Effect of Vagus Nerve Stimulation on the GASH/Sal Audiogenic-Seizure-Prone Hamster.

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1ß, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.

SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers.

Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m2/day), associating biweekly intravenous irinotecan (125 to 240 mg/m2/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m2/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m2 irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.

Propofol TCI Reductions Do Not Attenuate Significant Falls in Cardiac Output Associated With Anesthesia Induction and Knee-Chest Positioning in Spinal Surgery.

BACKGROUND: Induction of anesthesia and the knee-chest position are associated with hemodynamic changes that may impact patient outcomes. The aim of this study was to assess whether planned reductions in target-controlled infusion propofol concentrations attenuate the hemodynamic changes associated with anesthesia induction and knee-chest position. MATERILAS AND METHODS: A total of 20 patients scheduled for elective lumbar spinal surgery in the knee-chest position were included. In addition to standard anesthesia monitoring, bispectral index and noninvasive cardiac output (CO) monitoring were undertaken. The study was carried out in 2 parts. In phase 1, target-controlled infusion propofol anesthesia was adjusted to maintain BIS 40 to 60. In phase 2, there were 2 planned reductions in propofol target concentration: (1) immediately after loss of consciousness-reduction calculated using a predefined formula, and (2) before positioning-reduction equal to the average percentage decrease in CO after knee-chest position in phase 1. Changes from baseline in CO and other hemodynamic variables following induction of anesthesia and knee-chest positioning were compared. RESULTS: Induction of anesthesia led to decreases of 25.6% and 19.8% in CO from baseline in phases 1 and 2, respectively (P<0.01). Knee-chest positioning resulted in a further decrease such that the total in CO reduction from baseline to 10 minutes after positioning was 38.4% and 46.9% in phases 1 and 2, respectively (P<0.01). There was no difference in CO changes between phases 1 and 2, despite the planned reductions in propofol during phase 2. There was no significant correlation between changes in CO and mean arterial pressure. CONCLUSIONS: Planned reductions in propofol concentration do not attenuate anesthesia induction and knee-chest position-related decreases in CO. The knee-chest position is an independent risk factor for decrease in CO. Minimally invasive CO monitors may aid in the detection of clinically relevant hemodynamic changes and guide management in anesthetized patients in the knee-chest position.

Effect of Hemodynamic Changes in Plasma Propofol Concentrations Associated with Knee-Chest Position in Spinal Surgery: A Prospective Study.

BACKGROUND: Anesthesia induction and maintenance with propofol can be guided by target-controlled infusion (TCI) systems using pharmacokinetic (Pk) models. Physiological variables, such as changes in cardiac output (CO), can influence propofol pharmacokinetics. Knee-chest (KC) surgical positioning can result in CO changes. OBJECTIVES: This study aimed to evaluate the relationship between propofol plasma concentration prediction and CO changes after induction and KC positioning. METHODS: This two-phase prospective cohort study included 20 patients scheduled for spinal surgery. Two different TCI anesthesia protocols were administered after induction. In phase I (n = 9), the loss of consciousness (LOC) concentration was set as the propofol target concentration and CO changes following induction and KC positioning were quantified. In phase II (n = 11), based on data from phase I, two reductions in the propofol target concentration on the pump were applied after LOC and before KC positioning. Propofol plasma concentrations were measured at different moments in both phases: after induction and after KC positioning. RESULTS: Schnider Pk model showed a good performance in predicting propofol concentration after induction; however, after KC positioning, when a significant drop in CO occurred, the measured propofol concentrations were markedly underestimated. Intended reductions in the propofol target concentration did not attenuate HD changes. In the KC position, there was no correlation between the propofol concentration estimated by the Pk model and the measured concentration in plasma, as the latter was much higher (P = 0.013) while CO and BIS decreased significantly (P < 0.001 and P = 0.004, respectively). CONCLUSIONS: Our study showed that the measured propofol plasma concentrations during the KC position were significantly underestimated by the Schnider Pk model and were associated with significant CO decrease. When placing patients in the KC position, anesthesiologists must be aware of pharmacokinetic changes and, in addition to standard monitoring, the use of depth of anesthesia and cardiac output monitors may be considered in high-risk patients.

Relations between Sensorimotor Integration and Speech Disorders in Parkinson's Disease.

BACKGROUND: Sensorimotor integration mechanisms can be affected by many factors, among which are those involving neuromuscular disorders. Parkinson's disease (PD) is characterized by well-known motor symptoms, among which lately have been included motor speech deficits. Measurement of the acoustic startle reflex (ASR) and its modulations (prepulse inhibition and prepulse facilitation, PPI and PPF respectively) represent a simple and quantifiable tool to assess sensorimotor function. However, it remains unknown whether measures of the PPI and PPF are associated with motor speech deficits in PD. METHODS: A total of 88 subjects participated in this study, 52 diagnosed with PD and 36 control subjects. After obtaining written informed consent, participants were assessed with PPI at several interstimulus intervals, and PPF at 1000 ms using the SRH-Lab system (San Diego, CA). Percentage of change in the amplitude and latency of the ASR was analyzed between groups. Voice recordings were register of a specific text given to the subjects with a professional recorder and temporal patterns of speech were analyzed. RESULTS: Statistical analysis conducted in this study showed differences in PPI and PPF in subjects with PD compared to controls. In addition, discriminative parameters of voice abnormalities were observed in PD subjects related to control subjects showing a reduction in phonation time, vowel pulses, breaks, breakage and voice speech periods. CONCLUSIONS: PD presents a disruption in sensorimotor filter mechanisms and speech disorders, and there is a relationship between these alterations. The correlation between the PPI and PPF with an alteration of the voice in PD subjects contributes toward understanding mechanism underlying the neurophysiological alterations in both processes. Overall, easy and non-invasive tests such as PPI, PPF together with voice analysis may be useful to identify early stages of PD.

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

Twenty years' experience for reduction of ileocolic intussusceptions by saline enema under sonography control.

BACKGROUND: Ultrasonography is a well-established efficient diagnostic tool for ileocolic intussusceptions in children. It can also be used to control hydrostatic reduction by saline enemas. This reduction method presents the advantage of avoiding radiations. Parents can even stay with their children during the procedure, which is comforting for both. The purpose of this study was to present our 20 years' experience in intussusception reductions using saline enema under ultrasound control and to assess its efficiency and safety. MATERIAL AND METHODS: This retrospective single center study included patients with ileocolic intussusceptions diagnosed by ultrasound between June 1993 and July 2013. We excluded the data of patients with spontaneous reduction or who underwent primary surgery because of contraindications to hydrostatic reduction (peritonitis, medium or huge abdominal effusion, ischemia on Doppler, bowel perforation). A saline enema was infused into the colon until the reduction was sonographically confirmed. The procedure was repeated if not efficient. Light sedation was practiced in some children. RESULTS: Eighty-tree percent of the reductions were successful with a median of 1 attempt. Reduction success decreased with the number of attempts but was still by 16% after 4 attempts. The early recurrence rates were 14.5%, and 61.2% of those had a successful second complete reduction. Forty-six patients needed surgery (11 of them had a secondary intussusception). Sedation multiplies success by 10. In this period, only one complication is described. CONCLUSION: Ultrasound guided intussusception reduction by saline enema is an efficient and safe procedure. It prevents exposure of a young child to a significant amount of radiation, with similar success rate. We had very low complication rate (1/270 cases or 3‰). The success rate could be increased by standardized procedures including: systematic sedation, trained radiologists, accurate pressure measurement, and number and duration of attempts.