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// Charlotte Taylor 1, 2 , David Mannion 1, 2 , Fabrizio Miranda 1, 2 , Mohammad Karaminejadranjbar 1, 2 , Sandra Herrero-Gonzalez 1, 2 , Karin Hellner 1, 2 , Yiyan Zheng 1, 2 , Geoffrey Bartholomeusz 3 , Robert C. Bast Jr 3 , Ahmed Ashour Ahmed 1, 2 1 Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, OX3 9DS, UK 2 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women’s Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK 3 Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA Correspondence to: Ahmed Ashour Ahmed, email: ahmed.ahmed@obs-gyn.ox.ac.uk Keywords: ovarian cancer, paclitaxel, mitotic arrest, PFKFB4, PFKFB3 Received: July 26, 2016 Accepted: December 15, 2016 Published: January 31, 2017 ABSTRACT Taxanes represent some of the most commonly used chemotherapeutic agents for ovarian cancer treatment. However, they are only effective in approximately 40% of patients. Novel therapeutic strategies are required to potentiate their effect and improve patient outcome. A hallmark of many cancers is the constitutive activation of the PI3K/AKT pathway, which drives cell survival and metabolism. We discovered a striking decrease in AKT activity coupled with a significant reduction in glucose 6-phosphate and ATP levels during mitotic arrest in the majority of ovarian cancer cell lines tested, indicating a potential metabolic vulnerability. A high-content siRNA screen to detect novel metabolic targets in mitotically arrested ovarian cancer cells identified the glycolytic enzyme PFKFB4. PFKFB4 depletion increased caspase 3/7 activity, and levels of reactive oxygen species only in mitotically arrested cells, and significantly enhanced mitotic cell death after paclitaxel treatment. Depletion of PFKFB3 demonstrated a similar phenotype. The observation that some ovarian cancer cells lose AKT activity during mitotic arrest and become vulnerable to metabolic targeting is a new concept in cancer therapy. Thus, combining mitotic-targeted therapies with glycolytic inhibitors may act to potentiate the effects of antimitotics in ovarian cancer through mitosis-specific cell death.

Fifteen items in the Weekly Magazine have been attributed to Goldsmith. Our study uses traditional kinds of internal evidence (mainly verbal parallels) together with evidence from selected linguistic features. A preliminary analysis identifies features which best distinguish Goldsmith samples from those of a number of contemporary authors. Using this selection of features, we calculate the distances of the fifteen Weekly items from the cluster of Goldsmith samples; an item at too large a distance is unlikely to be his. A parallel investigation is based on sentence-length statistics. We conclude that seven essays may plausibly be assigned to Goldsmith, that he probably co-authored two pieces, and that in three cases he merely made minor additions to material from other sources.

The sentence-lengths of sixteen essays by Goldsmith are examined in relation to data from ten essays (we call these 'doubtfuls') which have been attributed to him. Comparisons between the 'doubtfuls' and the known Goldsmiths are made with reference to the X 2 goodness-of-fit test, and the method of reciprocal averaging. The Goldsmith essays form a close group, with four of the 'doubtful' essays well outside, two less remote and four within the Goldsmith cluster. Comparison with fifty essays by nine of Goldsmith's contemporaries reveals the distinctiveness of his sentence-length patterns, and strengthens the probability that the four least doubtful essays are his. In the case of Goldsmith, then, sentence-length may be considered a reliable stylistic marker.

Summary A 15 month old boy with a ventricular septal defect (VSD) underwent percutaneous device closure of the VSD. Five days later he collapsed; on arrival to hospital he was asystolic and received prolonged cardio-pulmonary resuscitation (CPR) with intermittent return of spontaneous circulation (ROSC). He had recurrent episodic complete heart block with no ventricular escape rhythm, associated with loss of cardiac output, unresponsive to transcutaneous pacing. He was transferred to theatre, while receiving CPR, for urgent removal of the VSD device. Estimated total ‘down time’ was 70 min. The device was removed and patch closure of the VSD was performed. He made a full neurological recovery. Device closure of septal defects has become widespread. We discuss the incidence and type of arrythmias associated with their use. This case highlights an uncommon but life threatening complication of a VSD device. It also highlights that good quality CPR may lead to positive outcomes following pediatric cardiac arrest.

Patients undergoing surgery for idiopathic scoliosis were studied to determine the incidence and aetiology of oliguria during the perioperative period and to evaluate the efficacy of low dose dopamine in preventing its occurrence. Thirty patients, aged 6-18 years undergoing elective surgery were studied. Anaesthesia was standardized. Patients were randomized to receive either dopamine infusion (3 micrograms.kg-1.min-1) (Group A) (n = 15) or dextrose infusion (control) (Group B) (n = 15). Serum and urinary electrolytes and osmolalities and serum antidiuretic hormone (ADH) concentrations were measured. Urine output and haemodynamic parameters were recorded. Intraoperative oliguria occurred in 7% of patients in Group A and 47% in Group B (P 0.05). Urine and serum biochemical analysis revealed a statistically significant decrease in serum sodium and osmolality (P < 0.005) and an increase in urinary sodium and osmolality in both groups. Serum ADH concentrations were increased in both groups (P < 0.05), returning to baseline 18 h postoperatively. We conclude that oliguria during corrective spinal surgery occurs in association with excess ADH secretion as opposed to perioperative hypovolaemia. Dopamine increases urine output in the perioperative period but does not prevent the release of ADH and its subsequent biochemical effects.

