The FRESH Study: Treatment of Intracranial Aneurysms with the New FRED X Flow Diverter with Antithrombotic Surface Treatment Technology-First Multicenter Experience in 161 Patients.

BACKGROUND AND PURPOSE: Flow diverters with antithrombotic coatings are increasingly used to improve the safety of flow diverter treatments of intracranial aneurysms. This study aimed to investigate the safety and short-term efficacy of the new FRED X flow diverter. MATERIALS AND METHODS: Medical charts and procedural and imaging data of a consecutive series of patients with intracranial aneurysms who were treated with the FRED X at 9 international neurovascular centers were retrospectively analyzed. RESULTS: One hundred sixty-one patients (77.6% women; mean age, 55 years) with 184 aneurysms (11.2% acutely ruptured) were included in this study. Most aneurysms were located in the anterior circulation (77.0%), most frequently at the ICA (72.7%). The FRED X was successfully implanted in all procedures. Additional coiling was performed in 29.8%. In-stent balloon angioplasty was necessary in 2.5%. The rate of major adverse events was 3.1%. Thrombotic events occurred in 7 patients (4.3%) with 4 intra- and 4 postprocedural in-stent thromboses, respectively (1 patient had both peri- and postprocedural thrombosis). Of these thrombotic events, only 2 (1.2%) led to major adverse events (ischemic strokes). Postinterventional neurologic morbidity and mortality were observed in 1.9% and 1.2%, respectively. The rate of complete aneurysm occlusion after a mean follow-up of 7.0 months was 66.0%. CONCLUSIONS: The new FRED X is a safe and feasible device for aneurysm treatment. In this retrospective multicenter study, the rate of thrombotic complications was low, and the short-term occlusion rates are satisfactory.

Optimisation of the AP abdomen projection for larger patient body thicknesses.

INTRODUCTION: This study aims to identify optimal exposure parameters, delivering the lowest radiation dose while maintaining images of diagnostic quality for the antero-posterior (AP) abdomen x-ray projection in large patients with an AP abdominal diameter of >22.3 cm. METHODOLOGY: The study was composed of two phases. In phase 1, an anthropomorphic phantom (20 cm AP abdominal diameter) was repetitively radiographed while adding 3 layers (5 cm thick each) of fat onto the phantom reaching a maximum AP abdominal diameter of 35 cm. For every 5 cm thickness, images were taken at 10 kVp (kilovoltage peak) intervals, starting from 80 kVp as the standard protocol currently in use at the local medical imaging department, to 120 kVp in combination with the use of automatic exposure control (AEC). The dose area product (DAP), milliampere-second (mAs) delivered by the AEC, and measurements to calculate the signal to noise ratio (SNR) and contrast to noise ratio (CNR) were recorded. Phase 2 included image quality evaluation of the resultant images by radiographers and radiologists through absolute visual grading analysis (VGA). The resultant VGA scores were analysed using visual grading characteristics (VGC) curves. RESULTS: The optimal kVp setting for AP abdominal diameters at: 20 cm, 25 cm and 30 cm was found to be 110 kVp increased from 80 kVp as the standard protocol (with a 56.5% decrease in DAP and 76.2% in mAs, a 54.2% decrease in DAP and 76.2% decrease in mAs and a 29.2% decrease in DAP and 59.7% decrease in mAs, respectively). The optimal kVp setting for AP abdominal diameter at 35 cm was found to be 120 kVp increased from 80 kvp as the standard protocol (with a 50.7% decrease in DAP and 73.4% decrease in mAs). All this was achieved while maintaining images of diagnostic quality. CONCLUSION: Tailoring the exposure parameters for large patients in radiography of the abdomen results in a significant reductions in DAP which correlates to lower patient doses while still maintaining diagnostic image quality. IMPLICATIONS FOR CLINICAL PRACTICE: This research study and resultant parameters may help guide clinical departments to optimise AP abdomen radiographic exposures for large patients in the clinical setting.

