in dental pulp, and lumen expansion were noted early after birth. Positivity was also detected in the odontoblast layer and sheath of Hertwig after birth, suggesting that these factors also play important roles in odontoblast differentiation and maturation and periodontal ligament and tooth root formation. We embryologically clarified lymphatic vessel formation in dental pulp and a process of lymphatic vessel formation from blood vessels, suggesting involvement of the surrounding tissue, odontoblasts, and sheath of Hertwig in vessel formation.

A modified rat model of neonatal anoxia: Development and evaluation by pulseoximetry, arterial gasometry and Fos immunoreactivity.

Neonatal anoxia is a worldwide clinical problem that has serious and lasting consequences. The diversity of models does not allow complete reproducibility, so a standardized model is needed. In this study, we developed a rat model of neonatal anoxia that utilizes a semi-hermetic system suitable for oxygen deprivation. The validity of this model was confirmed using pulse oximetry, arterial gasometry, observation of skin color and behavior and analysis of Fos immunoreactivity in brain regions that function in respiratory control. For these experiments, 87 male albino neonate rats (Rattus norvegicus, lineage Wistar) aged approximate 30 postnatal hours were divided into anoxia and control groups. The pups were kept in an euthanasia polycarbonate chamber at 36±1 °C, with continuous 100% nitrogen gas flow at 3 L/min and 101.7 kPa for 25 min. The peripheral arterial oxygen saturation of the anoxia group decreased 75% from its initial value. Decreased pH and partial pressure of oxygen and increased partial pressure of carbon dioxide were observed in this group, indicating metabolic acidosis, hypoxia and hypercapnia, respectively. Analysis of neuronal activation showed Fos immunoreactivity in the solitary tract nucleus, the lateral reticular nucleus and the area postrema, confirming that those conditions activated areas related to respiratory control in the nervous system. Therefore, the proposed model of neonatal anoxia allows standardization and precise control of the anoxic condition, which should be of great value in indentifying both the mechanisms underlying neonatal anoxia and novel therapeutic strategies to combat or prevent this widespread public health problem.

Impairment of recognition memory and hippocampal long-term potentiation after acute exposure to clioquinol.

Clioquinol (CQ) was associated with cases of transient global amnesia and with the neurodegenerative syndrome subacute myelo-optico-neuropathy (SMON) in humans. However, CQ forms lipophilic chelates with cations and has the potential as a scientific and clinical tool used for selective modulation of histochemically reactive zinc pools. The relationship among transient lack of synaptic zinc release, hippocampal long-term potentiation (LTP) induction and cognitive memory is poorly understood. To evaluate the role of synaptic zinc release, in the present study, hippocampal LTP induction and cognitive behavior were examined in young rats after i.p. injection of CQ (30 mg/kg). Intracellular zinc detected by Timm's stain and extracellular (synaptic cleft) zinc detected by ZnAF-2 were significantly decreased in the hippocampus 6 h after CQ injection. The molecular layer of the dentate gyrus, in which perforant path-granule cell synapses exist, was most responsive to CQ injection. Dentate gyrus LTP was induced similarly to the control 2 h after CQ injection, while significantly attenuated 6-24 h after CQ injection. In the training trial of the object recognition memory 2 h after CQ injection, there was no significant difference in learning behavior between the control and CQ-treated rats. In the test trial, CQ-treated rats showed normal recognition memory 1 h after the training, whereas recognition memory deficit 24 h after the training unlike the control rats. These results indicate that acute exposure to CQ impairs long-term (24 h) memory in the hippocampus of young rats. The CQ-mediated attenuation of dentate gyrus LTP, which may be associated with the transient lack of zinc release from zincergic neurons, seems to be involved in the impairment of the long-term memory.

Array-based genomic resequencing of human leukemia.

To identify oncogenes in leukemias, we performed large-scale resequencing of the leukemia genome using DNA sequence arrays that determine approximately 9 Mbp of sequence corresponding to the exons or exon-intron boundaries of 5648 protein-coding genes. Hybridization of genomic DNA from CD34-positive blasts of acute myeloid leukemia (n=19) or myeloproliferative disorder (n=1) with the arrays identified 9148 nonsynonymous nucleotide changes. Subsequent analysis showed that most of these changes were also present in the genomic DNA of the paired controls, with 11 somatic changes identified only in the leukemic blasts. One of these latter changes results in a Met-to-Ile substitution at amino-acid position 511 of Janus kinase 3 (JAK3), and the JAK3(M511I) protein exhibited transforming potential both in vitro and in vivo. Further screening for JAK3 mutations showed novel and known transforming changes in a total of 9 out of 286 cases of leukemia. Our experiments also showed a somatic change responsible for an Arg-to-His substitution at amino-acid position 882 of DNA methyltransferase 3A, which resulted in a loss of DNA methylation activity of >50%. Our data have thus shown a unique profile of gene mutations in human leukemia.

The relation between sexual interest and personality characteristics in men: an eye-tracking study.

There is a large individual deviation for men, which may be caused by a difference in personality characteristics, in sexual interest in response to sexual stimuli. In this study, we investigate whether attention to the sexual region in a video depends on the personality characteristics of men, assessing this with an eye-tracking system. The study included 30 healthy males with a normal psychological state, who viewed a sexual video in which the sexual region had been designated. Visual attention was measured across the designated region according to gaze duration. Ten types of personality characteristics were evaluated as a T-score by a questionnaire. By Pearson's correlation coefficient, the relations between gaze duration at the sexual region and T-scores of paranoia, psychasthenia and social introversion were found to be statistically significant. By multivariate stepwise regression analysis, only social introversion was negatively associated with the sexual region. Even normal variation of personality characteristics can affect the viewing period of the sexual region. This is the first report showing that subjects with a high degree of paranoia, psychasthenia and particularly social introversion have a tendency to view the sexual region for a shorter duration.

S100beta protein expression: gender- and age-related daily changes.

S100beta is a soluble protein released by glial cells mainly under the activation of the 5-HT1A receptor. It has been reported as a neuro-trophic and -tropic factor that promotes neurite maturation and outgrowth during development. This protein also plays a role in axonal stability and the plasticity underlying long-term potentiation in adult brains. The ability of S100beta to rapidly regulate neuronal morphology raises the interesting point of whether there are daily rhythm or gender differences in S100beta level in the brain. To answer this question, the S100beta expression in adult female and male rats, as well as in adult female CD-21 and S100beta -/- female mice, were investigated. Scintillation counting and morphometric analysis of the immunoreactivity of S100beta, showed rhythmic daily expression. The female and male rats showed opposite cycles. Females presented the highest value at the beginning of the rest phase (5:00 h), while in males the maximum value appeared in the beginning of the motor activity period (21:00 h). These results confirm previous S100beta evaluations in human serum and cerebrospinal fluid reporting the protein's function as a biomarker for brain damage (Gazzolo et al. in Clin Chem 49:967-970, 2003; Clin Chim Acta 330:131-133, 2003; Pediatr Res 58:1170-1174, 2005), similar behavior was also observed for GFAP in relation to Alzheimer Disease (Fukuyama et al. in Eur Neurol 46:35-38, 2001). The data should be taken into account when considering S100beta as a biomarker of health condition. In addition, the results raise questions on which structure or condition imposes these rhythms as well as on the physiological meaning of the observed gender differences.