More than twenty items in the British Magazine have been posthumously attributed to Goldsmith. A stylometric study of these doubtful pieces, based on samples from his authentic journalism, suggests that only four essays appear to deserve a place in the canon. We use a variety of statistical techniques - first, to identify, from a whole battery of tests, those tests which are sufficiently discriminatory as between Goldsmith and non-Goldsmith, and, secondly, to classify the doubtful texts across the range from 'very probably' Goldsmith's to 'very unlikely'to be his. Looking again at the Goldsmith essays, we were able to extract ten more large samples of material from them than were examined in our previous study. These extra samples enable a more unified treatment

L'A. expose les techniques statistiques utilisees pour determiner l'auteur reel de certains articles de periodiques parmi la centaine attribuee de facon posthume a Goldsmith : sur les onze cas examines, quatre semblent ouvoir sans aucun doute lui revenir

During the three centuries following Galileo, most astronomy was carried out with keen eyes glued to the telescope eyepiece, and records of the Sun, Moon, planets, and objects further out in the Universe were made in the form of written notes or observational sketches. Our knowledge of the Universe was improved through the observations of both amateur and professional astronomers, the distinction between which was often more than a little blurred in centuries past. Advances in telescope optics, including the invention of objective lenses that eliminated much of the false color produced by refracting telescopes, inventions of new forms of optical systems, along with engineering improvements, allowed for bigger and better instruments with which to probe the Universe.

Inhalation induction using isoflurane is associated with airway irritability, coughing, breath-holding and laryngospasm. These complications are more common in children. This study was designed to determine if humidification of isoflurane in oxygen/nitrous oxide would reduce respiratory complications and hypoxic episodes at induction.Fifty-nine unpremedicated children, aged three months to 12 yr, were enrolled in the study and randomised to receive either humidified isoflurane (n = 27, Group A), or non-humidified isoflurane (n = 32, Group B). All inductions of anaesthesia were with isoflurane 4% in 50% oxygen/nitrous oxide. Subjects were observed for the occurrence of breath-holding, coughing, laryngospasm, bronchospasm, secretions, and hiccoughs. The severity of each complication was graded on a scale of 0-3. The need to administer 100% oxygen and/or succinylcholine was also identified.Coughing (33% vs 53%) was more frequent in Group B (P0.05). Coughing severity scores (13 vs 36) and breath-holding severity scores (8 vs 19) were also greater in Group B (P0.05). A change in FIO2 was required more frequently in Group B (4% vs 16%). Although there was a high incidence of laryngospasm in both groups (52% vs 59%), no other differences were identified, breath-holding (26% vs 31%), secretions (30% vs 31%), hiccough (11% vs 12.5%) (P0.05).Humidification of inspired isoflurane reduces the frequency and severity of coughing, the severity of breath-holding, and the need to increase supplemental inspired oxygen concentration, when isoflurane is used for inhalation induction of anaesthesia in children. Humidification has no effect, however, on the frequency and severity of laryngospasm, or on the frequency of occurrence of arterial oxygen desaturation.

Background Spinal cord perfusion pressure may be reduced when sodium nitroprusside is used to control proximal aortic hypertension during thoracic aortic clamping. The effect of esmolol infusion on spinal cord perfusion pressure during thoracic aortic clamping is unknown. This study compares spinal cord perfusion pressure following control of proximal hypertension with either sodium nitroprusside or esmolol during thoracic aortic clamping. Methods The thoracic aorta was cross-clamped for 30 min in 18 dogs anesthetized with halothane. A control group (n = 6) received no treatment of proximal hypertension during cross-clamping. In two other groups, proximal arterial pressure was controlled (100 mmHg) by infusion of either sodium nitroprusside (n = 6) or esmolol (n = 6). Brachial and femoral arterial pressures, spinal cord perfusion pressure, pulmonary artery occlusion, central venous pressures, and cardiac output were monitored. Neurologic assessment was performed 24 h following surgery. Results Femoral arterial pressure was lower with nitroprusside (14 +/- 3 mmHg) compared to esmolol (24 +/- 4 mmHg) after 15 min of aortic cross-clamping. Cerebrospinal fluid pressure increased during aortic cross-clamping in the sodium nitroprusside group (from 7 +/- 5 to 16 +/- 6 mmHg) but not in esmolol or control groups. Spinal cord perfusion pressure was lower with nitroprusside at 15 min of aortic cross-clamping (2 +/- 4 mmHg) compared to control (15 +/- 7 mmHg) and esmolol groups (17 +/- 11 mmHg). Esmolol infusion reduced cardiac output and increased ventricular filling pressures compared to control and nitroprusside groups. Conclusions Esmolol was associated with greater spinal cord perfusion pressure, but adverse hemodynamic effects, when compared with nitroprusside during thoracic aortic cross-clamping. When only surviving dogs (4 control, 5 esmolol, 6 nitroprusside) are considered, the incidence of neurologic deficit was greater in nitroprusside-treated dogs than in either control or esmolol-treated dogs. No difference in outcome was present when all dogs are considered.