Evaluation of the Mediseus epidural simulator.

The demand for increased patient safety has led to greater use of simulation training of health professionals performing medical procedures. The study aim was to evaluate the usefulness of the Mediseus® Epidural Simulator in teaching basic epidural needle-handling skills. Three groups of 15 anaesthetists (Novice=zero to two year anaesthesia trainees; Intermediate=three- to five-year anaesthesia trainees; Expert=consultants and regional-specialist anaesthetists) from three different medical centres participated. Each participant performed 20 simulated epidural needle insertions and was scored on several parameters (e.g. time, success of the insertion, bone collisions). Following familiarisation with the simulator and the needle insertions, participants answered seven questions on the applicability of the simulator to the teaching of basic epidural needle-handling skills. There was a clear learning effect with regard to the simulation procedure time, this decreasing throughout the experiment (P=0.037). There was no significant influence of either group or experience with the simulator in the study on the number or type of errors made. The quality of the simulation was scored 2.3 out of 5.0 (for bone simulation) and 4.7 (for loss-of-resistance simulation). All groups considered that the simulator was best suited for training prospective anaesthetists. Each group rated the usefulness of the simulator for training novices at greater than 3.0 out of 5.0. The Mediseus® Epidural Simulator seems to be an appropriate training device for an introduction to epidural needle insertion. For medical professionals with procedural knowledge, the simulation is not realistic enough and the simulator did not distinguish between the groups based on the errors made.

Effect of the mode of administration of inhaled anaesthetics on the interpretation of the F(A)/F(I) curve--a GasMan simulation.

The effects of blood solubility, cardiac output and ventilation on the rise of the alveolar towards the inspired concentration, the F(A)/F(I) curve, of an inhaled anaesthetic are often thought to reflect how these factors affect wash-in of the central nervous system compartment and, therefore, speed of induction because F(A) is the partial pressure ultimately attained in the central nervous system (F(VRG)). These classical F(A)/F(I) curves assumed a constant F(I). We used GasMan to examine whether changes in solubility, cardiac output and ventilation affect the relationship between the F(A)/F(I) curve and F(VRG) differently while either F(I) or F(A) are kept constant. Using GasMan, we studied the effects of solubility (desflurane vs isoflurane), cardiac output (5 vs. 10 l x min(-1)) and minute ventilation (4 vs. 8 l x min(-1)) on F(A), F(I), F(A)/F(I) and F(VRG) with either F(I) kept constant or F(A) kept constant (at 1 minimum alveolar concentration). High fresh gas flows were used to avoid rebreathing, so that the delivered concentration matched F(I). Despite similar effects on the F(A)/F(I) curve, the effects on F(VRG) differed. With constant F(I), lower solubility or higher ventilation results in a higher F(VRG) and a higher cardiac output results in a lower F(VRG). With constant F(A), solubility has only a minimal effect on F(VRG); an increase in cardiac output hastens the rise of F(VRG) to the same plateau value; and a change in ventilation has minimal effect on F(VRG). Despite similar effects on the F(A)/F(I) curve, the effects of solubility, cardiac output and ventilation on the F(VRG) are different when either F(I) or F(A) are kept constant. With the F(I) kept constant, induction of anaesthesia is slower with a higher cardiac output, but with F(A) kept constant, induction of anaesthesia is faster with a higher cardiac output. The introduction of an end-expired closed-loop feedback administration of inhaled anaesthetics makes this distinction clinically relevant.

Derivation and prospective testing of a two-step sevoflurane-O2-N2O low fresh gas flow sequence.

Simple vaporiser setting (F(D)) and fresh gas flow (FGF) sequences make the practice of low-flow anaesthesia not only possible but also easy to achieve. We sought to derive a sevoflurane F(D) sequence that maintains the end-expired sevoflurane concentration (F(A)sevo) at 1.3% using the fewest possible number of F(D) adjustments with a previously described O2-N2O FGF sequence that allows early FGF reduction to 0.7 l min(-1). In 18 ASA physical status I to IH patients, F(D) was determined to maintain F(A)sevo at 1.3% with 2 l min(-1) O2 and 4 l min(-1) N2O FGF for three minutes, and with 0.3 and 0.4 l min(-1) thereafter. Using the same FGF sequence, the F(D) schedule that approached the 1.3% F(A)sevo pattern with the fewest possible adjustments was prospectively tested in another 18 patients. The following F(D) sequence approximated the F(D) course well: 2% from zero to three minutes, 2.6% from three to 15 minutes and 2.0% after 15 minutes. When prospectively tested, median (25th; 75th percentile) performance error was 0.8 (-2.9; 5.9)%, absolute performance error 6.7 (3.3; 10.6)%, divergence 18.2 (-5.6; 27.4)%.h(-1) and wobble 4.4 (1.7; 8.1) %. In one patient, FGF had to be temporarily increased for four minutes. One O2/N2O rotameter FGF setting change from 6 to 0.7 l min(-1) at three minutes and two sevoflurane F(D) changes at three and 15 minutes maintained predictable anaesthetic gas concentrations during the first 45 minutes in all but one patient in our study.

Caspase-dependent and -independent cell death of Jurkat human leukemia cells induced by novel synthetic ceramide analogs.

Ceramide metabolism has emerged as a potential target for anticancer therapy. Here, the potential usefulness of two novel synthetic ceramide analogs as anti-leukemic drugs was investigated. Compounds AD2646 and AD2687 were able to dose-and time-dependently decrease the viability of Jurkat leukemic cells. This was accompanied by an accumulation of endogenous ceramide owing to perturbed ceramide metabolism. Cytotoxicity involved caspase activation but also necrotic-like features, as evidenced by phosphatidylserine externalization, membrane permeability, hypodiploidy, caspase processing and only partial protection from cell death by a pan-caspase inhibitor. Ceramide analogs also induced cell death in Jurkat mutants that are deficient in cell death signaling proteins, including FADD, caspase-8 and 10, and RIP. While overexpression of Bcl-xL did not suppress ceramide accumulation, it conferred robust protection from caspase activation and cell death. Altogether, these novel ceramide analogs are able to kill leukemic cells through distinct pathways implicating caspase activation and mitochondrial events, and represent a new group of bioactive molecules with potential applications in anticancer therapy.

Preimplantation diagnosis of a lysosomal storage disorder by in situ enzymatic activity: 'proof of principle' in acid sphingomyelinase-deficient mice.

Genetic diagnosis of preimplantation embryos (PGD) can substantially reduce the chance that at-risk couples have children afflicted with inherited diseases. However, PGD requires DNA,which is usually obtained from single cells following embryo biopsy. In addition, PGD requires that the genetic defect(s) causing the disorder be known. We have therefore developed an alternative to PGD, which we term preimplantation enzymatic diagnosis (PED). PED has several advantages over PGD, including the facts that it does not require embryo biopsy and that the gene defect(s) causing the disorder need not be known. We have demonstrated 'proof of principle' for this approach using embryos obtained from a mouse model (ASMKO mice) of acid sphingomyelinase (ASM)-deficient Niemann-Pick disease, an inherited lysosomal storage disorder. For this technique, fluorescently (BODIPY)-conjugated sphingomyelin was used to detect ASM activity in situ. Wild-type, preimplantation embryos degraded the substrate following a short 'pulse-chase' period, resulting in markedly reduced fluorescence compared to ASMKO embryos, which retained the fluorescent substrate. Thus, the two embryo types could be easily distinguished by fluorescent microscopy. The fluorescent sphingomyelin was not toxic to the embryos, and the entire procedure could be accomplished within 48 h without embryo biopsy. We suggest that PED may be useful for the preimplantation diagnosis of lysosomal storage disorders, and perhaps other enzymatic defects where similar in situ assay methods are available.

Ceramide mediates growth inhibition of the Plasmodium falciparum parasite.

In mammalian cells, ceramide mediates death by chemotherapeutic drugs. We analysed, for the first time, the role of ceramide in inhibiting growth of the malaria-causing parasite Plasmodium falciparum. Added exogenously, ceramide significantly decreased the number of parasites, and this effect was abolished by sphingosine-1-phosphate, a biological antagonist of ceramide action. Ceramide can induce death of cancer cells by decreasing glutathione levels, and in our work it induced dose- and time-dependent depletion of glutathione in P. falciparum parasites. N-acetylcysteine, a precursor of glutathione, abrogated the cytotoxic effect of ceramide. Thus, ceramide can mediate growth inhibition of P. falciparum parasites by decreasing glutathione levels. The antimalarial drugs artemisinin and mefloquine induced the death of P. falciparum parasites by sphingomyelinase-generated ceramide and by decreasing parasite glutathione levels. Altogether, ceramide was identified as a signalling molecule capable of inducing growth inhibition of P. falciparum malarial parasites.

The effects of sevoflurane on isolated gravid human myometrium.

The volatile anaesthetic agents are known to influence uterine muscle tone. All of the agents studied to date have been found to produce uterine relaxation. This property has been used to produce therapeutic uterine relaxation for difficult obstetric deliveries and the Ex Utero Intrapartum Treatment (EXIT) procedure. This study describes the effects of sevoflurane on isolated human myometrium at concentrations of 0.1, 0.25, 0.5, 0.75, 1.0, 1.5, 2.5 and 3.5 MAC. Sevoflurane produces dose-dependent depression of uterine muscle contractility with an ED50 of 0.94 MAC. Frequency of contraction was increased at concentrations of 2.5 MAC and greater. At concentrations of 3.5 MAC and above, uterine activity was virtually abolished.

Airway management on placental support (AMPS)--the anaesthetic perspective.

Neonatal airway obstruction has been reported to have a high mortality. Antenatal diagnosis of this condition is now possible. Anaesthetic and surgical techniques have been developed that allow neonatal airway obstruction to be managed at delivery, while the fetus remains oxygenated via the placental circulation. Three case studies are presented, and the anaesthetic issues for mother and fetus/neonate are discussed with reference to previously published cases of airway management on placental support. In particular, techniques for uterine relaxation and maintenance of placental circulation are explored. The history of these procedures and issues of planning and logistics are also discussed.

The in-vitro effects of sevoflurane and desflurane on the contractility of pregnant human uterine muscle.

The effect of desflurane and sevoflurane on the contractility of the uterus was examined in vitro on strips of human myometrium obtained at the time of elective cesarean section. Small strips (1 mm x 2 mm x 10 mm) of muscle were prepared and suspended in an organ bath containing oxygenated physiological saline. Force of contraction was recorded continuously using an isometric tension transducer. Following the onset of regular spontaneous contractions, baseline measurements were obtained and the strips were exposed to varying concentrations of sevoflurane or desflurane corresponding to 0.5, 1.0 and 1.5 minimum alveolar concentration (MAC). Sevoflurane depressed contractility to 72 +/- 18% of control at 0.5 MAC, 37 +/- 15% at 1.0 MAC and 27 +/- 16% at 1.5 MAC compared with 65 +/- 14 of control at 0.5 MAC, 43 +/- 18% at 1.0 MAC and 22 +/- 11% at 1.5 MAC for desflurane. The degree of depression of uterine muscle contractility produced by both these agents was significantly different from control at all concentrations. In conclusion, both sevoflurane and desflurane depress the contractility of isolated pregnant human myometrium at concentrations of 0.5, 1.0 and 1.5 MAC. These agents produce a similar degree of depression of uterine muscle contractility.